Nickel Background EU Risk Assessment Report March 2008 Final Draft

Nickel and nickel compounds

Background Document in support of individual

RISK ASSESSMENT REPORTS

of nickel compounds prepared in relation to

Council Regulation (EEC) 793/93

Final version March 2008

Chapters 0, 1, 2, 4, 5, 6 and 7 – human health only.

Danish Environmental Protection Agency

R_NickelBackground_0308_hh_chapter0124567.doc

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Information on the Rapporteur. The Danish Environmental Protection Agency is the Rapporteur for the risk assessment reports of metallic nickel, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate. The Rapporteur is responsible for the contents of this report. Contact persons: Poul Bo Larsen & Henrik Tyle Chemicals Division Danish Environmental Protection Agency Strandgade 29 DK-1401 Copenhagen K DENMARK Tel: +45 72 54 40 00 E-mail: [email protected] / [email protected] / [email protected] Acknowledgements. The scientific assessments included in this Background report have been prepared by the following organisations by order of the Rapporteur:

• Danish National Working Environment Authority (Occupational Exposure, Chapter 4) • Danish Technological Institute (Aquatic effects Assessment, Chapter 3) • Department of Toxicology and Risk Assessment, Danish Food and Veterinary Research, (Consumer

and Indirect Exposure, Human health effects, Chapter 4) • National Environmental Research Institute, Denmark (Terrestrial effects Assessment, Chapter 3). • URS Corporation, London, UK (Chapter 3, UK environment exposure)

The Rapporteur would also like to acknowledge the contributions from the following individuals:

• Professor Aage Andersen and Dr. Tom K. Grimsrud of the Cancer Registry of Norway, Institute of Population-based Cancer Research, for their assistance in the preparation of the section on nickel carcinogenicity in Chapter 4,

• Ivor Kirman, London, UK for general information about nickel, • Drs. Hudson Bates, Adriana Oller, Katherine Heim, Lisa Ortego, and Chris Schlekat, NiPERA, Durham,

North Carolina, USA, for providing information on the health and environmental effects of nickel, • Jim Hart, Sherborne, Dorset, UK, for the preparation of Chapters 1, and 2, and sections of Chapters 4 and 7, • Professor Torkil Menné MD, Gentofte Hospital, Copenhagen, Denmark for his assistance in the preparation

and critical review of the sections on the sensitising effects of nickel in Chapter 4, • Dr. Sally Pugh Williams, Inco, Wales, UK for general information on nickel.


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Foreword to Draft Risk Assessment Reports Risk assessment of priority substances is carried out in accordance with Council Regulation (EEC) 793/93 (EEC, 1993b) on the evaluation and control of the risks of “existing” substances. Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment of these substances if they are produced or imported into the Community in volumes above 10 tonnes per year. There are four overall stages in the Regulation for reducing the risks: data collection, priority setting, risk assessment and risk reduction. Data provided by Industry are used by Member States and the Commission services to determine the priority of the substances which need to be assessed. For each substance on a priority list, a Member State volunteers to act as “Rapporteur”, undertaking the in-depth Risk Assessment and if necessary, recommending a strategy to limit the risks of exposure to the substance. Denmark is Rapporteur for five nickel substances: nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate. This Background Report has been prepared by the Rapporteur for a number of reasons. Firstly, this Background report includes general information about nickel that is common to all the individual reports. This is particularly relevant for information about the release of nickel into the environment, and many of the environmental properties of nickel. This background report also provides information about other nickel compounds for which separate reports are not being prepared, but where information on their properties is useful for drawing conclusions on the hazards and risks of the five specific substances under review. Finally, this report provides a brief review of the other nickel compounds on the EU market to provide a starting point for further assessment of their hazards and risks. Draft Risk Assessment Reports on nickel metal and other nickel compounds are currently under discussion in the Competent Group of Member State experts with the aim of reaching consensus. During the course of these discussions, the scientific interpretation of the underlying scientific information may change, more information may be included and even the conclusions reached in this draft may change. The Competent Group of Member State experts seek as wide a distribution of these drafts as possible, in order to assure as complete and accurate an information basis as possible. The information contained in these Draft Risk Assessment Reports do not, therefore, necessarily provide a sufficient basis for decision making regarding the hazards, exposures or the risks associated with the priority substances under consideration. This Draft Background Risk Assessment Report is the responsibility of the Member State rapporteur. In order to avoid possible misinterpretations or misuse of the findings in this draft, anyone wishing to cite or quote this report is advised to contact the Member State rapporteur beforehand.


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CONTENTS

0. OVERALL RESULTS OF THE RISK ASSESSMENT........................... 9

1. GENERAL SUBSTANCE INFORMATION ......................................... 10

1.1 NICKEL AND NICKEL COMPOUNDS 10 1.2 PHYSICO-CHEMICAL PROPERTIES OF SELECTED NICKEL COMPOUNDS. 10

1.2.1 Solubility of nickel compounds................................................................................................ 12 1.2.2 Summary....................................................................................................................................... 13

1.3 CLASSIFICATION. 14 1.3.1 Current classification................................................................................................................ 14

1.3.1.1 UN Transport labelling. 14 1.3.1.2 Classification according to Directive 67/548/EEC. 15

1.3.2 Proposed classification............................................................................................................. 22 1.3.2.1 UN Transport labelling. 22 1.3.2.2 Classification according to Directive 67/548/EEC. 22

2. GENERAL INFORMATION ON EXPOSURE TO NICKEL AND NICKEL COMPOUNDS......................................................................... 24

2.1 SOURCES OF NICKEL. 24 2.1.1 Industrial production and use of nickel and nickel compounds...................................................... 24

2.1.1.1 Production. 24 2.1.1.1.1 Mining .............................................................................................................................. 24 2.1.1.1.2 Beneficiation and smelting ............................................................................................... 26 2.1.1.1.3 Refining. ........................................................................................................................... 26 2.1.1.1.4 Nickel chemicals production. ........................................................................................... 26 2.1.1.1.4.1 High production volume nickel containing chemicals. 26 2.1.1.1.4.2 Low production volume nickel containing chemicals. 28 2.1.1.1.4.3 Other low production volume nickel containing chemicals. 30

2.1.1.2 Nickel Use. 31 2.1.1.2.1 Uses of nickel and nickel compounds .............................................................................. 32 2.1.1.2.1.1 High production volume nickel-containing chemicals. 32 2.1.1.2.1.2 Low production volume nickel-containing chemicals. 33 2.1.1.2.1.3 Other low production volume nickel-containing chemicals. 34 2.1.1.2.2 Uses of nickel containing products................................................................................... 35

2.1.1.3 Disposal. 35 2.1.1.4 Nickel emissions from production and use of nickel and nickel-containing chemicals and

products. 35 2.1.2 Other anthropogenic sources of nickel........................................................................................... 36

2.1.2.1 Non-ferrous metals production. 36 2.1.2.2 Combustion processes. 36 2.1.2.3 Other Industrial Processes. 37 2.1.2.4 Emission to soil. 38

2.1.3 Natural sources of nickel................................................................................................................ 38 2.1.3.1 Nickel emissions from natural sources. 39

2.1.4 Summary of nickel exposure information. ...................................................................................... 40 2.1.4.1 Trends in nickel emissions. 40

2.1.5 Nickel Lifecycle. ............................................................................................................................. 40 2.2 LEGISLATIVE CONTROLS. 41

2.2.1 General Measures. ......................................................................................................................... 41 2.2.1.1 Directive 67/548/EEC on dangerous substances. 41 2.2.1.2 Directive 1999/45/EC on dangerous preparations. 41 2.2.1.3 Other EU legislation. 41 2.2.1.4 National Initiatives. 42

2.2.2 Protection of workers. .................................................................................................................... 42 2.2.3 Protection of consumers. ................................................................................................................ 44


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2.2.3.1 Directive 98/83/EC on the quality of water intended for human consumption 45 2.2.3.2 Food contact materials, Food supplements, additives and contaminants. 45 2.2.3.3 Council Directive 90/385/EEC on active implantable Medical Devices, Council Directive

93/42/EEC on Medical Devices and Council Directive 98/79/EEC on in vitro-diagnostic Medical Devices 45

2.2.3.4 Council Directive 88/378/EEC on the Safety of Toys 46 2.2.3.5 Council Directive 89/106/EEC on Construction Products 46 2.2.3.6 Directive 2001/95/EC on general product safety 46

2.2.4 Emissions to water.......................................................................................................................... 46 2.2.4.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC) 46 2.2.4.2 Directive 76/464/EEC on pollution of the aquatic environment by certain dangerous

substances. 47 2.2.4.3 Directive 2000/60/EC establishing a framework for Community action in the field of water

policy. 47 2.2.4.4 Directive 80/68/EEC on the protection of groundwater against pollution caused by certain

dangerous substances 47 2.2.4.5 Directive 2000/76/EC on the incineration of waste. 48 2.2.4.6 National Legislation. 48

2.2.5 Emissions to air .............................................................................................................................. 49 2.2.5.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC) 49 2.2.5.2 Directive 96/62/EC on ambient air quality assessment and management. 49 2.2.5.3 Directive 2000/76/EC on the incineration of waste. 50 2.2.5.4 Directive 2001/80/EC on Large Combustion Plant Directive. 50 2.2.5.5 UN ECE Protocol on heavy metals. 50 2.2.5.6 National Legislation. 50 2.2.5.7 Other measures. 50

2.2.6 Soil.................................................................................................................................................. 51 2.2.6.1 Directive 86/278/EEC on Sludge in Agriculture. 51 2.2.6.2 National Legislation. 51

2.2.7 Waste management. ........................................................................................................................ 52 2.2.7.1 Directive 96/61/EC concerning integrated pollution prevention and control 52 2.2.7.2 Council Directive 91/689/EEC of 12 December 1991 on hazardous waste 52

3. ENVIRONMENT .................................................................................... 53

4. HUMAN HEALTH ................................................................................. 54

4.1 HUMAN HEALTH (TOXICITY) 54 4.1.1 Exposure assessment. ..................................................................................................................... 54

4.1.1.1 General 54 4.1.1.2 Occupational exposure. 54 4.1.1.3 Consumer exposure. 54

4.1.1.3.1 Exposure to nickel in food................................................................................................ 54 4.1.1.3.2 Exposure to nickel in water .............................................................................................. 57 4.1.1.3.3 Combined exposure to nickel from food and drinking water. .......................................... 58 4.1.1.3.4 Exposure to nickel from smoking..................................................................................... 59

4.1.1.4 Indirect exposure via the environment 59 4.1.2 Human health effects assessment.................................................................................................... 59

4.1.2.1 Toxico-kinetics, metabolism and distribution 60 4.1.2.1.1 Absorption........................................................................................................................ 60 4.1.2.1.1.1 Inhalation 60

4.1.2.1.1.1.1 Discussion and conclusion, absorption following inhalation ................................................ 62 4.1.2.1.1.2 Oral 64

4.1.2.1.1.2.1 Discussion and conclusion, absorption following oral administration .................................. 66 4.1.2.1.1.3 Dermal 67

4.1.2.1.1.3.1 Discussion and conclusion, absorption following dermal contact......................................... 68 4.1.2.1.1.4 Other routes 68 4.1.2.1.2 Distribution and elimination............................................................................................. 69 4.1.2.1.2.1 Transport 69 4.1.2.1.2.2 Distribution 69 4.1.2.1.2.3 Transplacental transfer 70


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4.1.2.1.2.4 Cellular uptake 71 4.1.2.1.2.5 Elimination 72 4.1.2.1.2.6 Transfer to the milk 73 4.1.2.1.3 Conclusions ...................................................................................................................... 74

4.1.2.2 Acute toxicity 75 4.1.2.2.1 Animal studies.................................................................................................................. 75 4.1.2.2.1.1 Inhalation 75 4.1.2.2.1.2 Oral 76 4.1.2.2.1.3 Dermal 76 4.1.2.2.1.4 Other routes 76 4.1.2.2.2 Human studies .................................................................................................................. 76 4.1.2.2.3 Discussion and conclusion ............................................................................................... 77 4.1.2.2.3.1 Inhalation 77 4.1.2.2.3.2 Oral 77 4.1.2.2.3.3 Dermal 77

4.1.2.3 Irritation /corrosivity 78 4.1.2.3.1 Animal studies.................................................................................................................. 78 4.1.2.3.1.1 Skin and eye irritation 78 4.1.2.3.1.2 Respiratory irritation 79 4.1.2.3.2 Human data....................................................................................................................... 79 4.1.2.3.2.1 Skin irritation 79 4.1.2.3.2.2 Respiratory irritation 80 4.1.2.3.2.3 Conclusion 80

4.1.2.4 Sensitisation 81 4.1.2.4.1 Skin sensitisation.............................................................................................................. 81 4.1.2.4.1.1 Animal studies 81 4.1.2.4.1.2 Human data 82

4.1.2.4.1.2.1 Nickel allergy........................................................................................................................ 82 4.1.2.4.1.2.2 Mechanism for the development of nickel allergy. ............................................................... 83 4.1.2.4.1.2.3 Immunological tolerance....................................................................................................... 83 4.1.2.4.1.2.4 Occurrence of nickel allergy ................................................................................................. 83 4.1.2.4.1.2.5 Hand eczema......................................................................................................................... 86 4.1.2.4.1.2.6 Experimental sensitisation .................................................................................................... 86 4.1.2.4.1.2.7 The ability of nickel salts, nickel and nickel alloys to elicit nickel allergy ........................... 86

4.1.2.4.1.2.7.1 Skin contact ................................................................................................................... 86 4.1.2.4.1.2.7.2 Oral challenge................................................................................................................ 89 4.1.2.4.1.2.7.3 Hyposensitisation .......................................................................................................... 90

4.1.2.4.1.2.8 Occupational nickel allergy .................................................................................................. 90 4.1.2.4.1.3 Conclusion on skin sensitisation 91

4.1.2.4.1.3.1 Thresholds for elicitation ...................................................................................................... 92 4.1.2.4.1.3.1.1 Skin................................................................................................................................ 92 4.1.2.4.1.3.1.2 Oral................................................................................................................................ 92

4.1.2.4.2 Respiratory sensitisation................................................................................................... 92 4.1.2.4.2.1 Conclusion on respiratory sensitisation 92 4.1.2.4.3 Conclusion........................................................................................................................ 93

4.1.2.5 Repeated dose toxicity 93 4.1.2.5.1 Animal studies.................................................................................................................. 93 4.1.2.5.1.1 Inhalation 95

4.1.2.5.1.1.1 NTP studies of nickel sulphate hexahydrate, nickel subsulphide and nickel oxide............... 95 4.1.2.5.1.1.1.1 16-day rat studies........................................................................................................... 95 4.1.2.5.1.1.1.2 16-day mouse studies..................................................................................................... 96 4.1.2.5.1.1.1.3 13-week rat studies ........................................................................................................ 97 4.1.2.5.1.1.1.4 13-week mouse studies .................................................................................................. 98 4.1.2.5.1.1.1.5 2-year rat studies............................................................................................................ 99 4.1.2.5.1.1.1.6 2-year mouse studies ..................................................................................................... 99

4.1.2.5.1.1.2 Other inhalation studies ...................................................................................................... 100 4.1.2.5.1.1.3 Supporting mechanistic data for lung effects ...................................................................... 101

4.1.2.5.1.2 Oral 102 4.1.2.5.1.3 Dermal 102 4.1.2.5.2 Conclusion...................................................................................................................... 102 4.1.2.5.2.1 Inhalation 102 4.1.2.5.2.2 Oral 103 4.1.2.5.2.3 Dermal 103

4.1.2.6 Mutagenicity 103


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4.1.2.6.1 Summary of mutagenicity test results for the five selected nickel compounds. ............. 103 4.1.2.6.1.1 Summary of mutagenicity test results in vitro. 103

4.1.2.6.1.1.1 DNA damage and repair. .................................................................................................... 103 4.1.2.6.1.1.2 Gene mutation..................................................................................................................... 104 4.1.2.6.1.1.3 Chromosomal effects. ......................................................................................................... 105 4.1.2.6.1.1.4 Cell transformation. ............................................................................................................ 106

4.1.2.6.1.2 Summary of mutagenicity test results in vivo. 106 4.1.2.6.1.2.1 DNA damage and repair. .................................................................................................... 106 4.1.2.6.1.2.2 Gene mutations. .................................................................................................................. 107 4.1.2.6.1.2.3 Chromosomal effects. ......................................................................................................... 107

4.1.2.6.2 Genotoxicity of other nickel compounds........................................................................ 108 4.1.2.6.2.1 Other soluble nickel compounds. 108 4.1.2.6.2.2 Insoluble compounds. 108 4.1.2.6.3 Conclusions on the mutagenicity of the five selected nickel compounds....................... 110

4.1.2.7 Carcinogenicity 112 4.1.2.7.1 Animal data .................................................................................................................... 112 4.1.2.7.1.1 Inhalation 112

4.1.2.7.1.1.1 Nickel sulphate ................................................................................................................... 112 4.1.2.7.1.1.2 Nickel metal........................................................................................................................ 112 4.1.2.7.1.1.3 Nickel chloride, nickel nitrate, and nickel carbonate .......................................................... 114 4.1.2.7.1.1.4 Nickel oxide........................................................................................................................ 114 4.1.2.7.1.1.5 Nickel subsulphide.............................................................................................................. 114

4.1.2.7.1.2 Oral 114 4.1.2.7.1.2.1 Nickel sulphate ................................................................................................................... 114 4.1.2.7.1.2.2 Nickel chloride, nickel nitrate, nickel carbonate, and nickel metal ..................................... 115 4.1.2.7.1.2.3 Nickel acetate...................................................................................................................... 115

4.1.2.7.1.3 Dermal 115 4.1.2.7.1.3.1 Nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal ........... 115 4.1.2.7.1.3.2 Other nickel compounds ..................................................................................................... 115

4.1.2.7.1.4 Other routes of administration 115 4.1.2.7.1.4.1 Nickel sulphate ................................................................................................................... 115 4.1.2.7.1.4.2 Nickel chloride.................................................................................................................... 116 4.1.2.7.1.4.3 Nickel nitrate....................................................................................................................... 117 4.1.2.7.1.4.4 Nickel carbonate ................................................................................................................. 117 4.1.2.7.1.4.5 Nickel metal........................................................................................................................ 117 4.1.2.7.1.4.6 Other nickel compounds ..................................................................................................... 118

4.1.2.7.1.5 Initiator-Promoter studies 118 4.1.2.7.1.5.1 Nickel sulphate ................................................................................................................... 118 4.1.2.7.1.5.2 Nickel chloride.................................................................................................................... 119 4.1.2.7.1.5.3 Nickel metal........................................................................................................................ 120 4.1.2.7.1.5.4 Nickel nitrate, nickel carbonate........................................................................................... 120 4.1.2.7.1.5.5 Other nickel compounds ..................................................................................................... 120

4.1.2.7.1.6 Discussion and conclusions, carcinogenicity in experimental animals 121 4.1.2.7.1.6.1 Inhalation ............................................................................................................................ 121 4.1.2.7.1.6.2 Oral ..................................................................................................................................... 123 4.1.2.7.1.6.3 Dermal ................................................................................................................................ 123 4.1.2.7.1.6.4 Other routes of administration ............................................................................................ 123 4.1.2.7.1.6.5 Initiator-Promoter studies ................................................................................................... 124 4.1.2.7.1.6.6 Conclusions in reviews on nickel compounds..................................................................... 125

4.1.2.7.1.6.6.1 CSTEE (2001) ............................................................................................................. 125 4.1.2.7.1.6.6.2 TERA (1999) ............................................................................................................... 125 4.1.2.7.1.6.6.3 IARC (1999)................................................................................................................ 125 4.1.2.7.1.6.6.4 NiPERA (1996) ........................................................................................................... 125 4.1.2.7.1.6.6.5 IPCS (1991) ................................................................................................................. 125 4.1.2.7.1.6.6.6 IARC (1990)................................................................................................................ 125

4.1.2.7.1.7 Conclusion, carcinogenicity in experimental animals 126 4.1.2.7.2 Human data..................................................................................................................... 126 4.1.2.7.2.1 Epidemiology 126 4.1.2.7.2.2 Exposures 127 4.1.2.7.3 Discussion ...................................................................................................................... 128 4.1.2.7.4 Overall Conclusion for carcinogenicity.......................................................................... 130

4.1.2.8 Toxicity for reproduction 131 4.1.2.8.1 Effects on fertility........................................................................................................... 131 4.1.2.8.1.1 Animal studies 131 4.1.2.8.1.2 Human data 132


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4.1.2.8.2 Developmental toxicity .................................................................................................. 132 4.1.2.8.2.1 Animal studies 132

4.1.2.8.2.1.1 Oral exposure...................................................................................................................... 132 4.1.2.8.2.1.2 Inhalation ............................................................................................................................ 132 4.1.2.8.2.1.3 Other routes ........................................................................................................................ 133

4.1.2.8.2.2 Human data 133 4.1.2.8.3 Conclusions .................................................................................................................... 133

4.1.3 Risk characterisation.................................................................................................................... 134 4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES) 134

4.2.1 Exposure assessment .................................................................................................................... 134 4.2.2 Effects assessment: ....................................................................................................................... 134

4.2.2.1 Explosivity 134 4.2.2.2 Flammability 134 4.2.2.3 Oxidising potential 134

4.2.3 Risk characterisation.................................................................................................................... 134

5. CONCLUSIONS/RESULTS................................................................. 135

6. REFERENCES ...................................................................................... 136

7. APPENDICES ....................................................................................... 154

7.1 WATER SOLUBILITY OF SELECTED NICKEL COMPOUNDS. 154 7.2 NICKEL AND NICKEL COMPOUNDS IN EINECS 155

7.2.1 Nickel, nickel compounds, and complex substances containing nickel included in EINECS. ...... 155 7.2.2 Nickel compounds included in Elincs ........................................................................................... 164 7.2.3 Additional Nickel compounds included in TSCA (through 08/2000) but not included in EINECS.

...................................................................................................................................................... 165 7.2.4 Additional Nickel compounds listed in ECICS (European Customs Inventory of chemical

substances), but not included in EINECS or the TSCA Inventory. ............................................... 166 7.2.5 Additional Nickel compounds in Annex I to Directive 67/548/EEC but not in EINECS or TSCA.166 7.2.6 Additional nickel compound found in the course of compiling the inventory of nickel compounds

...................................................................................................................................................... 166 7.2.7 Additional nickel hydroxycarbonate compounds not included in the lists above ......................... 167 7.2.8 Nickel containing minerals (from IARC, 1990 and NiPERA, 1996)............................................. 167

7.3 NICKEL CONTENT IN FOOD. 168


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0. OVERALL RESULTS OF THE RISK ASSESSMENT The risk assessment of the production and use of metallic nickel, nickel sulphate, nickel chloride, nickel carbonate and nickel nitrate is described in the individual risk assessment reports on these substances. A full risk assessment of the production and use of the other nickel compounds described in this report has not been attempted by the Rapporteur, as these other nickel compounds are not included in a priority list under the Existing Substances Regulation. However, the Rapporteur considers that the approach used in the risk assessments of the five nickel compounds listed above may prove helpful to others when preparing a risk assessment for specific nickel compounds. Risk characterisations of scenarios not directly related to the production and use of nickel and nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments.


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1. GENERAL SUBSTANCE INFORMATION

1.1 NICKEL AND NICKEL COMPOUNDS Nickel can be found in a variety of oxidation states ranging from 0 to IV. However, Ni (II) is the only oxidation state occurring in ordinary chemistry. Ni (III) and Ni (IV) occur in certain complexes and in specific oxide systems, the higher oxidation states, however, being considerably less stable than Ni (II). Ni (0) and Ni (I) compounds are scarce (Cotton & Wilkinson, 1968, quoted from Carlsen, 2001a). Ni (II) forms a wide variety of compounds ranging from simple inorganic complexes (salts) to complexes with various organic ligands. Ni can be found in various oxides. It appears that in the aqueous chemistry Ni (II) is the only oxidation state that has to be considered. In the absence of strong complexing agents Ni (II) appears in aqueous solution as the green hexaquonickel (II) ion Ni (H2O)6

2+ (Cotton & Wilkinson, 1968, quoted from Carlsen, 2001a). There are over three hundred entries in EINECS for nickel and nickel compounds and other, often complex, substances containing nickel. These are shown in Appendix 7.2.1. It should be noted that the EINECS reporting rules (CEC, 1982) implicitly include hydrates of the anhydrous salts listed in EINECS. Hence the numbers of substances (and the numbers of CAS numbers) implicitly included in EINECS is much greater than this figure. Three nickel compounds are included in Einecs (Appendix 7.2.2). An additional 40 nickel containing compounds not listed in EINECS but included in the US EPA TSCA inventory are shown in Appendix 7.2.3. A number of nickel compounds are included in the European Customs Inventory of Chemical Substances (ECICS, 1997). ECICS includes a numerical list showing correlations between the CAS number and the EU CUS number (a five-digit number). Appendix 7.2.1 also includes the CUS numbers where relevant. It can be seen that whilst most HPVC nickel compounds have individual CUS numbers, there are several LPVC chemicals that do not. Similarly, there are many nickel compounds that have individual CUS numbers, although according to the information in IUCLID, they do not appear to be marketed in significant quantities. Additional compounds listed in ECICS (the European Customs inventory of chemical substances) not included in either EINECS or TSCA are shown in Appendix 7.2.4. Substances in the ECICS are included in the European Community’s Combined Nomenclature (eight digit CN code). The CN is based on the “Harmonized Commodity Description and Coding System” emanating from WCO, in use throughout the world. Nickel metal, nickel sulphate and nickel chloride have CN numbers that identify these substances individually. Nickel oxides and hydroxides are identified under a separate CN No. (2825 40 00). However, other nickel compounds are included in CN numbers that also include varying numbers of other non-nickel-containing compounds. Appendix 7.2.5 shows additional substances included as part of group entries in Annex I to Directive 67/548/EEC but not included in the previous lists. Finally, other nickel containing compounds (including minerals and other nickel compounds listed in IARC) not included in any of the lists above are shown in Appendices 7.2.6, 7.2.7 and 7.2.8.

1.2 PHYSICO-CHEMICAL PROPERTIES OF SELECTED NICKEL COMPOUNDS.

Table 1.2.A shows the physical-chemical properties of some nickel compounds shown in order of decreasing water solubility. Data for the four high volume nickel compounds for which individual reports have been prepared are included for comparison. This data has been compiled from a number of reviews of nickel and nickel compounds. A more detailed discussion of the water solubility of nickel and nickel compounds is given in the following section.

Table 1.2.A: Summary of physical properties of selected nickel compounds (compiled from UK HSE, 1987, IARC, 1990, NiPERA, 1996, TERA, 1999)

Nickel compound:

Atomic weight

Physical State

Melting Point (°C)

Boiling Point (°C)

Density (g/cm3)

Oxidation state

Water Solubility 3)


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nickel chloride (hexahydrate)

237.70 solid - - 1.92 +2 2540 g/l at 20°C.

nickel nitrate (hexahydrate)

290.79 solid 56.7 136.7 1) 2.05 +2 2385 g/l at 0°C.

nickel sulphate (heptahydrate)

280.85 solid 99 - 1.95 +2 756 g/l at 20°C.

nickel chloride (anhydrous)

129.60 solid 973 2) 1001 3.55 +2 642 g/l at 20°C.

nickel sulphate (hexahydrate)

262.84 solid 53.3 - 2.07 +2 625 g/l at 20°C.

nickel ammonium sulphate (anhydrous)

286.88 - 1) +2 300 g/l at 20°C.

nickel sulphate (anhydrous)

154.75 solid 848 1) - 3.68 +2 293 g/l at 20°C.

nickel acetate (anhydrous)

176.78 solid 1) 16.6 1.80 +2 166 g/l at 20°C.

nickel acetate (tetrahydrate)

248.84 solid 1) 16 +2 160 g/l at 20°C.

nickel ammonium sulphate (hexahydrate)

394.94 - - 1.92 +2 104 g/l at 20°C.

nickel fluoride 96.69 solid +2 40 g/l at 25°C

nickel fluoroborate (hexahydrate)

340.42 solid 1) 2.14 Soluble

nickel formate 184.76 solid 2.15 +2 soluble

nickel sulphamate (tetrahydrate)

322.95 solid 200 1) +2 Soluble

nickel carbonyl

170.73 liquid - 25 43 1.32 0 0.18 g/l at 9.8°C

nickel hydroxide

92.7 solid 230 1) - 4.15 +2 0.13 g/l

nickel carbonate

118.70 solid 1) - 5.822 +2 0.0093 g/l at 25°C.

nickel sulphide (amorphous)

90.75 solid 797 - 5.5 +2 0.003618 g/l

nickel monoxide

74.69 solid 1990 - 4.83 / 6.67

+2 0.0011 g/l at 20°C.

basic nickel carbonate

376.17 solid 1) 2.6 +2 Insoluble

nickel hydroxy-carbonate

587.67 solid 1) - 2.6 +2 Insoluble

nickel chromate

174.71 solid - - 5.82 +2 Insoluble in water

Nickelocene 188.88 solid 171-173 - +2 Insoluble

nickel titantate 154.57 solid 1000 1) - +2 Insoluble


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nickel antimonide

180.44 solid 1158 1400 1) NS 4) Insoluble

nickel arsenide (NiAs)

133.61 solid 968 - 7.17 NS 4) Insoluble

nickel selenide 137.65 solid red heat - NS 4) Insoluble

nickel subselenide

333.99 solid - - Insoluble

nickel subsulphide

240.19 solid 790 - 5.82 NS 4) Insoluble in cold water

nickel telluride 186.29 solid 600 – 900 1) - NS 4) Insoluble 1) Decomposes. 2) Sublimes 3) Further details are given in the following section. 4) NS: Not Specified; mixed formal oxidation states of nickel and/or complex coordination in the solid form.

1.2.1 Solubility of nickel compounds. In the Table above, the water solubility of many of these compounds are described as either “soluble” or “insoluble”. Many substances commonly considered as “insoluble” are however sufficiently soluble under certain conditions to give rise to effects of concern. This simple distinction is not always helpful. The available literature of the solubility of inorganic (Carlsen, 2001a) and organic (Carlsen, 2001b) Ni (II) species has been reviewed. This review was carried out in order to provide a systematic basis on which to group in particular inorganic nickel compounds on the basis of their solubility in water. For inorganic nickel compounds, a grouping of inorganically based nickel species has been suggested. Nickel metal and nickel metal compounds (see Appendix 7.1.1) can all be considered as insoluble. Nickel oxides and mixed metal oxides are also very similar in terms of their solubility (Carlsen, 2001a). In Table 1.2.B a grouping of the nickel ligands with Group 13, 14, 15, 16 and 17 ligands is suggested. The term ‘insoluble’ means that the solubility of the species is less that 10-4 mol/l, ‘slightly soluble’ covers the solubility range 10-4 - 10-2 mol/l, ‘soluble’ the range 10-2 - 5·10-1 mol/l and ‘very soluble’ refers to solubility above 5·10-1 mol/l (Carlsen, 2001a). The grouping made in Table 1.2.B is based exclusively on water as the medium. Thus, the apparent increased solubility of otherwise slightly - or even insoluble - nickel species observed in biological fluids (Maximilien, 1989) is not covered in the grouping made below (Carlsen, 2001a). A few species, i.e., NiXN and NiTeO4 are not included in Table 1.2.B. No indications concerning the solubility of these species have been retrieved (Carlsen, 2001a).

Table 1.2.B: Grouping of nickel species based on inorganic ligands in water (Carlsen, 2001a).

Group 13 Group 14 Group 15 Group 16 Group 17 Misc.

Insoluble NiXBa NiXSia NiXPYa

NiXAsa

NiXSbYa

Ni2P2O7

Ni3(AsO3)2a

Ni3(AsO4)2

Ni(AsO3)2a

NiXSY

NiXSe

NiXTe

Ni2Fe(CN)6

Slightly soluble

Ni(CO)4

Ni(CN)2

NiCO3

Ni(HCO3)2

Ni3(PO4)2

Ni[NiP2O7]

NiSO3a

NiSeO3

Ni(IO3)2 Ni2Fe(CN)5NOb


13

Soluble NiK2(SO4)2 NiF2

Very soluble

NiB6O10

Ni(BF4)2

Ni(SCN)2

NiSiF6

Ni(NO3)2

Ni(H2PO2)2

NiSO4

Ni(SO3NH2)2a

NiSeO4

NiCl2

Ni(ClO3)2

Ni(ClO4)2

NiBr2

Ni(BrO3)2

NiI2

a No quantitative data have been retrieved b Placed due to the possible higher solubility as discussed by Linke (1965). It is noted that the solubility in general follows the ‘rules of thumb’ for inorganic salts. Thus, halides are easily soluble, apart from the fluoride, nitrates are easily soluble, carbonates and phosphates are typically only slightly soluble, hydroxides of non-alkali metals are often very slightly soluble, etc. (Carlsen, 2001a). In the study by Carlsen (2001a) the focus is on the concentration of the free nickel (II) ion, Ni(H2O)6

2+ as responsible for biological effects of nickel compounds. However, the free ligands and/or the intact nickel complexes may also give rise to biological effects. It should be emphasized that the grouping in Table 1.2.B is made without taking into account the possible lowering of the concentration of the free nickel ions due to complex formation. For hazard and risk assessment purposes this corresponds to a conservative approach to the possible maximum concentration of Ni(H2O)6

2+ (Carlsen, 2001a). No comparable grouping of organic ligands has yet been carried out (Carlsen, 2001b). In contrast to the inorganic nickel compounds it is not obvious how to group the organically based species based on solubility alone. Aqueous solubility is, not unexpectedly, seen to decrease with increasing molecular weight and increasing carbon content of the ligand. On the other hand, the introduction of hydrophilic and/or polar functional groups, such as OH, C=O, COO-, NH, SH and SO3

- cause increased solubility. Further it should be emphasized that the solubility of the complexes cannot immediately be related to the solubility of the single ligands (Carlsen 2001b). Hence, it seems more appropriate to group organically based nickel complexes based on the stability of the complexes. As a first attempt, grouping the individual complexes based on the nature of the ligand appears as an obvious choice, even though significant variations in stability may prevail within the single groups. Monocarboxylic acids serve as an example to illustrate the applicability of this concept. It appears that the stability constant for the first complex typically is found in the range around 1 and the second in the range of 1-2. Significant outliers are the sulphur-containing acids thiolactic acid and (phenylthio)acetic acid. Apart from the sulphur-containing acids, it would seem appropriate to treat nickel monocarboxylate complexes as a single group, based on the salts of formic and acetic acid. Both these salts are highly soluble: thus, the approach would be conservative. In order to evaluate the possible concentration of free nickel ions, as well as other nickel containing species in solution, it is important to take the actual acidity of the solution into consideration (Carlsen, 2001b).

1.2.2 Summary The availability of physical chemical data for the nickel compounds in Appendix 7.1 is very variable. However, there is data available for the water solubility of many inorganic nickel (II) compounds, although there are many complex nickel-containing substances with no solubility data. Grouping many of the conventional inorganic nickel (II) compounds on the basis of their water solubility is fairly straightforward. Grouping the much larger numbers of organic complexes is a more complicated process. Many legislative controls group all nickel compounds together (see Chapter 2.2). In other cases, nickel compounds are divided into groups on the basis of their water solubility (e.g. TERA, 1999). This grouping of compounds reflects the assumption that the biological effects of nickel reflect the activity of the nickel ion, Ni(H2O)6

2+. NiPERA (1996) groups nickel compounds into five main classes: metallic nickel, nickel carbonyl, oxidic nickel (e.g. nickel oxides, hydroxide, silicates, carbonates, complex nickel oxides), sulphidic nickel (e.g. nickel sulphide, nickel subsulphide), and water-soluble nickel compounds (e.g. nickel sulphate hexahydrate, nickel chloride hexahydrate). The group of “oxidic nickel” includes substances with a range of different water solubility, from compounds of very low solubility (e.g. nickel oxide) to compounds with a water solubility a hundred times greater (e.g. nickel hydroxide). There is little difference in the water solubility of sulphidic nickel and that of nickel oxides. Whilst these groupings reflect the substances encountered in nickel metal production, they do not reflect well the wider range of HPVC and LPC substances seen in practice (see Chapter 2).


14

However, it is important to be able to recognise similarities and differences in biological behaviour across groups of chemically related compounds. Derogation statements by Industry for not carrying out testing for particular endpoints is based on the recognition of similarities in effects between nickel-containing compounds where data is available, and other related compounds where experimental data is not available. Assumptions are made in the risk assessment reports of the individual compounds reviewed by the Rapporteur about the possibility to extrapolate data between these compounds. The data reviewed for the five individual substances can also be used as a basis for similar extrapolations to other related nickel compounds.

1.3 CLASSIFICATION.

1.3.1 Current classification

1.3.1.1 UN Transport labelling. Four nickel compounds are included as specific entries in the UN Recommendations on the Transport of Dangerous Goods (UN, 2001) and ADR (UN ECE 2001b). UN Number Class Subsidiary

risk Packaging Group

Nickel carbonyl (nickel tetracarbonyl) 1259 6.1 3 I

Nickel cyanide (Nickel (II) cyanide) 1653 6.1 II

Nickel nitrate (Nickel (II) nitrate, nickelous nitrate) 2725 5.1 III

Nickel nitrite (Nickel (II) nitrite, nickelous nitrite) 2726 5.1 III None of these four entries are included in Annex B.2 – Appendix 4 of the ADN (UN ECE, 2001a). According to information supplied by Industry to the Rapporteur, nickel containing compounds and products are classified under the following n.o.s. entries: UN Name UN Number Class Subsidiary

risk Packaging Group

nickel carbonate Environmentally hazardous substance, solid, n.o.s

UN 3077 9 M7 III

nickel chloride (solid) Toxic solid, inorganic. n.o.s.

UN 3288 6.1 T5 III

nickel chloride (liquid) Toxic liquid, inorganic. n.o.s.

UN 3287 6.1 T4 III

Lithium nickel batteries

Lithium batteries. UN 3091 9, M4 II

nickel catalyst, dry, metal catalyst, dry, UN 2881 4.2 I / II

nickel catalyst, spent flammable solid, organic n.o.s.

UN 1325 4.1 III

nickel metal powder with very fine particle size (e.g. INCO 210)

metal powder, flammable, n.o.s.

UN 3089 4.1 II

nickel powder less than 100 microns

Environmentally hazardous substance, solid n.o.s

UN 3077 9 M7 III.

nickel sulphate Environmentally hazardous substance solid n.o.s.

UN 3077 9 M7 III

The Rapporteur has no information on the Transport classification used for other nickel compounds


15

1.3.1.2 Classification according to Directive 67/548/EEC. Thirteen nickel compounds are included in Annex I to Directive 67/548/EEC (EEC, 1992a) as separate entries. Three of these are notified substances. The classification of all these entries (including substances reviewed in the individual risk assessment reports are shown below. In some cases, a number of different compounds have the same classification. Individual entries are classified as follows: Nickel carbonyl: 028-001-00-1 (EC No.: 236-669-2, CAS No.: 13463-39-3) (25th ATP, EC 1998b)

Classification

F; R11 Carc. Cat. 3; R40 Repr. Cat. 2; R61 T+; R26 N; R50-53

Labelling

Symbols F; T+; N

R Phrases 61-11-26-40-50/53 (Nota E)

S-Phrases 53-45-60-61

Nickel: 028-002-00-7 (EC No.: 231-111-4, CAS No.: 7440-02-0) (19th ATP, EEC, 1993d1)

Classification

Carc. Cat. 3; R40 R43

Labelling

Symbols Xn

R Phrases 40-43

S-Phrases (2-)22-36

Nickel monoxide: 028-003-00-2 (EC No.: 215-215-7, CAS No.: 1313-99-1) (28th ATP, EC 2001e) Nickel dioxide: 028-004-00-6 (EC No.: 234-823-3, CAS No.: 12035-36-8) (28th ATP, EC 2001e) Nickel trioxide: 028-005-00-3 (EC No.: 215-217-8, CAS No.: 1314-06-3) (28th ATP, EC 2001e)2

Classification

Carc. Cat. 1; R49 R43 R53

Labelling

Symbols T

R Phrases 49-43-53

S-Phrases 53-45-61

1 This entry has been revised in the 30th ATP which was adopted by a Technical Progress Committee in February 2007, but not yet adopted by the Commission or published in the Official Journal. The revised entry is classified as: Carc. Cat. 3; R40; T; R48/23 and R43. An additional entry for particle size < 1 mm including calssification as R52-53 has been agreed by the TC C&L and included in a draft 31 ATP sent for comment in July 2007. 2 Changes to these entries have been agreed by the TC C&L and included in a draft 31 ATP sent for comment in July 2007. The revised entries are classified as: Carc. Cat. 1; R49; T; R48/23, R43 and R53.


16

Nickel sulphide: 028-006-00-9 (EC No.: 240-841-2, CAS No.: 16812-54-7) (28th ATP, EC 2001e)3

Classification

Carc. Cat. 1; R49 R43 N; R50-53

Labelling

Symbols T; N

R Phrases 49-43-50/53

S-Phrases 53-45-60-61

Nickel subsulphide 1: 028-007-00-4 (EC No.: 234-829-6, CAS No.: 12035-72-2) (28th ATP, EC 2001e) 3

Classification

Carc. Cat. 1; R49 R43 N; R51-53

Labelling

Symbols T; N

R Phrases 49-43-51/53

S-Phrases 53-45-61 1) Heazlewoodite given as a synonym by NiPERA (1996). Nickel dihydroxide: 028-008-00-X (EC No.: 235-008-5, CAS No.: 12054-48-7) (28th ATP, EC 2001e)4

Classification

Carc. Cat. 3; R40 Xn; R20/22 R43 N; R50-53

Labelling

Symbols Xn; N

R Phrases 20/22-40-43-50/53

S-Phrases (2-)22-36-60-61

Nickel sulphate: 028-009-00-5 (EC No.: 232-104-9, CAS No.: 7786-81-4) (25th ATP, EC 1998b)5

Classification

Carc. Cat. 3; R40 Xn; R22 R42/43 N; R50-53

Labelling

Symbols Xn; N

R Phrases 22-40-42/43-50/53

S-Phrases (2-)22-36/37-60-61

3 Changes to this entry has been agreed by the TC C&L and included in a draft 31 ATP sent for comment in July 2007. The revised entry is classified as: Carc. Cat. 1; R49; Muta. Cat. 3; R68; T; R48/23, R43 and N; R50-53. 4 Changes to this entry has been agreed by the TC C&L and included in a draft 31 ATP sent for comment in July 2007. The revised entry is classified as: Carc. Cat. 1; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23, Xi; R38; R42/43 and N; R50-53. 5 This entry has been revised in the 30th ATP. The revised entry is classified as: Carc. Cat. 1; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23; (SCL of 1%); Xi; R38; (SCL of 20%); R42; R43 (SCL of 0.01%) and N; R50-53.


17

Nickel carbonate 1: 028-010-00-0 (EC No.: 222-068-2, CAS No.: 3333-67-3) (25th ATP, EC 1998b)6

Classification

Carc. Cat. 3; R40 Xn; R22 R43 N; R50-53

Labelling

Symbols Xn; N

R Phrases 22-40-43-50/53

S-Phrases (2-)22-36/37-60-61

1): NiPERA (1996) also lists two other substances, not mentioned in Annex I as included in the same Annex I entry (028-010-00-0). These are the 1:2 nickel hydroxycarbonate, with the EINECS name: [carbonato(2-)] tetrahydroxytrinickel), CAS and EC Nos. 12607-70-4 and 235-715-9, and 2NiCO3.3Ni(OH)2.4H2O shown with CAS No. 12122-15-5 and EC No. 235-715-9 (for comments on these CAS & EC Nos. see risk assessment report on nickel carbonate). Tetrasodium (c-(3-(1-(3-(e-6-dichloro-5-cyanopyrimidin-f-yl(methyl)amino)propyl)-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridylazo)-4-sulfonatophenylsulfamoyl)phtalocyanine-a,b,d-trisulfonato(6-))nickelato II, where a is 1 or 2 or 3 or 4,b is 8 or 9 or 10 or 11, c is 15 or 16 or 17 or 18, d is 22 or 23 or 24 or 25 and where e and f together are 2 and 4 or 4 and 2 respectively: 607-288-00-2 (EC No.: 410-160-7, CAS No.: 148732-74-5) (26th ATP, EC 2000a; repeated in 28th. ATP, EC 2001e)

Classification

Xi; R36 R43 R52-53

Labelling

Symbols Xi

R Phrases 36-43-52/53

S-Phrases (2-)22-26-36/37-61

Trisodium (1-(3-carboxylato-2-oxido-5-sulfonatophenylazo)-5-hydroxy-7-sulfonatophthalen-2-amido)nickel(II): 611-103-00-0 (EC No.: 407-110-1, CAS No.: -) (29th ATP, EC 2004a)

Classification

Xi; R41 R43 N; R51-53

Labelling

Symbols Xi; N

R Phrases 41-43-51/53

S-Phrases (2-)24-26-37/39-61

Hexasodium (di(N-(3-(4-[5-(5-amino-3-methyl-1-phenylpyrazol-4-yl-azo)-2,4-disulfo-anilino]-6-chloro-1,3,5-triazin-2-ylamino)phenyl)-sulfamoyl](disulfo)-phthalocyaninato)nickel: 611-122-00-2 (EC No.: 417-250-5, CAS No.: 151436-99-6) (29th ATP, EC 2004a)

Classification

Xi; R41

Labelling

Symbols Xi

R Phrases 41

S-Phrases (2-)26-39

6 This entry has been revised in the 30th ATP. The revised entry is classified as: Carc. Cat. 1; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23; Xi; R38; R42; R43 and N; R50-53.


18

In addition, 25 other nickel compounds are included in Annex I to Directive 67/548/EEC as part of group entries7. The classification of these entries reflects the hazards of the main functional group forming the basis of the group entry, and is not based on hazards related to nickel. Nickel compounds in EINECS are included in group entries in Annex I to Directive 67/548/EEC for salts of hydrogen cyanide (006-007-00-5), fluorosilicates (009-013-00-6), chromium (VI) compounds (024-017-00-8), arsenic compounds (033-002-00-5), salts of arsenic acid (033-005-00-1), selenium compounds (034-002-00-8), antimony compounds (051-003-00-9), barium compounds (056-002-00-7), lead compounds (082-001-00-6), uranium compounds (092-002-00-3) salts of oxalic acid (607-007-00-3) and metal salts of thiocyanic acid (615-032-00-6). EINECS name Annex I entry EC No. CAS No. Classification

nickel (II) cyanide (1)

006-007-00-5 209-160-8 557-19-7 T+; R26/27/28 R32 N; R50-53

nickel(2+), bis(1,2-ethanediamine-N,N')-, bis[bis(cyano-C)aurate(1-)]

006-007-00-5 273-379-5 68958-89-4 T+; R26/27/28 R32 N; R50-53

Copper(2+), bis(1,2-ethanediamine-N,N')-, (SP-4-1)-tetrakis(cyano-C)nickelate(2-) (1:1)

006-007-00-5 264-136-4 63427-32-7 T+; R26/27/28 R32 N; R50-53

Nickelate(2-), tetrakis(cyano-C)-, disodium, (SP-4-1)-

006-007-00-5 237-877-6 14038-85-8 T+; R26/27/28 R32 N; R50-53

silicate(2-), hexafluoro-, nickel(2+) (1:1)(1)

009-013-00-6 247-430-7 26043-11-8 Xn; R22

nickel chromate (1)

024-017-00-8 238-766-5 14721-18-7 Carc. Cat. 2; R49 R43 N: R50-53

nickel dichromate (1)

024-017-00-8 239-646-5 15586-38-6 Carc. Cat. 2; R49 R43 N: R50-53

nickel diarsenide (1)

033-002-00-5 235-103-1 12068-61-0 T; R23/25 N; R50-53

nickel arsenide (1)

033-002-00-5 248-169-1 27016-75-7 T; R23/25 N; R50-53

nickel (II) arsenate (1)

033-005-00-1 236-771-7 13477-70-8 Carc. Cat. 1; R45 T; R23/25 N; R50-53

Nickel selenide (NiSe) (1)

034-002-00-8 215-216-2 1314-05-2 T; R23/25 R33 N; R50-53

selenious acid, nickel(2+) salt (1:1) (1)

034-002-00-8 233-263-7 10101-96-9 T; R23/25 R33 N; R50-53

selenic acid, nickel(2+) salt (1:1) (1)

034-002-00-8 239-125-2 15060-62-5 T; R23/25 R33 N; R50-53

antimony, compd. with nickel (1:1)

051-003-00-9 234-827-5 12035-52-8 Xn; R20/22 N; R51-53

7 Two nickel acrylates and two nickel methacrylates were excluded from the Annex I group entries for these compounds in the 28th. ATP (EC 2001e) when the nomenclature was changed to specify monoalkyl or monoaryl or monoalkylaryl esters only.


19

antimony, compd. with nickel (1:3)

051-003-00-9 235-676-8 12503-49-0 Xn; R20/22 N; R51-53

C.I. Pigment Yellow 53, (Antimony nickel titanium oxide yellow,) (2)

051-003-00-9 232-353-3 8007-18-9 Xn; R20/22 N; R51-53

antimony oxide (Sb203), solid soln. with nickel oxide (NiO) and titanium oxide

051-003-00-9 277-627-3 73892-02-1 Xn; R20/22 N; R51-53

Priderite, nickel (1)

056-002-00-7 271-853-6 68610-24-2 Xn; R20/22

Speiss, lead, nickel-contg.

082-001-00-6 308-765-5 98246-91-4 Repr. Cat. 1; R61; Repr. Cat. 3; R62

Xn; R20/22; R33

N; R50-53

Residues, copper-iron-lead-nickel matte, sulfuric acid-insol.

082-001-00-6 310-050-8 102110-49-6 Repr. Cat. 1; R61; Repr. Cat. 3; R62

Xn; R20/22; R33

N; R50-53

uranate(2-), tetrakis(acetato-O)dioxo-,nickel(2+)(1:1), (OC-6-11)-

092-002-00-3 275-994-4 71767-12-9 T+; R26/28 R33 N; R51-53

uranic acid (H2U3O10), nickel(2+) salt (1:1) (1)

092-002-00-3 239-876-6 15780-33-3 T+; R26/28 R33 N; R51-53

ethandioic acid, nickel salt (1)

607-007-00-3 243-867-2 20543-06-0 Xn; R21/22

ethandioic acid, nickel(2+) salt (1:1) (1)

607-007-00-3 208-933-7 547-67-1 Xn; R21/22

thiocyanic acid, nickel(2+) salt (1)

615-032-00-6 237-205-1 13689-92-4 Xn; R20/21/22 R32 N; R50-53

1) Chemical included in draft 31st ATP 2) Low production volume chemical. See chapter 2.1.1.1.4. Classification discussed in preparation of draft 31st ATP (Hart, 2007). For nickel compounds not included in Annex I, Industry is required to evaluate the available data to assess the hazard, and to apply a provisional classification. Information is available from Industry for the provisional classifications of the HPVC nickel compounds reviewed by the Rapporteur:8 Com-pound

Classification Reference

Nickel chloride

T; R25 Xn; R40/20 Xi; R36/37 R42/43 N; R50 Eramet, 2002

Nickel O; R8 Xn; R22 R43 HEDSET

8 These two compounds have now been included in the 30th ATP. Nickel dichloride is classified as: Carc. Cat. 1; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; T; R23/25; T; R48/23; (SCL of 1%); Xi; R38; (SCL of 20%); R42; R43 (SCL of 0.01%) and N; R50-53. Nickel dinitrate is classified as: O; R8; Carc. Cat. 1; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23; (SCL of 1%). Xi; R38 (SCL of 20%); Xi; R41; R42; R43 (SCL of 0.01%) and N; R50-53


20

nitrate (2002a)

Carc. Cat. 1; R45 T; R23/24/25 C; R34 IUCLID, 2001

O; R8 Carc. Cat. 3; R40 Xn; R22 C; R34 R42/43 HEDSET (2002b)

O; R8 Carc. Cat. 1; R45 (1)

Xn; R22 R43 HEDSET (2003a)

O; R8 Carc. Cat. 3; R40 Xn; R22 C; R34 R43 N; R50/53 IUCLID (2003b)

O; R8 Carc. Cat. 3; R40 Xn; R22 R42/43 (2)

N; R50/53 IUCLID (2003b)

O; R8 Xn; R22 Xi; R38/41 HEDSET (2003b)

1) The classification category is not shown. Category 1 is assumed on the basis of the IARC conclusion and the lack of any animal data. 2) R42 is applied when the nickel solution is used as an aerosol (IUCLID, 2003b). Only one of the HPVC nickel compounds not specifically reviewed by the Rapporteur (see Table 2.1.1.C) is included in Annex I. This is nickel oxide (Annex I entry 028-003-00-2). None of the remaining 14 substances includes a provisional classification in the IUCLID database at the ECB (IUCLID 2002). Several of the files include the remark that “UVCB-Stoffe sind zum größten teil nicht eingestuft” (UVCB substances are not normally classified). There is no derogation from the requirement for provisional classification for complex UVCB substances in the Directive, and guidance on the classification of these substances is given in section 1.7.2.1. of Annex VI (EC, 2001e). However, some information is available. Section C.5 of the IUCLID file for “ferronickel manufacturing slags” (EC No. 273-729-7) considers the substance fulfils the criteria for classification as Carc. Cat 3; R40 and R43. Section 1.15. 5 of the IUCLID file for “nickel matte” (EC No. 273-746-9) recognises that the main component is nickel subsulphide which is classified as Carc. Cat. 1 in Annex I (Annex I entry 028-007-00-4). It states that the dust is irritating for the respiratory tract and that it may also be a respiratory sensitiser. A comment in the IUCLID file for “Frits, chemicals” (EC No. 266-047-6) notes that classification depends on the composition of an individual product. One manufacturer’s IUCLID file for “Leach residues, zinc ore-calcine, cadmium-copper ppt.” (EC No. 293-311-8) includes a provisional classification as Xn; R20 (harmful by inhalation) (IUCLID, 1996). This provisional classification is not included in the main IUCLID file. (IUCLID 2002). One manufacturer’s IUCLID file for “Leach residues, zinc ore-calcine, iron contg.,” (EC No. 293-312-3) includes a classification with R45, R46 and R61 (May cause cancer, may cause heritable genetic damage, may cause harm to the unborn child). It also includes a classification as T; R23/25 (Toxic by inhalation and if swallowed), Xn; R20/21/22) (Harmful by inhalation, in contact with skin and if swallowed); and R33 (danger of cumulative effects). This evaluation is based on the classification of the main components, lead, cadmium and arsenic. (IUCLID, 1995). This provisional classification is not included in the main IUCLID file. This does however include a comment under section 1.15 from another manufacturer noting a composite classification based on the properties of lead and arsenic (IUCLID 2002). These “classifications” are shown in the table below. Compound Classification Reference

Slags, ferronickel-manufg.

Carc. Cat. 3; R40 R43 C.5 in IUCLID (2002)

nickel matte (1) Carc. Cat. 1; R45 Xi; R37 R42 from section 1.15.5 in IUCLID (2002)

Leach residues, zinc ore-calcine, cadmium-copper ppt

Xn; R20 IUCLID (1996)

Leach residues, zinc ore-calcine, iron contg.

Carc. Cat. 1; R45 Muta. Cat. 2; R46 Repr. Cat. 1; R61

T; R23/25 Xn; R21 R33 IUCLID (1995)


21

Carc. Cat. 1; R45 Repr. Cat. 1; R61

Xn; R20/22

R33 from section 1.15 in IUCLID (2002)

1) Chemical included in draft 31st ATP There is no assessment of “Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfate”, EC No. 295-859-3, in the IUCLID file (IUCLID, 2002), even though the EINECS description of the substance indicates nickel sulphate which is included in Annex I (028-009-00-5) as a main component. Some HPVCs, such as Ceramic materials and wares, chemicals (EC No. 266-340-9) are regarded as non-hazardous. For others, e.g. Slags, copper smelting EC No. 266-968-3 the substance is not classified due a lack of information on the effects of the substance. The nickel-containing LPVCs are listed in Table 2.1.1.D. Nickel hydroxide (028-008-00-X) and nickel sulphide (028-006-00-9) are both included in Annex I. C.I. Pigment Yellow (EC No. 232-353-3) is an antimony compound and, as such is included in the group entry (051-003-00-9). Nickel, [carbonato(2-)]tetrahydoxytri- (EC No. 235-715-9) is regarded by NiPERA as included in the nickel carbonate entry (028-010-00-0) although it is not actually listed as part of the entry. The IUCLID data sets are not available for LPVCs in ESIS (IUCLID, 2002). The 37 IUCLID data sets submitted by the producers of the 22 LPVCs not included in Annex I with specific entries have been supplied by the ECB to the Danish Rapporteur. The Table below summarises the classifications shown in these files. Compound Classification Reference.

Nickel, [carbonato(2-)]tetrahydroxytri-

Carc. Cat. 3; R40 Xn; R22 R43 IUCLID, 2003a (1)

Carc. Cat. 3; R40 Xn; R22 Xi; R36 R42/43 Nickel fluoride (NiF2)

Carc. Cat. 3; R40 R43

IUCLID, 2003a (2,3)

Nickel bromide (NiBr2) no data available for classification

IUCLID, 2003a

Carc. Cat. 3; R40 Xn; R22 Xi; R36/38 R42/43 Sulfamic acid, nickel(2+) salt (2:1)

Carc. Cat. 3; R40 Xn; R22 R42/43

IUCLID, 2003a (2)

Acetic acid, nickel(2+) salt Carc. Cat. 3; R40 R43 IUCLID, 2003a

Acetic acid, nickel salt Carc. Cat. 3; R40 Xn; R22 R42/43 IUCLID, 2003a

Octanoic acid, nickel(2+) salt

Carc. Cat. 3; R40 Xn; R20/21/22

C; R35 R42/43 IUCLID, 2003a

Xi; R39 Xi; R36 Nickel, bis(dibutylcarbamodithioato-S,S’)-, (SP-4-1)- no dangerous

properties

IUCLID, 2003a (2, 4, 5)

Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1-one oximato-N(2)-,O(1))-

no dangerous properties

IUCLID, 2003a (5)

Nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-,N(3)-]-


IUCLID, 2003a (5)

Nickel, bis[2,3-bis(hydroxyimino)-N-(2-methoxyphenyl)butanamidato]-


IUCLID, 2003a (5)

Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, (SP-4-1)-

no data available for classification

IUCLID, 2003a

Nickel, (1- R52/53 IUCLID, 2003a (2)


22

butanamine)[[2,2’-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O’,S]-

Xn; R20 R52/53

Nickel, 5,5’-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes


IUCLID, 2003a (5)

Nickel, acetate carbonate C8-C10-branched fatty acids C9-C11-neofatty acids complexes

Carc. Cat. 3; R40 Xn; R22 R42/43 IUCLID, 2003a

Antimony-nickel-titanium-oxide-yellow-, C.I. Pigment Yellow 53


IUCLID, 2003a (2, 5, 6, 7)

Cobalt-nickel-gray-periclase-, C.I. Pigment Black 25.


IUCLID, 2003a (2, 3, 5,7)

Nickel-ferrite-brown-spinel-, C.I. Pigment Brown 34


IUCLID, 2003a (5, 7)

Nickel-iron-chromite-black-spinel-, C.I. Pigment Black 30


IUCLID, 2003a (2, 5, 7)

Lead alloy, base, dross not applicable as this is an UVCB

IUCLID, 2003a

Ashes (residues), heavy fuel oil fly

no data available for classification

IUCLID, 2003a

Slimes and Sludges, copper electrolyte refining, decopperised

Carc. Cat. 3; R40 (R61 included on the label)

T; R23/25 R42/43 R33 IUCLID, 2003a (3, 8)

1) As for nickel carbonate in Annex I but without the classification for the environment. Now included together with other nickel hydroxycarbonates in 30th ATP 2) Different provisional classifications from different IUCLID data sets. 3) Included in draft 31st ATP. 4) R39 is associated with the symbol “T+” or “T” and not “Xn”. In addition Annex VI to Directive 67/548/EEC (EC, 2001e) requires the route of administration to be included in the classification. 5) The file contains no experimental data to support the claim that there are no dangerous effects. 6) There are five producers of this substance. As an antimony compound, the group entry in Annex I requires the substance to be classified as Xn; R20/22, N; R51-53. 7) The substance is a complex nickel oxide. Nickel oxide is classified as a Category 1 carcinogen in Annex I. 8) Based on a composite classification of components: arsenic, lead compounds, nickel sulphate.

1.3.2 Proposed classification

1.3.2.1 UN Transport labelling. The International Council of Chemical Associations (ICCA) (UN CETDG, 2002) has made a proposal for a schematic classification of organometallic substances (which would include many of the nickel compounds shown in the Appendix) to the Committee of Experts on the Transport of Dangerous Goods (UN CETDG) and on the Globally Harmonised System of classification and labelling of chemicals

1.3.2.2 Classification according to Directive 67/548/EEC. Nickel chloride is problematic for Norway under the EEA Treaty. Norway has made a proposal to the European Commission (European Commission, 1995a) to classify nickel chloride as: Carc. Cat. 1; R45, Muta. Cat. 3; R40 T; R25 R42/43 N; R50-53 (1) 1) The environmental classification proposal was added later.


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A further proposal for the classification of this substance was made by Denmark as a result of the findings of the risk assessment. Nickel dichloride, together with nickel dinitrate has been included in Annex I to Directive 67/548/EEC as part of the 30th. ATP (see 1.3.1.2 above). Proposals from Denmark for the revision of a number of the other current entries for nickel compounds in Annex I have also been discussed in the TC C&L and recommended for inclusion in the draft 31st ATP. These entries include the entries for the nickel oxides (028-003-00-2, 028-004-00-6 and 028-005-003), for the sulfidic nickel compounds (028-006-00-9 and 028-007-00-4) and for nickel dihydroxide (028-008-00X) (see 1.3.1.2 above). In addition, Norway has made a proposal to the European Commission for a group classification of inorganic nickel compounds in EINECS, not covered by individual entries in Annex I to Directive 67/548/EEC (European Commission, 1995b). The document included a list of inorganic nickel compounds in EINECS covering approximately 125 nickel substances. This list is similar to but not identical with the inorganic and diverse nickel compounds shown in Annex 7.2.1. The classification proposed for the group entry is: Carc. Cat. 1; R49, R42/43 N; R50-53 More recently, Sweden has made a proposal for the environmental classification of metals which includes an entry for “Inorganic compounds of nickel” not covered by individual entries in Annex VI (ECBI/89/04). The classification proposal covers only environmental effects and is also N; R50-53. The Rapporteur has also prepared a proposal for group classification of many of the nickel compounds listed in Appendix 7.2 (ECBI/96/04 – Add. 2). This proposal has been discussed in the TC C&L, and entries for a number of additional nickel compounds (including many of the compounds for which self-classification is shown in section 1.3.1.2) have been recommended for inclusion in the draft 31st ATP. These proposals and the discussion in the EU Technical Committees have been described by Hart (2007).


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2. GENERAL INFORMATION ON EXPOSURE TO NICKEL AND NICKEL COMPOUNDS.

There are three broad source types which lead to exposure of man and the environment to nickel and nickel compounds. Exposure due to the deliberate industrial production and use of nickel and nickel compounds is the main concern of Risk assessment reports prepared under Existing Chemicals Regulation (EEC) 793/93 (EEC, 1993b). This use is described in detail for the five nickel compounds currently under review by the Rapporteur. Nickel has also a significant presence in fossil fuels and hence all combustion processes generally emit nickel to the environment. And as a naturally occurring chemical, nickel is present in all compartments of the environment (including organisms) due to natural processes (URS, 2001). As a result, ‘ambient’ nickel concentrations observed in the environment (URS, 2001) result from a combination of: ‘anthropogenic’ nickel arising from the ‘nickel industry’ i.e. the production and use of nickel metal, nickel

alloys and nickel-containing compounds. This includes nickel extracted through mining, then processed into a variety of end products, resulting in environmental emissions at each stage in the life cycle. These emissions may also contribute to nickel levels in sewage and sewage sludge due to corrosion of domestic and industrial products.

‘anthropogenic’ nickel arising from combustion of fossil fuels, as well as waste incineration and wood combustion; this component of ambient nickel may also be deemed to include significant diffuse sources, particularly road transport and the agricultural application of fertiliser, manure and sewage sludge.

‘natural background’: natural sources of atmospheric nickel include wind-blown dusts, derived from weathering of rocks and soil, and volcanic emissions; natural sources of aqueous nickel derive from biogenic cycles and solubilisation of nickel compounds from soils.

2.1 SOURCES OF NICKEL.

2.1.1 Industrial production and use of nickel and nickel compounds. The industrial production and use of nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate are described in the individual risk assessment reports. The following section summarises briefly the information in these reports, and includes a brief description of the uses of other nickel compounds not described in the individual reports.

2.1.1.1 Production.

2.1.1.1.1 Mining The most important nickel-containing minerals occurring in nickel deposits are listed in Table 2.1.1.A below. This Table is taken from Kerfoot (1991).

Table 2.1.1.A: Nickel-containing minerals (modified from Boldt & Queneau, 1967, quoted from Kerfoot, 1991).

Name CAS Number 1) Chemical composition

Nickel content %

Sulphides

Pentlandite 53809-86-2, 12174-14-0 2 (Fe,Ni)9S8 2 34.22

Millerite 1314-04-1 NiS 64.67

Heazlewoodite 12035-71-1 Ni3S2 73.30

Polydymite Ni3S4 57.86

Siegenite (Co,Ni)3S4 28.89

Violarite Ni2FeS4 38.94

Arsenides

Niccolite, nickeline 1303-13-5 NiAs 43.92


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Rammelsbergite NiAs2 28.15

Gersdorffite 12255-11-7 NiAsS 35.42

Antimonides

Breithauptite 12125-61-0 NiSb 32.53

Silicates and oxides

Garnierite (Ni, Mg)SiO3.nH2O < 47

Nickeliferous limonite (Fe,Ni)O(OH).nH2O low 1) The CAS numbers of these minerals have been added to the Table (see also Appendix 7.2.5). 2) CAS No. 53809-86-2 corresponds to Fe9Ni9S16; CAS No. 12174-14-0 corresponds to (Fe0.4-0.6Ni0.4-0.6)9S8 (NiPERA, 1996). Some of the minerals shown above are relatively uncommon, and only pentlandite, garnierite and nickeliferous limonite are of economic importance (Kerfoot, 1991). Garnierite is commonly used as a generic name for a series of mixed nickeliferous silicates with a wide range of nickel contents, and can include colloidal mixtures of silica and nickel hydroxide (Kerfoot, 1991). Garnierite is a fieldname normally used for laterite ores found in New Caledonia, and named after the discovery, Jules Garnier. An alternative name is sarpolite (EniG, 2003). Nickeliferous limonite is the term used to describe poorly crystalline nickel-bearing ferric oxide of which the main constituent is goethite (α-FeO.OH) (Kerfoot, 1991). These ores are known as laterite ores (see risk assessment report for nickel metal). Additional sulphidic ores include nickeliferous pyrrhotite (see below) and two ores containing copper as well as nickel. These ores are chalcopyrite (CuFeS2) and cubanite (CuFe2S3) (Kerfoot, 1991). An additional arsenide mineral, maucherite, Ni11As8, CAS No. 12044-65-4 (not included in EINECS), is given in NiPERA (1996). A list of nickel-containing minerals is also included by IARC (1990). This list, taken from Grandjean (1986) includes many of the ores are shown in Table 2.1.1.A above, and also includes a number of additional nickel-containing minerals shown in Table 2.1.1.B.

Table 2.1.1.B: Additional nickel-containing minerals (modified from Grandjean, 1986, quoted from IARC, 1990.).

Name CAS Number 1) Chemical composition

Vaesite 12035-50-6 NiS2

Pyrrhotite, nickeliferous (Fe,Ni)1-xS

Zaratite (basic nickel carbonate, tetrahydrate) 39430-27-8 NiCO3.2Ni(OH)2.4H2O

Bunsenite 34492-97-2 NiO

Morenosite (nickel sulphate heptahydrate) NiSO4.7H2O 1) The CAS numbers of these minerals have been added to the Table shown in IARC (see also Appendix 7.2.5). Pyrrhotite (CAS No. 1317-37-9) was not included in the minerals shown in Table 2.1.1.A. because it is an iron sulphide, and nickel is not essential to its composition. Small amounts of nickel may substitute for the iron, making some pyrrhotite nickeliferous (Kerfoot, 1991). In addition, basic nickel carbonate, nickel oxide and nickel sulphate (heptahydrate) occur as minerals (Zaratite, Bunsenite and Morenosite respectively). Nickel is mined in significant quantities in 21 countries (Eurométaux, 1998). Ores used for the production of nickel are mined in Europe. The main EU deposit of sulphidic ores for the production of metallic nickel is located in Finland. The main EU deposit of oxidic laterite ore for the production of ferronickel, used as a source of nickel in steel production, is in Greece. In addition, nickel is obtained from ores mined for their content of other metals (e.g. chalcopyrite containing copper), and the nickel recovered from these ores in the form of nickel salts (see risk assessment report for nickel sulphate).


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2.1.1.1.2 Beneficiation and smelting Nickel matte and ferronickel are obtained by further processes including beneficiation and smelting of the ores. Following the removal of nickel ore from waste rock, the nickel ore is treated by beneficiation. Sulphidic ores are crushed, ground and concentrated and oxidic ores are homogenised. These processes normally take place close to the site where the ore is mined. Further refinement takes place at smelters. The intermediary product of the smelting (and converting) process of sulphidic ores is nickel matte, and the intermediate product of the smelting process for oxidic ores is ferro-nickel. Melting processes are also used in the recovery of metal from secondary materials. Melting processes can produce a matte similar to that produced from nickel ore. Nickel matte is used in the production of both nickel metal and of nickel salts (e.g. nickel chloride, nickel sulphate). Ferronickel is used in the production of stainless steel.

2.1.1.1.3 Refining. Nickel refining processes uses nickel derived from ores produced in the EU as well as imported material. Nickel refining processes lead to the production of pure nickel metal in a variety of forms (sheets or other forms produced from nickel cathodes, pellets, briquettes, powder) as well as the nickel salts (sulphate, chloride) associated with the electrowinning processes.

2.1.1.1.4 Nickel chemicals production. In some cases, nickel chemicals production is closely linked to the processes involved in the production of nickel metal (see processes described above). In other cases, it occurs as a separate activity.

2.1.1.1.4.1 High production volume nickel containing chemicals. There are a substantial number of nickel compounds and nickel-containing substances that are produced in high volumes (> 1000 t/y). The Existing Substances Regulation (EEC, 1993b) places a duty on producers and importers of chemicals to provide information on substances. This information is included in IUCLID. Lists of substances included in this database have been prepared by the European Chemicals Bureau in Ispra (European Commission, 2000a, 2000b). The four nickel compounds, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate, are all high production volume chemicals (HPVCs). Production methods for these four substances are described in the individual risk assessment reports. Production methods for other HPVC nickel compounds are described briefly below. Other HPVC nickel compounds than the five nickel substances currently under review are shown in Table 2.1.1.C (European Commission, 2000a).

Table 2.1.1.C: Other High production volume nickel compounds (European Commission, 2000a)

EC No CAS No. EINECS name

215-215-7 1313-99-1 Nickel oxide (NiO)

273-729-7 69012-29-9 Slags, ferronickel-manufg.

273-749-6 69012-50-6 Matte, nickel

266-046-0 65997-17-3 Glass, oxide, chemicals

266-047-6 65997-18-4 Frits, chemicals

266-340-9 66402-68-4 Ceramic materials and wares, chemicals

232-490-9 8052-42-4 Asphalt

266-967-8 67711-91-5 Matte, copper

266-968-3 67711-92-6 Slags, copper smelting

268-627-4 68131-74-8 Ashes, residues

273-701-4 69011-60-5 Lead alloy, base, Pb, Sn, dross


27

273-720-8 69012-20-0 Waste solids, copper electrolyte purifn. cathodes

293-311-8 91053-46-2 Leach residues, zinc ore-calcine, cadmium-copper ppt.

293-312-3 91053-47-3 Leach residues, zinc ore-calcine, iron contg.

295-859-3 92129-57-2 Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfate The CAS number 1313-99-1 (EC 215-215-7) relates to nickel (mon)oxide. The synonyms given by IARC (1990) for this CAS number include both black nickel oxide and green nickel oxide. Green nickel oxide, a finely divided relatively pure form of nickel monoxide, is produced by firing a mixture of nickel powder and water in air at 1000 °C. Black nickel oxide, a finely divided, pure nickel monoxide, is produced by calcining nickel hydroxycarbonate or nickel nitrate at 600 °C (Antonsen, 1981, quoted from IARC, 1990). According to Chemical Information Services Ltd. (1988, quoted from IARC, 1990), green nickel oxide is produced by two companies in the UK and one in Germany and black nickel oxide is produced by one company in the UK. Outside the EU, green nickel oxide is produced by two companies in the USA, and six in Japan, and black nickel oxide is produced by one company each in Argentina, Brazil, Canada, Japan, Mexico, and the US (Chemical Information Services Ltd. 1988, quoted from IARC, 1990). Nickel oxide sinter (a coarse, somewhat impure form of nickel monoxide) is manufactured by roasting a semi pure nickel subsulfide (produced from nickel matte) at or above 1000 °C or by decomposing nickel hydroxycarbonate. These sinters contain either 76% nickel or, in partly reduced form, 90% nickel. Nickel oxide sinter is produced in Australia, Canada and Cuba (Sibley, 1985, quoted from IARC, 1990). The IUCLID data set for nickel oxide (EC No. 215-215-7) includes nickel oxide sinter (or nickel oxide sinter 75) as a synonym for this substance. Two companies also include “catalyst” or “nickel oxide catalyst” as synonyms (IUCLID, 2002). The production of nickel matte and of ferro-nickel slags are described in the risk assessment report for nickel metal. (It should be noted that ferronickel and slags from nickel matte production are not included in EINECS, and so are not included in this list, even though the quantities involved are also likely to qualify them as HPVCs.) The EINECS entries for “Glass, oxide”, “and “Ceramic materials and wares” list the various chemicals manufactured in the production of inorganic glasses and in the production of ceramics. The elements listed in these EINECS entries are principally present as components of oxide systems, but some may be present in other forms (EEC, 1990a). The EINECS entries for “Frits, chemicals”, describes the production of frits as a mixture of chemicals substances produced by rapidly quenching a molten, complex combination of materials, confining the chemical substances thus manufactured as non-migratory components of glassy solid flakes or granules. This category includes all of the chemical substances specified in the entry (EINECS includes a list of 35 elements, including nickel) when they are intentionally manufactured in the production of frit. The primary members of this category are oxides of some or all the listed elements. Fluorides of these elements may also be included in combination with these primary substances (EEC, 1990a). The production of nickel containing frits from nickel oxide and nickel hydroxide has been described by Eurocolour (2002), an umbrella organisation under CEFIC. Asphalt is obtained as the non-volatile residue from distillation of crude oil or by separation as the raffinate from a residual oil in a deasphalting or decarbonisation process (EEC, 1990a). Asphalt is a very complex combination of high molecular weight organic compounds containing a relatively high proportion of hydrocarbons having carbon numbers predominantly greater than C25 with high carbon-to-hydrogen ratios. Asphalt also contains small amounts of various metals such as nickel, iron or vanadium (EEC, 1990a). The nickel content in asphalt reflects the nickel content in many fossil fuels, and, as such, is related to the anthropogenic emissions described in chapter 2.1.2. Copper matte is defined in EINECS as “the product of smelting roaster calcines concentrates or cement copper with flux in reverberatory or electric furnaces. The matte is composed primarily of copper and copper, iron and lead sulphides with minor sulphides of other metals” (EEC, 1990a). Copper matte is produced from primary raw materials (ores/concentrates) by flash smelting at four sites in the EU, or by smelting roasted concentrates in electric furnaces at one site in the EU (Laine, 2003). Copper matte produced from nickel-containing copper ores can contain some nickel sulphide. The production process for copper matte is similar to the production of nickel matte described in the risk assessment report for metallic nickel.


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Copper smelting slags are slags resulting from the smelting of a heterogeneous mixture of copper and precious metals from primary and secondary sources and plant reverts. Major constituents are iron-calcium-aluminium silicates, with minor amounts of copper, lead, nickel and various non-ferrous metals and oxides (EEC, 1990a). The production process for copper smelting slag is similar to the production of the slags described in the risk assessment report for metallic nickel. The remaining six HPVC nickel containing complex substances are all secondary products from other industrial processes. Ashes (residues) are the residues from the burning of a combination of carbonaceous materials. The following elements may be present as oxides: aluminium, calcium, iron, magnesium, nickel, phosphorous, potassium, silicon, sulfur, titanium and vanadium (EEC, 1990a). Lead alloy, base, Pb, Sn, dross are the oxides formed during melting, refining, and casting of solders. Major constituents are oxides of tin, lead and antimony; minor constituents are iron, nickel, sulfur, arsenic, copper and silver (EEC, 1990a). Waste solids, copper electrolyte purifn. cathodes are impure copper cathodes formed during the electrolytic demetallizing of spent copper refining electrolyte. They consist primarily of copper with varying levels of antimony, arsenic, bismuth, lead and nickel (EEC, 1990a). Leach residues, zinc ore-calcine, cadmium-copper ppt. is an insoluble material precipitated by hydrolysis during hydrometallurgical treatment of crude zinc sulfate solution. It consists primarily of cadmium, cobalt, copper, lead, manganese, nickel, thallium, tin and zinc (EEC, 1990a). Leach residues, zinc ore-calcine, iron-contg. is an insoluble material precipitated by hydrolysis during hydrometallurgical treatment of crude zinc sulfate solution. It consists primarily of ferric oxide and, as impurities, arsenic, cadmium, cobalt, copper, lead, nickel, thallium, tin and zinc (EEC, 1990a). Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfate is a product obtained from recycling of the end electrolyte of copper refining electrolysis followed by evaporation to separate the residual sulphuric acid. It consists primarily of nickel and iron sulfates with small amounts of the sulphates of zinc, alkali earths and alkali metals (EEC, 1990a). The first three substances will normally contain well-defined amounts of nickel. The amounts present in the remaining substances may vary considerably. Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfate contains a high proportion of nickel (mainly as nickel sulphate). In most of the remaining substances, nickel is present either as a minor component or as an impurity.

2.1.1.1.4.2 Low production volume nickel containing chemicals.

Table 2.1.1.D: Low production volume nickel compounds (European Commission, 2000b).

EC No CAS No. EINECS name

235-715-9 12607-70-4 Nickel, [carbonato(2-)]tetrahydroxytri-

235-008-5 12054-48-7 Nickel hydroxide (Ni(OH)2)

240-841-2 16812-54-7 Nickel sulfide (NiS)

233-071-3 10028-18-9 Nickel fluoride (NiF2)

236-665-0 13462-88-9 Nickel bromide (NiBr2)

237-396-1 13770-89-3 Sulfamic acid, nickel(2+) salt (2:1)

206-761-7 373-02-4 Acetic acid, nickel(2+) salt

239-086-1 14998-37-9 Acetic acid, nickel salt

225-656-7 4995-91-9 Octanoic acid, nickel(2+) salt

237-696-2 13927-77-0 Nickel, bis(dibutylcarbamodithioato-S,S’)-, (SP-4-1)-

274-916-6 70833-37-3 Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1-one oximato-N(2)-,O(1))-


29

249-503-9 29204-84-0 Nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-,N(3)-]-

255-924-9 42739-61-7 Nickel, bis[2,3-bis(hydroxyimino)-N-(2-methoxyphenyl)butanamidato]-

237-893-3 14055-02-8 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, (SP-4-1)-

238-523-3 14516-71-3 Nickel, (1-butanamine)[[2,2’-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O’,S]-

270-944-8 68511-62-6 Nickel, 5,5’-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes

291-673-1 90459-30-6 Nickel, acetate carbonate C8-C10-branched fatty acids C9-C11-neofatty acids complexes

232-353-3 8007-18-9 Antimony nickel titanium oxide yellow, C.I. Pigment Yellow 53

269-051-6 68186-89-0 Cobalt nickel gray periclase, C.I. Pigment Black 25; C.I. No. 77332.

269-071-5 68187-10-0 Nickel ferrite brown spinel, C.I. Pigment Brown 34; C.I. No. 77497

275-738-1 71631-15-7 Nickel iron chromite black spinel, C.I. Pigment Black 30

273-700-9 69011-59-2 Lead alloy, base, dross

297-402-3 93571-76-7 Ashes (residues), heavy fuel oil fly

305-433-1 94551-87-8 Slimes and Sludges, copper electrolyte refining, decopperised The term used by the European Commission in reporting substances with production volumes from 10 to 1000 t/year is “Low Production Volume Chemicals”, LPVCs. Other nickel-containing substances that are not included in the lists prepared by the European Chemicals Bureau are discussed in a later section. Nickel, [carbonato(2-)]tetrahydroxytri- is produced as the tetrahydrate (CAS No. 29863-10-3) by precipitation from a nickel solution, usually the sulphate, with sodium carbonate. The exact composition depends on the temperature and the concentrations of the components in solution (Lascelles et al., 1991). The production of nickel carbonate is described in the risk assessment report for this substance. Nickel hydroxide (CAS No. 12054-48-7) is prepared by treating a nickel sulphate solution with sodium hydroxide to yield a gelatinous nickel hydroxide which forms a fine precipitate when neutralised. Alternatively, nickel hydroxide is prepared by electrodeposition at an inert cathode using metallic nickel as the anode and nickel nitrate as the electrolyte or by extraction with hot alcohol of the gelatinous precipitate formed by nickel nitrate solution and potassium hydroxide (Antonsen, 1981, quoted from IARC, 1990). According to Chemical Information Services Ltd. (1988, quoted from IARC, 1990) nickel hydroxide is produced by one company in Germany and one in the UK. Nickel hydroxide is also produced outside the EU by four companies in Japan and three in the US (Chemical Information Services Ltd. 1988, quoted from IARC, 1990). Purified nickel sulphide can be prepared by fusion of nickel powder with molten sulphur or by precipitation using hydrogen sulphide treatment of a buffered solution of a nickel(II) salt (Antonsen, 1981, quoted from IARC, 1990). Nickel sulphide (CAS No. 1314-04-1, not included in EINECS) also occurs naturally as millerite (Antonsen, 1996). Nickel sulphide and nickel subsulphide are produced as intermediates in processing sulphidic and silicate-oxidic ores and are traded in bulk for further processing (IARC, 1990). The CAS No. 16812-54-7 which is associated with the EINECS No. 240-841-2 is used to describe the nickel sulphide catalyst used when high concentrations of sulphur are present in the hydrogenation of petroleum distillates (Antonsen, 1996). Nickel fluoride (NiF2) is prepared as the tetrahydrate (CAS No. 13940-83-5) by the reaction of hydrofluoric acid on nickel carbonate. Nickel bromide (NiBr2) is prepared as the hexahydrate (CAS No. 18721-96-5) by the reaction of black nickel oxide and HBr (Antonsen, 1996). The anhydrous halides can be made by direct reaction of the elements at high temperature or in non-aqueous solution, although the fluoride is better made indirectly. They are also formed by dehydration of the hydrates in a stream of the hydrogen halide gas to prevent formation of nickel oxide (Lascelles et al., 1991) Sulfamic acid, nickel(2+) salt (2:1) is prepared as the tetrahydrate (CAS No. 13770-89-3) by dissolving nickel powder in a hot solution of sulphamic acid. Soluble nickel oxide, hydroxide or carbonate can be used as well. Short reaction times are need for the preparation because sulphamic acid hydrolyses readily to form sulphuric acid. The substance is commercially available not as a solid but as a solution containing about 11% nickel (Lascelles et al., 1996).


30

Nickel acetate is listed in EINECS under two entries: Acetic acid, nickel(2+) salt (EC 306-761-7) and Acetic acid, nickel salt (EC 239-086-1). Both are listed as LPVCs. Nickel acetate is produced by heating nickel hydroxide with acetic acid in the presence of metallic nickel (Sax & Lewis, 1987, quoted from IARC, 1990). The tetrahydrate (CAS No. 6018-89-9) is prepared when solutions of nickel(II) hydroxide or carbonate in acetic acid are evaporated at room temperature (Lascelles et al. 1991). No specific description of octanoic acid, nickel(2+) salt preparation is given in Antonsen (1996) or Lascelles et al. (1991). Nickel salts of simple organic acids can be prepared by reaction of the organic acid and nickel carbonate or hydroxide; reaction of the acid and a water solution of a simple nickel salt; and, in some cases, by the reaction of the acid and fine nickel powder or black nickel oxide (Antonsen, 1996). No specific description of the preparation of the next eight complex nickel substances shown in Table 2.1.1.D. is given in Antonsen (1996) or Lascelles et al. (1991). One of these substances, nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-,N(3)-]-, is a pigment (CI Pigment Yellow 153) produced by Eurocolour (2002). The starting materials for this colorant, like the other nickel-containing colorant listed below, are nickel oxide and nickel hydroxide (Fischer, 2002). C.I. Pigments Yellow 53, Black 25, Brown 34 and Black 30 are all nickel-containing colorants. Their production from nickel oxide and nickel hydroxide has been described by Eurocolour (2002). Colorants are produced in closed facilities by mixing raw materials and subsequent calcination at temperatures above 1000° C. The products produced are insoluble in water (Eurocolour, 2002). According to Eurocolour (2002), three of these substances are identical to other EINECS entries. C.I. Pigment Yellow 53 (EC No. 232-353-3) is identical with Antimony oxide (Sb2O3), solid soln. with nickel oxide (NiO) and titanium oxide (TiO2) (EC No. 277-627-3); C.I. Pigment Brown 34 (EC No. 269-071-5) is identical with Iron nickel oxide (Fe2NiO4) (EC No. 235-335-3) and C.I. Pigment Black 30 (EC No. 269-051-6) is identical with Cobalt nickel oxide (CoNiO2) (EC No. 261-346-8). The remaining three LPVC nickel containing complex substances are all secondary products from other industrial processes. Lead alloy, base, dross is a scum formed on the surface of molten lead-base alloys. It includes those cases in which aluminium is used to remove arsenic, nickel and antimony (EEC, 1990a). Ashes (residues), heavy fuel oil fly are ashes from the flue gas collection of a steam generator fired with heavy heating oil. It consists predominantly of oxides and sulfates of aluminium, calcium, iron, nickel, sodium and vanadium among others. It is used as a raw material, for obtaining primarily V2O5 (EEC, 1990a). Slimes and Sludges, copper electrolyte refining, decopperised is a substance obtained as a powdery cathodic precipitate during the electrolytic decoppering stage of copper refining electrolysis. It consists primarily of copper with antimony, arsenic, lead and nickel in metallic form as well as oxides and sulfates (EEC, 1990a). No information on the nickel concentration in these last three LPVC substances is available in IUCLID.

2.1.1.1.4.3 Other low production volume nickel containing chemicals. Nickel trioxide, Ni2O3, (CAS number 1314-06-3) is also listed by IARC (1990) with black nickel oxide as a synonym (the same for the monoxide). According to NiPERA (1996), black nickel oxide is occasionally sold labelled incorrectly as “nickel(III) oxide, Ni2O3”. The trioxide is included in EINECS (EC 215-217-8), and in Annex I to Directive 67/548/EEC with the same classification as the monoxide (see Chapter 1.3.1.2). Lascelles et al. (1991) note that higher oxides such as Ni2O3, “have been proposed, but there is little evidence for their existence free of water”. A number of complex inorganic nickel-containing pigments are produced as colorants by Eurocolour companies (Eurocolour, 2002). These include CI Pigment Yellow 161 (EC No. 271-892-9), Nickel icosatitanium pentatriacontaoxide diwolframate (NiO47Ti2W2) (EC No. 273-686-4), and C.I. Pigment Green 50 (EC No. 269-047-4). Nickel ammonium sulphate is prepared by reacting nickel sulphate with ammonium sulphate and crystallising the salt from a water solution (Antonsen, 1981, Sax & Lewis, 1987 quoted from IARC 1990). Reaction of nickel carbonate with hydriodic acid is used to prepare nickel iodide (NiI2) as the hexahydrate (CAS No. 7790-34-3), with phosphoric acid to form nickel phosphate (Ni3(PO4)2) as the heptahydrate (CAS No.


31

14396-43-1), with a water solution of arsenic anhydride to form nickel arsenate (Ni3(AsO4)2 as the octahydrate (CAS No. 7784-48-7), and with fluoroboric acid to prepare nickel fluoroborate (Ni(BF4)2) as the hexahydrate (CAS no. 14708-14-6) (Antonsen 1996). Nickel cyanide (Ni(CN)2) is made by the reaction of potassium cyanide and nickel sulphate (Antonsen, 1996). Nickel carbonyl can be prepared by the carbonyl process described in the risk assessment report for metallic nickel. In the US, nickel carbonyl was prepared commercially by the reaction of carbon monoxide with nickel sulphate solution (Antonsen, 1981, quoted from IARC, 1990). Nickelocene (CAS No. 1271-28-9) is formed by the reaction of nickel halides with sodium cyclopentadienide (Antonsen, 1981, quoted from IARC, 1990). An organic nickel colorant manufactured by Eurocolour companies is C.I. Solvent Brown 53 (Nickel, [2,3'-bis[[(2-hydroxyphenyl)methylene]amino]-2-butenedinitrilato(2-)-N(2)-,N(3)-,O(2)-,O(3)-]-, (SP-4-2), EC No. 265-022-7). The production from nickel oxide and nickel hydroxide is similar to that of C.I. Pigment Yellow 153 described above (Eurocolour 2002). Another organic nickel compound is listed in Einecs with a C.I. Index number (nickel, 3-[(4-chlorophenyl)azo]-4-hydroxy-2(1H)-quinolinone complex; C.I. 12775, EC No. 262-934-7) (EC 2002b). Antonsen (1996) and Lascelles et al. (1991) include details of production methods for a range of organo-nickel complexes.

2.1.1.2 Nickel Use. The following figure shows the estimated distribution of nickel by end use.

Figure 2.1.1.A: Estimated distribution of nickel by end-use in 1996 (NiPERA, 1997).

A utom o tive 15%

R a ilw ay 2%

A erospace 4%

M arine 2%

O the r transport 1%

C onsum er p roduc ts 18%E lec tron ics

8%B atte ries

3%

O the r com m erc ia l 1%

C hem ica l 8%

O the r p rocess equ ipm ent

11%

P ow er genera tion 2%

P e tro leum indus try 1%

N icke l chem ica ls 1%

B u ild ing & cons truc tion m a te ria ls

22%

O ther indus tria l

1%

Nickel statistics are complicated by the fact that much of the use of nickel metal, nickel-containing alloys and nickel salts are interrelated. Nickel chloride and nickel sulphate are used in nickel metal production, recycled nickel alloys are used to produce a matte that is used to produce nickel sulphate. As a result, strict specification of nickel use for each individual nickel substance is not always easy or even useful. The Table above shows the use of nickel in its various forms rather than the use of metallic nickel alone.


32

2.1.1.2.1 Uses of nickel and nickel compounds The use of nickel as metal and in alloys is described in detail in the risk assessment of metallic nickel. As the figure above shows, this accounts for by far the largest proportion of nickel use. In 1994 the annual worldwide use and price of nickel compounds is given in Antonsen (1996).

Table 2.1.1.E: Annual worldwide use of nickel compounds (Antonsen, 1996)

Compound Structure Use: t x 103 Price: $/kg.

nickel oxide sinter NiO 100 4.00

nickel sulphate hexahydrate NiSO4.6H2O 15 2.50

green nickel oxide NiO 10 4.50

nickel nitrate Ni(NO3)2.6H2O 8 3.50

black nickel oxide NiO 6 6.00

nickel carbonate NiCO3.6H2O 5 4.00

nickel chloride NiCl2.6H2O 3 4.00

others (including nickel acetate) 5 5.00

2.1.1.2.1.1 High production volume nickel-containing chemicals. For details of the uses of metallic nickel, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate, see individual reports on nickel metal and the individual nickel salts. Nickel oxide sinters, either in the form of rondelles containing partially reduced nickel oxide, compacts containing about 90% Ni or compacts of nickel oxide sinter containing about 75% Ni sinters are important Class II nickel products (see Chapter 1.2 of the risk assessment report for nickel metal). These sinters are the feedstock for the nickel carbonyl refinery process at Inco, Clydach, UK (See Chapter 2.1 of the risk assessment report for nickel metal), and are used in the manufacture of alloys, steels and stainless steels (Antonsen, 1981, quoted from IARC, 1990). Information from ECMA, the European Catalysts Manufacturers Association confirms the use of nickel oxide in catalyst production (ECMA, 2002). Nickel oxide is used in the production of colorants, glazes and frits (Eurocolour, 2002). In speciality ceramics, it is added to frit compositions used for porcelain enamelling of steel; in the manufacture of magnetic nickel-zinc ferrites used in electric motors, antennas and television tube yokes; and as a colorant in glass and ceramic stains used in ceramic tiles, dishes, pottery and sanitary ware (Antonsen, 1981, quoted from IARC, 1990). Black nickel oxide is used in the manufacture of nickel salts and speciality ceramics. It is also used to enhance the activity of three-way catalysts containing rhodium, platinum and palladium used in automobile exhaust control. Like green nickel oxide, black nickel oxide is used for nickel catalyst manufacture and in the ceramics industry (Antonsen, 1981, quoted in IARC, 1990). Information from the Swedish Product Register lists nickel oxide as used for “Catalysts”, “Process regulators”, “Insulating materials, electricity”, “Absorbents and adsorbents” and “Other Uses” (Kemi, 2002). The use of nickel matte and of ferro-nickel slags are described in the risk assessment report for nickel metal. No further information on the use of nickel-containing “Glass, oxide”, “and “Ceramic materials and wares” is available. Eurocolour (2002) has estimated the European market for frits as about 5000 t/year. Frits are used for steel enamel (Eurocolour, 2002). The remaining seven substances on this list contain varying amounts of nickel. No further information on the uses of these substances is available.


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2.1.1.2.1.2 Low production volume nickel-containing chemicals. Nickel, [carbonato(2-)]tetrahydroxytri-, is a basic nickel carbonate. The uses of nickel carbonate are described in the risk assessment report for nickel carbonate. Nickel hydroxide is used in the production of nickel-cadmium batteries. It is also used as a catalyst intermediate (Antonsen, 1981, quoted in IARC, 1990). From the information available to the Rapporteur, nickel hydroxide is present in the production process for both batteries and catalysts (see appropriate sections in nickel metal risk assessment report). It is not clear however, whether this use reflects the deliberate use of the substance (i.e. following purchase of nickel hydroxide produced in a separate process), or whether nickel hydroxide occurs as a non-isolated intermediate in the production process. Nickel hydroxide is used in the production of colorants, glazes and frits (Eurocolour, 2002) Nickel sulphide is used as a catalyst in petrochemical hydrogenation when high concentrations of sulphur are present in the distillates (IARC, 1990). Antonsen (1996) reports a limited used of nickel bromide in plating. Information on nickel electroplating supplied by Eramet (2001) in the description of electroplating included in the Annex to the risk assessment report on nickel metal does not include any description of the use of nickel bromide as a component of the plating baths described. The reaction of nickel bromide (like nickel chloride) with dimethoxyethane yields ether-soluble NiX2.2C2H4(OCH3)2 compounds which are useful as nickel-containing reagents for a variety of reactions used to form coordination compounds of nickel (Antonsen, 1996). Nickel fluoride is used for cold sealing of anodic coatings on aluminium (Antonsen, 1996). According to Lascelles et al. (1991), the use of nickel halides such as nickel fluoride or nickel bromide is “minor”. Nickel sulphamate is used as a component in certain electroplating bath solutions (Eramet, 2001). Production volumes for nickel acetate have been reported under two separate EC numbers: 206-761-7 and 239-086-1, suggesting that similar chemicals are marketed under two different EC numbers. Nickel acetate is used as a catalyst intermediate, as an intermediate in the formation of other nickel compounds, as a dye mordant, as a sealer for anodised aluminium and in nickel electroplating (Antonsen, 1981, quoted in IARC, 1990). No information has been received from the catalyst industry that suggests that nickel acetate is used as a feedstock in nickel catalyst production (ECMA, 2002). Information on nickel electroplating supplied by Eramet (2001) does not include any description of the use of acetate as a component of the plating baths described. One of the organic nickel-containing substances in Table 2.1.1.D is a colorant, also known as C.I. Pigment Yellow 153 (EC No. 249-503-9). The last four substances in Table 2.1.1.D above are also colorants. Colorants are widely used for the colouration of articles. Technical literature distinguishes between pigments and dyes. Pigments are mainly used for the colouration of plastics, paints and ceramics; dyes are mainly used for the colouration of textiles, leather and paper (Eurocolour, 2002). The estimate for the size of the European market for colorants other than frits produced by Eurocolour companies is roughly 3400 t/y, of which CI Pigment Yellow 53 is by far the largest individual substance with a market of about 2500 t/year (Eurocolour, 2002). 46% of the total use of these colorants is for plastics, 17% for paints and 36% for ceramics. Details are shown in Table 2.1.1.F below.

Table 2.1.1.F: Use of nickel colorants (other than frits) (Eurocolour, 2002).

% application 2 in Name. EC Number Estimated use (t/year) 1

Plastics Paints Ceramics

C.I. Pigment Yellow 53 232-353-3 3 2500 50 20 30

C.I. Pigment Green 50 269-047-4 4 300 90 10

C.I. Pigment Black 30 275-738-1 200 20 80

C.I. Pigment Yellow 161 271-892-9 4 100 100

Nickel titanium oxide tungstate 273-686-4 4 100 100

C.I. Pigment Black 25 269-051-6 100 100

C.I. Pigment Yellow 153 249-503-9 50 100


34

C.I. Pigment Brown 34 269-071-5 10 100

C.I. Solvent Brown 53 265-022-7 not available 1) Estimate of European market for nickel containing colorants carried out by Eurocolour 2) Estimate of use in different sectors carried out by Eurocolour 3) European Commission shows this as LPVC (i.e. production volume less than 1000 t/year) (European Commission, 2000b). 4) European Commission does not include this in the list of LPVCs (i.e. production volumes between 10 and 1000 t/year) reported to the European Chemicals Bureau (European Commission, 2000b). Nickel, bis(dibutylcarbamodithioato-S,S')-, (SP-4-1)- (EC 237-696-2), (dibutyldithiocarbamate nickel), is used as an additive in plastics as a uv-quencher in polyolefins (Antonsen, 1996). There is no additional information available to the Rapporteur about the uses of the other nickel-containing substances in Table 2.1.1.D.

2.1.1.2.1.3 Other low production volume nickel-containing chemicals. Nickel carbonyl is produced as an intermediate in the Mond carbonyl refining process in the production of nickel metal (Antonsen, 1991, quoted in IARC, 1990). For further details of this production process, see Risk assessment report on metallic nickel. Other uses of nickel carbonyl are in chemical synthesis as a catalyst, as a reactant in carbonylation reactions such as the synthesis of acrylic and methacrylic esters from acetylene and alcohols, in the vapour plating of nickel, and in the fabrication of nickel and nickel alloy components and shapes (Antonsen, 1981, quoted in IARC, 1990). Whilst produced in large volumes as an intermediate in nickel metal production, nickel carbonyl is not included on either of the European Commission list of HPVCs or LPVCs (European Commission, 2001a, 2001b). The use of nickel ammonium sulphate is described in IARC (1990) as limited use as a dye mordant, in metal-finishing compositions and as an electrolyte for electroplating (Sax & Lewis, 1987, quoted in IARC, 1990). Its use as a component of electroplating bath solutions is described by Eramet (2001). This substance does not however appear on either the list of high or low production chemicals (European Commission, 2000a, 2000b). Additional organic nickel colorants are described by Antonsen (1996). These include the nickel disazomethine complex (CAS No. 61312-95-6, not included in EINECS or the TSCA inventories), Nickel Azo Yellow (EC No. 257-521-3) which is a commercially important pigment with excellent light fastness and good heat stability and bleed resistance, and other nickel azo pigments including Nickel Azo Gold and Nickel Azo Red (Antonsen, 1996). A number of other complex inorganic nickel-containing pigments are included in EINECS. According to Fischer (2002), information supplied during the compilation of EINECS included entries which are no longer manufactured. The substances listed in the Table 2.1.1.G below are not currently used entries (Fischer, 2002).

Table 2.1.1.G: Other complex inorganic nickel-containing pigments (Eurocolour, 2002).

marketed product EC No.

EINECS name Other name

234-825-4 Nickel titanium oxide (NiTiO3) Nickel titanate

235-752-0 Nickel-titanium-oxide-

234-636-7 Chromium nickel oxide (Cr2-NiO4)

274-755-1 Nickel zirconium oxide (NiZrO3)

306-902-3 Iron nickel zinc oxide (Fe2-NiZnO4)

271-112-7 Olivine, nickel green CI Pigment Green

271-853-6 Nickel barium titanium primrose priderite

305-835-7 Spinels, cobalt nickel zinc grey

309-018-6 Cassiterite, cobalt manganese nickel grey


35

Nickel compounds are used as catalysts. This includes nickel silicide (EC No. 235-379-3) which, upon caustic leaching, activates a nickel surface (Antonsen, 1996). Nickel boride (EC No. 234-493-0) when activated with caustic is a reactive hydrogenation catalyst (Antonsen, 1996). Nickel compounds are used as plastics additives. The most important application is as uv-quenchers in polyolefins. These include the dibutyldithiocarbamate compound included in Table 2.1.1.1.D as well as nickel thiobisphenolates, and nickel amide complexes of bisphenol sulphides (Antonsen, 1996). Nickel compounds have been used as light stabilisers in high density polyethylene (HDPE) and ABS polymers, but are not commercially important for use with PVC because of objectionable colouring of the plastic (Antonsen, 1996). Nickel compounds have been claimed for use as agricultural chemicals. Nickel chemicals afford little more efficacy than the non-nickel containing derivatives (Antonsen, 1996). A number of the substances given as examples for a variety of uses in Antonsen (1996) with CAS numbers are not included in either EINECS or the TSCA inventory. These include nickel niobium, NiNb, (CAS No. 59913-35-8), although NiNb is included in EINECS as EC No. 234-807-6. Nickel dibutyldithiocarbamate (CAS No. 56377-13-0) is used as an oxidation inhibitor in synthetic elastomers, but is not in EINECS, although dibutyldithiocarbamate nickel (EC No. 237-696-2) (see above for use as a uv-quencher) is included. A number of silicides, Ni3Si (CAS No. 12059-22-2), Ni5Si2 (CAS No. 12059-27-7) and NiSi (CAS No. 39467-10-2) used as electroconductive materials are not in EINECS, although Ni2Si (EC No. 235-033-1) (see above) is used. Other substances given as examples which are not included in EINECS or the TSCA Inventory are nickel aluminide (CAS No. 12003-81-5), a high strength, light, ductile material, the nickel disazomethine complex pigment (CAS No. 61312-95-6), nickel bis-(3,5 di-tert-butylsalicylate) (CAS No. 68569-24-4) used for colour stabilisation of colour copy paper and nickel (2-hydroxy-4-methoxybenzophenone-5-sulphate) (CAS No. 130543-71-4) used to reduce ultraviolet photofading of certain dyes (Antonsen, 1996).

2.1.1.2.2 Uses of nickel containing products. Use of nickel-containing batteries, welding rods and catalysts have been described in the risk assessment report for metallic nickel. Information on production and use of colorants has been supplied by Eurocolour (2002). Ceramic frits and glazes are used to give colour and protection to ceramic surfaces. Final products as tableware, floor and wall tiles, artistic ceramic and steel enamelled parts do not release nickel in considerable amounts (Eurocolour, 2002). The fate of ceramic articles is normally landfill. In the case of plastics and paints only a small part of the waste ends up in landfill, where as the major part ends up in thermal waste treatment. The nickel containing pigments withstand firing temperatures above 1000° C without alteration and can be found in the ash (Eurocolour, 2002).

2.1.1.3 Disposal. The recycling of the metallic nickel products has been described in the report of the risk assessment of nickel metal. As this section shows, nickel is extensively recycled at many stages of the life cycle. The recycling process can often involve the production of specific nickel compounds (e.g. nickel sulphate) which in turn are frequently used in the production of other nickel-containing products. The life cycles of the different nickel compounds are therefore closely linked.

2.1.1.4 Nickel emissions from production and use of nickel and nickel-containing chemicals and products.

Nickel is released to the atmosphere from emissions from nickel mining and refinery operations, from the use of metals in industrial processes and from incineration of wastes (Sunderman, 1986a, US EPA, 1986, quoted from IARC, 1990). Estimates of nickel emission to the global atmosphere are reported in IARC (1990), based on Bennett (1984). The anthropogenic emissions are from the mid-1970s.

Table 2.1.1.H: Anthropogenic emissions of nickel related to nickel production and use (Bennett, 1984, quoted from IARC, 1990)

Source Emission rate (106 kg/year)


36

Nickel mining and refining 7.2

Steel production 1.2

Industrial applications 1.0

Waste incineration 5.1

Total 14.5 The two categories “Industrial applications” and “waste incineration” may include emissions related to other sources of nickel than deliberate nickel production and use (see section 2.1.2.3 below). Nriagu (1989) gives totals for nickel emission from nickel mining and Cu/Ni production as 8.4 . 106 kg/year, iron and steel manufacture 3.7 . 106 kg/year and refuse incineration as 0.4 . 106 kg/year. His total for anthropogenic emissions directly related to intentional nickel production and use are 12.5 . 106 kg/year . This total is similar to the total quoted in Table 2.1.1.H above. The Ambient Air Pollution Position paper (European Commission, 2000) gives a similar estimate for nickel emissions associated with intentional industrial use of nickel. The contribution of non-ferrous metal production (9.6 x 106 kg/y) and waste incineration (3.4 x 106 kg/y) gives a total contribution of 13 x 106 kg/y. The figures quoted in the Position paper are taken from a diagram showing the atmospheric portion of the global nickel cycle from Nriagu (1980).

2.1.2 Other anthropogenic sources of nickel. The section above describes the emissions associated with primary nickel production and use. This is mainly related to nickel and nickel alloy production and to the production of nickel containing chemicals. This section describes other industrial activities that lead to nickel release.

2.1.2.1 Non-ferrous metals production. Mining for other metals than nickel may involve release of nickel present as a minor component of the ore. Nickel is an important by-product of copper production (see risk assessment report for nickel sulphate). An ambient air quality level of 10 ng/m3 is unlikely to be achievable for all sites of copper or lead production (Entec, 2001). Nickel release from zinc production is lower (Entec, 2001).

2.1.2.2 Combustion processes. Nickel is released to air from combustion of fossil fuels in stationary and mobile power sources (Sunderman, 1986a, US EPA 1986, quoted from IARC, 1990, European Commission, 2000). Stationary sources include power generation from coal- and oil-fired plants. Mobile sources include road, rail and air transport. They also include emissions from ships burning bunker fuel (Entec, 2001)

Table 2.1.2.A: Anthropogenic emissions of nickel related to fuel combustion (Bennett, 1984, quoted from IARC, 1990).


Residual and fuel oil combustion 27

Gasoline and diesel fuel combustion 0.9

Coal combustion 0.7

Total 28.6 In addition to coal and oil combustion, wood combustion also contributes to emissions to the atmosphere (URS, 2001). The Ambient Air Pollution Position paper (European Commission, 2000) gives an estimate for nickel emissions from fossil fuel combustion of 28.0 x 106 kg/y and “Others” of 6.0 x 106 kg/y. The figures quoted in the Position paper are taken from a diagram showing the atmospheric portion of the global nickel cycle from Nriagu (1980). The figures for nickel emission from coal and oil combustion given by Nriagu (1989) are substantially higher, at 41 x 106 kg/year. Fuel wood combustion gives an additional 1.2 x 106 kg/year. Other anthropogenic sources of


37

nickel emission are lead production (0.33 x 106 kg/year), phosphate fertilisers (0.41 x 106 kg/year) and cement production (0.49 . 106 kg/year). Niagu (1989) gives a total of 43.4 x 106 kg/year for anthropogenic emissions not directly related to the intentional production and use of nickel. The most significant emission source for nickel is found in the branch “stationary combustion” (Berdowski et al. 1997, quoted from European Commission, 2000) Traces of nickel are found in fossil fuels like lignite (brown coal), hard coal and heating oil. Emission of heavy metals such as nickel is only relevant for fuels burning with a significant ash residue. Combustion of natural gas and extra light heating oil is not a significant source of emission of nickel (dust content < 0.1 mg/m3). Nickel concentrations vary not only between different fuel categories, but also within the same category. The nickel emitted is not only due to the nickel content in the fuel, but also combustion conditions and temperatures and secondary abatement systems play an important role (European Commission, 2000). The role of stationary combustion compared to other sources of anthropogenic nickel emissions has been estimated by TNO for the 15 EU Member States in 1990 (Van der Most, 1992, quoted in European Commission, 2000). The contribution from stationary sources is roughly 60%, with an additional 30% from “Other mobile sources and machinery”. “Production processes” and “Road transport” comprise less than 10% of the anthropogenic emissions. Figures from Germany in 1995 and France and the UK in 1996 show figures of > 90% from stationary sources. Only in Germany was emission from production processes significant (10%) (European Commission, 2000). The source of emissions in the transport sector has changed considerably in the last 30 years in the UK (Entec, 2001). In 1970 5.7 tonnes of nickel derived from rail, sea and air transport compared to 0.7 tonnes from road transport. In 1995 the comparable figures are 0.1 and 1.3 tonnes (data from UK DETR, 1997 quoted by Entec, 2002).

2.1.2.3 Other Industrial Processes. The three processes considered by Entec (2001) are petroleum refining, cement manufacture, incineration and glass production. The amounts estimated by Bennett (1984) for “Industrial applications” and “waste disposal” are shown in Table 2.1.2.A above. It is not clear whether these emissions result from industrial processes strictly linked with nickel production and use or whether they are, at least in part, related to the processes described below. Nickel is the key metal of interest for the petroleum refining sector. Vanadium and nickel are present in significantly greater quantities than arsenic, cadmium or mercury in those process streams which result in emissions to air from petroleum refining (Entec, 2001). Petroleum refining is not included as a specific source of nickel emissions by Bennett (1984) or by the Position paper (European Commission, 2000).

Table 2.1.2.B: Heavy Metals in Crude Oils (Jones, 1988, quoted from Entec, 2001)

Metal as element Typical range in crude oils, ppm

Lowest value reported, ppm

Highest value reported, ppm

Arsenic <0.01 –0.1/0.2 Nil 2.3

<0.01 – 0.037, average 0.014 (1)

- -

<0.0002 – 26.2 (2)

Cadmium Not detected - -

0.0004 – 0.0053, 0.0016 average (1)

0.0004 (limit of detection)

-

<0.0001 – 0.50, typical values 0.0024, 0.050 (2)

- -

Mercury <0.05 0.01 29 (3)

0.0014-0.007 (4) - -

Nickel 3 – 25 0.01 150

Nickel in crudes run by surveyed petroleum refineries in Western

3.6 (non weighted average)

0.0 32.0


38

Europe (5)

Brent blend, North Sea 0.8 (6)

Nigerian 7 (6)

Iranian light 15 (6)

Kuwait 9 (6) 1) Data from measurements of eight crude oils (80% of The Netherlands consumption), Stigter, 2000. 2) Data from literature cited by Stigter, 2000; includes some references cited by Jones, 1988. 3) This is the atypical Cymric field, California, which was sited within a deposit of mercury ore. 4) Liang, 2000; analyses of limited number of crude oils 5) Concawe, 2000 (analyses of various crude oils also quoted) 6) Data from Table 8.1 in Entec (2001). Nickel ambient air concentrations associated with nickel refineries quoted by Entec (2001) range from 1 ng/m3 (UK Texaco Pembroke refinery) to 16 ng/m3 at Schiedam, Rotterdam, the Netherlands. Petroleum refinery combustion emissions are estimated as 67.37 t/year in the UK, with the largest emission from a single refinery being 453 kg/year (Entec, 2001). Cement manufacturing is regarded as a minor source of atmospheric emissions of nickel from high temperature processes. During cement manufacturing, nickel is emitted either as a component of the clays, limestones, and shales (raw materials) or as an oxide formed in high-temperature process kilns (European Commission, 2000). Incineration of waste and sewage sludge is shown as a source of nickel emissions (IPCS, 1991). Bennett (1984, quoted from IARC, 1990) estimates an emission rate of 5.1 x 106 kg/year (see Table 2.1.1.H above). The glass industry contributes to a small extent of less than 1 % to the European nickel emissions (European Commission, 2000). Following consultation with the International Crystal Federation, Entec (2001) considers that the contribution of this sector to emissions of nickel does not warrant further analysis.

2.1.2.4 Emission to soil. In addition to atmospheric deposition, other sources of emission to soil include fertiliser, manure and sewage sludge (URS, 2001). Atmospheric deposition of nickel to the soil and inputs by waste disposal and through the application of fertilizers are estimated to be 5.5 x 10-4 kg/a and 1.4 x 10-4 kg/a respectively (IPCS, 1991).

2.1.3 Natural sources of nickel Nickel is the fifth most abundant element by weight after iron, oxygen, magnesium, and silicon, and the 24th most abundant element in the earth's crust, with an average concentration estimated to be about 75-80 mg/kg (Mance & Yates, 1984; UK EGVM, 1999; IPCS, 1991, quoted from URS, 2001). Eisler (1998) has published an inventory of nickel in various global environmental compartments. This is shown in Table 2.1.3.A.

Table 2.1.3.A: Inventory of nickel in various global environmental compartments (from Eisler, 1998).

Compartment Mean concentration (mg/kg) Nickel in compartment (metric tons)

Lithosphere, down to 45 km 75 4,300,000,000,000,000

Sedimentary rocks 48 120,000,000,000,000

Soils, to 100 cm 16 5,300,000,000,000

Oil shale deposits 30 1,400,000,000,000

Dissolved organic 0.0006 840,000,000

Nickel ore reserves > 2,000 160,000,000

Coal deposits 15 150,000,000


39

Terrestrial litter 15 33,000,000

Terrestrial plants 6 14,000,000

Suspended oceanic particulates

95 6,600,000

Crude oil 10 2,300,000

Terrestrial animals 2.5 50,000

Swamps and marshes 7 42,000

Lakes and rivers, total 0.001 34,000

Consumers/reducers (biological)

3.5 11,000

Atmosphere 0.3 1,500

Oceanic plants 2.5 500

Lakes and rivers, plankton 4 230

2.1.3.1 Nickel emissions from natural sources. Nickel and its compounds are naturally present in the earth’s crust, and releases to the atmosphere occur from natural processes such as windblown dust and volcanic eruption, as well as from anthropogenic activities. These latter releases are mainly in the form of aerosols (US ATSDR, 1997).

Table 2.1.3.B: Natural emissions of nickel to the atmosphere (Bennett, 1984, quoted from IARC, 1990).


Wind-blown dusts 4.8

Volcanoes 2.5

Vegetation 0.8

Forest fires 0.2

Meteoric dusts 0.2

Sea Spray 0.009

Total 8.5 Estimates by Nriagu for natural emissions are much higher. Table 2.1.3.C below shows considerably higher estimates for emissions from windblown soil particles, volcanoes, sea salt spray, and wild forest fires. Nriagu does not include meteoric dusts in his estimates. The estimate of total median nickel release is 26 - 30 x 106 kg/y; between 3 and 4 times higher than the figures quoted above.

Table 2.1.3.C: Natural emission rates of nickel in 106 kg/y (Pacyna, 1986, Nriagu, 1989).

Source Pacyna, (1986), quoted by European Commission (2000)

Nriagu (1989), quoted by Mukherjee (1998)

Wind-blown dusts 20 (0.2 – 44) (1) 11.3

Volcanoes 3.8 (2.4 – 82) (1) 14

Biogenic processes (Vegetation) 1.6 (1.6 –21) (1) 0.8

Forest fires 0.6 (0.05 – 3.3) (1) 2.3

Sea Spray 0.04 (0.01 – 0.05) (1) 1.3

Total emission (median value) 26 30


40

1) The Table shows Nriagu (1979) as the source of nickel data.. The values in brackets give the range of the emissions estimated by different authors. The main figure is the most acceptable value according to Pacyna. The source of the other estimates shown in the brackets is not clear from the Table. A figure some 60 times higher has recently been calculated by Richardson et al. (2000). This gives a mean figure for nickel of 1.8 x 109 kg/y for nickel metal flux. The 5th percentile is 2.2 x 108, the 50th percentile 1.3 x 109 and the 95th percentile 4.9 x 109 kg/y. The difference is mainly attributed to underestimates of the contribution from biogenic sources.

2.1.4 Summary of nickel exposure information. The Tables shown above give the emissions to the atmosphere from intentional industrial production and use of nickel as 14. 5 x 106 kg/year (Table 2.1.1.H). This is more than the natural emissions (8.5 x 106 kg/year, Table 2.1.3.B) but substantially less than the emissions from fuel combustion (28.6x 106 kg/year, Table 2.1.2.A). Eisler (1998) quotes a figure of 16% of the atmospheric nickel burden due to natural sources, and 84% due to anthropogenic sources, which agrees with the figures from these Tables shown above. The US ATSDR (1997) and CONCAWE (1999) assessments also use these figures as an estimate of the balance between natural nickel emission and the different forms of anthropogenic emission. These estimates are based on data that is nearly 30 years old, and it is not clear how well these figures represent current emissions. The figures given for emissions of nickel to the atmosphere due to intentional production and use of nickel are all fairly similar at around 13 x 106 kg Ni/y. There are larger differences in the estimates for the contribution from other anthropogenic sources. These range from 28.6 x 106 kg Ni/y (Bennett, 1984) to gives a total of 43.4 . 106 kg/year (Niagu, 1989). This difference is however very small compared to the range of estimates for emissions from natural sources which range from 8.5 x 106 kg/year (Bennett, 1984) to 1800 x 106 kg/year (Richardson et al. 2001). The uncertainties in the estimates of nickel emissions from processes not related to intentional nickel production suggests that the relative contribution of nickel emission associated with intentional nickel production and use may have been overestimated in earlier reviews. Chemical and physical degradation of rocks and soils, atmospheric deposition of nickel-containing particulates, and discharges of industrial and municipal waste release nickel into ambient waters (US EPA, 1986, quoted from Eisler, 1998). The main anthropogenic sources of nickel in water are primary nickel production, metallurgical processes, combustion and incineration of fossil fuels, and chemical and catalyst production (US EPA, 1986, quoted from Eisler, 1998). These are the same sources that contribute to emissions to the atmosphere. The primary anthropogenic sources of nickel to soils are emissions from smelting and refining operations and disposal of sewage sludge or application of sludge as a fertiliser. Secondary sources include automobile emissions from electric power utilities (US EPA 1986 quoted from Eisler 1998). Weathering and erosion of geological materials also release nickel into soils (Eisler, 1998).

2.1.4.1 Trends in nickel emissions. Emissions of nickel to the atmosphere are falling. Annual emissions of nickel in the UK have fallen from roughly 1200 t/y in 1970 to roughly 300 t/y in 1996 (from Fig.1.11a, European Commission, 2000). Much of this fall is due to changes in the types of fuels used in power generation. Nickel emissions in Germany have fallen to a third in the decade from 1985 to 1995 (from Table 1.8, European Commission, 2000). This fall is attributed to reductions mainly in the production sector in the former German Democratic Republic. Emissions at Harjavalta in Finland have fallen from 3.1 t Ni in 1990 to 1.7 t Ni in 1998. Estimates for 1999 are 0.87 t Ni (European Commission, 2000). The fall in emissions has been accompanied by a fall in ambient air levels. A reduction of 65% was seen in the Rhine-Ruhr area of Germany between 1982 and 1990. A smaller decrease has been seen in other less industrialised regions of Germany. Only a small decrease in ambient air concentrations has been seen in the UK (European Commission, 2000).

2.1.5 Nickel Lifecycle. No figures showing the total lifecycle for nickel are included here. Diagrams showing the lifecycle of the individual substances and of some of the products such as catalysts and batteries, plated nickel and nickel alloy production are included in the individual risk assessment reports.


41

2.2 LEGISLATIVE CONTROLS. The following section follows the description of risk reduction measures described in the Nordic Risk Reduction report (NMR, 2002) and the TGD for risk reduction (European Commission, 1998)

2.2.1 General Measures.

2.2.1.1 Directive 67/548/EEC on dangerous substances. Eleven nickel compounds are included in Annex I to Directive 67/548/EEC (EEC 1992a) with separate harmonised classifications. The entries for the ten existing chemicals were first introduced in the 15th. ATP (EEC, 1991b). Most of these entries have subsequently been revised to include the classification for dangers to the environment in either the 25th. (EC, 1998b) or the 28th. ATP (EC, 2001e). An additional 18 substances are included in the Annex as part of group entries. For details of these classifications, see Chapter 1.3. The manufacturer or importer of substances not included in the Annex is required to evaluate available data and to apply a provisional classification. Some of the provisional classifications given by Industry are shown in Chapter 1.3. Additional information on provisional classifications for substances not included in Annex I should be available in the IUCLID database. Nickel compounds in EINECS are listed in Appendix 7.1.1. For many of these compounds there is little data, and, as a result, it would appear likely that only a limited number of the nickel compounds shown in Appendix 7.1.1. are classified as hazardous. Harmonised classifications for many of these substances have been agreed by the TC C&L (see Chapter 1.3). Professional users of users of hazardous substances have to be provided with a Safety data sheet by the manufacturer or supplier. The format for Safety data sheets is described in a separate Directive, EC (2001d).

2.2.1.2 Directive 1999/45/EC on dangerous preparations. This Directive (EC, 1999) should be implemented into national law by the Member States by 30th. July 2002. It replaces Directive 88/379/EEC (EEC, 1988). Classification of hazards of preparations containing nickel compounds follows the general rules set out in the Directive. Where health or environment hazards are based on a calculation method, the general concentration limits set out in the Directive apply. None of the current nickel entries in Annex I to Directive 67/548/EEC include specific concentration limits. Hence, for preparations containing nickel, current classification based on the calculation method will be based on the general limits included in the Directive. It should be noted that specific concentration limits for some of the nickel entries have been introduced in the 30th ATP, together with a note on the classification of nickel-containing alloys on the basis of nickel release rather than on nickel content.

2.2.1.3 Other EU legislation. Some uses of nickel metal are specifically controlled by Directive 76/769/EEC on restrictions on the marketing and use of certain dangerous substances and preparations (see Risk Assessment report on metallic nickel). Some nickel oxides and sulphides are classified in Annex I as Category 1 carcinogens. In addition, nickel chromate and dichromate are classified as Category 2 carcinogens as part of the group entry on chrome(VI) compounds, and nickel arsenate is classified as a Category 1 carcinogen as part of the entry on salts of arsenic acid. The 14th. Amendment of Directive 76/769/EEC (EC 1994b) introduced a general restriction on the sale of carcinogenic substances and preparations in categories 1 and 2 for consumer use. The Directive also introduces a labelling requirement for these substances and preparations in addition to the requirements in Directive 67/548/EEC. The sentence: “Restricted to professional users” is also required. Exemptions are made for medicinal, veterinary, and cosmetic products, motor fuels and artists paints. Regulation (EC) No. 304/2003 (EC 2003a) of 28 January 2003 on the export and import of dangerous chemicals does not include nickel in the Annex on the basis of the restrictions on marketing and use in Directive 76/769/EEC. This regulation replaces Regulation (EEC) No 2455/92 (EEC, 1992c) There are a number of nickel compounds that fall within the scope of Community major accident legislation Directive 2003/105/EC (EC, 2003b) on the control of major-accident hazards involving dangerous substances on the basis of their classification for inhalational toxicity. These include four substances (nickel carbonyl; nickel (II) cyanide; uranate(2-), tetrakis(acetato-O)dioxo-, nickel (2+)(1:1), (OC-6-11) and uranic acid (H2U3O10),


42

nickel (2+) salt (1:1)), classified as very toxic by inhalation (T+; R26) and two further substances (selenious acid, nickel (2+) salt (1:1) and selenic acid nickel(2+) salt, (1:1)), classified as toxic by inhalation (T; R23). The classifications of most other nickel compounds do not include hazards that bring them within the scope of this Directive. In the Netherlands, a Safety report and emergency plan is required for installations where > 1 t of inhalable nickel compounds (nickel monoxide, dinickeltrioxide, nickel dioxide, nickel sulfide, trinickel sulphide) in powder form are stored (Netherlands, 1999.)

2.2.1.4 National Initiatives. The Danish list of undesirable substances (Danish EPA, 2000) includes nickel and nickel compounds.

2.2.2 Protection of workers. The occupational use of hazardous chemicals is covered by the provisions of Directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work (EC, 1998a). The Directive (Article 3) provides a framework for setting occupational exposure limit values and biological limit values. The Directive requires that risks arising from chemical agents are identified by employers through risk assessment (Article 4) and reduced by application of a set of general principles (Articles 5 and 6), which include substitution, prevention, protection and control. In those instances where a national OEL is exceeded, the employer is to remedy the situation through preventative and protective measures. The OELs at present in force generally group the nickel compounds for which OELs apply as either water insoluble inorganic nickel compounds or as water soluble nickel species. There are also specific limits for nickel carbonyl.

Table 2.2.A: Occupational Exposure Limits (OEL) 1 for nickel compounds in force in various countries (NIPERA, 1996 with updates).

Country/Body mg/m3 (as Ni)

Comments

Austria 0. 05 nickel metal and alloys, nickel sulphide, sulphidic ores, oxidic nickel and nickel carbonates in inhalable dust, as well as any nickel compound in the form of inhalable droplets.

0.05 soluble Ni compounds

0.05 nickel carbonyl

Belgium 1.0 insoluble Ni compounds



Denmark 0.05 metallic nickel; Arbejdstilsynet (2000).

0.05 insoluble nickel compounds; Arbejdstilsynet (2000).

0.01 soluble Ni compounds , Arbejdstilsynet (2000)

France 1.0 nickel carbonate, nickel dihydroxide, nickel subsulphide, nickel monoxide, nickel sulphide, nickel trioxide, and for other chemical forms not otherwise specified such as “insoluble nickel compounds” and nickel sulphide roasting fume and dust. VME (Valeur Moyenne d’exposition).

0.1 soluble Ni compounds, VME (Valeur Moyenne d’exposition)

Finland 1.0 metallic nickel;

0.1 nickel oxide, nickel carbonate compounds

0.1 soluble nickel compounds

0.12 (15 min) 0.007

nickel carbonyl

Germany 0.5 metallic nickel, nickel carbonate. TRK (Technische Richtkonzentrationen) (2) (TRGS 900, 2000)


43

0.5 nickel dioxide, nickel sulphide and sulphidic ores. TRK (Technische Richtkonzentrationen) (2) (TRGS 900, 2000).

0.05 nickel compounds as inhalable droplets (e.g. nickel sulphate, nickel chloride, nickel acetate). TRK (Technische Richtkonzentrationen) (2, 3) (TRGS 900, 2000)

Greece not available not available

Ireland 1.0 insoluble Ni compounds



Italy 1.0 insoluble Ni compounds



Luxembourg 1.0 insoluble Ni compounds



The Netherlands

1.0 metallic nickel

0.1 nickel oxide, nickel carbonate



Portugal 1.0 insoluble Ni compounds



Spain 1.0 insoluble Ni compounds



Sweden 0.5 metallic nickel. LLV (Level Limit Value); occupational exposure limit for exposure during one working day.

0.1 nickel oxide, nickel carbonate

0.01 nickel subsulphide



United Kingdom

0.5 metallic nickel and insoluble Ni compounds. MEL (Maximum Exposure Limit) based on ’total inhalable’ aerosol as measured with the seven-hole sampler (UK HSE, 2000).

0.1 soluble Ni compounds . MEL (Maximum Exposure Limit).’total inhalable’ aerosol as measured with the seven-hole sampler (UK HSE, 2000).

0.24 (OES) nickel carbonyl

EU (proposed) [1.0] metallic nickel. NiPERA (1996) proposal under discussion in SCOEL.

[0.5] oxidic nickel. NiPERA (1996) proposal under discussion in SCOEL.

[0.1] sulphidic nickel. NiPERA (1996) proposal under discussion in SCOEL.

[0.1] soluble nickel species. NiPERA (1996) proposal under discussion in SCOEL.

[0.24 (OES)] nickel carbonyl. NiPERA (1996) proposal under discussion in SCOEL.

Norway 0.05 nickel and nickel compounds


44

USA (OSHA) 1.0 insoluble Ni compounds. Soluble nickel compounds PEL (Permissible exposure limit)

1.0 soluble nickel compounds PEL (Permissible exposure limit)

0.007 nickel carbonyl PEL (Permissible exposure limit) 1): 8-hour TWA (Time-Weighted Average) unless otherwise noted. 2): In Germany, nickel metal and nickel compounds are classified by MAK as Carc. Cat. 1 if they occur in respirable form as dusts or aerosols, and therefore MAK values cannot be fixed for these substances. The MAK list also notes the risk of sensitisation of the skin and respiratory tract caused by nickel and nickel compounds (BAuA, 2003). 3) According to German national regulations, soluble nickel compounds, nickel chloride, nickel sulphate and nickel acetate are classified as Carc. Cat. 1 (TRGS 905, 2002, in connection with EU Regulations) (BAuA, 2003) ACGIH (1998) has the following inhalable Threshold Limit Values (TLVs) for nickel and nickel compounds: 1.5 mg Ni/m3 for metallic nickel, 0.2 mg Ni/m3 for insoluble nickel, 0.1 mg Ni/m3 for nickel subsulfide and 0.1 mg Ni/m3 for soluble nickel. Some nickel oxides and sulphides are classified in Annex I to Directive 67/548/EEC as Category 1 carcinogens. In addition, nickel chromate and dichromate are classified as Category 2 carcinogens as part of the group entry on chrome(VI) compounds, and nickel arsenate is classified as a Category 1 carcinogen as part of the entry on salts of arsenic acid. These substances are covered by the provisions of Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at work (EEC, 1990c). Changes to the classification agreed by the TC C&L when included in Annex I will bring more nickel compounds into the scope of this Directive. A number of nickel compounds are covered by the provisions of Directive 92/85/EEC on the introduction of measures to encourage improvements in the safety and health at work of pregnant workers and workers who have recently given birth and are breastfeeding (EEC, 1992d). As well as the Category 1 & 2 carcinogens listed above, the category 3 carcinogens in Annex I to Directive 67/548/EEC are also covered. These are nickel carbonyl, nickel metal, nickel dihydroxide, nickel sulphate and nickel carbonate. For such workers, this Directive requires that the employer shall assess the nature, degree and duration of exposure in the undertaking and/or establishment concerned, of pregnant workers, workers who have recently given birth and workers who are breast feeding in all activities liable to involve a specific risk of exposure to the agents. Changes to the classification agreed by the TC C&L when included in Annex I will bring more nickel compounds into the scope of this Directive as well. The possibility for young people to work with nickel compounds and preparations containing nickel compounds that are classified as harmful under Directive 88/379/EEC is covered by the provisions of Directive 94/33/EC (EC, 1994a) on the protection of young people at work. This Directive prohibits the employment of young people for work involving exposure to such harmful agents. The use of personal protective equipment at the workplace is regulated by Directive 89/656/EEC (EEC, 1989b). The labelling required by Directive 67/548/EEC will often include Safety advice phrases such as: S22 (Do not breath dust), S36 (Wear suitable protective clothing) and S37 (Wear suitable gloves).

2.2.3 Protection of consumers. Consumer exposure to nickel comes mainly from contact with metallic nickel and nickel-containing alloys. This legislation is described in detail in the risk assessment report for nickel metal. With the exception of the use of nickel sulphate and nickel chloride as a source of nickel in food supplements, there would appear to be little or no consumer exposure to nickel sulphate, nickel chloride, nickel nitrate or nickel carbonate (see individual risk assessment reports). Information on consumer exposure to the other nickel compounds described in this Background report is limited. Whilst many do not appear to have direct consumer uses, compounds such as those used as plastic additives may give rise to exposure from food contact materials or from toys, whilst nickel in pigments may give rise to exposure from other articles. Eramet (2002) has provided information on the use of nickel chloride to produce pigments used in both textiles and wallpaper. Some of the legislative controls provided in consumer protection legislation may therefore be relevant for certain nickel-containing compounds.


45

2.2.3.1 Directive 98/83/EC on the quality of water intended for human consumption Directive 98/83/EC (EC, 1998d) sets a limit for nickel in drinking water of 20 μg/l. The EC Drinking water standard set in Directive 98/83/EC is lower than the previous limit of 50 μg/l set in Directive 80/778/EEC (EEC, 1980b) which it replaced in December 2003, and is the same as the provisional drinking water guideline set by the World Health Organisation in 1993 (WHO, 1993). It should be noted that this limit applies to nickel ion in drinking water rather than to nickel derived from any specific nickel compound.

2.2.3.2 Food contact materials, Food supplements, additives and contaminants. The general requirements in article 2 of Directive 89/109/EEC on materials and articles intended to come into contact with foodstuffs (EEC, 1989c) should be taken into account when evaluating the safe use of materials in contact with food. The requirements for nickel and nickel alloys have been described in the Risk Assessment report for nickel metal. However, a number of nickel compounds are used as additives to plastics (see section 2.1.1.2.1 above). It is not clear to what extent materials containing these nickel-containing additives are used as food contact materials. The Council of Europe has published a policy statement concerning materials and articles intended to come into contact with foodstuffs (Council of Europe, 2001). Appendix II contains data indicating that the mean intake of nickel via food is 2.8 mg/week, which is greater than 100% of the PTWI (Provisional Tolerated Weekly Intake) estimated as 2.1 mg/week. Finland has set limits for the release of nickel from food contact materials of 2.0 mg per dm2 (Finland, 1992). The UK and Germany have a number of standards for certain food contact materials (for references see Council of Europe, 2001). Nickel or nickel compounds are not permitted as food supplements in Directive 2002/46/EC of the European Parliament and the Council on food supplements in foodstuffs for human consumption (EC, 2002c) or in Council Directive 70/524/EEC concerning additives in feedingstuffs for animal nutrition (EEC, 1970). It should be noted that the validity of Directive 2002/46/EC has been challenged at the European Court of Justice, and that the opinion of the Advocate General is that the Directive is invalid (European Court, 2005). The case is expected to be decided before the end of July 2005. Nickel compounds are not included in the list of additives for specific nutritional purposes in foods for particular nutritional uses (Commission Directive 2001/15/EC of 15 February 2001, EC 2001c). There are no limits set for nickel as a contaminant in food (Council Regulation (EEC) No 315/93, EEC 1993a). There are limits set for nickel in the specific criteria of purity concerning certain polyolen sweeteners for use in foodstuffs (EEC, 1995 and amendments). A limit of 2 mg/kg nickel expressed as dry weight is set for E420 sorbitol, E421 mannitol, E953 isomalt, E965 malitol, E966 latitol and E967 xylitol. Scientific advice was previously provided by the Commission Scientific Committee on Food (SCF) and the Commission Scientific Committee on Animal Nutrition (SCAN). Since the establishment of the European Food Safety Authority, the relevant committees are the Panel on food additives, flavourings, processing aids and materials in contact with food (AFC), the Panel on dietetic products, nutrition and allergies (NDA), the Panel on contaminants in the food chain (CONTAM) and the Panel on additives and products or substances used in animal feed (FEEDAP). The Scientific Panel on Dietetic Products, Nutrition and Allergies has prepared an opinion on the tolerable upper limit of nickel in response to a request from the Commission (NDA, 2005). During the decision making process for the adoption of Directive 2002/46/EC on Food Supplements, the Parliament requested that nickel should be allowed to be used in food supplements. This opinion is a supplement to the previous opinions on individual vitamins and minerals evaluated by the SCF. The NDA was unable to establish a tolerable upper intake level for nickel due to the absence of adequate dose-response data.

2.2.3.3 Council Directive 90/385/EEC on active implantable Medical Devices, Council Directive 93/42/EEC on Medical Devices and Council Directive 98/79/EEC on in vitro-diagnostic Medical Devices

Community legislation to regulate implantable medical devices was introduced in 1990 (EEC, 1990b), and this Directive was amended in 1993 (EEC, 1993c) to cover a much wider range of medical devices. The latter include non-active implantable, medical devices (e.g. bone screws) as well as a wide range on non-implant devices (e.g. scalpels, forceps and much dental instruments). Directive 98/79/EC (EC, 1998c) covers in vitro


46

diagnostic medical devices. These legislative controls required by these Directives are described in the Risk Assessment report for metallic nickel. Scientific advice on medical devices is provided by the Commission Scientific Committee on Medicinal Products and Medical Devices.

2.2.3.4 Council Directive 88/378/EEC on the Safety of Toys Directive 88/378/EEC on the safety of toys (EEC, 1988a) makes no specific mention to nickel; however, toys must conform to the essential requirements of the Directive. Discussions on a revision of the Directive are taking place. Scientific advice is provided by the Commission Scientific Committee on Health and Environmental Risks (SCHER).

2.2.3.5 Council Directive 89/106/EEC on Construction Products Council Directive 89/106/EEC on the approximation of laws, regulations and administrative provisions of the Member States relating to construction products (EEC, 1989a) is described in the Risk Assessment report for metallic nickel.

2.2.3.6 Directive 2001/95/EC on general product safety Directive 92/59/EEC (EEC, 1992b) has recently been replaced by Directive 2001/95/EC of the European Parliament and of the Council of 3 December 2001 on general product safety (EC, 2001h). The purpose of the Directive is to ensure that products are safe (Art. 1, 1). The Directive places a general obligation on the importers and manufacturers of products intended for consumer use to ensure that their products are safe based on compliance with European and national standards (Art. 3). The manufacturer is also required to provide consumers with the relevant information to enable them to assess the risk inherent in a product under normal and reasonably foreseeable conditions of use, and to take precautions against those risks (Art. 5).

2.2.4 Emissions to water

2.2.4.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC)

The aim of the Directive (EC, 1996a) is to lay down measures designed to prevent or control emissions in order to achieve a high level of protection of the environment as a whole. It integrates provisions and measures dealing with emissions to air, water and land, including measures concerning wastes. The directive covers medium-sized and large industrial installations, and waste management installations (Annex I) (NMR, 2002). Annex I includes many of the processes described earlier in this Chapter. These include: 2. Production and processing of metals 2.1. Metal ore (including sulphide ore) roasting or sintering installations …….. 2.5. Installations

(a) for the production of non-ferrous crude metals from ore, concentrates or secondary raw materials by metallurgical, chemical or electrolytic processes

(b) for the smelting, including the alloyage, of non-ferrous metals, including recovered products, (refining, foundry casting, etc.) with a melting capacity exceeding 4 tonnes per day for lead and cadmium or 20 tonnes per day for all other metals

2.6. Installations for surface treatment of metals and plastic materials using an electrolytic or chemical process where the volume of the treatment vats exceeds 30 m³ 4. Chemical industry Production within the meaning of the categories of activities contained in this section means the production on an industrial scale by chemical processing of substances or groups of substances listed in Sections 4.1 to 4.6 ……. 4.2. Chemical installations for the production of basic inorganic chemicals, such as: …….


47

(d) salts, such as ammonium chloride, potassium chlorate, potassium carbonate, sodium carbonate, perborate, silver nitrate (e) non-metals, metal oxides or other inorganic compounds such as calcium carbide, silicon, silicon carbide. Installations listed in Annex I have to have a permit. New installations have to have a permit in accordance with the IPPC directive before they are put into operation. Existing installations (in operation before October 2000) have to have a permit in accordance with this directive at the latest 2007. (Art. 4 and 5). An application for a permit has to include inter alia descriptions of raw and auxiliary materials, nature and quantities of foreseeable emissions, proposed technology or other techniques for preventing or reducing emissions, and measures planned to monitor emissions. (Art. 6). The permit shall include emission limit values for pollutants likely to be emitted from the installations in significant quantities. Annex III includes an indicative list of main polluting substances to be taken into account when considering emission limits (Art 9.3) (NMR, 2002). Annex III includes “Metals and their Compounds” for emissions to both air and to water. Emission limit values shall be based on best available techniques. (Art 9.4) Annex IV includes issues to be taken into account when determining best available techniques. For instance the use of less hazardous substances (point 2), the nature, effects and volume of the emissions concerned (point 6), and the consumption and nature of raw materials (point 9) have to be considered. The Commission shall organise an exchange of information between Member States and the industries on best available techniques. (Art. 16) The results of this information exchange are published as IPPC BAT Reference Documents (BREFs). The BREFs aim at providing reference information for the permitting authority to be taken into account when determining emission limit values (NMR, 2002). The Commission has published eight BREFs on Best Available techniques in a number of industries (EC, 2002). The permit shall contain suitable release monitoring requirements. (Art 9.5). Permit conditions have to be reconsidered and updated periodically. (Art 13). The Council can set common emission limit values for the categories of installations listed in Annex I and for the substances referred to in Annex III. (Art 18) (NMR, 2002).

2.2.4.2 Directive 76/464/EEC on pollution of the aquatic environment by certain dangerous substances.

Nickel is included in List II of families and groups of substances covered by the Directive (EEC, 1976). List II contains

• substances belonging to the families and groups of substances in List I for which the limit values referred to in Article 6 of the Directive have not been determined, and

• certain individual substances and categories of substances belonging to the families and groups of substances listed below, and which have a deleterious effect on the aquatic environment, which can, however, be confined to a given area and which depend on the characteristics and location of the water into which they are discharged.

Nickel is one of the families and groups of metalloids and metals and their compounds referred to in the second indent. Under this legislation, pollution from List II substances has to be reduced by pollution control measures. A basic requirement is that discharges of these substances require authorisation. Scientific advice is provided by the Commission Scientific Committee Health and Environmental Risks (SCHER).

2.2.4.3 Directive 2000/60/EC establishing a framework for Community action in the field of water policy.

Nickel and nickel compounds are specifically listed in the Decision (EC, 2001g) establishing the list of priority substances in the field of water policy and amending Directive 2000/60/EC (EC, 2000b). According to the Directive, the Commission shall submit proposals for environmental quality standards (EQSs) applicable to concentrations of the priority substances in surface water, sediments or biota.

2.2.4.4 Directive 80/68/EEC on the protection of groundwater against pollution caused by certain dangerous substances

Nickel is included in List II of families and groups of substances covered by the Directive (EEC, 1980a).


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The purpose of the Groundwater Directive is to prevent the pollution of groundwater by groups of substances in lists I and II in the Annex and as far as possible to check or eliminate the consequences of pollution which have already occurred. The Directive obliges the Member States to limit the introduction of substances in list II so as to avoid pollution. According to the Water Policy Framework Directive (EC, 2000b) the Groundwater Directive will be repealed with effect from 13 years after the data of entry into force of the Directive, that is 22.12.2013.

2.2.4.5 Directive 2000/76/EC on the incineration of waste. The aim of the Directive (EC, 2000c) is to prevent or to limit as far as practicable negative effects on the environment, in particular pollution by emission into air, soil, surface water and ground water, and the resulting risk to human health, from the incineration and co-incineration of waste. Annex III sets emission limit values for discharges of waste water from the cleaning of exhaust gases for nickel and its compounds, expressed as nickel (Ni): 0.5 mg/l.

2.2.4.6 National Legislation. In Finland, the IPPC Directive is implemented by the Environmental Protection Act (2000/86) (Finland, 2000). In addition to installations listed in Annex I of the IPPC Directive, several other activity categories and activities not exceeding capacity thresholds set in the IPPC Directive require a permit according to the Finnish Act. Concerning nickel emissions, the most important difference is that all surface treatment installations using electrolytic or chemical process require a permit regardless of the capacity. So far permit conditions for nickel have been included in permits issued for the following sectors: mines, smelters, metal refiners, primary and secondary steel production, electrolytic and chemical metal plating (including aluminium anodising) and waste handling (Heiskanen, 2003). The Netherlands has a number of regulations concerning nickel in water. There is a general prohibition on discharge of nickel to surface water (Netherlands, 1974). The concentration of nickel (individual) in purified groundwater to inject in a provision for collection and transport of wastewater should be < 500 μg/l (Netherlands 2001a). This legislation is part of an implementation of Council Directive 91/689/EEC on hazardous waste (EEC, 1991c, see 2.2.7.2 below) and Council Directive 91/271/EEC on urban wastewater treatment (EEC, 1991a). The same limit value applies to polluted ground water discharges to surface water during soil remediation (Netherlands, 1997a). The limit value for water to be infiltrated into soil is 15 g/l (Netherlands, 1993). The Netherlands environmental quality standards for fresh surface water and for groundwater are shown in Tables 2.2.4.A and 2.2.4.B.

Table 2.2.4.A: Environmental Quality Standards for fresh surface water in the Netherlands (NL Chemical Substances Bureau, 2002)

Dissolved (µg/l) Total (µg/l)

Background Concentration

Target Value

Maximal Permissible Concentration


Target Value

Maximal Permissible Concentration

3.3 3.3 5.1 4.1 4.1 6.3 Target Value (TV) and Maximal Permissible Concentration (MPC) figures include Background Concentration (BC). The values for water (total) are derived for water containing 30 mg/L of suspended solids (that contains 20% of organic matter and 40% of clay). The Kp-value for nickel that is used for suspended solids-water is 8,000 L/kg, and for soil-water or sediment-water is 5,300 L/kg.

Table 2.2.4.B: Environmental Quality Standards for nickel dissolved in groundwater in the Netherlands (NL Chemical Substances Bureau, 2002)

Deep (>10m) (µg/l) Superficial (<10m) (µg/l) Dissolved (µg/l)


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Target Value Background Concentration

Target Value Intervention value

2.1 2.1 15 15 75 Target Value (TV) includes Background Concentration (BC). The intervention value is a trigger for high concern, when a concentration exceeds this value, immediate research must be carried out to determine the urgency of sanitation. The value is based on ecotoxicological and human toxicological data, and in addition on generic exposure scenarios. A number of environmental quality standards (EQSs) apply in the UK for protection of aquatic life in surface waters (URS, 2001). For freshwater, the current EQS ranges from 50 to 200 μg/l dependent on water hardness, although a lower range of 8-40 μg/l has been proposed in R&D work funded by the UK Department of Environment Transport and the Regions9 (Hunt & Hedgecott, 1992). The EQS in legislation for marine waters is 30 μg/l (DoE, 1989), although again a lower 15 μg/l limit has been proposed (Hunt & Hedgecott, 1992).

Table 2.2.4.C: Freshwater environmental quality standards for nickel in UK inland waters (URS 2001).

Total hardness

(mg CaCO3/l) EQS (μg/l)

(DoE Circular 7/89)

Proposed EQS (μg/l)

(Hunt & Hedgecott, 1992)

0-50 50 8

50-100 100 20

100-150 150 20

150-200 150 40

>200 200 40

2.2.5 Emissions to air

2.2.5.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC)

See Chapter 2.2.5.1 above. Annex III includes an indicative list of the main polluting substances to be taken into account if they are relevant or fixing emission values. Metals and their compounds are included as item 5 in the list for emissions to air.

2.2.5.2 Directive 96/62/EC on ambient air quality assessment and management. This Directive sets levels for a number of air pollutants which are to be taken into account in the assessment and management of ambient air quality. Annex I part II includes nickel among such pollutants. A Directive on ambient air quality for nickel, cadmium, arsenic, mercury and polycyclic aromatic hydrocarbons (EC 2004b) identifies nickel as a genotoxic carcinogen and sets a target value of 20 ng Ni/m3. Measures to achieve this target value involve the use of Best Available Technology (BAT). The reference method for the measurement of nickel concentrations in ambient air is currently being standardised by CEN and shall be based on manual PM10 sampling equivalent to EN 12341, followed by digestion of the samples and analysis by Atomic Absorption Spectrometry or ICP Mass Spectrometry. Before making proposals for this Directive, the Commission prepared a Position paper on ambient air pollution by nickel compounds (European Commission, 2000). This paper has been reviewed by the CSTEE (CSTEE, 2001). For non-cancer effects, the CSTEE found that a limit value of 20 ng/m3 was supported by the data. For cancer effects, the CSTEE supported the recommendation from WHO (1999) of a unit risk of 3.8 x 10-4 (μg Ni/m3)-1. This corresponds to concentrations of 25 ng Ni/m3 and 2.5 ng Ni/m3 for increased lifetime risks of 1:100 000 and 1: 1 000 000 respectively. In view of the fact that these estimates are conservative in nature, the CSTEE concluded that the limit value of 20 ng/m3 is likely to provide reasonable protection of the general population to both the carcinogenic and non-carcinogenic effects of nickel compounds in ambient air (CSTEE, 2001). 9 The UK DoE, DETR and MAFF are now the Department of Environment, Food and Rural Affairs (DEFRA).


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2.2.5.3 Directive 2000/76/EC on the incineration of waste. The Directive (EC, 2000c) sets air emission limit values for nickel and its compounds, expressed as nickel (Ni) of either a total of 0.5 mg/m3 or 1 mg/m3 (all average values over the sample period of a minimum of 30 minutes and a maximum of 8 hours) depending on when the plant was granted its permit to operate.

2.2.5.4 Directive 2001/80/EC on Large Combustion Plant Directive. This Directive is expected to have implications on heavy metal emissions from existing coal and oil fired plants as it will set limit values to total dust emissions. It will apply to new plants licensed after 1987 while older plants have to comply from 2008 on. More substantial impacts on heavy metal emissions could result from the review due in 2004.

2.2.5.5 UN ECE Protocol on heavy metals. The 1998 Aarhus Protocol on Heavy Metals is a Protocol under the UN ECE convention on Long-range transport of atmospheric pollutants. Whilst this protocol is primarily directed at limiting the release of cadmium, lead and mercury, many of the installations that can be affected by the Protocol also emit nickel. The Protocol has been signed by all Member States and the European Commission, and ratified or approved by Denmark, Finland, France, Luxembourg, the Netherlands and Sweden. Norway has also ratified the Protocol. The protocol has been ratified or approved by Canada, the Czech Republic, the Republic of Moldova, Switzerland, the US and the European Community.

2.2.5.6 National Legislation. In Finland, the IPPC Directive is implemented by the Environmental Protection Act (2000/86) (Finland, 2000). See Chapter 2.2.4.6 above. Emissions of nickel and its compounds are regulated in Germany by TA Luft (2002) under section 5.2.2 (inorganic dusts) in hazard class II, with emission limits expressed as nickel of 2.5 g/h or 0.5 mg/m3. Nickel and its compounds (with the exception of nickel metal, nickel alloys, nickel carbonate, nickel hydroxide and nickel tetracarbonyl) are also included in section 5.2.7.1.1. (Carcinogens) with emission limits expressed as nickel of 1.5 g/h or 0.5 mg/m3. The Netherlands Emissions Guidelines for air (NeR) regard nickel and nickel compounds as category C.2 carcinogens. C2 carcinogens are carcinogens without a threshold value and compulsory minimisation of emissions is required. Specifically, in the case of an untreated mass flow of 5.0 grams per hour or more, an emission standard of 1.0 mg/mo

3 (calculated as nickel) applies (Netherlands, 2001b). From 1. April, 2003, nickel and nickel compounds are regarded as carcinogens for which compulsory minimisation applies. For an untreated mass flow of 0.15 g/hr, an emission standard of 0.05 mg/m3 applies. An immission assessment must be carried out once every five years. (InfoMil, 2003) CEPN (Centre d’étude sur l’évaluation de la protection dans le domaine nucléaire) performed a risk assessment based on the respiratory cancer effects in animals and humans. This report did not recommend an actual air quality standard, but suggested that an exposure range between 0.01 and 0.03 μg Ni/m3 (10 – 30 ng Ni/m3) would be protective of public health (Lepicard et al., 1997, quoted in CONCAWE, 1999). The Netherlands is the only EU country with an ambient air quality standard in national legislation (European Commission, 2000). The Netherlands target value for nickel in air (yearly average) is 0.0025 μg/m3 with a Maximum Permissible concentration of 0.25 μg/m3. In Denmark airborne emissions of nickel from industrial sources should be reduced to be well below 0.01 mg/normal m3 by filtering the air through an absolute (HEPA-) filter. An air concentration at ground level of 0.0001 mg Ni/m3 for the surrounding neighbourhood should also be observed (Danish EPA, 2002). Belgium (Flanders) uses a non-legally binding target value of 5 ng/m3 (annual means) to assess the concentrations of nickel (European Commission, 2000).

2.2.5.7 Other measures. CONCAWE (1999) has recommended an Air quality standard for soluble nickel compounds of 0.6 μg/m3 (60 ng Ni/m3) and 6 μg Ni/m3 (600 ng Ni/m3) for less soluble nickel compounds based on cancer epidemiology.


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CONCAWE (1999) quotes acceptable nickel ambient air concentration regulations and recommended exposure limits from the US and Canada. The annual average recommended ambient limit ranges from 0.0002 μg/m3 (for nickel subsulphide, set by New York State Department of Health in 1989) to 3.37 μg/m3 (for metallic and insoluble nickel compounds, set by New York State Department of Environmental Conservation in 1988).

2.2.6 Soil

2.2.6.1 Directive 86/278/EEC on Sludge in Agriculture. The EC Sludge in Agriculture Directive, Council Directive 86/278/EEC, (EEC, 1986) stipulates a maximum permissible addition of 3 kg/ha/y of nickel in sewage sludge to agricultural land, not to result in a concentration higher than 30-75 mg/kg dry weight in soil at pH 6-7. The limit value for nickel in sewage sludge has been set at 300-400 mg/kg dry weight.

2.2.6.2 National Legislation. Immissions of nickel and its inorganic compounds are regulated in Germany by TA Luft (2002) under section 4.5.1 (Immission values for the deposition of harmful substances). The immission limits expressed as nickel are 15 μg/m2/d, measured as the mean value for 1 year. The bagatelle limit for the immission of these substances is 0.025 kg/h. In the Netherlands, the standard for clean soil is < 35 mg/kg dry weight (Netherlands, 1995, see also below). There is a general prohibition against discharge of liquids containing nickel into soil, although exceptions are possible (Netherlands, 1997b). The environmental quality standards used for sediment and soil in the Netherlands are shown in the Table below.

Table 2.2.6.A Environmental Quality Standards for sediment and soil in the Netherlands (NL Chemical Substances Bureau, 2002).

Sediment & Soil (mg/kg s.b.) Sediment (mg/kg s.b.) Sediment & Soil (mg/kg s.b.)


Target Value Maximal Permissible Concentration – sediment

Intervention value

35 35 44 210 Maximal Permissible Concentration (MPC) for sediment includes Background Concentration (BC) s.b.: standard soil or sediment, based on dry weight; (Dutch) standard soil or sediment contains 10% organic matter and 25% lutum (clay). The intervention value is a trigger for high concern, when a concentration exceeds this value, immediate research must be carried out to determine the urgency of sanitation. The value is based on ecotoxicological and human toxicological data, and in addition on generic exposure scenarios. The standards for a particular soil type (Nb) can be related to the standard for standard soil (Ns) by the following formula: Nb = Ns x A + (B x % lutum) + (C x % organic substance)

A + (B x 25) + (C x 10) For nickel, A = 10, B = 1 and C = 0. In addition there are standards for a number of products. The limit value for dredging sludge is 35 mg/kg d.w.. The standards for sewage sludge are 30 mg/kg d.w., for compost: 20 mg/kg d.w. and for very clean compost: 10 mg/kg d.w.. The UK Ministry for Agriculture, Fisheries and Food (MAFF10) has also set limits for metals in agricultural soils receiving sewage sludge (see Table 2.2.6.B) (URS, 2001). The 75 mg Ni/kg limit for agricultural soils at pH 6.0-7.0 is exceeded in relatively few places in England and Wales (McGrath & Loveland, 1992). These locations are often in areas of mineralisation of rocks and soil, e.g. over carboniferous limestone in Derbyshire and serpentine in south Cornwall (URS, 2001).

10 The UK DoE, DETR and MAFF are now the Department of Environment, Food and Rural Affairs (DEFRA).


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Table 2.2.6.B: Maximum permissible and advisable concentrations of potentially toxic elements (PTEs) in soil after application of sewage sludge to agricultural land (UK MAFF, 1988, from URS, 2001).

Maximum permissible concentrations of PTE1 at various pH values

Maximum permissible average over a 10-year period (kg/ha)

5.0 –5.5 5.5-6.0 6.0-7.0 >7.0 - PH

Nickel (mg/kg) 50 60 75 110 3 kg/ha 1PTE – Potentially Toxic Elements The UK Environment Agency use an environmental assessment level (EAL) of 50 mg/kg nickel in soil for the purposes of monitoring releases under IPPC. In addition to this soil value, a maximum rate of deposition to soil of 0.11 mg nickel/m2/d is also specified (URS, 2001). The UK Inter-departmental Committee on the Redevelopment of Contaminated Land (ICRCL) has set a threshold concentration of 70 mg/kg nickel above which soil may be toxic to plants. Guideline Values (GVs) for the assessment of soil contamination from a human health protection perspective are under development by UK DEFRA but have yet to be published (URS, 2001). In Denmark a health based soil quality criteria of 30 mg Ni/ kg soil has been set for the use of soil/area for sensitive uses e.g. kindergartens and domestic gardens (Danish EPA 2001). In Sweden, the nickel content of sludge for agricultural use should not exceed 50 mg/kg dry weight (Kemi, 2003).

2.2.7 Waste management.

2.2.7.1 Directive 96/61/EC concerning integrated pollution prevention and control See Chapter 2.4.4.1 above.

2.2.7.2 Council Directive 91/689/EEC of 12 December 1991 on hazardous waste Annex II of the Directive (EEC, 1991c) includes C5 nickel compounds as constituents of wastes in Annex IB which render them hazardous when they have the properties described in Annex III of the Directive. Lists of hazardous wastes of hazardous wastes have been published as two Commission Decisions (EC, 2001a, 2001b). Decision 2001/118/EC (EC, 2001a) divides wastes into different chapters. These include a number of categories relevant to the production and use of nickel and nickel compounds: 01 Wastes resulting from exploration, mining, quarrying, physical and chemical treatment of minerals 04: Wastes from the leather, fur and textiles industries. 06 Wastes from inorganic chemical processes 08: Wastes from the manufacture, formulation, supply and use (MFSU) of coatings (paints, varnishes and vitreous enamels), adhesives, sealants and printing inks. 10 Wastes from thermal processes 11 Wastes from chemical surface treatment and coating of metals and other materials; non-ferrous hydro-metallurgy 12 Wastes from shaping and physical and mechanical surface treatment of metals and plastics Spent batteries and catalysts are included in Chapter 16: Wastes not otherwise specified in the list. In general, wastes are classified as hazardous if they fulfil the same classification criteria for dangerous substances and preparations given in Directives 67/548/EEC and 88/379/EEC.


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3. ENVIRONMENT Please consult separate document.


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4. HUMAN HEALTH

4.1 HUMAN HEALTH (TOXICITY)

4.1.1 Exposure assessment.

4.1.1.1 General The human population may be exposed to nickel at the workplace, as a consumer or indirectly via the environment.

4.1.1.2 Occupational exposure. Occupational exposure in the production and use of metallic nickel, nickel sulphate, nickel chloride, nickel carbonate and nickel nitrate is described in the individual risk assessment reports on these substances. Occupational exposure in the production and use of other nickel compounds described in Chapter 2.1.1 is not covered here. The approach used in the risk assessments of the five nickel compounds listed above may prove helpful in preparing occupational exposure assessments for specific compounds. Occupational exposure in other scenarios described in Chapter 2.1.2 not involving the production and use of nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments.

4.1.1.3 Consumer exposure. Consumer exposure to metallic nickel and nickel sulphate is described in the individual risk assessment reports on these substances. Consumers are also exposed to nickel in food, water and by tobacco smoking.

4.1.1.3.1 Exposure to nickel in food Nickel in foodstuffs is measured as total nickel and thus does not give any information as to the content or dietary intake of individual nickel species in foodstuffs. It is generally assumed that nickel in food occurs in the form of complex bound organic nickel, which has different physico-chemical and possibly also different biological properties than inorganic nickel. Nickel from both natural and anthropogenic sources is contained in foodstuffs such as cocoa products (9.8 mg/kg), soy beans (5.2 mg/kg), nuts (1.9 mg/kg), other dried legumes (1.7 mg/kg), oatmeal (1.2 mg/kg), seeds (0.8 μg/kg) and other cereals (0.6 mg/kg), (Danish Veterinary and Food Administration, 2000, Ellen et al., 1978, Flyvholm et al., 1984). Spinach and mushrooms can also contain levels above 1 mg/kg (Grandjean, 1984). These figures are similar to other values found in Denmark, Germany and the UK (Veien & Andersen, 1986, Smart & Sherlock, 1987, Scheller et al., 1988, quoted from IARC, 1990). Beverages, such as tea and vegetable juices, also contain amounts of nickel that could significantly contribute to daily intake. Human milk contains from 20 – 500 μg/l whilst cows’ milk contains < 100 μg nickel/l (Clemente et al., 1980, quoted from Grandjean 1984). Casey & Neville (1987, quoted from California, 2001) monitored nickel levels in milk of 13 women between delivery and 38 days postpartum. They reported that nickel concentrations in human milk did not change over that period of time; the overall average in the 46 milk samples analysed was 1.2±0.4 µg/l. Camara & Kirkbright (1982 as cited in Casey & Neville, 1987) analysed 179 milk samples from several different countries and found a range of 3-50 µg/l (quoted from California, 2001). Nickel concentrations of 100 μg/l have been found in wine; average levels of about 30 mg/l were measured in beer (Grandjean, 1984). In mineral water levels of a few micrograms per litre have been found (Grandjean, 1984). In Germany, the mean concentration of nickel in mineral waters was 10 μg/l with a maximal value of 31 μg/l (Scheller et al., 1988, quoted from IARC, 1990). Detailed figures for individual products are shown in Grandjean et al., (1989, quoted in IARC, 1990) and in Council of Europe (2001). These figures are shown in Appendix 7.3.


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The nickel content in food has been investigated in Denmark for many years. The results of individual food items analysis have been combined with food consumption data in order to estimate the Danes’ dietary intake of trace elements. The highest nickel intake comes from dairy products, grains and beverages (especially tea and coffee). (Danish Veterinary and Food Administration, 2000).

Figure 4.1.1.3: Nickel Intake in foods, μg/day 1993 – 1997. (Danish Veterinary and Food Administration, 2000)

0 10 20 30 40 50 60

Nickel Intake, µg/day

Beverages

Sugars and Preserves

Oils and fats

Eggs

Poultry

Fish

Meat products

Fruits

Vegetables

Miscellaneous Cereals

Cheeses

Milk

A similar investigation from the United Kingdom (UK EGVM, 2002) indicates results in good agreement with the Danish investigations. The Total Diet Study shows that the food groups with the highest concentrations of nickel are nuts, sugar and preserves and canned vegetables. The main contributors to dietary intake of nickel are sugars & preserves, beverages, bread, miscellaneous cereals and canned vegetables (UK EGVM, 2002).

Table 4.1.1.3.A: Concentrations of Nickel in 1997 Total Diet samples and estimated average intake (UK EGVM, 2002).

Food group (TDS) Mean nickel concentrations (1) (mg/kg fresh weight)

Intake of nickel: μg/day (2)

Bread 0.13 14

Miscellaneous cereals 0.177 18

Carcase meat 0.115 3

Offal 0.016 0.02

Meat products 0.08 4

Poultry 0.024 0.5

Fish 0.116 2


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Oils & fats 0.04 1

Eggs 0.017 0.24

Sugars & preserves 0.42 26

Green vegetables 0.088 3

Potatoes 0.062 8

Other vegetables 0.078 6

Canned vegetables 0.313 10

Fresh fruit 0.038 3

Fruit products 0.048 2

Beverages 0.025 23

Milk 0.005 1

Dairy produce 0.039 2

Nuts 1.77 4

Total intake (mg/day) 0.13 mg/day 1) upper-bound means across the 20 TDS towns, i.e. concentrations below limit of detection taken as the limit of detection 2) upper-bound intake, i.e. concentrations below limit of detection taken as the limit of detection The Total Diet Study is a model of the average domestic diet in the UK. A total of 119 categories of food and drink are specified for inclusion in the Total Diet. These are assigned to one of twenty broad food groups. The quantities and relative proportions of each food that make up the Total Diet are largely based on data from the National Food Survey (NFS) and are updated annually. The population average intake of a particular food constituent can be estimated from its concentration in each food group and consumption of each group as determined by the NFS (UK EGVM, 2002). However, it should be noted that Total Diet Studies and estimates of dietary exposure from different countries are not directly comparable because of differences in study design and dietary habits.

Table 4.1.1.3.B: Dietary nickel exposure in mg/day

Dietary Exposure (mg/day)

Mean 95th %ile 97.5th %ile Reference.

0.139 0.231 Larsen et al, (2002) (1).

0.130 0.210 Gillian et al, (1999) (1, 2).

0.120 0.210 UK EGVM (2002) (3) 1) numerical values derived from a 60 kg person 2) Result of the UK 1997 Total Diet Study (TDS) . The population average intake of nickel is 0.13 mg/day. This value is unchanged from that obtained from the analysis of samples from the 1994 Total Diet Study (from UK EGVM, 2002). 3) Mean and upper level (97.5 percentile) nickel intake for adults has been estimated using the 1997 TDS concentrations combined with consumption data from the 1986/87 Dietary and Nutritional Survey of British Adults. These figures are also unchanged from the 1994 TDS. This estimate should be used with caution due to the differences between the Total Diet Study and Adults Survey food groups (UK EGVM, 2002). The UK EGVM (2002) report includes data on dietary nickel intakes. This includes data from Sweden (Solomons et al., 1982, quoted from UK EGVM, 2002) showing a mean intake of 0.75 mg/day with a range from 0.2 to 4.460 mg/day and from Italy showing a daily intake of 0.3 mg/day. Other investigations confirm an average daily intake of nickel between 0.1 and 0.7 mg/day (UK MAFF, 1985, Codex Alimentarius Commission, 1995).


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A report on the impact of nickel on a contaminated site in Ontario includes estimates for the daily intake of nickel from supermarket food for different age groups (Table A4-4 quoted from Ontario, 2002)

Table 4.1.1.3.C: Estimated daily dietary intake of nickel in various countries in μg/day (Ontario, 2002)

Nickel intake μg / day (range) Age Group

Age range

CEPA (1994) Dabeka (1989), Dabeka & McKensie (1995)

US FDA TDS 95th %ile IOM (2001)

UK TDS 1997 95th %ile Ysart et al., (2000)

Infant 0 – 6 months 154 109.2 (1) (72.2 – 146.2)

9 (37, recalculated)

39 (68, calculated)

Toddler 1 – 4 year 208 190 81 (153, recalculated)

68 (120, calculated)

Child 5 – 11 year 270 251 107 (199, recalculated)

105 (184, reported)

Teen 12 – 19 year 325 313 125 (250, recalculated)

120 (210, reported)

Adult > 19 year 308 307 119 (233, recalculated)

102 (178, calculated)

1) Diet A assumes that the infant only consumes breast milk for the first six months; Diet B assumes that the infant only consumes formula for the first six months; Diet C assumes that the infant consumes breast milk or formula for the first three months, and this diet is then supplemented by vegetables, cereal and bread, ands fruit and fruit juices. The CEPA results and the two Dabeka studies both reflect Canadian intake. The report recognises that the levels in these Canadian studies are higher than the levels seen in the US (IOM, 2001) or the UK (Ysart et al., 2000). The values in the Table above have in some cases been recalculated to match the Canadian age class groups. These figures do however provide a basis on which to estimate the effects of oral intake of nickel in different age groups. In general, nickel intake via foodstuffs does not cause hazards for the majority of consumers (Codex Alimentarius Commission, 1995). The figures shown above relate to concentrations of nickel in food. The nickel present may be due to natural concentrations in the soil or to environmental or soil contamination (see section on Indirect exposure via the environment). These figures do not include release of nickel to food during processing, storage or cooking. Release of nickel from nickel-containing food contact materials and kitchen utensils is described in chapter 4.1.1.3.2.1 of the risk assessment report for metallic nickel. See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”

4.1.1.3.2 Exposure to nickel in water Nickel concentration in drinking water in European countries were reported to range in general from 2-13 μg/l (mean, 6 μg/l) (Amavis et al., 1976, quoted from IARC, 1990). Other studies suggested low background levels in drinking water, e.g. in Finland an average of about 1 μg/l (Punsar et al., 1975, quoted from IARC, 1990) and in Italy mostly below 10 μg/l (Clemente et al., 1980, quoted from Grandjean, 1984). Drinking water from groundwater in Germany (GDR) showed an average level of 10 μg/l, slightly below the amount present in surface water (Schuhmann, 1980, quoted from Grandjean, 1984). The mean concentration of drinking water in the BRD was 9 μg/l with a maximal value of 34 μg/l (Scheller et al., 1988, quoted from IARC, 1990). The nickel content of groundwater is normally below 20 μg/l (US EPA, 1986, quoted from IARC, 1990), and the levels appear to be similar in raw, treated and distributed municipal water. In US drinking water, 97% of all samples contained < 20 μg/l, while about 90% had < 10 μg/l (US National Research Council, 1975, quoted from IARC, 1990).


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The WHO has established a TDI (Tolerable daily intake) of 0.005 mg/kg bodyweight for the intake of nickel from drinking water. This results in a Guideline level for nickel in drinking water of 20 μg/litre (WHO, 1996). Ingestion of water is often taken as 2 litres/day for an adult. Assuming a concentration of 20 μg/l, the WHO (1996) Guideline level for nickel in drinking water would result in a daily intake of 40 μg/day. A report on the impact of nickel on a contaminated site in Ontario includes estimates for the daily intake of nickel from supermarket food for different age groups (Table A3-2 quoted from Ontario, 2002)

Table 4.1.1.3.D: Estimated daily intake of nickel from drinking water (Ontario, 2002)

Age group Age range (1) Metal concentration in drinking water (μg/l) (2)

Ingestion rate of drinking water (l/day)

Nickel Intake from drinking water (μg/day)

Infant 0 – 6 month 1.3 0.3 0.39

Toddler 7 months - < 5 years 1.3 0.6 0.78

Child 5 - < 12 years 1.3 0.8 1.0

Teen 13 - < 20 years 1.3 1.0 1.3

Adult 20 + years 1.3 1.5 2.0 1) Note there are differences in the age ranges for the different groups compared to Table 4.1.1.3.C. The concentration of nickel in drinking water is the actual concentration at the site under evaluation. This figure of 1.3 μg/l is at the bottom end of the range of figures reported for EU drinking water. Using a figure of 10 μg/l for mean nickel concentration in drinking water (cf. the figures for Germany shown above) the figures would rang from 3 to 15 μg/day. Intake of nickel from drinking water therefore represents very roughly 10% of the estimated intake from food. The figures shown above relate to concentrations of nickel in drinking water. The nickel present may be due to natural concentrations in the soil or to environmental or soil contamination (see section on Indirect exposure via the environment). The figures do not include release of nickel to drinking water from pipes or taps used to supply the drinking water or from kettles or other heating devices. Release of nickel from taps and pipes is described in chapter 4.1.1.3.2.3 and release of nickel from kettles and immersion heaters is described in section 4.1.1.3.2.2 of the risk assessment report for metallic nickel. See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”

4.1.1.3.3 Combined exposure to nickel from food and drinking water. The total amounts of nickel intake from dietary food and water have been estimated by Council of Europe (2001) and UK EGVM (2003). The UK EGVM have calculated the daily intake from food and water as 0.21 mg/day for the food intake (the 95.5th %ile of the UK EGVM, 2002, figures - see Table 4.1.1.3.B) and the water intake as 0.04 mg/day, calculated on the basis of a nickel concentration of 20 μg/l and a drinking water intake of 2 litres/day. This gives a total intake of 0.25 mg/day. The Council of Europe figure is 0.4 mg/day (Council of Europe, 2001). Estimates for children are very much more uncertain. The figures from Table 4.1.1.3.C suggest that the intake from food for the child age group is very similar to the adult (105 μg/day vs. 102 μg/day, for the UK 1997 TDS figures). The main difference in water intake is the slightly lower daily water intake estimated for children. The total intake in children is therefore expected to be similar to the estimated adult intake. The average weight for a 3 – 12 year old boy or girl is 28 kg and for an adult is 72 kg (US EPA, 1997). This would mean that the nickel intake from food and water expressed as mg/kg for a child would be roughly twice that of an adult.


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The Scientific Panel on Dietetic products, Nutrition and Allergies (NDA, 2005) was unable to establish a tolerable upper intake level for nickel due to the absence of adequate dose-response data. See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”

4.1.1.3.4 Exposure to nickel from smoking Nickel is present in tobacco and is present in tobacco smoke. Sunderman & Sunderman (1961) and Szadkowski et al. (1969) found average nickel contents of 2.2 and 2.3 μg/cigarette with a range of 1.1 – 3.1 (quoted from IARC, 1990). The same range is given in Sunderman (1986, quoted in US ATSDR, 1997). Pipe tobacco, cigars and snuff have been reported to contain nickel at levels of the same magnitude (2 – 3 μg/g tobacco) (National Research Council, 1975, quoted from IARC, 1990). Szadkowski et al. (1969) also showed that 10-20% of the nickel in cigarettes is released in mainstream smoke; most of the nickel was in the gaseous phase (quoted from IARC, 1990). The nickel content of mainstream smoke ranges from 0.005 to 0.08 μg/cigarette (Klus & Kuhn, 1982, quoted from IARC, 1990). Mainstream smoke produced by five samples each of five brands of Canadian cigarettes contained from 0.25 to 0.58 µg Ni (mean = 0.43 µg Ni) per cigarette. Levels of nickel present in side-stream smoke were similar, ranging from 0.25 to 0.53 µg (mean = 0.37 µg) per cigarette (Labstat Incorporated, 1991, quoted from Canada, 1994). Cigarette smoking may contribute rather more than ambient air to daily absorption of nickel by inhalation if about 0.2 μg Ni is inhaled from each cigarette. Smoking one pack per day could cause a daily absorption of about 1 μg Ni (Grandjean, 1984). US ATSDR (1997) gives a higher estimate of 2-12 µg Ni inhaled for each pack of cigarettes. See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”

4.1.1.4 Indirect exposure via the environment For data on local and regional indirect human exposure see the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”

4.1.2 Human health effects assessment Individual nickel compounds now under review under EU Regulation 793/93 are nickel metal, nickel sulphate, nickel chloride, nickel nitrate, and nickel carbonate. The results of studies carried out on these nickel compounds are described in the individual reports for each substance. This section includes a summary review of these studies. However, studies performed with other nickel compounds can also be relevant for the assessment of the five specific nickel substances, and this document includes these studies where considered relevant. Information on nickel and nickel compounds has been provided by industry in the context of EU Regulation 793/93. Much additional data on nickel and nickel compounds have been published. Much of these data have been reviewed in good quality reviews including UK HSE (1987), IARC (1990), IPCS (1991, 1996), US ATSDR (1997) and a Nordic Expert Group (Aitio, 1995). The effects of nickel on the skin have also been reviewed (Maibach & Menné, Eds. 1989). NiPERA in collaboration with Eurométaux have also produced a criteria document for nickel and nickel compounds for the European Commission (NiPERA 1996). Toxicology Excellence for Risk Assessment (TERA) has prepared a toxicological review of soluble nickel salts for Metal Finishing Association of Southern California Inc., US-EPA and Health Canada (TERA1999).


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These reviews plus (where considered relevant) the primary literature, have been used widely in this risk assessment report as it is felt that much of the essential data to establish possible hazards and risks of nickel for human health has already been adequately evaluated. This implies that not all the studies cited in this risk assessment report have been checked and studies have often been described in a summary form. When information is cited from reviews, the primary source is given with the notation “quoted from”. Whilst there is extensive data on the health effects of some of the substances under review, for others there is much more limited data. Where data is lacking for a particular endpoint, the effects have been evaluated using data from other relevant nickel compounds. It is assumed that the nickel cation is the determining factor for systemic toxicity. Ideally, the actual or bioavailable concentration, which is important for the systemic toxicity should form the basis for the effect assessment in both experimental animals and in humans. Nickel exists in different forms, some of which are more bioavailable than others. The bioavailability depends on various characteristics of the individual nickel compounds of which solubility is considered as being particularly important for the release of nickel ion and thus the systemic bioavailability of the nickel ion. Ideally, data on the solubility of the nickel compounds in biological fluids are preferable; however, no data are available regarding the solubility of any of the five prioritised nickel compounds in biological fluids. For the purpose of risk characterisation the water solubility will be used as a prediction of the solubility in biological fluids although realising that such a prediction might not be correct as some data indicate that compounds insoluble or slightly soluble in water might be more soluble in biological fluids. With respect to local effects, the nickel ion may not be responsible for the toxic effects in all situations. Therefore, use of data on other nickel compounds in evaluations of local effects of an individual nickel compound is considered on a case-by-case basis. When expressing results, the term “significant” is used only if the result is statistically significant at a p-level lower than 0.05.

4.1.2.1 Toxico-kinetics, metabolism and distribution

4.1.2.1.1 Absorption Nickel and its inorganic compounds can be absorbed in humans and in animals via the gastrointestinal tract as well as the respiratory passages. Percutaneous absorption is negligible quantitatively. The relative amounts of nickel absorbed are determined, not only by the quantities administered, but also by the physical and chemical characteristics of the nickel compound. Solubility is an important factor in all routes of absorption. Soluble nickel compounds dissociate readily in the aqueous environment of biological membranes, thus facilitating their transport as metal ions. Conversely, insoluble nickel compounds are relatively poorly absorbed. It is possible that other factors, such as host, nutritional and physiological status, or stage of development, also play a role, but these have not been studied. (IPCS 1991).

4.1.2.1.1.1 Inhalation Exposure to nickel compounds by inhalation may be in the form of aerosols (dusts) or attached to particles. Whether particles are inhaled depends on the particle size (aerodynamic diameter) and particles with aerodynamic diameters below 100 µm have the potential to be inhaled (inhalable fraction) and deposited in the respiratory tract. The deposition patterns in the respiratory tract also depend on the particle size as well as on the shape, density, hygroscopicity, and electric charge the respiratory dynamics of the individual (breathing pattern and thus, the respiratory minute volume). In humans, particles with aerodynamic diameters of 5-30 µm are mainly deposited in the upper airways, the nasopharyngeal region. Particles with aerodynamic diameters of 1-5 µm pass through the nasopharyngeal region and enter the tracheobronchial region where they are deposited. Particles with aerodynamic diameters in the lower end of this size fractions and smaller enter the alveolar region of the lungs where they are deposited. The fate and uptake of deposited particles depend on the clearance mechanism present in the different parts of the airways. In the nasopharyngeal region, most material will be cleared rapidly, either by expulsion (not the case for oral breathers) or by translocation to the gastrointestinal tract; a small fraction will be subjected to more prolonged retention, which can result in absorption from this region. From the tracheobronchial region, the largest part of the deposited material will be cleared to the pharynx mainly by mucociliary clearance and subsequently be swallowed into the gastrointestinal tract; only a small fraction will be retained and may result in absorption from this region. Higher absorption may occur from the pulmonary region than from the nasopharyngeal and tracheobronchial regions.


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Solids must dissolve into the fluids lining the airways before absorption can occur and the solubility of the nickel compound is thus an important factor for absorption. Absorption from the respiratory tract may therefore be limited by the solubility of nickel compounds in biological fluids. Consequently, soluble nickel compounds, such as nickel chloride, nickel sulphate, and nickel nitrate, are expected to be absorbed readily from the pulmonary region, whereas poorly soluble nickel compounds, such as nickel metal, nickel oxide and nickel subsulphide, are expected to be retained in the lung tissue and accumulate thereby having a long half-life. The data on absorption of nickel in particulate form are limited and generally, the absorbed fraction of inhaled nickel has not been quantified. Furthermore, there are no data available on nickel compounds to estimate the part that is cleared to the gastrointestinal tract either by translocation from the nasopharyngeal region or by mucociliary clearance from the tracheobronchial region. Once translocated into the gastrointestinal tract, absorption will be in accordance with oral absorption kinetics. Below, the available data regarding the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant for the conclusion on the absorbed fraction of nickel following inhalation of the five prioritised nickel compounds. No studies providing specific information about the absorbed fraction of nickel following inhalation or intratracheal instillation of nickel sulphate have been located. However, studies in experimental animals provide some information in relation to absorption of nickel sulphate. No human data are available. An inhalation study by Benson et al. (1995) showed that clearance of nickel sulphate (nickel sulphate hexahydrate aerosol, mean mass median aerodynamic diameters (MMADs) ranging from 2.0 to 2.4 µm) from the lungs of rats and mice is extensive with 99% of inhaled nickel sulphate being cleared with a half-time of 2 to 3 days in rats and with 80-90% being cleared with a half-time of less than one day in mice. Repeated inhalation of nickel sulphate hexahydrate aerosol did not result in accumulation of nickel in the lungs of either rats or mice and did not affect the clearance of 63NiSO4 inhaled after either 2 or 6 months of nickel sulphate hexahydrate exposure. No nickel sulphate particles were observed histologically in the lungs of nickel sulphate exposed animals. Nickel levels in blood and urine were not measured, so this study does not provide evidence for whether clearance was via absorption from the lungs into the blood stream or by clearance from the respiratory tract via the mucociliary mechanisms. An intratracheal instillation study by Medinsky et al. (1987) showed that nickel sulphate (administered as a solution in isotonic saline) is rapidly absorbed from the lungs into the blood in a dose dependent manner as the urinary excretion of nickel increased with increasing dose levels (50% at the two lower dose levels and 80% at the high dose level). Inhalation studies in rats (Benson et al. 1988, NTP 1996a) indicate that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to around 0.8 mg Ni/m3) in the inhaled air as well as with duration of exposure. A third study (Dunnick et al. 1989) found similar concentrations of nickel in the lungs of rats and mice after 4, 9, and 13 weeks of inhalation to nickel sulphate (0.02 to 0.4 mg Ni/m3). Of nickel remaining in the body after 96 hours following a single dose of nickel sulphate administered by intratracheal administration, over 50% was in the lungs (Medinsky et al. 1987). No studies providing specific information about the absorbed fraction of nickel following inhalation or intratracheal instillation of nickel chloride have been located. Three studies in experimental animals indicate that absorption from the respiratory tract does occur as low retention of nickel in the lungs and extensive excretion in the urine have been observed following intratracheal instillation of nickel chloride in rats. The absorption from the respiratory tract might be extensive in rats as indicated by a urinary elimination of 96.5% of the initial body burden at day 21 post-instillation in the study by Carvalho & Ziemer (1982), an average of 70% of the instilled nickel being excreted by the third day after instillation in the study by English et al. (1981), and 90% of the instilled nickel being excreted, mainly in the urine (75%) by 72 hours after instillation in the study by Clary (1975). However, the experimental design in these studies could not distinguish between nickel absorbed from the lungs and nickel cleared from the lungs, swallowed, and absorbed from the gastrointestinal tract. No human data are available. For metallic nickel exposure of rats to nickel powder at 1, 4 and 8 mg/m3 for a period of 13 weeks resulted in accumulation of nickel particles in the lung and increased nickel blood levels (WIL Research Laboratories 2003). From this study and using kinetic data on clearance rates an absorbed fraction of approximately 6 % as an upper estimate of the inhaled fraction was calculated by the rapporteur. No studies regarding absorption and retention of nickel in humans or experimental animals following inhalation or intratracheal instillation of nickel nitrate or nickel carbonate have been located.


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According to TERA (1999), several human studies indicate that exposure of electroplating workers to soluble nickel salts results in nickel absorption. In studies on electroplating workers (workroom air concentrations ranging from 0.03-0.16 mg Ni/m3), the urinary and plasma nickel concentrations were higher in post-shift samples than in pre-shift ones, and a close positive correlation was found between the air nickel concentrations and the urine and plasma nickel concentrations (Tola et al. 1979, Bernacki et al. 1980, Ghezzi et al. 1989). When the nickel concentration in electroplating workers’ urine was measured before, in the middle, and at the end of the work shift, urinary nickel concentration increased over the course of a regular working day (Bernacki et al. 1980). Workers in nickel roasting/smelting are exposed to less-soluble nickel compounds (such as nickel subsulphide and nickel oxide). These compounds are also absorbed after inhalation as evidenced by elevated nickel concentrations in the plasma and urine of exposed workers. These less-soluble compounds were absorbed less efficiently than the soluble nickel salts, since workers exposed to nickel subsulphide and nickel oxide had lower plasma and urinary nickel concentrations than workers exposed to lower concentrations of soluble nickel. Higher nickel concentrations in nasal mucosa resulted from exposure to nickel subsulphide and nickel oxide than from exposure to soluble nickel, indicating that the lower plasma levels result from reduced clearance from the lung, rather than from reduced deposition. (Torjussen & Anderson 1979 – quoted from TERA 1999). No other quantitative human data on the amount and rate of absorption are available (TERA 1999). In a study by Benson et al. (1995), experimental animals (rats and mice) were exposed (whole-body, 6 hours/day, 5 days/week for up to 6 months) to nickel oxide by inhalation (aerosol, mean mass median aerodynamic diameters (MMADs) ranging from 2.1 to 2.3 µm, concentrations of 0.62 or 2.5 mg NiO/m3 for rats and of 1.25 or 5.0 mg NiO/m3 for mice). Nickel accumulated in the lungs of both rats and mice, but to a greater extent in lungs of rats. During 4 months after the end of exposure, some clearance of the accumulated nickel burden occurred from the lungs of rats and mice exposed to the lower, but not to the higher nickel oxide exposure concentrations. When Syrian golden hamsters were exposed to nickel oxide (not specified) particles (mass mean aerodynamic diameters (MMADs) of 1.0-2.5 µm) by inhalation for 2 days (7 hours/day) at a concentration of 10-290 mg/m3, absorption seemed to be negligible. At 45 days after exposure, approximately 50% of the total amount inhaled still remained in the lungs. (Wehner & Craig 1972 – quoted from IPCS 1991, US ATSDR 1995). Benson et al. have also evaluated the absorption and clearance of inhaled nickel subsulphide in experimental animals (Benson et al. 1994 – quoted from TERA 1999). They found that inhaled nickel subsulphide had a relatively rapid clearance half-time of 4 days, which, according to the citation in TERA (1999) in interpreted as although nickel subsulphide is nearly insoluble in water, it is dissolved rapidly in the lung, and behaves like a relatively soluble particle. (TERA 1999). When nickel subsulphide (63Ni3S2) was administered intratracheally to mice (11.7 µg/animal), the total lung burden at 4 hours after instillation was 85% of the administered dose. Thirty-five days after instillation, 10% of the administered dose was still retained by the lung. (Valentine & Fisher 1984 – quoted from IPCS 1991).

4.1.2.1.1.1.1 Discussion and conclusion, absorption following inhalation The data on absorption of nickel in particulate form are limited and based on the available data for various nickel compounds and from a single inhalation study with metallic nickel exposure. Furthermore, there are no data available on nickel compounds to estimate the part that is cleared to the gastrointestinal tract either by translocation from the nasopharyngeal region or by mucociliary clearance from the tracheobronchial region. Once translocated into the gastrointestinal tract, absorption will be in accordance with oral absorption kinetics. The deposition pattern of dust particles in the respiratory tract is related to the particle size (aerodynamic diameter) as well as to other characteristics of the particles (shape, density, hygroscopicity, and electric charge) and the respiratory dynamics of the individual. Therefore, precise deposition patterns for dusts cannot be predicted. As a rough guide, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Particles with aerodynamic diameters of above 1-5 µm have the greatest probability of settling in the nasopharyngeal region (non-respirable particles) whereas particles with aerodynamic diameters below 1-5 µm are most likely to settle in the tracheobronchial or pulmonary regions (respirable particles). Deposited non-respirable particles will predominantly be cleared from the respiratory tract by mucociliary action and translocated into the gastrointestinal tract whereas deposited respirable particles may either be absorbed from the lung or remain deposited in the lung tissues depending on the solubility in biological fluids of the nickel compound. In order to evaluate whether clearance of nickel particulate from the respiratory tract might be due to absorption, deposition or mucociliary action, one essential characteristic is thus the particle size. For the purpose of risk characterisation of the five prioritised nickel compounds, it is assumed that nickel particulates with aerodynamic diameters above 5 µm predominantly will be cleared from the respiratory tract by mucociliary


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action and subsequently be translocated into the gastrointestinal tract and absorbed. For nickel particulates with aerodynamic diameters below 5 µm, it is assumed that clearance from the respiratory tract is due to either absorption from the lung or deposition in the lung tissues. Solids must dissolve into the fluids lining the airways before absorption can occur and the solubility of the nickel compound is thus an important factor for absorption. Absorption from the respiratory tract may therefore be limited by the solubility in biological fluids of the nickel compound. No data are available regarding the solubility of the five prioritised nickel compounds in biological fluids. For the purpose of risk characterisation of these five compounds, the water solubility is used as a prediction of the solubility in biological fluids. It should be noted that such a prediction might not be correct as data on nickel subsulphide indicate, according to TERA (1999), that this compound, which is nearly insoluble in water, is dissolved rapidly in the lung, and thus behaves like a relatively soluble particle; however, based on the citation in TERA (1999) it is not clear whether clearance of inhaled nickel subsulphide was due to absorption, deposition or by mucociliary clearance. As the absorption of nickel from the respiratory tract into the blood stream depends on the solubility of the nickel compound inhaled, different conclusions on the absorbed fraction of nickel following inhalation of soluble or insoluble and slightly soluble nickel compounds for the purpose of risk characterisation are taken. Most of the studies in experimental animals of soluble nickel compounds (nickel sulphate and nickel chloride) have used intratracheal instillation of the compound in solution. According to TERA (1999), the absorption kinetics following inhalation exposure would be expected to be similar to the kinetics of intratracheally instilled nickel. For the purpose of risk characterisation of the five prioritised nickel compounds, it is assumed that the absorbed fraction of inhaled nickel is comparable to that following intratracheal instillation. It should be born in mind that this assumption may not be correct as the solubility of a given compound may depend on the solvent used for the intratracheal instillation. Soluble nickel compounds, such as nickel sulphate, nickel chloride, and nickel nitrate, are expected to be absorbed from the respiratory tract following inhalation exposure. This is supported by data from one study of nickel sulphate in rats (Medinsky et al. 1987) using intratracheal instillation of nickel sulphate (as a solution in saline), which showed that 50 to 80% of a dose (dependent on the dose) of nickel sulphate can be absorbed from the respiratory tract. Studies in rats using intratracheal instillation of nickel chloride (Carvalho & Ziemer 1982, English et al. 1981, Clary 1975) showed that up to approximately 97% of a dose of nickel chloride can be absorbed from the respiratory tract. By assuming that the absorption of nickel following inhalation exposure to nickel chloride is similar to absorption following intratracheal instillation, the absorption of nickel from the respiratory tract following inhalation of nickel chloride might be as high as about 97%. Furthermore, the inhalation study on nickel sulphate (Benson et al. 1995) showed that clearance of nickel sulphate from the lungs of rats and mice is rapid and extensive (up to 99% with a half-time of 2-3 days in rats; 80 to 90% with a half-time of less than one day in mice). By assuming that the clearance of nickel sulphate particles (respirable particles, MMADs ranging from 2.0 to 2.4 µm) from the lungs in the inhalation study (Benson et al. 1995) is due to absorption rather than to deposition or by mucociliary action, the absorption of nickel from the lungs following inhalation of nickel sulphate might be as high as up to 99% (at concentrations up to 0.11 mg Ni/m3 in rats and up to 0.22 mg Ni/m3 in mice). Other inhalation studies in rats (Benson et al. 1988, NTP 1996a) indicate that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to about 0.8 mg Ni/m3) in the inhaled air as well as with duration of exposure. No data are available regarding the absorption of nickel following exposure by inhalation to nickel nitrate. As nickel nitrate, like nickel sulphate and nickel chloride, is very soluble in water, it is considered that the absorption of nickel following inhalation of nickel nitrate is comparable to that following inhalation of nickel sulphate and nickel chloride. In conclusion, the available data on nickel sulphate and nickel chloride indicate that the absorption of nickel following inhalation of the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) might be as high as up to 97-99%; it should be noted that the fraction absorbed apparently depends on the concentration of the nickel compound in the inhaled air as well as on the duration of exposure. For the purpose of risk characterisation, a value of 100% is taken forward to the risk characterisation for the absorbed fraction of nickel from the respiratory tract following exposure by inhalation of the prioritised soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) for particulates with an aerodynamic diameter below 5 µm (respirable fraction). For nickel particulates with aerodynamic diameters above 5 µm (non-respirable fraction), the absorption of nickel from the respiratory tract is considered to be negligible as these particles predominantly will be cleared from the respiratory tract by mucociliary action and translocated into the gastrointestinal tract and absorbed. Hence, for the non-respirable fraction, 100% clearance from the respiratory tract by mucociliary action and translocation into the gastrointestinal tract is assumed and the oral absorption figures can be taken. Insoluble and slightly soluble nickel compounds, such as nickel metal, nickel carbonate, nickel oxides and nickel sulphides, are expected to be absorbed from the respiratory tract following inhalation exposure to a more limited extent compared to the soluble compounds.


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Depending on the particle size, insoluble and slightly soluble particles are expected to be retained in different regions of the airways and to be removed to some extent by the mucociliary action and translocated into the gastrointestinal tract. It should be noted that data on nickel subsulphide indicate, according to TERA (1999), that this compound, which is nearly insoluble in water, is dissolved rapidly in the lung, and thus behaves like a relatively soluble particle. Also data on workers in nickel roasting/smelting, which are exposed to less-soluble nickel compounds (such as nickel subsulphide and nickel oxide) indicate, according to TERA (1999), that these compounds are absorbed after inhalation as evidenced by elevated nickel concentrations in the plasma and urine of exposed workers. However, based on the citations in TERA (1999) it is not clear whether clearance of inhaled nickel subsulphide or nickel oxide was due to absorption or by mucociliary action and subsequent absorption from the gastrointestinal tract. Data from one study of nickel oxide in Syrian hamsters (Wehner & Craig 1972 – quoted from IPCS 1991, US ATSDR 1995) indicate that absorption seems to be negligible after inhalation and that approximately 50% of the total amount inhaled still remained in the lungs at 45 days after exposure. Another study of nickel oxide (Benson et al. 1995) showed that nickel accumulated in the lungs of rats and mice following repeated inhalation. Furthermore, one study of nickel subsulphide in mice (Valentine & Fisher 1984 – quoted from IPCS 1991) using intratracheal instillation showed that 35 days after instillation, 10% of the administered dose was still retained by the lung. No data are available regarding the absorption of nickel following exposure by inhalation to nickel carbonate. For metallic nickel exposure of rats to nickel powder at 1, 4 and 8 mg/m3 for a period of 13 weeks resulted in accumulation of nickel particles in the lung and increased nickel blood levels (WIL Research Laboratories 2003). Increased nickel blood levels for up to 90 day after exposure has stopped indicated that the accumulated nickel particles continuously were dissolved and absorbed into the blood. From this study and using kinetic data on clearance rates an absorbed fraction of approximately 6 % (as an upper estimate) of the inhaled fraction was calculated by the rapporteur. In conclusion, the available data on nickel oxide indicate that the absorption of nickel from the respiratory tract following inhalation is very limited. However, data on metallic nickel indicate an absorbed fraction of up to approximately 6% after inhalation (i.e. both absorption from respiratory tract and the gastrointestinal tract). . For the purpose of risk characterisation, an overall absorbed fraction of 6% is used in relation to inhalation of metallic nickel.

4.1.2.1.1.2 Oral Absorption of nickel from the gastrointestinal tract occurs after ingestion of various nickel compounds in food, beverages, or drinking water. In the occupational environment, an appreciable amount of nickel dust may be swallowed via the mucociliary clearance mechanisms. The rate of nickel absorption from the gastrointestinal tract is dependent on the chemical form and thus, the solubility. Furthermore, absorption may be suppressed by binding or chelating substances, competitive inhibitors, or redox reagents. On the other hand absorption is often enhanced by substances that increase pH, solubility, or oxidation, or by chelating agents that are actively absorbed. While soluble nickel compounds are better absorbed than relatively insoluble ones, the contribution of the poorly soluble compounds to the total nickel absorption may be more significant, since they are more soluble in the acidic gastric fluids. (IPCS 1991). Below, the available data regarding the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant for the conclusion on absorption of nickel following oral administration. Absorption of nickel following oral ingestion of nickel sulphate has been evaluated in a number of human studies; however, it is impossible to give a general estimate for the fraction of nickel absorbed after oral administration of nickel sulphate. The available studies indicate that the extent of absorption is influenced by whether nickel sulphate is administered in drinking water, to fasting subjects, or together with food. One study in human volunteers (Sunderman et al. 1989) showed that 27% of a dose was absorbed when nickel sulphate was administered in drinking water to fasting subjects compared with around 1% when administered together with food to fasting subjects. Another study (Christensen & Lagesson 1981 – quoted from IARC 1990) supports an absorption of about 1 to 5% when nickel sulphate was administered in lactose. A higher absorption fraction of 4 to 20% was observed after ingestion of nickel sulphate during fasting (Cronin et al. 1980 – quoted from IARC 1990). In addition, absorption of nickel was apparently slower when administered together with food compared with water. One study in rats (Ishimatsu et al. 1995) showed an absorption of 11% when nickel sulphate was administered in a 5% starch saline solution.


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Absorption of nickel following oral ingestion of nickel chloride has been evaluated in a few studies in experimental animals; no human data have been located. When non-fasting rats were dosed by gavage with nickel chloride, 3 to 6% of the nickel was absorbed regardless of the administered dose (Ho & Furst 1973 - quoted from TERA 1999 and IPCS 1991). Another study in rats (Ishimatsu et al. 1995) showed an absorption of 9.8% when nickel chloride was administered in a 5% starch saline solution. In mice, the intestinal absorption was estimated to be 1.7 to 10% when nickel chloride was administered orally by gastric intubation (Nielsen et al. 1993). Absorption of nickel following oral ingestion of nickel nitrate has been evaluated in one study in rats (Ishimatsu et al. 1995), which showed an absorption of 34% when nickel nitrate was administered in a 5% starch saline solution. No human data have been located. No studies providing specific information about the absorbed fraction of nickel in humans or experimental animals following oral administration of nickel carbonate have been located. However, there is evidence that nickel carbonate is absorbed after oral administration. Metabolic data from nickel-balance studies carried out by Phatak & Padwardhan (1950 - quoted from IPCS 1991) demonstrated that appreciable quantities of nickel from the nickel-containing diets were retained and tissue accumulation was significant. According to the authors, this was attributed to ready solubility of the compound in the stomach and the easier absorption from the intestine. Another study in calves (O’Dell et al. 1971 – quoted from IPCS 1991) showed pronounced increases in nickel levels in the pancreas, testes, and bone at the highest dietary level (1000 mg/kg bw/day). No specific studies regarding absorption and retention of nickel following oral administration of nickel metal have been located neither in humans nor in experimental animals. As water-insoluble compounds may be more soluble in the acidic gastric fluids, absorption from the gastrointestinal tract may take place. This is supported by one study in rats (Hayman et al. 1984 – quoted from NiPERA 1996) showing peak nickel concentrations in blood about 6 hours following dosing with insoluble Raney nickel suspended in polyethylene glycol 200. Another study in rats (Ishimatsu et al. 1995) showed an absorption of 0.09% when nickel metal was administered in a 5% starch saline solution. Nielsen et al. (1999) have examined the influence of fasting and food intake on the absorption and retention of nickel added to drinking water. Eight non-allergic male volunteers received nickel (compound not specified) in drinking water (12 µg Ni/kg bw) and, at different time intervals, a standardised 1400 kJ portion of scrambled eggs. Before each nickel intake, the volunteers fasted for 12 hours (overnight). When nickel was ingested in water 30 minutes or one hour prior to the meal, peak nickel concentrations in serum occurred one hour after the water intake, and the peak was 13-fold higher than the one seen one hour after simultaneous intake of nickel-containing water and scrambled eggs. In the latter case, a smaller, delayed peak occurred 3 hours after the meal. Within 3 days, the amount of nickel excreted in the urine corresponded to 2.5% of the nickel ingested when it was mixed into the scrambled eggs. Increasing amounts were excreted as the interval between the water and the meal increased, with 25.8% of the administered dose being excreted when the eggs were served 4 hours prior to the nickel-containing drinking water. In a second experiment (Nielsen et al. 1999), a stable nickel isotope (61Ni, compound not specified) was administered in the drinking water (12 µg Ni/kg bw) to 20 nickel-sensitised women and 20 age-matched controls, both groups having vesicular hand eczema. The course of nickel absorption and excretion in the allergic groups did not differ and was similar to the pattern seen in the first study, although the absorption in the women was less (nickel-sensitised: 10.8%; control: 11.2% - at 72 hours after administration of the dose). Nickel balance studies have been performed on 10 male volunteers (aged 17 years), who ingested a mean of 289 ± 23 mg Ni/day (range 251-309 mg, compound not specified). Faecal elimination of nickel averaged around 89% (258 ± 23 mg Ni/day). (Nodiya 1972 – quoted from IPCS 1991). Diamond et al. (1998) have used a biokinetic model to estimate nickel absorption, based on experimental data from various studies. The results showed that estimated nickel absorption ranged from 12-27% of the dose when nickel was ingested after a fast, to 1-6% when nickel was administered either in food, in water, or in a capsule during (or in close proximity to) a meal. Ishimatsu et al. (1995) administered 8 different nickel compounds (10 mg Ni) orally to male Wistar rats by gavage in 5% starch saline solution. The nickel compounds used were nickel metal, nickel oxide (green), nickel oxide (black), nickel subsulphide, nickel sulphide, nickel sulphate, nickel chloride, and nickel nitrate. Nickel oxides and nickel metal were considered to be insoluble with a solubility in saline and in distilled water of less than 5 mg/l. The solubility of nickel sulphide was about 2000 mg/l and of nickel subsulphide about 500 mg/l. The solubility of these compounds in saline solution was greater than in distilled water. The absorbed fraction of nickel at 24 hours after administration was 0.01% for nickel oxide (green), 0.04% for nickel oxide (black), 0.09% for nickel metal, 0.47% for nickel subsulphide, 2.12% for nickel sulphide, 9.8% for nickel chloride,


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11.12% for nickel sulphate, and 33.8% for nickel nitrate; the estimated absorbed fraction increased with the increase of the solubility.

4.1.2.1.1.2.1 Discussion and conclusion, absorption following oral administration Based on the available studies, it is impossible to give a general estimate for the fraction of nickel absorbed after oral administration of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal). As the absorption of nickel from the gastrointestinal tract into the blood stream depends on the solubility of the nickel compound ingested, the absorbed fraction of nickel following ingestion of soluble or insoluble and slightly soluble nickel compounds is expected to be different. However, some insoluble and slightly soluble nickel compounds may be more soluble in the acidic gastric fluid than in water thus facilitating the absorption from the gastrointestinal tract; however, no data are available elucidating this aspect. The extent of absorption from the gastrointestinal tract is influenced by whether the nickel compound is administered in drinking water, to fasting subjects, or together with food. For the purpose of risk characterisation, different conclusions on the absorbed fraction of nickel for fasting and non-fasting individuals are drawn. Soluble nickel compounds, such as nickel sulphate, nickel chloride, and nickel nitrate, are expected to be absorbed from the gastrointestinal tract following oral intake. Absorption of nickel following oral ingestion of nickel sulphate has been evaluated in a number of human studies; no human data are available for the other prioritised soluble compounds (nickel chloride and nickel nitrate). One study (Sunderman et al. 1989) has shown that absorption of nickel can be as high as 27% when nickel sulphate was administered in drinking water to fasting individuals compared with about 1%, when administered together with food to fasting individuals. Another human study on volunteers (Nielsen et al. 1999), in which the nickel compound administered was not specified, showed similar results with 25.8% of the administered dose being excreted in the urine following administration of nickel in drinking water to fasting individuals compared with 2.5% when nickel was mixed into a meal. Based on experimental data from various human studies, Diamond et al. (1998) used a biokinetic model to estimate nickel absorption; the results showed that estimated nickel absorption ranged from 12-27% of the dose when nickel was ingested after a fast, to 1-6% when nickel was administered either in food, in water, or in a capsule during (or in close proximity to) a meal. One study in rats (Ishimatsu et al. 1995) showed an absorption of 11% for nickel sulphate, of 9.8% for nickel chloride, and of 34% for nickel nitrate when the compound was administered in a 5% starch saline solution. Other studies of nickel chloride in experimental animals have shown an absorption of 3-6% in rats (non-fasting, gavage in 0.1N hydrochloric acid) and of 1.7-10% in mice (gavage). Insoluble and slightly soluble nickel compounds, such as nickel metal, nickel carbonate, nickel oxides and nickel sulphides, are expected to be absorbed from the gastrointestinal tract following oral exposure to a limited extent. However, some insoluble and slightly soluble nickel compounds may be more soluble in the acidic gastric fluid than in water thus facilitating absorption from the gastrointestinal tract. No human data are available regarding absorption of insoluble and slightly soluble nickel compounds. One study in rats (Phatak & Padwardhan 1950 - quoted from IPCS 1991) has demonstrated that appreciable quantities of nickel from diets containing nickel carbonate were retained and tissue accumulation was significant; according to the authors, this was attributed to ready solubility of the compound in the stomach and the easier absorption from the intestine. Another study in rats (Hayman et al. 1984 – quoted from NiPERA 1996) has shown peak nickel concentrations in blood about 6 hours following dosing with insoluble Raney nickel suspended in polyethylene glycol 200. In rats (Ishimatsu et al. 1995), an absorption of 0.09% was observed when nickel metal was administered in a 5% starch saline solution; the absorbed fraction was 0.01% for nickel oxide (green), 0.04% for nickel oxide (black), 0.47% for nickel subsulphide, and 2.12% for nickel sulphide. In conclusion, the available data on the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) indicate that the absorption of nickel following administration in the drinking water to fasting individuals might be as high as up to about 25-27% and about 1-6% when administered to non-fasting individuals and/or together with (or in close proximity to) a meal. The available data on insoluble and slightly soluble nickel compounds (nickel metal, nickel carbonate, nickel oxides and nickel sulphides) indicate that absorption of nickel from the gastrointestinal tract may occur following oral exposure; however, the data are too limited for an evaluation of the absorbed fraction of nickel. For the purpose of risk characterisation, a value of 30% is taken forward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel sulphate, nickel chloride and nickel nitrate in the exposure scenarios where fasting individuals might be exposed to these nickel compounds based on the data for soluble nickel compounds. The same figure is also used for nickel carbonate, since there is evidence of oral absorption of this compound. In all the other exposure scenarios, a value of 5% is used for the absorbed fraction of nickel from the gastrointestinal tract.


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Based on the study in rats by Ishimatsu et al. (1995), which indicates, by direct comparisons of the absorbed fractions, a 100-fold lower absorption of nickel following administration of nickel metal than for soluble nickel compounds, values of 0.05% and 0.3% are taken forward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel metal for non-fasting and for fasting individuals, respectively.

4.1.2.1.1.3 Dermal Dermal absorption is a complex process. The extent to which a compound is absorbed across the skin is influenced by many factors, e.g., physico-chemical properties of the compound, vehicle, occlusion, concentration, exposure pattern, skin site of the body, etc. In order to cross the skin, a substance must first penetrate into the dead stratum corneum and may subsequently reach the viable epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to penetration by highly lipophilic compounds. When considering dermal absorption, a distinction should therefore be made between penetration of a compound into skin and percutaneous transport, where the compound is transported through the skin and into the blood stream. Studies in humans and experimental animals indicate that nickel can penetrate the skin following dermal contact to various nickel compounds. Below, the available data regarding the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant for the conclusion on absorption of nickel following dermal contact. In a recent human in vivo study of nickel sulphate (Hostýnek et al. 2001a), a large part of the administered dose remained on the surface of the skin after 24 hours or, according to the authors, was adsorbed in the uppermost layers of the stratum corneum. In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum from cadaver leg skin), about 97% of the dose was recovered in the donor solution after 96 hours, with about 1% in the receptor fluid and 0.6% in the stratum corneum. Limited data obtained from other in vitro studies using human skin (Fullerton et al. 1986, Samitz & Katz 1976 – quoted from IPCS 1991) indicate that absorption following dermal contact may have a significant lag time. Studies in experimental animals indicate that nickel can be absorbed through the skin of rats (Mathur et al. 1977 – quoted from IPCS 1991) and guinea-pigs and rabbits (Norgaard 1957 – quoted from IPCS 1991). Another study in guinea pigs (Lindberg et al. 1989 – quoted from NiPERA 1996) showed that nickel only penetrated into the stratum corneum. No human in vivo studies providing information about the absorbed fraction of nickel following dermal contact to nickel chloride have been located. One study in guinea pigs (Lloyd 1980 - quoted from IPCS 1991) indicate that nickel chloride can be absorbed following dermal contact, but only to a very limited extent (indicated by low levels in blood plasma and in urine up to 24 hours of exposure). In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum from cadaver leg skin), 98.7% of the dose was recovered in the donor solution after 96 hours, with about 0.7% in the receptor fluid and 0.2% in the stratum corneum. Limited data obtained from in vitro studies using human skin (Fullerton et al. 1986, Spruit et al. 1965 - quoted from IPCS 1991) indicate that absorption following dermal contact may have a significant lag time; the study by Spruit et al. (1965 - quoted from IPCS 1991) also showed that nickel was bound by the dermis. No in vivo studies providing specific information about the absorbed fraction of nickel in humans or experimental animals following dermal contact to nickel nitrate have been located. In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum from cadaver leg skin), about 82.5% of the dose was recovered in the donor solution after 96 hours, with about 0.5% in the receptor fluid and 1% in the stratum corneum. No in vivo or in vitro studies providing information about the absorbed fraction of nickel in humans or experimental animals following dermal contact to nickel carbonate have been located. In a recent human in vivo study of nickel metal as powder (Hostýnek et al. 2001b), a large part of the administered dose remained on the surface of the skin after 96 hours with a minor part (about 0.2%) having penetrated into the stratum corneum. No studies in experimental animals have been located. Nickel can be released from nickel alloys by solutions of artificial sweat (Katz et al. 1975 – quoted from NiPERA 1996). It has also been shown that artificial sweat is capable of releasing nickel ions from a pure nickel surface (Hemingway & Molokhia 1987 – quoted from NiPERA 1996). The process where nickel metal gives rise to nickel ion is to a large extent described in the section on General exposure considerations concerning the mechanism for corrosion.


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In a study in humans employing a sensitive x-ray micro-analysis detection system, it was impossible to detect stratum corneum penetration of nickel (soluble compound, not specified) under patch test despite the occurrence of clinical allergic reactions. The authors concluded that biologically significant amounts of nickel were penetrating rapidly, although identifiable physical penetration was minimal. (Kalimo et al. 1985 – quoted from NiPERA 1996). Percutaneous absorption of nickel is of negligible significance, quantitatively, but is clinically important in the pathogenesis of contact dermatitis (IPCS 1991). The stratum corneum has a considerable capacity to trap nickel and absorption is likely to be mainly limited to the sweat ducts and hair follicles (Wells et al. 1991 – quoted from NiPERA 1996). Kolpakov (1963 - quoted from IPCS 1991), using skin from humans, found that the Malphigian layer of the epidermis, the dermis, and the hypodermis were readily permeable to nickel. In a study performed on guinea-pigs, it was found that the radioactive nickel accumulated within one hour in the highly keratinised areas, the stratum corneum, and hair shafts, showing a route of entry via the hair follicles and sweat glands (Lloyd 1980 - quoted from IPCS 1991).

4.1.2.1.1.3.1 Discussion and conclusion, absorption following dermal contact The data on dermal uptake of nickel following dermal contact to nickel compounds are limited and based on the available studies, it is impossible to give a general estimate for the fraction of nickel absorbed after dermal contact to the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal). Dermal absorption is a complex process and the extent to which a compound is absorbed across the skin is influenced by many factors, e.g., physico-chemical properties of the compound, vehicle, occlusion, concentration, exposure pattern, skin site of the body, etc. Furthermore, skin injury or increased water content of the stratum corneum may significantly increase absorption through the skin as well as some solvents and detergents also may increase percutaneous absorption. When considering dermal absorption, it should also be born in mind that a distinction should be made between penetration of nickel into the skin and percutaneous transport (absorption), where nickel is transported across the skin and into the blood stream. Recent human in vivo studies of nickel sulphate and nickel metal (Hostýnek et al. 2001a,b) has shown that a large part of the administered dose remained on the surface of the skin after 24 hours or had penetrated into the stratum corneum. No human in vivo studies have been located regarding the other prioritised nickel compounds (nickel chloride, nickel nitrate, and nickel carbonate). In vitro studies using human skin support the findings in the human in vivo studies as most of the dose remained in the donor solution and only minor amounts were found in the receptor fluid; the in vitro studies also indicate that absorption following dermal contact may have a significant lag time. Some in vivo studies (Mathur et al. 1977 – quoted from IPCS 1991, Norgaard 1957 – quoted from IPCS 1991, Lloyd 1980 - quoted from IPCS 1991) in experimental animals (rats, guinea pigs and rabbits) indicate that nickel can be absorbed through the skin following dermal contact. The data indicate that experimental animals absorb nickel to a greater extent following dermal contact than humans do, which is in accordance with the general understanding that the permeability of human skin is often lower than that of animal skin. In conclusion, the available data indicate that absorption of nickel following dermal contact to various nickel compounds can take place, but to a limited extent with a large part of the applied dose remaining on the skin surface or in the stratum corneum. The data are too limited for an evaluation of the absorbed fraction of nickel following dermal contact to the five prioritised nickel compounds. The in vitro study of soluble nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, and nickel acetate) using human skin (Tanojo et al. 2001) showed about 98% of the dose remained in the donor solution, whereas 1% or less was found in the receptor fluid and less than 1% was retained in the stratum corneum. According to the revised TGD, the amount absorbed into the skin, but not passed into the receptor fluid, should also be included in the estimate of dermal absorption. For the purpose of risk characterisation, a value of 2% is taken forward to the risk characterisation for the absorbed fraction of nickel following dermal contact to nickel sulphate, nickel chloride, nickel nitrate, and nickel carbonate. It is likely that this figure is an overestimate for nickel carbonate, as the compound is much less water-soluble than other three nickel salts under evaluation. For nickel metal, a value of 0.2% is taken forward to the risk characterisation based on the data from the in vivo study in humans (Hostýnek et al. 2001).

4.1.2.1.1.4 Other routes In humans, absorption of nickel may occur from a variety of implanted nickel-containing medications, metallic devices, and prostheses, which release nickel by leaching, i.e. absorption via iatrogenic exposures. This consideration is supported by some studies in experimental animals. For further details, the reader is referred to the risk assessment report for nickel metal.


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Other routes of exposure than inhalation, oral intake and dermal contact are not considered as being relevant for the risk characterisation of the other prioritised nickel compounds (nickel sulphate, nickel nitrate, nickel carbonate, nickel chloride).

4.1.2.1.2 Distribution and elimination

4.1.2.1.2.1 Transport Upon entry into the bloodstream, the nickel ion is bound to specific serum components and rapidly distributed throughout the body. In serum, nickel is present in three forms: 1) as a complex associated with albumin; 2) as a complex associated with a nickel-metalloprotein (nickeloplasmin); and 3) as ultrafiltrable material. The most important nickel-binding protein in serum is albumin, which has a high binding capacity for nickel in most species tested, including humans, rats, rabbits, and cows, while the nickel-binding capacity of albumin from dogs and pigs is much lower. The high-molecular weight nickeloplasmin serum protein has been identified as a macroglobulin and it has been shown that purified nickeloplasmin is an α-2-macroglobulin in rabbit serum and a 9.5S α-glycoprotein in human serum. The predominant low molecular weight form of nickel in serum, including human serum, is a complex of nickel with the amino acid L-histidine, which play an important role in extracellular transport and in the elimination of nickel in urine. In human serum, 40% of the nickel is present as ultrafiltrable material, 34% is associated with albumin, and 26% is associated with nickeloplasmin. (TERA 1999, IPCS 1991). In vitro, L-histidine had a greater affinity for nickel than serum albumin and nickel binding to human albumin became evident only when no more L-histidine was available. In vivo, the concentration of albumin was much higher than the concentration of L-histidine and most of the nickel was associated with albumin. The equilibrium between L-histidine-nickel and serum-albumin-nickel may be biologically significant. The L-histidine nickel complex, which has a much smaller molecular size than the albumin-nickel complex, may mediate the transport through a biological membrane by virtue of the equilibrium between these two molecular species of nickel. Nickel can exchange between albumin and free L-histidine via a ternary complex that binds the nickel ion very tightly. The amount of nickel in each compartment varies from species to species and this may be due, in part, to species variation in the affinity of albumin for nickel. (TERA 1999, IPCS 1991). The predominant intracellular form of nickel has been observed to vary among tissues. In the lung and liver of mice, nickel was bound predominantly to a high-molecular-weight protein; in the kidney, it was bound mainly to low-molecular-weight ultrafiltrable ligands. (TERA 1999).

4.1.2.1.2.2 Distribution Below, the available data on distribution for the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to the individual risk assessment reports. Relevant information from reviews is also included. Two inhalation studies in rats (Benson et al. 1988, NTP 1996a) indicate that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to around 0.8 mg Ni/m3) in the inhaled air as well as with duration of exposure. The study by Benson et al. (1988) indicates that the lung nickel burden may rise to a steady state level as the lung nickel burdens were almost similar in rats exposed to 15 or 30 mg/m3. A third study (Dunnick et al. 1989) found similar concentrations of nickel in the lungs of rats and mice after 4, 9, and 13 weeks of inhalation to nickel sulphate (0.02 to 0.4 mg Ni/m3). Of nickel remaining in the body after 96 hours following a single dose of nickel sulphate administered by intratracheal administration, over 50% was in the lungs. The deposition of nickel in the lungs of rats is apparently greater than in the lungs of mice. Following intratracheal instillation to rats, the highest concentrations of nickel at 96 hours after instillation were found in the lung, trachea, larynx, kidney, urinary bladder, adrenals, blood, large intestine, and thyroid (Medinsky et al. 1987). No human data have been located. Two drinking water studies in rats have reported some differences in tissue distribution. Following administration to rats in the drinking water (100 mg Ni/l) for 6 months, the highest concentrations of nickel were found in the liver followed by the kidney (Severa et al. 1995). In the other drinking water study (13 weeks, about 45-225 mg Ni/l) in male rats, the concentration in different organs was increased with increasing concentrations of nickel in the drinking water; the relative order of bioaccumulation of nickel (at 225 mg Ni/l) was kidneys > testes > lung = brain > spleen > heart = liver (Obone et al. 1999). In mice, nickel levels were higher in kidney than in liver (Dieter et al. 1988 – quoted from NiPERA 1996). No human data have been located.


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Following intratracheal instillation of nickel chloride to rats (English et al. 1981, Carvalho & Ziemer 1982, Clary 1975) or oral administration by gavage to mice (Nielsen et al. 1993), the highest concentrations of nickel were found in the lungs, kidneys, and liver. No human data have been located. No studies regarding distribution of nickel in humans or in experimental animals following exposure to nickel nitrate have been located. Nickel from diets containing nickel carbonate has been reported to accumulate in tissues of rats (bones > heart > kidney > blood > spleen > intestine > testes > skin > liver at 100 mg nickel carbonate per 100 g diet for 9 weeks) (Phatak & Padwardhan 1950 - quoted from IPCS 1991) and of calves (serum > kidney > vitreous humour > lung > testis > bile > tongue > pancreas > rib > spleen > brain > liver > heart at 1000 mg nickel carbonate per kg dietary supplementation for 8 weeks) (O’Dell et al. 1971 – quoted from IPCS 1991). No data regarding distribution of nickel carbonate following inhalation in experimental animals and no data in humans have been located. In a 13 week inhalation study where rats were exposed to nickel powder distribution of nickel to the blood from accumulated nickel particles in the lung tissue was observed (WIL Research Laboratories 2003). Metabolic data from nickel-balance studies carried out by Phatak & Padwardhan (1950 - quoted from IPCS 1991) who fed rats nickel metal catalyst (250, 500, or 1000 mg/kg in the diet for 2 months) demonstrated that tissue accumulation of nickel from the nickel-containing diets was not significant. Limited information exists on nickel tissue distribution in humans after inhalation. Animal studies show that inhaled soluble nickel salts primarily distribute to the lung and kidney, with some distribution to the liver and other tissues. (TERA 1999). Very limited information exists on the human tissue distribution of nickel after oral exposure. Animal studies show that after the ingestion of soluble nickel salts, the highest nickel level is observed in the kidney. In studies, where the lung was examined, the second highest nickel concentration was observed in this tissue. (TERA 1999). Workers occupationally exposed to nickel have higher lung burdens of nickel than the general population. Nickel content of the lungs at autopsy has been reported to be 330 ± 380 µg/g dry weight in roasting and smelting workers exposed to less soluble compounds, 34 ± 48 µg/g dry weight in electrolysis workers exposed to soluble nickel compounds, and 0.76 ± 0.39 µg/g dry weight in unexposed controls. Nickel levels in the nasal mucosa have also been reported to be higher in workers exposed to insoluble, relative to soluble, nickel compounds. Higher serum nickel levels have been found in occupationally exposed individuals compared to non-exposed controls and levels were found to be higher in workers exposed to soluble nickel compounds compared to workers exposed to insoluble nickel compounds. Nickel sensitised individuals had similar nickel levels in blood, urine and hair relative to non-sensitised individuals. An autopsy study of individuals not occupationally exposed to nickel have shown the highest concentrations in the lungs, followed by the thyroid, adrenals, kidney, heart, liver, brain, spleen, and pancreas. (US ATSDR 1995). There are few data on human tissue concentrations of nickel; the data indicate that the retained nickel is widely distributed in very low concentrations in the body (IPCS 1991). In conclusion, nickel tends to deposit in the lungs of workers occupationally exposed to nickel and in experimental animals following inhalation or intratracheal instillation of nickel compounds. Upon entry into the bloodstream, the nickel ion is bound to specific serum components and rapidly distributed throughout the body. In serum, nickel is present in three forms: 1) as a complex associated with albumin; 2) as a complex associated with a nickel-metalloprotein (nickeloplasmin); and 3) as ultrafiltrable material. In human serum, 40% of the nickel is present as ultrafiltrable material, 34% is associated with albumin, and 26% is associated with nickeloplasmin. The tissue distribution of nickel in experimental animals does not appear to depend significantly on the route of exposure (inhalation/intratracheal instillation or oral administration) although some differences have been observed. Low levels of accumulation in tissues are observed (generally below 1 ppm). A primary site of elevated tissue levels is the kidney. In addition, elevated concentrations of nickel are often found in the lung, also after oral dosing, and in the liver. Elevated nickel levels are less often found in other tissues. Limited information exists on tissue distribution in humans.

4.1.2.1.2.3 Transplacental transfer Transplacental transfer provides an initial body burden that will be augmented by later exposures. For this reason, and in view of the possible adverse effects associated with the exposure of pregnant women to nickel during early pregnancy, transplacental transfer is important. Placental transfer is influenced by gestational age and the availability of nickel in the maternal blood. Species differences in placental structure and implantation, which may possibly influence nickel transfer, must also be considered. (IPCS 1991).


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Nickel has been shown to cross the human placenta. It has been found in both the foetal tissue (Schroeder et al. 1962 – quoted in IPCS 1991) and the umbilical cord serum, where the average concentration from 12 new-born babies was 3 ± 1.2 µg/l (range 1.7-4.9 µg/l) and was identical with that in the mother’s serum, immediately after delivery (McNeely et al. 1971 – quoted in IPCS 1991). Measurable concentrations have been found in various foetal tissues with concentrations in liver, kidney, brain, heart, lung, skeletal muscle, and bone being similar to those in adults ranging from 0.24-0.69 mg/kg dry matter. (IPCS 1991). Several reports indicate that transplacental transfer of nickel occurs in experimental animals: The newborn offspring of rats fed nickel carbonate or nickel metal catalyst in the diet showed whole-body levels of 12-17 or 22-30 mg Ni/kg bw, when dams received 500 or 1000 mg Ni/kg diet, respectively (Phatak & Padwardhan 1950 - quoted from IPCS 1991). Following intraperitoneal injection (on day 16 of gestation) of nickel chloride to pregnant mice, the concentrations of nickel in the maternal blood and the placenta were found to be at a maximum 2 hours after injection; the maximum concentration in foetal tissues was reached 8 hours after injection, and only a slight and gradual decrease in concentration was observed up to 24 hours (Lu et al. 1981 – quoted from IPCS 1991). In another study by Lu et al. (1979 – quoted from IPCS 1991), the concentration of nickel retained in embryonic tissues was 800 times higher in the exposed animals than in controls when pregnant mice were given an intraperitoneal injection of nickel chloride on day 8 of gestation. When pregnant mice were given a single intraperitoneal injection (on day 18 of gestation) of nickel chloride, passage of nickel from mother to foetus was rapid and concentrations in foetal tissues were generally higher than those in the dam (Jacobsen et al. 1978 – quoted from IPCS 1991). Sunderman et al. (1978 – quoted from IPCS 1991) administered nickel (compound not specified) intramuscularly to pregnant rats on days 8 or 18 of gestation and determined maternal and foetal tissue concentrations by autoradiography. The mean nickel concentration in the foetuses of dams injected on day 8 of gestation was equivalent to that in the maternal animals whereas in dams injected on day 18 of gestation, nickel was localised in the placenta, in the yolk sacs and foetuses; the foetal organ with the highest concentration was the urinary bladder. When nickel (compound not specified) was administered to rats in the drinking water for 7 months before, and during, pregnancy, the nickel content increased in the placentas, but not in the foetuses (Nadeenko et al. 1979 – quoted from IPCS 1991). In conclusion, nickel has been shown to cross the human placenta. Transplacental transfer has also been demonstrated in rats administered nickel carbonate or nickel metal catalyst in the diet, in mice following administration of nickel chloride by intraperitoneal injection, and in rats following administration of nickel by intramuscular injection.

4.1.2.1.2.4 Cellular uptake Nickel can enter animal cells by three different mechanisms: uptake via metal ion transport systems, diffusion of lipophilic nickel complexes through the membrane, and phagocytosis. Differences in cellular uptake of soluble and insoluble forms of nickel compounds play an essential role in the observed differences in the toxicity among these compounds. Several reviews have been published regarding the different mechanisms by which cells uptake different nickel compounds; the data are summarised below according to TERA (1999). A number of studies have shown that cellular uptake of the insoluble nickel compounds, nickel subsulphide and nickel sulphide particles, occurs via phagocytosis. Small amounts of nickel subsulphide may also dissolve outside the cell, and enter the cell as soluble nickel. In a comparison of a number of insoluble nickel compounds (similar particle sizes), transformation activity in Syrian hamster embryo (SHE) cells correlated with the phagocytic activity of the compound. Soluble nickel chloride had lower transforming activity than the well-phagocytised compounds, which is attributed to more efficient uptake and better retention of insoluble nickel entering via phagocytosis compared to soluble nickel entering via diffusion or transport. (TERA 1999). The process by which soluble nickel enters the cell is less clearly understood. Uptake of soluble nickel into cells may occur as a result of transport or diffusion of nickel complexes through the cell membrane. (TERA 1999). In enteric cells, nickel interacts with cell membranes in a manner similar to the interactions of cadmium and other heavy metals, i.e., via passive diffusion, without the need for assuming specific transport systems. Similar passive diffusion mechanisms may exist in lung cells. Passive diffusion of nickel across cell membranes is markedly reduced under normal physiological conditions, when nickel is bound to proteins or amino acid ligands, forming hydrophilic complexes. In vitro studies have shown that serum inhibits the uptake of nickel into cells and that metal-binding amino acids such as cysteine and histidine appear to account for the majority of the inhibitory activity of serum. By contrast, packaging soluble nickel compounds in liposomes increases nickel transport by this mechanism. (TERA 1999).


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Uptake of nickel via ion transport systems, particularly via the magnesium transport system, has been reported as a major route in microbial cells; the same mechanism may also exist in mammalian cells. Results from studies in animals are consistent with the hypothesis that the magnesium ion transport system is responsible for the uptake of soluble nickel salts into cells, although this process has not been directly demonstrated in mammalian cells. Uptake of nickel via the magnesium transport mechanism is also less efficient than phagocytosis as magnesium concentrations inside and outside the cell are in the millimolar range, so nickel would not compete effectively with magnesium for uptake under normal exposure conditions, which would result in nickel concentrations well below the millimolar range. (TERA 1999). The differences between the processes by which soluble and insoluble nickel enter the cell are reflected in differences in disposition once the nickel is inside the cell. Soluble nickel directly enters the cytoplasm, where it binds to cellular proteins thereby decreasing the bioavailability of soluble nickel to enter the nucleus and interact with DNA. Small amounts of nickel subsulphide may also be dissolved in the extracellular fluid and be taken up by cells via this pathway. The presence of nickel ion in the cytoplasm increases the potential for cytotoxicity. By contrast, phagocytosed (insoluble) nickel particles are retained in vacuoles thereby decreasing the opportunity for insoluble nickel to interact with cytosolic macromolecules and thus decreasing the potential for cytotoxicity or for interactions that render the nickel unavailable for interacting with DNA. The vacuoles migrate to the region near the nucleus where they interact with lysosomes. This interaction decreases the pH of the vacuole and thereby increasing the rate of dissolution of nickel ion in close proximity to the nuclear membrane, where they can interact with DNA. The net result of these differences is that exposure to insoluble nickel compounds results in much higher nuclear nickel concentrations and higher DNA binding than exposure to similar levels of soluble nickel compounds. (TERA 1999). In conclusion, the cellular uptake of soluble and insoluble nickel compounds are different as insoluble nickel compounds enter the cell via phagocytosis, while soluble nickel compounds are not phagocytised, but enter the cell via metal ion transport systems (particularly the magnesium transport system or through membrane diffusion. The latter two processes are much less efficient implicating that the same extracellular levels of soluble and insoluble nickel compounds lead to lower intracellular nickel levels for soluble nickel compounds. Soluble forms of nickel interact with the cell in a way that maximises cytotoxicity and minimises nickel delivery to the nucleus, while insoluble forms of nickel interact with cells in a way that decreases the cytotoxic potential while increasing the delivery of nickel to the nucleus.

4.1.2.1.2.5 Elimination Below, the available data on elimination for the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to the individual risk assessment reports. Relevant information from reviews is also included. The major route of excretion of nickel in rats following a single dose of nickel sulphate administered by intratracheal instillation was in urine; the extent of excretion increased and the half-time decreased with increasing dose (Medinsky et al. 1987). No data on excretion of nickel sulphate in experimental animals following other exposure routes have been located. In humans, absorbed nickel is predominantly excreted in the urine following oral intake of nickel sulphate with 20 to 30% of a dose being excreted in the urine when nickel sulphate is administered in drinking water to fasting subjects or to fasting subjects compared with around 1 to 5% when administered together with food (Sunderman et al. 1989, Cronin et al. 1980 – quoted from IARC 1990). From biological monitoring in small groups of electroplaters exposed to nickel sulphate and nickel chloride, the half-life for urinary elimination of nickel has been estimated to range from 17 to 39 hours (Sunderman et al. 1988 – quoted from TERA 1999, US ATSDR 1995). The major route of excretion of nickel in rats following intratracheal instillation of nickel chloride was in urine with 70 to 80% of a dose being eliminated via the urine within 3 days following instillation and approximately 97% by 21 days after instillation (Carvalho & Ziemer 1982, Clary 1975). No data on excretion of nickel chloride in experimental animals following other exposure routes have been located. From biological monitoring in small groups of electroplaters exposed to nickel sulphate and nickel chloride, the half-life for urinary elimination of nickel has been estimated to range from 17 to 39 hours (Sunderman et al. 1988 – quoted from TERA 1999, US ATSDR 1995). No studies regarding elimination in humans or in experimental animals following exposure to nickel nitrate have been located.


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One study in mice indicates that most of the nickel was eliminated 12 days after intratracheal instillation of nickel carbonate (Furst & Al-Mahrouq 1981 - quoted from IPCS 1991). No data regarding elimination of nickel carbonate following oral administration to experimental animals and no data in humans have been located. After 13 weeks exposure to metallic nickel powder, elimination of the accumulated particles in the lung took place with a half life of 30 to 60 days. The increased nickel blood levels during the elimination period indicated that the elimination was dependent on dissolution of the nickel particles in the lung and the following uptake and elimination from the blood stream (WIL Research Laboratories 2003). When soluble nickel salts are inhaled or injected intratracheally, most of the nickel is absorbed and then excreted through the urinary route, although appreciable faecal excretion has also been observed. Animal data indicate that the rate of urinary nickel excretion increases at higher, when compare to lower, intratracheal doses. The half-life of nickel in the lungs after exposure to soluble nickel salts varied with the solubility of the nickel species indicating that clearance is related to nickel solubility. The half-life of nickel in the lungs of rats administered nickel sulphate was about 21-36 hours, while the half-life was 4 days and 120 days for nickel subsulphide and nickel oxide, respectively. In humans, most ingested nickel salts are not absorbed but are excreted in the faeces; absorbed nickel is excreted primarily through the urinary route with the maximal excretion in the first 8-9 hours after ingestion. The half-life for urinary excretion in humans is about 20-30 hours. About 23-26% of the dose is excreted in the urine following administration of soluble nickel in water to fasting individuals, but only 2-3% if nickel is administered with a meal. A similar pattern of nickel excretion has been observed in experimental animals. In addition to excretion through the urinary route, small amounts of absorbed nickel can also be excreted through other routes, such as via sweat, bile, and milk. (TERA 1999). Absorbed nickel is excreted in the urine, regardless of the route of exposure. In nickel workers, an increase in urinary excretion was found from the beginning to the end of the shift and also as the workweek progressed. Nickel is also excreted in the faeces of nickel workers, but this is most likely resulting from mucociliary clearance of nickel from the respiratory system to the gastrointestinal tract. Higher nickel levels were found in the urine of workers exposed to soluble nickel compounds as compared to workers exposed to insoluble nickel compounds. In humans, most ingested nickel is excreted in the faeces; however, the nickel that is absorbed from the gastrointestinal tract is excreted in the urine. Similar patterns of nickel excretion have been observed in experimental animals. (US ATSDR 1995). The elimination routes for nickel in humans and animals depend, in part, on the chemical form of the nickel compound and on the exposure route. Following oral exposure, the elimination of nickel is primarily in the faeces due to the relatively low gastrointestinal absorption. Urinary excretion is usually the major clearance route for absorbed nickel. Other routes of elimination, which are of minor importance, include hair, saliva, sweat, tears, and milk. (IPCS 1991). In conclusion, absorbed nickel is excreted in the urine, regardless of the route of exposure; the half-life for urinary excretion in humans has been reported to be about 20-30 hours. Most ingested nickel is excreted via faeces due to the relatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake of soluble nickel compounds accounts for 20-30% of a dose when the nickel compound is administered in drinking water to fasting subjects or to fasting subjects compared with 1-5% when administered together with food or in close proximity to a meal. Small amounts of absorbed nickel can also be excreted through other routes, include hair, saliva, sweat, tears, and milk. Inhaled nickel particles that are deposited in the respiratory tract can be eliminated from the airway by absorption from the lung or by removal via the mucociliary action. This latter fraction may subsequently be swallowed and enter into the gastrointestinal tract..

4.1.2.1.2.6 Transfer to the milk Appreciable amounts of nickel have been found in breast milk of women (IPCS 1991). The nickel concentration in milk specimens obtained from 102 American mothers averaged 17 ± 2 and 14 ± 1 µg/kg at 4-7 days postpartum and at 30-45 days postpartum, respectively (Feeley et al. 1983 – quoted from TERA 1999). Dostal et al. (1989 – quoted from IPCS 1991 and TERA 1999) studied the effects of nickel on lactating rats, their suckling pups, and the transfer of nickel via the milk. Dose-dependent increases were observed in the concentrations of nickel in the milk and plasma, 4 hours after a single subcutaneous injection of nickel chloride to lactating dams giving a milk/plasma nickel ratio of 0.02. Peak plasma nickel concentrations in the dams occurred 4 hours after the injection, while the peak concentration in the milk was observed at 12 hours and remained elevated at 24 hours. Daily subcutaneous injections of dams for 4 days increased the milk/plasma nickel ratio to 0.10. Significant alterations in milk composition included increased solids and lipids (42 and


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110%, respectively) and decreased milk protein and lactose (29 and 62%, respectively). In multiple dose studies (subcutaneous injection once daily, on days 12-15 of lactation), the plasma-nickel concentrations in suckling were 24-48 µg/litre dependent on the dose administered. No data regarding transfer of nickel to milk following exposure to nickel sulphate, nickel nitrate, nickel carbonate, nickel metal as well as to other nickel compounds have been located. In conclusion, nickel has been found in breast milk of women and in milk from lactating rats administered nickel chloride by subcutaneous injection.

4.1.2.1.3 Conclusions The available data on nickel sulphate and nickel chloride indicate that the absorption of nickel following inhalation of the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) might be as high as up to 97-99%; it should be noted that the fraction absorbed apparently depends on the concentration of the nickel compound in the inhaled air as well as on the duration of exposure. For the purpose of risk characterisation, a value of 100% is taken forward to the risk characterisation for the absorbed fraction of nickel from the respiratory tract following exposure by inhalation of the prioritised soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) for particulates with an aerodynamic diameter below 5 µm (respirable fraction). For nickel particulates with aerodynamic diameters above 5 µm (non-respirable fraction), the absorption of nickel from the respiratory tract is considered to be negligible as these particles predominantly will be cleared from the respiratory tract by mucociliary action and translocated into the gastrointestinal tract and absorbed. Hence, for the non-respirable fraction, 100% clearance from the respiratory tract by mucociliary action and translocation into the gastrointestinal tract is assumed and the oral absorption figures can be taken. The available data on nickel oxide indicate that the absorption of nickel from the respiratory tract following inhalation is very limited. However, data on metallic nickel indicate an absorbed fraction of up to approximately 6% after inhalation (i.e. both absorption from respiratory tract and the gastrointestinal tract). The available data on the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) indicate that the absorption of nickel following oral administration in the drinking water to fasting individuals might be as high as up to about 25-27% and about 1-6% when administered to non-fasting individuals and/or together with (or in close proximity to) a meal. The available data on insoluble and slightly soluble nickel compounds (nickel metal, nickel carbonate, nickel oxides and nickel sulphides) indicate that absorption of nickel from the gastrointestinal tract may occur following oral exposure; however, the data are too limited for an evaluation of the absorbed fraction of nickel. For the purpose of risk characterisation, a value of 30% is taken forward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel sulphate, nickel chloride, nickel nitrate, and nickel carbonate in the exposure scenarios where fasting individuals might be exposed to nickel compounds. In all the other exposure scenarios, a value of 5% is used for the absorbed fraction of nickel from the gastrointestinal tract. Values of 0.05% and 0.3% are taken forward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel metal for non-fasting and for fasting individuals, respectively. The available data indicate that absorption of nickel following dermal contact to various nickel compounds can take place, but to a limited extent with a large part of the applied dose remaining on the skin surface or in the stratum corneum. The data are too limited for an evaluation of the absorbed fraction of nickel following dermal contact to the five prioritised nickel compounds. For the purpose of risk characterisation, a value of 2% is taken forward to the risk characterisation for the absorbed fraction of nickel following dermal contact to nickel sulphate, nickel chloride, nickel nitrate, and nickel carbonate. For nickel metal, a value of 0.2% is taken forward to the risk characterisation. Nickel tends to deposit in the lungs of workers occupationally exposed to nickel and in experimental animals following inhalation or intratracheal instillation of nickel compounds. Upon entry into the bloodstream, the nickel ion is bound to specific serum components and rapidly distributed throughout the body. In serum, nickel is present in three forms: 1) as a complex associated with albumin; 2) as a complex associated with a nickel-metalloprotein (nickeloplasmin); and 3) as ultrafiltrable material. In human serum, 40% of the nickel is present as ultrafiltrable material, 34% is associated with albumin, and 26% is associated with nickeloplasmin. The tissue distribution of nickel in experimental animals does not appear to depend significantly on the route of exposure (inhalation/intratracheal instillation or oral administration) although some differences have been observed. Low levels of accumulation in tissues are observed (generally below 1 ppm). A primary site of elevated tissue levels is the kidney. In addition, elevated concentrations of nickel are often found in the lung, also after oral


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dosing, and in the liver. Elevated nickel levels are less often found in other tissues. Limited information exists on tissue distribution in humans. Nickel has been shown to cross the human placenta. Transplacental transfer has also been demonstrated in rats administered nickel carbonate or nickel metal catalyst in the diet, in mice following administration of nickel chloride by intraperitoneal injection, and in rats following administration of nickel by intramuscular injection. The cellular uptake of soluble and insoluble nickel compounds are different as insoluble nickel compounds enter the cell via phagocytosis, while soluble nickel compounds are not phagocytised, but enter the cell via metal ion transport systems (particularly the magnesium transport system or through membrane diffusion. The latter two processes are much less efficient implicating that the same extracellular levels of soluble and insoluble nickel compounds lead to lower nickel levels intracellularly for soluble nickel compounds. Soluble forms of nickel interact with the cell in a way that maximises cytotoxicity and minimises nickel delivery to the nucleus, while insoluble forms of nickel interact with cells in a way that decreases the cytotoxic potential while increasing the delivery of nickel to the nucleus. Absorbed nickel is excreted in the urine, regardless of the route of exposure; the half-life for urinary excretion in humans has been reported to be about 20-30 hours. Most ingested nickel is excreted via faeces due to the relatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake of soluble nickel compounds accounts for 20-30% of a dose when the nickel compound is administered in drinking water to fasting subjects or to fasting subjects compared with 1-5% when administered together with food or in close proximity to a meal. Small amounts of absorbed nickel can also be excreted through other routes, include hair, saliva, sweat, tears, and milk. Inhaled nickel particles that are deposited in the respiratory tract can be eliminated from the airway by absorption from the lung or by removal via the mucociliary action. This latter fraction may subsequently be swallowed and enter into the gastrointestinal tract. An elimination half life of 30-60 days has been estimated for metallic nickel particles accumulated in lung tissue. The elimination is dependent on dissolution of the accumulated nickel particles followed by absorption and elimination of nickel from the blood.

4.1.2.2 Acute toxicity

4.1.2.2.1 Animal studies

4.1.2.2.1.1 Inhalation Data on the inhalation toxicity of nickel and different nickel compounds comes from studies of nickel metal, nickel carbonyl and nickel chloride. None of the studies on nickel metal or nickel chloride are sufficient and none of them allow the determination of a lethal concentration. A one-hour nickel metal powder dust aerosol exposure at the nominal concentration of 10.2 mg Ni/l did not cause mortality or signs of toxicity (FDRL, 1985). Nickel carbonyl appears to be exceptionally toxic by inhalation as evidenced by a number of human poisoning accidents (NIPERA, 1996). In the rat, a 30-minute LC50 of 0.24 mg/l has been reported, presumably the dose is reported as nickel carbonyl (Kincaid et al., 1953, Sunderman et al., 1959; both quoted from UK HSE, 1987). Data is available for some nickel compounds following intratracheal administration (see UK HSE, 1987), but is not discussed further here because the relevance of this method of administration for the inhalation route is not known. It is not considered possible to predict an LC50 by extrapolation from oral acute toxicity data, as the toxico-kinetics and type of effect are expected to differ greatly between the two routes. Data for repeated dose inhalation studies are available, which allow the determination of concentrations, which are not associated with lethality (please see the section on repeated dose toxicity for further study details). For metallic nickel (representing insoluble nickel compounds), concentrations up to 24 mg Ni/m3 (whole-body exposure) 6h/day, 5d/week for 4 weeks were not associated with mortality (WIL Research Laboratories, 2002). Two other insoluble nickel compounds, nickel oxide and nickel subsulphide, were tested by NTP (1996b, 1996c) in 16-day studies in mice and rats. Nickel oxide did not cause mortality in the tested concentrations up to and including 23.6 mg Ni/m3. Nickel subsulphide, however, appeared more toxic, especially in mice. The highest concentration of nickel subsulphide which did not cause excess mortality was equivalent to 3.65 mg Ni/m3. The LOAEC of this study was 7.33 mg Ni/m3. For soluble nickel compounds, a NOAEC/LOAEC (lethality) from the 16-day repeated dose toxicity study of nickel sulphate hexahydrate by NTP (1996a) can be used (LOAEC of 0.7 mg Ni/m3 (3.7 mg/m3 NiSO4

.6H2O) for reduced body weight and adverse effects in the respiratory tract (atrophy and inflammation).


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4.1.2.2.1.2 Oral A number of studies on the acute oral toxicity of nickel and different nickel compounds have been carried out. These studies are summarised in Table 4.1.2.2A which is based on the review by UK HSE (1987).

Table 4.1.2.2.A: Summary of acute oral toxicity studies in rats. (quoted from UK HSE, 1987).

solubility in water

Sex LD50, mg/kg (mg Ni/kg)

reference (all quoted from UK HSE, 1987)

male

female

430 (105)

529 (130)

Itskova et al. (1969) Nickel chloride

very soluble

male

female

210 (51)

175 (43)

FDRL (1983a) test substance NiCl2

.6H2O

Nickel nitrate very soluble

1620 (330) Smyth et al. (1969)

500 (190) Kosova (1979) Nickel sulphate

very soluble

male

female

325 (73)

275 (61)

FDRL (1983b) test substance NiSO4

.6H2O

Nickel acetate soluble male

female

350 (119)

360 (116)

Haro et al, 1968

Nickel carbonate slightly soluble

male

female

1305 (625)

840 (402)

FDRL (1983c)

nickel hydroxide very slightly soluble

male

female

1500 (915)

1700 (1037)

FDRL (1983d)

nickel trioxide insoluble male, female

> 5000 (> 3548) FDRL (1983e)

nickel oxide insoluble male, female

> 5000 (> 3930) FDRL (1983f)

nickel subsulphide (crystalline)

insoluble male, female

> 5000 (> 3663) FDRL (1983g)

nickel subsulphide (amorphous)

insoluble male, female

> 5000 (> 2620) FDRL (1983h)

iron nickel powder insoluble male, female

> 5000 (> 1475) FDRL (1983i)

1) Figures in brackets are mg Ni/kg

4.1.2.2.1.3 Dermal There are no relevant data available on the acute toxicity of soluble or insoluble nickel compounds following cutaneous administration. Absorption via this route is expected to be negligible, and further testing is not considered relevant.

4.1.2.2.1.4 Other routes Data for effects following intraperitoneal or intramuscular administration is available for some nickel compounds (see UK HSE, 1987), but these routes of administration are not discussed further here, because these routes are not considered relevant for the human exposure situation.

4.1.2.2.2 Human studies In the 19th century, nickel salts were used medicinally, and 325 mg nickel sulphate in solution or in pill form produced nausea and giddiness (Da Costa, 1883, quoted in UK HSE 1987). According to NIPERA, 1996, severe toxic effects of inhalation exposure to nickel carbonyl have been recognized for many years. The initial stage of poisoning involves headache, chest pain, weakness, dizziness, nausea, irritability, and a metallic taste in the mouth. A general remission of 8-24 hours’ duration then occurs, followed by a second phase of chemical


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pneumonitis, with evidence of cerebral poisoning in severe cases. Common signs in severe cases include tachypnoea, cyanosis, tachycardia, and hyperaemia of the throat, and radiological signs of pulmonary oedema or pneumonitis.

4.1.2.2.3 Discussion and conclusion

4.1.2.2.3.1 Inhalation There is no data for acute inhalational toxicity from properly conducted Annex V inhalation tests for any of the nickel compounds. In the absence of such data, data from repeated dose inhalation studies is used for the risk characterisation. These data do not indicate a solubility-related difference in toxicity. The use of results from these repeated dose studies is considered to be a conservative approach, since greater toxicity is expected from repeated exposure compared to a single 4h exposure as in the Annex V test. Data from repeated dose studies are not directly useful for classification, since greater toxicity is expected from repeated exposure (12 exposures during 16 days) compared to a single 4h exposure as in the Annex V test. However, there is evidence for acute oral toxicity for the soluble as well as the less soluble compounds (but not insoluble or metallic nickel) (see below); absorption via inhalation is considerably greater than via the oral route, and the NTP 16 day repeated dose toxicity study (NTP, 1996a) showed mortality in rats at a level roughly 30 times lower than the lower cut-off for classification for T; R23 and 100% of the female and 40% of the male rats died at the highest dose before the end of the study. The TC C&L has agreed to classify nickel chloride with T; R23 and nickel sulphate, nickel nitrate and the nickel carbonates with Xn; R20. These classifications are included in the 30th ATP. It should be noted that nickel hydroxide (which has a solubility similar to that of the nickel hydroxycarbonates) is already classified in Annex I with Xn; R20.

4.1.2.2.3.2 Oral A number of nickel compounds of varying solubility have been tested in acute oral toxicity tests. Although some of the variability in results is probably explained by differences in laboratory procedures etc., the results show that soluble nickel compounds are more toxic by the oral route than the insoluble salts. The oral LD50 levels for the three soluble nickel salts, nickel sulphate, nickel chloride and nickel nitrate, tested as hydrates in the rat, ranged from 175 to 1620 mg compound/kg. The corresponding figures expressed as mg Ni/kg were 43 –330. Since all three compounds are very soluble, these studies could be considered as estimates of the toxicity of the nickel ion. However, the very soluble nickel nitrate appears to be less toxic than the other two soluble nickel compounds, with a LD50 comparable to that for the sparingly soluble salts. The nickel nitrate LD50 study was reported in 1969 and may not be comparable to more recent studies, as the study was carried out in non-fasted animals and is probably an underestimate of the acute toxicity. However, a more recent toxic class method study (Pycher 2003a) showed no mortality or signs of toxic symptoms at 200 mg nickel nitrate hexahydrate/kg. The less soluble carbonate and hydroxide showed values of from 840 – 1700 mg compound/kg (402-1037 mg Ni/kg). This is consistent with the evidence of oral absorption seen for nickel carbonate described above (see 4.1.2.1.1.2). The insoluble oxides and sulphides showed LD50 values over 5000 mg compound/kg. For the risk characterisation, different values are used based on the solubility of the substance in question. For nickel sulphate, nickel chloride and nickel nitrate, an oral LD50 value of 43 mg Ni/kg is used based on results from nickel chloride (FDRL, 1983a). For nickel carbonate, an oral LD50 value of 402 mg Ni/kg based on results for the substance (FDRL, 1983c) is used. For nickel metal, the LD50 is in excess of 5000 mg/kg. The TC C&L has agreed to classify nickel chloride with T; R25 and nickel sulphate, nickel nitrate and the nickel carbonates with Xn; R22. These classifications are included in the 30th ATP . It should be noted that nickel hydroxide is already classified for this effect in Annex I with Xn; R22. The insoluble compounds and the metal should not be classified for acute oral toxicity.

4.1.2.2.3.3 Dermal There is no data on toxicity following cutaneous administration. Dermal absorption is expected to be very limited. Therefore, this endpoint is not considered in the risk characterisation, and no classification for acute toxicity via the dermal route is proposed.


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4.1.2.3 Irritation /corrosivity Information on the pH of nickel sulphate, nickel chloride and nickel (hydroxy)carbonate solutions is available from the main EU producers. The pH of a 100g sample of nickel (hydroxy)carbonate added to 1 litre of water varied between 7.8 and 8.9. The pH of a nickel chloride solution is 3.7 + 0.4, and that of a nickel sulphate solution is between 3 and 3.5. Commercially available nickel nitrate may contain nitric acid, either as an impurity from the production process at concentrations from 0 – 4%, or as an additive at a concentration of up to ca. 10%. These nickel nitrate products are normally classified as C; R34, based either on the nitric acid content or on the basis of extreme pH (pH < 2).

4.1.2.3.1 Animal studies

4.1.2.3.1.1 Skin and eye irritation Neither the NIPERA (1997), the US ATSDR (1997) nor the TERA (1999) reviews discuss skin or eye irritation of soluble or insoluble nickel compounds. In the UK HSE (1987) review it is mentioned that no data were found on the skin and eye irritancy of insoluble nickel compounds. Data for nickel metal and the soluble nickel sulphate and nickel nitrate have been found (table 4.1.2.3.A). Nickel metal did not cause skin irritation in an Annex V skin irritation test. Nickel sulphate gave slight irritation (erythema) in an Annex V skin irritation test. In two other studies, the application was repeated for 30 days, and resulted in adverse effects on the skin. Nickel nitrate hexahydrate was irritant in an Annex V test (as well as a second sample and a solution). Nickel sulphate gave slight eye irritation (slight degree of conjunctival redness and oedema, and iris lesions) in an Annex V eye irritation test. Nickel nitrate hexahydrate is a severe eye irritant in an Annex V test, as irritation persists at the end of a 21-day observation period.

Table 4.1.2.3.A: Summary of skin and eye irritation studies

Nickel compound

Species Result Grading (irritation scores)

Method Reference

Skin

Metal rabbit not irritant 0.5 (erythema)

0.00 (oedema)

Annex V SLI 1999a

Sulphate rabbit not irritant 0.42 (erythema)

0.00 (oedema)

Annex V SLI 1999b

Sulphate rabbit pustules seen on wounded skin but not intact skin

50% aqueous solution Wahlberg & Maibach 1981

Sulphate rat skin atrophy, acanthosis and hyperkeratinisation

40 – 100 mg Ni/kg

repeated application for 30 days

Mathur et al. 1977

Sulphate rat erythema, eschar 50% aqueous solution daily for 30 days

Kosova (1979 - quoted from UK HSE 1987)

Nitrate rabbit irritant 3.1 (erythema)

1.1 (oedema)

Annex V Phycher 2003b

Eye


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Nickel compound

Species Result Grading (irritation scores)

Method Reference

Sulphate rabbit not irritant 0. 00 (corneal opacity)

0.33 (iris lesion)

0.67 (conjunctival redness)

0.44 (conjunctival oedema)

Annex V SLI 1999c

Nitrate rabbit severe eye irritant as effects persist to end of observation period

1.0 (corneal opacity)

1.0 (iris lesion)

2.0 (conjunctival redness)

2.7 (conjunctival oedema)

Annex V Phycher 2003c

4.1.2.3.1.2 Respiratory irritation No studies examining the respiratory irritation caused by a single exposure to nickel or nickel compounds have been found. Several studies have shown lung inflammation and degeneration of the olfactory epithelium following relatively short periods of exposure to the very soluble nickel sulphate (Benson et al. 1988 (aerosol inhalation 12 days), Dunnick et al. 1989 (inhalation – 13 weeks), Benson et al. 1989 (aerosol inhalation 13 weeks) - all quoted from NiPERA 1996). Nickel sulphate induced atrophy of the olfactory epithelium and lung inflammation in mice and rats after only 16 days inhalation exposure (NTP 1996a). The lowest dose tested was equivalent to 0.7 mg Ni/m3 and this was a LOAEC. In similar 16-day studies, the insoluble nickel compounds nickel oxide and nickel subsulphide were also shown to cause respiratory effects (NTP 1996b, 1996c). Nickel subsulphide was more potent than oxide, and caused lung inflammation and atrophy of the nasal olfactory epithelium in all exposed groups with a LOAEC of 0.44 mg Ni/m3. Based on these data it is not possible to relate the type or severity of respiratory effect to solubility characteristics of the nickel compounds.

4.1.2.3.2 Human data

4.1.2.3.2.1 Skin irritation In a study performed to develop a new test for skin irritancy, nickel sulphate was included as one of the test agents (Frosch & Kligman, 1976). A volume of 0.1 ml of nickel sulphate in various concentrations was pipetted on to a disc of two thicknesses of non-woven cotton cloth. The disc was mounted in a chamber designed for use in tests of contact sensitisation, which was sealed to the skin with non-occlusive tape or Dermicel®. The advantage of the chamber compared with the use of patches was that there was no loss of test material and uniform contact with the skin. The test subjects were groups of 5-10 light-skinned, young Caucasians. The test material was applied on the mid-volar forearm once daily for 3 days with readings made at 72h, 30 min after removal. The test was conducted on both intact and scarified skin. The reactions were graded on a five-point scale from 0 to 4 (1:erythema, 2: increased erythema, 3: severe erythema with partial confluency with or without other lesions, 4: confluent severe erythema sometimes associated with oedema, necrosis or bulla formation). On scarified skin nickel sulphate gave a dose-dependent response in the test, ranging from a score of 1 at a concentration of 0.13% to 4 at 1%. The dose-response plot is very steep for nickel sulphate. The authors describe their results as “a marginal irritant” at 0.13% but “a ferocious one at 1%”. The sensitivity of the assay on scarified skin was compared with the sensitivity on normal skin. No details of the results on normal skin are shown. The threshold concentration to produce “just an irritation reaction in 3 days” on normal skin was 20.0% while on scarified skin it was 0.13%. The ratio of threshold concentration on normal skin and threshold concentration on scarified skin was 154. This was the highest ratio among the substances tested, which included surfactants, inorganic salts, antimicrobials, and acids (Frosch & Kligman, 1976).


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Skin irritancy of nickel chloride and nickel sulphate has also been reported in studies primarily concerned with skin sensitisation. Vandenberg & Epstein (1963) reported that irritancy was directly proportional to concentration and duration of application. They concluded that a 10% nickel chloride solution causes too much irritation to have value as a predictive patch test, whilst a 5% solution ordinarily will not be a primary irritant. 5% nickel chloride caused irritation under occlusion. Kalimo & Lammintausta (1984) tested nickel chloride and nickel sulphate in patch tests with 24 and 48 h exposures. A 5% nickel chloride solution also caused irritation under occlusion, whilst a 2.5% solution could be used for patch testing. The standard patch test material for nickel sulphate (assumed to be 5%) was also irritant after occlusion. Fullerton et al. (1989) tested various concentrations of nickel chloride hexahydrate in a hydrogel as a possible alternative to the standard patch test material of 5% nickel sulphate pet. A 5% standard nickel sulphate patch, as well as the 0.5% - 2% nickel chloride hydrogels caused some irritation. Storrs et al. (1989) recorded 8 cases of irritancy in 1123 subjects patch tested with 2.5% nickel sulphate in petrolatum. Wahlberg (1990) reported that nickel chloride is more irritating than nickel sulphate when applied in equimolar concentrations. Twenty-five healthy volunteers with no previous history of eczema underwent 5 patch tests with nickel sulphate in concentrations of 5, 10, and 20%, and 2 control areas. It was concluded that in non-nickel-sensitive subjects aqueous solutions of nickel sulphate between 5 and 20 % did not evoke irritation on the skin (Seidenari et al. 1996b).

4.1.2.3.2.2 Respiratory irritation A number of case reports describe the relation between nickel sulphate and occupational asthma. Please see section 4.1.2.4.2. No information on non-allergic respiratory irritation in relation to short-term exposure has been found.

4.1.2.3.2.3 Conclusion The available data for skin irritation produced by the soluble nickel salts indicates that they are skin irritants, although the data are not entirely consistent. Nickel sulphate causes only a slight degree of skin irritation in an Annex V study, whilst irritation is seen in humans. Nickel chloride is also irritant in humans, and is more irritating than nickel sulphate at equimolar concentrations. Nickel nitrate is a skin irritant in an Annex V study. The presence of nitric acid (either as an impurity or as an additive) can give rise to sufficiently extreme pH to justify classification with C; R35. The insoluble nickel metal did not cause skin irritation in an Annex V study. The pH of nickel (hydroxy)carbonate does not lead to classification for this effect on the basis of extreme pH. The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates as skin irritants: Xi; R38. These classifications are included in the 30th ATP. The TC C&L has also agreed to classify nickel hydroxide with Xi; R38. The more limited data for eye irritation produced by the soluble nickel salts is not consistent. Nickel sulphate causes only a slight degree of eye irritation in an Annex V study, whilst nickel nitrate is a severe eye irritant in an Annex V study as irritation persists at the end of the observation period. There is no data on the eye irritation caused by insoluble nickel metal, but industry have expressed a concern for mechanical irritation from metal powders. A similar concern (leading to a provisional classification as Xi; R36) has been expressed by one producer of nickel chloride. The TC C&L has agreed to classify nickel nitrate as a severe eye irritant: Xi; R41 on the basis of the experimental data11, whilst no classification is suggested for the other nickel compounds. In should be noted that for these local effects, the nickel ion alone may not be entirely responsible for the effects, as the counter-ion may itself show irritant properties. Short-term repeated inhalation of very soluble as well as insoluble nickel compounds is associated with lesions in the olfactory and lung epithelium. No data have been found regarding respiratory irritation following a single inhalation exposure. Respiratory irritation will not be taken forward as a separate endpoint for risk characterisation, but will be dealt with in relation to repeated dose inhalation toxicity.

11 This classification is included in the 30th ATP.


81

4.1.2.4 Sensitisation

4.1.2.4.1 Skin sensitisation Nickel is well known as a skin sensitiser, and is one of the most frequent skin sensitisers in man. The Ni2+ ion is considered exclusively responsible for the immunological effects of nickel (Menné 1994). Most cases of primary nickel sensitisation are caused by skin contact with metallic items such as ear ornaments, ear stickers, jewellery, jeans buttons, and other nickel releasing items (European Environmental Contact Dermatitis Group, 1990). Solutions of soluble nickel salts may also induce sensitisation e.g. nickel sulphate in the nickel-plating industry. Nickel sensitisation is diagnosed by patch testing with 5% nickel sulphate in petrolatum in Europe and several other countries, while some countries (including North America) use 2.5% nickel sulphate. The patch is placed under occlusion in 48 hours to enhance skin penetration. A positive patch test shows that the patient is allergic to nickel ions. The patch test result does not indicate the source of nickel ions responsible for the primary sensitisation. There is an abundance of reports on human sensitisation with nickel. The following is based mainly on reviews.

4.1.2.4.1.1 Animal studies A number of studies on skin sensitisation in guinea pigs have been performed with nickel sulphate. Some of these studies are summarised in Table 4.1.2.4.1.A. Studies with nickel chloride are summarised in Table 4.1.2.4.1.B

Table 4.1.2.4.1.A: Skin sensitisation studies with nickel sulphate in animals

Species Result Method Reference

Guinea pig 11/22*, 4/7 Skin painting Lammintausta et al. (1985, 1986)

Guinea pig 20/20, 7/20, 12/20 Optimization test Maurer et al. (1979)

Guinea pig 13/14 Intradermal 1%, challenge 2% Bezian et al. (1965)

Guinea pig 21/30, 27/30 Open adm. + SLS + potassium alun injections

Zissu et al. (1987)

Guinea pig Maximum response 40% positive after 3% i.d. induction

GPMT I.d. induction 0.01%-3% aqueous Topical induction 0.25%-10% pet Challenge 1% pet

Rohold et al. (1991)

Guinea pig 1% lanolin: 57-93% pos.

3% lanolin: 60-100% pos.

1% hydroxypropyl cellulose: 67-75% pos.

Open epicutaneous pretreatment SLS 0.3%-3% in lanolin or 0.3%-3% in hydroxypropyl cellulose i.d. injections of adjuvant

Nielsen et al. (1992)

* Number of positive animals/animals tested

Table 4.1.2.4.1.B: Skin sensitisation studies with nickel chloride in animals


Guinea pig 1/10* GPMT Induction : Intradermal injection 0.25% Patch 2% Challenge: Patch 0.1%

Goodwin et al. (1981)


82


Guinea pig 0/10 SIAT (single injection adjuvant test) Induction: Intradermal injection 0.1% Challenge: Patch 0.15%


Guinea pig 0/10 Modified Draize test Induction: Injection 0.375% Challenge: Injection 0.15% Application 10%


Guinea pig 8/12 GPMT Induction: Intradermal injection 1% Challenge: Patch 2.5%

Hicks et al. (1979)

Guinea pig 0/10 Split adjuvant Induction Injection 0.5% + 0.05% Challenge: Injection 2% Application 0.5%

Hicks et al. (1979)

Guinea pig Intradermal 4/8

Application 2/8

Method of Polak Induction: 0.2% + FCA intramuscularly Challenge: Intradermal injection Application + occlusion

Hicks et al. (1979)

Guinea pig 0/8 Method of Gross Induction: 0.2% + FCA subcutaneously Challenge: Intradermal injection 0.05%

Hicks et al. (1979)

* Number of positive animals/animals tested No animal data on sensitisation with nickel metal, nickel nitrate or nickel carbonate have been found.

4.1.2.4.1.2 Human data

4.1.2.4.1.2.1 Nickel allergy Nickel allergy is a Type IV allergic reaction. Characteristic for this type of reaction is that it is cell mediated (mediated by T-lymphocytes) and delayed (the reaction appears 24-72 hours after exposure). Nickel allergy manifests itself as allergic contact dermatitis, which is an inflammatory reaction in the upper part of the skin (epidermis) with erythema, infiltrations, and vesicles. Dermatologists use the terms allergy and sensitisation synonymously, as well as eczema is used as a synonym for dermatitis. Menné (1992) describes that initially in 1889 nickel dermatitis was recognised as “Das Galvanizierekzem”. In 1925 patch testing proved nickel allergy to be the cause of dermatitis in the electroplating industry. Occupational nickel dermatitis was common in the 1920’s and 1930’s while consumer nickel dermatitis first appeared in the early 1930’s. In 1992, five decades after the recognition of nickel dermatitis as a common disease in workers, it is still very common, now as a disease in the general population. Nickel dermatitis in consumers appears to have increased in these five decades (Menné, 1982, Peltonen, 1979), although the prevalence now seems to have stabilised (Menné 1998). Nickel related sensitisation is normally diagnosed by patch testing with 5% nickel sulphate in petrolatum applied to the back of the person tested under occlusion for 2 days. The reaction to the patch test is not immediate, and for this reason the result is read after 2 days, at which time a positive effect is clearly visible. Individuals sensitised to nickel fall into three groups: • those with previous eczema present under nickel-releasing objects in direct and prolonged contact with the

skin. They do not show signs of eczema, as they avoid contact with nickel objects. • those with current eczema, because they are currently exposed to nickel released from items in direct and

prolonged contact with the skin • those suffering from chronic vesicular hand eczema


83

In Denmark, legislation limiting the use of nickel-releasing objects in close and prolonged contact with the skin was introduced in 1991 (Danish EPA, 1991). As a result of this, exposure to nickel-releasing (>0.5 μg Ni/cm2/week) objects in direct and prolonged contact with the skin has been prevented, and at the same time, patients with current eczema, because they are currently exposed to nickel released from items in direct and prolonged contact with the skin has nearly disappeared in Denmark (Menné 1998). The Danish legislation is based on the use of the dimethylglyoxime test. This test is rather less sensitive than the draft EN 1811 described (Haudrechy et al. 1993). The nickel release rate of 0.5 μg/cm2/week which is specified in the nickel Directive (EC, 1994b) measured by the EN 1811 reference method adopted in 1998 (CEN, 1998) is a cut-off value intended to both prevent sensitisation in individuals that have not been previously sensitised to nickel and elicitation of symptoms in previously sensitised individuals. There may however be individuals that react to release levels lower than this cut-off value (Andersen et al. 1993, Uter et al. 1995).

4.1.2.4.1.2.2 Mechanism for the development of nickel allergy. The mechanism for development of nickel allergy has been reviewed by Menné (1996). Development of nickel allergy includes two steps, induction (also called sensitisation) and elicitation. Nickel allergy is induced by direct and prolonged skin exposure to elemental nickel, which is corroded (release of ions) by contact with sweat (see 4.1.1.1), or by skin exposure to other nickel compounds where Ni ions penetrate into the skin. In order to induce an allergic response, the nickel ion as a hapten must react with a protein in the skin to form a complete allergen, which is then taken up by a macrophage for antigen presentation to a T-lymphocyte. The Langerhans cells of the skin are believed to be responsible for transporting the allergen to the T-lymphocytes in the peripheral lymph node, where antigen presentation takes place. Here, the nickel will be presented to naive T-lymphocytes, and a sensitisation specific to nickel will take place, resulting in clones of specific sensitive memory- and effector-T-cells. This process lasts about 14 days. The next time the individual is exposed to nickel, the specific sensitised T-lymphocytes will elicit an inflammatory response in the epidermis (elicitation) at the site of exposure and possibly elsewhere.

4.1.2.4.1.2.3 Immunological tolerance Systemic exposure to nickel orally or by inhalation in individuals without contact allergy to nickel does not result in sensitisation but may result in immunological tolerance, meaning that the individual is unable to develop contact allergy to nickel at subsequent exposures. Evidence suggesting that previous exposure may prevent sensitisation was recently obtained in two epidemiological studies. The frequency of sensitisation was remarkably low in a group of junior nurses who had oral contact with this allergen through orthodontic dental treatments (van der Burg et al., 1986). In a second investigation among dermatological patients, a reduced frequency of sensitisation to nickel was observed in patients who have had oral contact with nickel releasing appliances (dental braces) at an early age, but only if this took place prior to ear piercing (van Hoogstraten et al., 1991). A study by Kerosuo et al., (1996) found that in individuals where orthodontic treatment preceded ear piercing, nickel sensitisation was prevented completely (0% prevalence). This mechanism is confirmed by the fact that earlier, in guinea pigs, the induction of immunological tolerance to nickel by oral administration before attempted sensitisation was demonstrated (Vreeburg et al., 1984). Further, in mouse models with other allergens, intravenously and orally induced tolerance have been demonstrated to depend on suppresser cell action (Gautam & Battisto, 1985, Knop et al., 1981, Asherson et al., 1985).

4.1.2.4.1.2.4 Occurrence of nickel allergy In order to quantify the problem, two methods can be used. Clinical patch test studies can be used which involve collection of data from consecutively patch tested patients at dermatological centres. Secondly, epidemiological investigations of different populations, the general population included can also be used. The first method is a relative inexpensive method for monitoring the sensitisation pattern in a given population, whereas the latter method is necessary in order to measure the frequency of sensitised individuals in the general population, even though the technique is much more expensive. Table 4.1.2.4.1.C below is modified from Menné et al. (1989) and shows the results of clinical patch test studies:

Table 4.1.2.4.1.C: Results of clinical patch test studies (modified from Menné et al. 1989)

Number of patients tested Percentage positive to nickel Study Country

Male Female Total Male Female Total

Fregert et al. (1969) Europe 2039 2786 4825 1.8 10.2 6.7


84

Oleffe et al. (1972) Belgium 184 116 300 3.8 18.1 9.3

NACDG (1973) U.S. 509 691 1200 5.6 15.0 11.0

Husain (1977) Scotland 603 709 1312 5.0 26.0 16.0

Moriearty et al. (1978) Brazil 271 265 536 2.6 11.7 7.1

Sugai et al. (1979) Japan 291 447 738 4.8 4.3 4.5

Hammershøj (1980) Denmark 1451 1774 3225 - - 6.4

Olumide (1985) Nigeria 230 223 453 11.0 12.4 11.7

Angelini et al. (1986) Italy 3587 3483 7070 4.6 20.0 12.0

Schubert et al. (1987) Eastern Europe

913 1487 2400 2.1 10.5 7.3

Table 4.1.2.4.1.D below shows the results of other more recent clinical patch test studies:

Table 4.1.2.4.1.D: Results of clinical patch test studies

Country Year Number of patients tested Percentage positive to nickel

Study

Male Female Total Male Female Total

1972-76 1945 6.7

1977-81 2082 6.3

Lunder (1988) Yugoslavia

1982-86 2373 9.1

1977-83 11962 2.6 13.7 9.2 Enders et al. (1989) Germany

1987 1845 4.5 23.9 16.7

Christophersen et al. (1989) Denmark 1985-86 696 1470 2166 5.1 20.7 15.6

Storrs et al. (1989) North America

1984-85 1123 9.7

Nethercott & Holness (1990) Canada 1981-87 335 294 629 5.1 16.7 10.5

Shehade et al. (1991) UK 4719 18.5

Nethercott et al. (1991) North America

1985-89 2170 2876 5046 10.5

Lim et al. (1992) Singapore 1986-90 2634 2923 5557 17.7

McDonagh et al. (1992) UK 248 364 612 4.4 32.7 21.2

Schnuch et al. (1997) Germany 36720 4.8 18.3 12.9

Marks et al. (1998) North America

1994-96 3108 14.3

1982 307 493 800 7 22 16 Dawn et al. (2000) Scotland

1997 191 669 860 7 26 22

1985-86 397 835 4.2 18.3 Johansen et al. (2000) Denmark

1997-98 423 844 4.9 20.0

Kanerva et al. (2001) Finland 1693 14.6 Some results of epidemiological investigations of different populations, the general population included, are given in Table 4.1.2.4.1.E, which shows the prevalence of sensitisation. By the prevalence is meant: the proportion of sensitised persons in the total population at risk, at a given point in time.

Table 4.1.2.4.1.E: Prevalence of nickel allergy in different populations


85

Reference Study population Number of persons investigated

Prevalence %

M F Total M F Total

Menné (1978) Female non-dermatological inpatients

- 213 213 - 9.4

Prystowsky et al. (1979)

Paid adult volunteers 460 698 1158 0.9 9.0

Peltonen (1979) General population 478 502 980 0.8 8.0

Kieffer (1979) Veterinary students 247 168 415 2.8 9.8

Magnusson & Möller (1979)

Orthopaedic patients 106 168 274 1.0 10.0

Menné et al. (1982)1) General population - 1976 1976 - 14.5

Boss & Menné (1982) Hairdressers – school - 53 53 - 20

Menné & Holm (1983) Female twins - 1546 1546 - 9.6

Larsson-Stymme & Windström (1985)

Schoolgirls - 960 960 - 9.0

Schmiel (1985) Surgical inpatients and hospital staff

244 259 503 1.6 7.7

von Hums (1986) Schoolchildren 135 131 266 - 7.0

Nursing (school) 29 188 217 - 13 van der Burg et al. (1986)

Hairdressers (school) 12 74 86 17.0 27.0

Widström & Erikssohn (1987)

Young men (military service) 216 - 216 1.4

Dotterud & Falk (1994) School children 223 201 424 8.5 21.9 14.9

Meijer et al. (1995) Young men (military service) 520 - 520 1.9

Mangelsdorf et al. (1996)

Aged population (age 68-87) 35 47 82 6

Mattila et al. (2000) University students 96 188 284 3.1 38.8 26.8

Adult population 1990 290 2.2 16.9 Nielsen et al. (2001)

Adult population 1998 469 2.1 17.2 1): In the investigation by Menné et al. (1982) the nickel allergy was diagnosed by history only. The outcome of the studies presented above are rather uniform, with a prevalence among females in the most recent studies above 15% which is much higher than the prevalence among men. The different studies must be compared with caution because the investigated groups are more or less selected and the age structure differs among the studies. School children are included in three of the studies and exhibit the same high prevalence rate of nickel sensitisation as adults, possibly indicating that the problem will become worse with time. A Danish population study found 11.1% of the females and 2.2% of the males sensitised to nickel. Among the 16 to 35 year old females, 19.6% gave a positive patch test to nickel. (Nielsen & Menné 1992). Whilst the overall prevalence of nickel allergy was increasing earlier (Menné et al. 1982, Peltonen 1979), it now seems to have stabilised, although at a high level (Menné 1998, Nielsen et al. 2001). In the age group 0-18 years the prevalence of nickel sensitisation has decreased from 24.8% in 1985-86 to 9.2% in 1997-98 (Johansen et al. 2000). Other studies have also demonstrated decreased prevalence to nickel allergy in the young population (Veien et al. 2001, Nielsen et al. 2001, Jensen et al. 2002). In the young age groups, ear piercing is the main cause of nickel sensitisation. The major causes of sensitisation vary, depending on fashion and other factors which influence exposure. In the 1950’s most patients were sensitised from suspenders, with the mean age for sensitisation being 30 to 35 years (Calnan 1956, Wilson 1956). The mean age for sensitisation has gradually declined in the last decades, and today most females develop their contact sensitivity to nickel as teenagers. Besides ear piercing, jewellery, jeans buttons, and other nickel


86

containing items may induce ACD to nickel. Allergic contact dermatitis is lifelong, and the most important preventive measure to avoid relapses of dermatitis in already sensitised persons is to avoid exposure. It is commonly accepted by dermatologists that sensitisation requires more intense exposure than provocation or elicitation of nickel dermatitis in already sensitised persons. Among already sensitised persons the degree of reactivity to nickel varies. Many have been shown to react to 5% nickel sulphate in petrolatum which is the concentration used in diagnostic patch testing. A minority can react at concentrations as low as 0.001% (Uter et al. 1995). The threshold for reactivity is lower when the area is occluded compared to when it is not occluded, and further the threshold is lower on irritated skin compared to normal non-irritated skin in the absence of any form of occlusion (Menné & Calvin 1993) as well as on closed exposure (Allenby & Basketter 1993).

4.1.2.4.1.2.5 Hand eczema Eczema under earrings or other jewellery, spectacle frames, watches, buttons, zippers etc. is often obvious to the affected person. Such exposures, when recognised, may be avoided rather easily. A much larger problem related to nickel allergy is however the increased risk of hand eczema, which in the general population appears with a prevalence of 10%. In populations sensitised to nickel, up to 40% have been shown to develop hand eczema, indicating that nickel allergy is one of the most prominent risk factors for hand eczema (Menné et al. 1982, Meding & Swanbeck 1990). A study by, Wilkinson & Wilkinson (1989), examined both the prevalence of nickel sensitivity in patients with hand eczema as well as the prevalence of hand eczema in nickel-sensitive patients. In the former instance, they found that nickel sensitivity in hand eczema patients appeared to be in the range of 12 to 17 percent; in the latter instance, the incidence of current hand eczema in nickel-sensitised patients appeared to lie between 17 to 24 percent. Hand eczema related to nickel allergy may result in chronic suffering, sick leave, change of jobs, early retirement, and large costs for the society (Menné & Bachman 1979). It should be underlined that even though nickel allergy is a risk factor for hand eczema, it is not understood how these two diseases are connected mechanistically. Epidemiological studies demonstrate that there is a high risk of hand eczema in populations sensitised to nickel. In individual cases, interpretation is more difficult.

4.1.2.4.1.2.6 Experimental sensitisation Kligman (1966) established a human maximisation test with the purpose to test whether a given substance was able to induce skin sensitisation. Further, the test was designed to yield allergenicity ratings depending on the frequency of sensitisation in a group of 25 test persons. The test was carried out for nickel sulphate, where the induction procedure consisted of 5 sequences of 48 hours treatment with 10% nickel sulphate. The treatments were performed on the same place on one extremity (forearm or calf of the leg) under occlusion. Whether the subjects became sensitised or not were tested with the challenge concentration of 2.5% nickel sulphate. Twelve out of 25 attempts were successful, data, which the author interprets as categorising, nickel sulphate as a moderate human sensitiser.

4.1.2.4.1.2.7 The ability of nickel salts, nickel and nickel alloys to elicit nickel allergy

4.1.2.4.1.2.7.1 Skin contact Elicitation of skin reactions can be provoked by patch testing with nickel salts or nickel alloys releasing sufficient nickel. In patch tests material is applied under occlusion for 48 hours in order to enhance the penetration. The concentration of free nickel ion is decisive for frequency and severity of reactions (see table 4.1.2.4.1.F, G and H).

Table 4.1.2.4.1.F: Total/threshold reactions (modified after Uter et al., 1995)


87

Of all reactions a) µg Ni++/ cm2 Ni conc

%(+) %(++) %(+++) No.

+-+++/thresh N

(tested)

264.0 5% 36.7 50.0 13.3 39 462

105.6 2% 42.2 47.1 10.7 17

52.8 1% 49.4 42.5 8.1 37

26.4 0.5% 60.7 31.4 7.9 70

372

5.3 0.1% 68.3 26.0 5.7 65

2.64 0.05% 68.9 24.6 6.5 30

0.53 100 ppm 83.8 16.2 - 19

329

0.264 50 ppm 100 - - 5

0.053 10 ppm 100 - - 4

0.026 5 ppm - - -

92

0 0 ppm - **) - - 462 a) %s are calculated from all reactions to a given concentration ‘all reactions’ are equal to or more than the cumulative frequency of threshold reactions, as patients without a determinable threshold) are included here. Patients without a determinable threshold are those with a negative reaction (few) or a questionable reaction to the next higher concentration. **) Uter (2003). In the study by Uter et al. (1995) 462 nickel allergic patients were patch tested with serial dilutions of nickel sulphate. 92 patients were tested with the low nickel doses. Patient reactions could be negative, questionable or positive. The positive reactions are scored as +, ++ or +++. This is a diagnostic test where the one + reaction is considered positive. 5 patients reacted to 0.264µg/cm2 and 4 to 0.053µg/cm2 with a one + reaction. The 4 positive patients correspond to 4.3% with a 95% confidence interval of [1.2 % - 10.8 %]. The 5 patients correspond to 5.4 % with a 95% confidence interval of [1.8 % - 12.2 %]. No patients reacted to 0.026µg/cm2, the lowest dose used. This gives 0.0% positive responses with a 95% confidence interval of [0.0 % - 3.9 %]. None of the 462 patients developed a positive reaction to petrolatum only (Uter, 2003). On the basis of the above figures from the Uter et al. study it is not possible to set a concentration limit were no nickel allergic patients will react after close and prolonged contact with Ni-ions. Andersen et al. (1993) tested 72 nickel-sensitive patients with a 10-step nickel sulphate dilution series (using the TRUE test) and two placebo patches. The position of the patches was rotated and the readings were performed blind. The results were analysed using a logistic dose-response model. A control group of 25 individuals without apparent skin disease, or history of metal sensitivity, was tested with the same panel to exclude irritation. Nine of the patients had positive readings to one of the two placebo patches. The authors explain these positive placebo reactions as possibly related to defective recordings of readings. The 25 control persons did not have any placebo reactions, which supports the ‘misreading story’. The data are used to calculate a dose-response curve without taking into account the positive placebo reactions. This opens the study for criticism, but it still can be used to illustrate dose-response relationships.

Table 4.1.2.4.1.G: Inverse estimation of nickel doses (µg Ni2+/cm2) causing patch-test reactions at given frequencies of doubtful (+?) and positive (+, ++, +++) reactions among nickel-sensitive patients (modified after Andersen et al. 1993).

Patch-test reaction (1)

Response frequency ≥ +? ≥+

Positive %

25 0.09 (0.07-0.13) 0.27 (0.18-0.40)

33 0.18 (0.11-0.25) 0.51 (0.36-0.74)

50 0.60 (0.42-0.83) 1.65 (1.18-2.32)


88

67 1.94 (1.34-2.90) 5.22 (3.64-7.98)

75 3.72 (2.52-5.93) 9.88 (6.58-16.15) 1) The 0.95 confidence limits are given in parenthesis Table 4.1.2.4.1.G shows the relationship between nickel patch test dose and estimated number of patch test positive patients. It illustrates the difficulties of setting NOAEL’s and LOAEL’s based on patch test studies in nickel sensitive patients. It also illustrates the shape of the dose-response curve. When the frequency of positive responders increase by a factor 2 (from 33% to 67%) the corresponding nickel dose is increased by a factor 10 (0.18-1.94 or 0.51-5.22 µg Ni2+/cm2). Both in the Uter and the Andersen studies there are patients reacting to very low nickel doses representing the very most sensitive persons in the population. The biological relevance of the results is supported by the reactivity in nickel sensitive patients to alloys with a very low nickel release rate (see also Table 4.1.2.4.1.I) . On the basis of the available data it is not possible to set a scientifically based threshold for elicitation (NOEL) in nickel sensitised individuals. Data gathered after the Danish legislation limiting nickel release from consumer items came into force suggest that the majority of the population are protected by a release rate of 0.5µg Ni/cm2/week for items in close and prolonged contact with the skin. It is the experience that the Danish legislation has also prevented current eczema in nickel sensitive patients (Menné 1998). This suggests that this rate of release is sufficient to prevent elicitation of symptoms in a significant proportion of nickel-sensitised individuals. It is possible that not all subjects with nickel allergy in all circumstances of exposure will be protected by the 0.5 µg/cm2 limit as studies with nickel sulphate has shown that the lowest concentration resulting in a positive patch test in nickel sensitive subjects corresponds to 0.05µg Ni/cm2 (Uter et al., 1995). Exposure to nickel sulphate in a patch test lasting 48 hours can be considered as a direct and prolonged contact. Whilst it is not possible to equate this figure of 0.05µg Ni/cm2 with the release rate of 0.5 µg Ni/cm2/week, the result would suggest that a lower release rate would be needed to ensure that symptoms are prevented in all nickel sensitive patients in all circumstances. This is supported by the results shown in Table 4.1.2.4.1.F, which show a decrease in elicitation rates with decreasing nickel release rates. Alloys with a nickel release of ≤ 0.5 µg Ni/cm2/week elicit a positive skin reaction in < 30% of subjects with prior sensitisation (LGC, 2003).

Table 4.1.2.4.1.H: Patch test results in patients already sensitised to nickel using nickel sulphate, chloride or nitrate as patch test material.

Number of patients tested

Percent patch test positive patients

Nickel sulphate 253µg/cm2 (1) 151 100

Nickel sulphate 94µg/cm2 101 60

Nickel chloride 94µg/cm2 101 61

Nickel nitrate 94µg/cm2 101 58

Nickel sulphate 24µg/cm2 50 34

Nickel chloride 24µg/cm2 50 46

Nickel nitrate 24µg/cm2 50 46 1) The concentration of nickel is given as Ni2+. Menné et al (1987) patch tested 173 nickel sensitive patients with discs of 15 different nickel alloys. The alloys were also tested for release of nickel in synthetic sweat pH 6.5. The results can be seen in Table 4.1.2.4.1.I.

Table 4.1.2.4.1.I: Reactivity to different alloys and nickel release in synthetic sweat

Alloy Nickel release (µg/cm2/week) 1)

Nickel release (µg/cm2/week) 2)

% reactivity in nickel-sensitised patients with 5% confidence limits

Safe alloys

Stainless steel 0.04 0.01 3 (0-11)


89

White gold 0.3 0.02 11 (4-25)

Nickel tin 0.5 0.1 23 (14-33)

Sensitising alloys

Nickel silver 40 20 81 (69-89)

Nickel chemical (2) 20 32 56 (41-69)

Nickel electrochemical 10 40 76 (62-87)

Nickel chemical (1) 70 45 79 (67-87)

Nickel iron 80 65 79 (65-90) 1): Data for nickel release after 1 weeks exposure estimated from Fig 1 and 2 in Menné et al. (1987). 2): Data for nickel release after 3 weeks exposure Nickel chemical (1) (2). Nickel alloy with 92% Ni, 8% P. (Menné et al. 1987 in Menné, 1994). Repeated immersion in nickel solutions has also been studied. Immersion of the hands in 1 ppm Ni (0.0001%) 2x10 min/day for one week where penetration was enhanced with the skin irritant sodium dodecyl sulphate did not result in elicitation of allergic reaction in nickel sensitive subjects (Allenby & Basketter 1994). In a study of 35 patients with hand eczema immersion of a finger in 10 ppm Ni as nickel chloride 10 min/day for one week followed by immersion in 100 ppm Ni the next week resulted in statistically significant increase in eczema symptoms (Nielsen et al. 1999).

4.1.2.4.1.2.7.2 Oral challenge

Table 4.1.2.4.1.J: Challenge studies in nickel-sensitive patients with an oral dose of nickel given as sulphate (updated after Menné et al., 1994).

Author Type of study Allergen dose (mg elemental nickel)

Duration of exposure

Response frequency

Christensen & Møller (1975) Double-blind 5.6 Single exposure 9/12

Kaaber et al (1978) Double-blind 2.5 Single exposure 17/28

0.6 Single exposure 1/11


Kaaber et al (1979) Double-blind


Veien et al (1979) Open 4.0 Single exposure 4/7

Jordan & King (1979) Double-blind 0.5 2 repeated days 1/10



Cronin et al (1980) Open


2.0 2 repeated days 9/22 Burrows et al (1981) Double-blind

4.0 2 repeated days 8/22

Goitre et al (1981) Open 4.4 Single exposure 2/2

2.8 Repeated dose 34/43 Single-blind

5.6

Sertoli et al (1985) Open 2.2 Single exposure 13/20



Gawkrodger et al (1986) Double-blind


Veien et al. (1987) Double-blind 2.5 Single exposure 55/131


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Santucci et al. (1988) Open 2.2 Single exposure 18/25

Nielsen et al. (1999) Single-blind 0.72 (12 µg/kg) Single exposure 9/20

1 Single exposure 2/10 Hindsén et al. (2001)

3 Single exposure 9/9 In order to investigate whether oral administration of nickel sulphate were able to worsen hand eczema Christensen & Möller (1975) gave 5.6 mg nickel as nickel sulphate orally to nickel allergic patients with hand eczema in a double-blind investigation and observed worsening of hand eczema. Flare up of contact dermatitis after oral challenge has been studied in a variety of studies thereafter with varying results (see Table 4.1.2.4.1.J). The variability may be due to variation in study design, patient groups and challenge conditions. Two studies have showed flare of dermatitis after a single oral dose of 0.6 mg nickel (Kaaber et al., 1979, Cronin et al., 1980) and one study after two weekly doses of 0.5 mg nickel (Jordan & King, 1979). In the study by Nielsen et al. (1999) 12 µg Ni /kg (equivalent to 720 µg/ 60 kg person) was given on an empty stomach to 20 nickel sensitised women and 20 age-matched controls, both groups having vesicular hand eczema. The same dermatologist, who was blinded with regard to nickel sensitisation, examined the patients. Nine of the 20 nickel allergic patients had a worsening of their hand eczema after the nickel administration, and three also developed maculopapular exanthema. No exacerbation was seen in the control group. Foodstuffs such as drinks that are often consumed in large quantities are of particular interest, as they may contribute a fairly large single dose of nickel, even though the concentration does not seem excessive. Moreover, nickel dissolved in water is more bioavailable than nickel in foods (Solomons et al. 1982, Sunderman et al., 1989). The bioavailability is highly influenced by ingestion of food. Nielsen et al. (1999) showed that when nickel was ingested in water, after an overnight fast, 30 min or 1 h prior to a meal of scrambled eggs, peak nickel concentration in serum was 13-fold higher than the one seen when nickel containing water and scrambled eggs were ingested simultaneously. It is likely that nickel intake from water will be accumulated as the median nickel half-times found in the Nielsen study was 19.9-26.7 h. A considerable number of nickel-sensitive patients have dermatitis at sites other than those in direct contact with nickel-releasing items. A fraction of these patients will benefit from a nickel-restricted diet (Veien & Menné 1990, Veien et al. 1993). Nickel is an ubiquitous element. In Denmark the mean daily dietary intake of nickel is 167µg/day with a 95% percentile of 278µg/day. The main food sources of nickel are cereal products, in particular bran, müesli and similar products, pulses, legumes and oilseeds, cocoa beans, and nuts (Larsen et al. 2002). It is possible to reduce the diet to around 100µg nickel/day (Danish Veterinary and Food Administration 1998).

4.1.2.4.1.2.7.3 Hyposensitisation Systemic exposure may also result in hyposensitisation. In one attempt, fifty-one patients presenting a dermatological allergy (erythema, urticaria, angioedema, contact dermatitis) to nickel were treated over 3 years with oral doses of 0.1 ng nickel sulphate per day, following a low-nickel diet. Diagnostic tests comprised patch and oral provocation tests. Among the 30 cases that went through the whole follow-up, symptomatology totally disappeared in 29 cases, and a partial alleviation was achieved in 1 case after 1 year of treatment. Oral provocation tests with these 30 patients showed an overall increase of tolerance. Patch tests showed no variation in 20 cases, a diminution in 5, and were negative in 5. Although the study was not conducted double blind, the results of this attempt to cure nickel allergy are statistically significant (Panzani et al. 1995). In another attempt, thirty-nine patients with nickel allergy as diagnosed by results of clinical history and intradermal testing with nickel sulphate were treated by sublingual hyposensitisation. Intradermal testing was accurate and titration showed the degree of sensitivity. The immunologic principle of oral tolerance was used in treatment. Eighty-five percent of the thirty-nine patients showed subjective improvement in their dermatitis and all showed objective evidence of decreased intradermal sensitivity. None of the patients' conditions worsened (Morris 1998).

4.1.2.4.1.2.8 Occupational nickel allergy In Denmark occupational nickel dermatitis is the second most common dermatological disease giving rise to compensation for occupational skin diseases. Irritant contact dermatitis is first, nickel second, and rubber dermatitis third. In most of the compensated occupational cases in Denmark, primary nickel sensitisation has been caused by consumer items such as buttons, ear piercing etc. (European Environmental Contact Dermatitis Group, 1990). Lidén (1994) studied occupational nickel allergy among men. The most common occupations among the nickel-allergic male patients were plating, building, mechanical and electrical work and transportation. The majority had hand eczema, and some had dermatitis on the face. There are unexpected


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exposures e.g. a black nickel-plated metal piece in an optical instrument and aluminium sheets that had been cold sealed with nickel. Lidén states that occupational nickel exposure is often overlooked both by the patient and the dermatologist and that more knowledge of the possible sensitisation by occupational exposure is needed. Evidence suggests that humid environments are more likely to favour the release of the nickel ion from metallic nickel and nickel alloys, whereas dry, clean operations with moderate or even intense contact to nickel objects will seldom, alone, provoke dermatitis (Fisher, 1989). It should be borne in mind that in some occupations for which hand eczema has been reported in higher proportion than the general populace (e.g. cleaning, hairdressing and hospital wet work), the wet work is, in and of itself, irritating, and decreases the barrier function of the skin. Often it is the combination of irritant dermatitis and compromised skin barrier that produces the allergic reaction (Fisher, 1989).

Table 4.1.2.4.1.K: Occupations with potential significant exposure to nickel and nickel compounds (Fischer, 1989)

Auto mechanic (nickel alloys) Ink maker (nickel containing chemicals)

Butcher (nickel alloys) Jeweller (nickel alloys)

Carpenter (nickel alloys) Mechanic (nickel alloys)

Cashier (nickel alloys) Metal worker and welder (nickel and nickel alloys)

Ceramic Worker (nickel containing chemicals) Office worker (nickel alloys)

Cleaner and hospital worker (nickel alloys) Painter (nickel containing chemicals)

Dentist (nickel alloys) Plumber (nickel alloys)

Dryer (nickel alloys) Printer (nickel containing chemicals)

Electrician (nickel alloys) Radio and television electronic (nickel alloys)

Electroplater (nickel containing chemicals) Repairmen (nickel alloys)

Enamel worker (nickel containing chemicals) Rubber worker (nickel catalyst)

Food manufacturer and restaurant personnel (nickel alloys)

Shop assistant (nickel alloys)

Hairdresser and barber (nickel alloys) Textile worker (nickel alloys)

Household worker (nickel alloys) Veterinarian (nickel alloys)

4.1.2.4.1.3 Conclusion on skin sensitisation Nickel metal and nickel sulphate are skin sensitiser in humans and meets the criteria for classification with R43. The Ni2+ ion is considered exclusively responsible for the immunological effects of nickel. A wide range of nickel compounds release sufficient nickel to cause skin sensitisation, and that even nickel compounds with very low water solubility can release sufficient nickel to produce the effect. However, it has been shown that certain nickel-containing oxides with specific crystal structures (spinel and rutiles) lead to a very limited release of nickel ions, and these compounds are not considered as sensitisers (see the report on the classification of a group of nickel compounds (Hart, 2007). Hence, a wide range of nickel compounds should be classified with R43.

4.1.2.4.1.3.1 Thresholds for sensitisation For nickel metal there is evidence that the Danish legislation limiting the use of nickel in objects in direct and prolonged contact with the skin to a release less than 0.5 µg Ni/cm2/week as measured by the dimethylglyoxime assay has resulted in decreased prevalence of sensitisation in the younger population (Johansen et al, 2000, Nielsen et al, 2001, Veien et al 2001, Jensen et al. 2002.). This suggests that this rate of release contributes to prevention of new cases of nickel allergy. There are no data from skin exposure to nickel sulphate, chloride, carbonate or nitrate to allow an estimate of the dose of these salts that may cause skin sensitisation. The empirical elicitation threshold of 0.3 µg Ni/cm2 is suggested to be used as the best estimate of a threshold for sensitisation. As sensitisation is assumed to require higher doses than elicitation this estimate for sensitisation is more conservative than the estimate for elicitation.


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4.1.2.4.1.3.2 Thresholds for elicitation

4.1.2.4.1.3.2.1 Skin It is the experience that the Danish legislation has also prevented current eczema in nickel sensitive patients (Menné 1998). This suggests that this rate of release is sufficient to prevent elicitation of symptoms in a significant proportion of nickel-sensitised individuals. It is possible that not all subjects with nickel allergy in all circumstances of exposure will be protected by the 0.5 µg/cm2 limit as studies with nickel sulphate has shown that the lowest concentration resulting in a positive patch test in nickel sensitive subjects corresponds to 0.05µg Ni/cm2 (Uter et al., 1995). Exposure to nickel sulphate in a patch test lasting 48 hours can be considered as a direct and prolonged contact. Whilst it is not possible to equate this figure of 0.05µg Ni/cm2 with the release rate of 0.5 µg Ni/cm2/week, the result would suggest that a lower release rate would be needed to ensure that symptoms are prevented in all nickel sensitive patients in all circumstances. This is supported by the results shown in Table 4.1.2.4.1.F, which show a decrease in elicitation rates with decreasing nickel release rates. Alloys with a nickel release of ≤ 0.5 µg Ni/cm2/week elicit a positive skin reaction in < 30% of subjects with prior sensitisation (LGC, 2003). Empirically a patch test concentration of 2.5 or 5% nickel sulphate (132 or 264µg Ni/cm2) induces a positive reaction in nickel allergic individuals. As can be seen from Table 4.1.2.4.1.H, patch test results with nickel sulphate, nickel chloride and nickel nitrate are comparable. Thus it is the concentration of nickel ion that determines the outcome of the patch test. On the basis of the available data it is not possible to set a scientifically based threshold for elicitation (NOEL) in nickel sensitised individuals. For use in the risk characterisation of occupational exposure an empirical threshold based on the data from Uter et al. (1995) may be estimated. In the Uter study a significant number of patients react to a 48 hours patch with 0.5 µg Ni/cm2 (19/329). In the next dose group 5/92 patients react to 0.26 µg Ni/cm2. These patients only react with a one plus reaction and must be considered to belong to the very most sensitive part of the population. As it is unlikely that an occupational exposure will last for 48 hours and that workers in the nickel industry have extremely sensitive nickel allergies. an empirical threshold (NOEL) of 0.3 µg Ni/cm2 is suggested.

4.1.2.4.1.3.2.2 Oral It is not possible to establish a NOAEL for oral challenge in patients with nickel dermatitis. The LOAEL established after provocation of patients with empty stomach is 12µg/kg body weight (Nielsen et al. 1999). This figure is not far from the dose found in the study by Hindsén et al (2001) where a total dose of 1 mg (17µg/kg body weight) resulted in a flare up of dermatitis in an earlier patch test site in 2/10 nickel sensitive patients. It should be noted that the dose of 12µg/kg body weight is the acute LOAEL in fasting patients on a 48h diet with reduced nickel content. A LOAEL after repeated exposure may be lower and a LOAEL in non-fasting patients is probably higher because of reduced absorption of nickel ions when mixed in food.

4.1.2.4.2 Respiratory sensitisation The Technical Guidance Document underscores that respiratory hypersensitivity is a term that is used to describe asthma and other related respiratory conditions, irrespective of the mechanism by which they are caused. Five single cases of work related asthma due to exposure to nickel sulphate in electro- or metal plating have been reported (Block & Yeung, 1982, Malo et al., 1982, Malo et al., 1985, McConnell et al. 1973, Novey et al., 1983). In all five cases, the diagnosis was based on clinical picture and specific bronchial inhalation test with nickel sulphate. Nickel sulphate is already classified as a respiratory sensitiser, R42. There are a number of reports of occupational asthma associated with exposure to metallic nickel (Block & Yeung, 1982, Estlander et al. 1993, Shirakawa et al. 1990). Whilst there is no proper epidemiologic study that has specifically looked at incidence of asthma, there are many studies that have looked at mortality from non-malignant respiratory diseases (including asthma) among nickel workers with metallic nickel exposures. These studies support the contention that the number of reported cases of nickel induced asthma is insufficient to warrant a classification compared to the large population exposed. The TC C&L does not consider that these reports provide adequate evidence for classification for this effect. For nickel chloride, nickel nitrate and nickel carbonate no data regarding respiratory sensitisation in humans have been located. As the soluble salt nickel sulphate induces respiratory sensitisation, and given the potential for respiratory sensitisation shown by the metal, it must be assumed that nickel carbonate, nickel nitrate and nickel chloride have also the potential to induce respiratory sensitisation.

4.1.2.4.2.1 Conclusion on respiratory sensitisation Nickel sulphate is a respiratory sensitiser in humans and meets the criteria for R42.


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The Ni2+ ion is considered exclusively responsible for the immunological effects of nickel. As the soluble salt nickel sulphate induces respiratory sensitisation it must be assumed that nickel chloride, nickel nitrate and nickel carbonate have also the potential to induce respiratory sensitisation and have been classified with R42 in the 30th ATP. Metallic nickel has also been reported to cause respiratory sensitisation, but the effect is not sufficient to justify classification with R42. It is not possible to set a threshold for sensitisation or elicitation.

4.1.2.4.3 Conclusion Nickel metal is a skin sensitiser in humans and should be classified as R43. Metallic nickel has also been reported to cause respiratory sensitisation, but the effect is not sufficient to justify classification with R42. It is considered necessary to include a proposal for setting a specific release limit for the classification of alloys containing nickel for skin sensitisation. It is recognised that the limits for expressing this threshold is related not to the concentration of nickel in the metal or alloy but rather to the rate of nickel release expressed as µg Ni/cm2/week from the material. A specific concentration limit based on a new Note relating to the labelling of preparations in the Foreword to Annex I has been included in the 30th ATP. The draft note reads: “Alloys containing nickel are classified for skin sensitisation when the release rate of 0.5 μg Ni/cm2/week as measured by the European Standard reference test method, EN 1811 is exceeded.” The suggested level to prevent sensitisation after direct and prolonged contact with nickel releasing alloys in a substantial proportion of a non-sensitised population is 0.5µg Ni/cm2/week. The suggested level to prevent elicitation in nickel allergic patients is 0.5µg Ni/cm2/week. Complete protection for the most sensitive sensitised persons may only be achieved at lower levels. Alloys with a nickel release of ≤ 0.5 µg Ni/cm2/week elicit a positive skin reaction in < 30% of subjects with prior sensitisation (LGC, 2003). It is not possible to set thresholds for sensitisation and elicitation after intermittent and semi-direct exposures. Nickel sulphate is already classified as a skin and respiratory sensitiser (R42/43). The TC C&L has agreed that nickel chloride, nickel nitrate and the nickel carbonates should also be classified as skin and respiratory sensitisers (R42/43). A specific concentration limit of 0.01% for R43 has also been agreed for nickel sulphate, nickel chloride and nickel nitrate12. It is not possible to set a scientifically based threshold for skin elicitation and sensitisation caused by nickel salts after direct and prolonged exposure. For use in the risk characterisation of occupational exposure an empirical threshold of 0.3 µg Ni/cm2 is suggested. It is not possible to set a threshold for respiratory sensitisation or elicitation. An acute LOAEL for oral challenge of 0.012 mg Ni/kg is used in the risk assessment.

4.1.2.5 Repeated dose toxicity

4.1.2.5.1 Animal studies Data from the risk assessments of nickel metal, nickel carbonate, nickel sulphate, nickel chloride and nickel nitrate are shown in Table 4.1.2.5.A. In addition, the table contains data for two other nickel compounds, nickel oxide and subsulphide, where relevant studies of good quality have been performed. A more detailed description is given in sections 4.1.2.5.2 to 4.1.2.5.4.

Table 4.1.2.5.A: Summary of repeated dose toxicity studies for nickel compounds.

Inhalation Oral Dermal Compound-specific conclusion

Nickel metal

(insoluble)

28-day rat study (WIL Research Laboratories, 2002).

13-week rat study (WIL Research Laboratories,

No studies found No studies found Inhalation LOAEC 1 mg Ni/ m3 (lung inflammation, WIL Research Laboratories, 2003).

12 These classifications and specific concentration limits are included in the 30th ATP.


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2003).Five studies (Hueper 1958, Hueper & Payne 1962)

no oral, no dermal conclusion

Nickel (hydroxy)carbonate

(slightly soluble)

No studies found calves 8 weeks dietary (O’Dell et al., 1970)

monkeys 4 months dietary (Phatak & Patwardham, 1950, quoted from UK HSE, 1987)

No studies found Available data insufficient for conclusion

Nickel chloride

(very soluble)

No studies on systemic effects found.

A number of studies of effects on lung macrophages in rabbits (Johansson et al., 1980, 1986, 1987 and 1988; Berghem et al., 1987; Lundborg & Camner, 1981-82,1984; Camner et al., 1984).

rats 25 weeks drinking water (Kurokawa et al., 1985)

rats 91 days gavage (American Biogenics Corporation, 1988)

rats 77 days dietary (Nation et al., 1985)

rats 28 days drinking water (Weischer et al., 1980)

No studies found Inhalation LOAEC 0.2 mg Ni/m3 (effects in lung macrophages, Johansson et al., 1980, 1986, 1987 and 1988; Berghem et al., 1987; Lundborg & Camner, 1981-82,1984; Camner et al., 1984)

oral LOAEL of 5 mg Ni/kg bw/day (mortality, American Biogenics Corporation, 1988)

no dermal conclusion

Nickel sulphate

(very soluble)

2-year studies, 13 weeks studies (NTP, 1996a); Benson et al. , 1989,1992, 1995; Kosova, 1979 – quoted from UK HSE 1987)

rats 90-day oral gavage study (SLI, draft not dated, submitted 2002)

rats drinking water ad libitum for 13 weeks (Obone et al. 1999)

rats 2-year feeding study (Ambrose et al. 1976)

rats gavage 7 months (Itskova et al. 1969 – quoted from UK HSE 1987)

dogs dietary 2 years (Ambrose et al. 1976)

rats drinking water for 6 months (Vyskocil et al. 1994)

mice drinking water 180 days

(Dieter et al. 1988)

mice dietary 4 weeks

(Schiffer et al. 1991, quoted from TERA, 1999)

rats 15 or 30 days (Mathur et al., 1977)

No NOAEC identified

LOAEC of 0.056 mg Ni/m3 (inflammation and fibrosis), (NTP, 1996a).

oral LOAEL of 6.7 mg Ni/kg bw/day (decreased survival rate (females), reduced body weight gain (both sexes)) and NOAEL of 2.2 mg Ni/kg bw/day (however, associated with a slight decrease in body weight gain (both sexes) and survival in females (CRL 2005)

available dermal data insufficient for conclusion


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rats (gavage) for 2 years (CRL 2005)

Nickel nitrate

(very soluble)

No studies found No studies found No studies found Available data insufficient for conclusion

Other nickel compounds

Nickel subsulphide

(insoluble)

6 studies: 16 days, 13 weeks, 2 years in rats and mice (NTP 1996c)

78 weeks (Ottolenghi et al. 1975, quoted from UK HSE, 1987)

Inhalation LOAEC of 0.15 mg Ni/m3 (chronic lung inflammation and fibrosis in 2-year rat study, NTP, 1996c)

Nickel oxide

(insoluble)

6 studies: 16 days, 13 weeks, 2 years in rats and mice (NTP 1996b), a number of studies referred in UK HSE (1987)

Inhalation LOAEC of 0.5 mg Ni/m3 (chronic lung inflammation in 2-year rat study, NTP, 1996b)

4.1.2.5.1.1 Inhalation Data for inhalation toxicity have been found for nickel sulphate hexahydrate, nickel subsulphide, nickel oxide, nickel chloride, and metallic nickel. The principal effects following inhalation of nickel compounds are found in the respiratory tract. Atrophy of olfactory epithelium and chronic active lung inflammation with fibrosis are typical findings. Accumulation of macrophages has in some studies been found to occur at lower concentrations than other lesions, and it has been debated whether the reaction should be interpreted as an adaptive repair response, or as an adverse event in a sequence leading ultimately to fibrosis. A definitive conclusion regarding the biological significance of macrophage accumulation is not possible according to the TERA review (1999).

4.1.2.5.1.1.1 NTP studies of nickel sulphate hexahydrate, nickel subsulphide and nickel oxide. The United States National Toxicology Program has carried out a series of inhalation studies in rats and mice with three nickel compounds (NTP 1996a, 1996b, 1996c). The three nickel compounds were the soluble nickel sulphate hexahydrate, and the insoluble compounds nickel subsulphide and nickel oxide. The present section gives a review of the studies and focuses on a comparison of the results. The data on nickel sulphate hexahydrate have already been described in the Risk Assessment Report for this substance, but are included here for the sake of comparison. Nickel sulphate hexahydrate: Male and female F344/N rats and B6C3F1 mice were exposed to nickel sulphate hexahydrate (mass mean diameter 1.8-3.1 micrometer ± 1.6-2.9; greater than 98% pure) by inhalation for 16 days, 13 weeks, or 2 years. Nickel oxide: Male and female F344/N rats and B6C3F1 mice were exposed to nickel oxide (high temperature, green nickel oxide; mass median diameter 2.2 ± 2.6 micrometer; at least 99% pure) by inhalation for 16 days, 13 weeks, or 2 years. Nickel subsulphide. Male and female F334/N rats and B6C3F1 mice were exposed to nickel subsulphide (at least 97% pure; the mean value for the mass median aerodynamic diameter at each exposure concentration ranged from 2.0 to 2.2 micrometer) by inhalation 6 hours per day, 5 days per week, for 16 days, 13 weeks, or 2 years.

4.1.2.5.1.1.1.1 16-day rat studies All three studies used inhalation exposure for 6 h/day, 5 d/week for a total of 12 exposure days during a 16-day period (core studies). The group size was 5 males and 5 females. Additional groups of five male and five female rats were exposed for tissue burden studies, these studies are not described in the present section.


96

A comparison of the results of the three compounds studied shows similar types of effects, including atrophy of olfactory epithelium, lung tissue inflammation, and increased relative and absolute lung weights, however to a varying degree of incidence and severity depending on the compound and dose. The following order of toxicity, based on mg nickel/m3, is indicated: Nickel sulphate hexahydrate>nickel subsulphide>nickel oxide.

Table 4.1.2.5.B: 16-day rat studies

Nickel sulphate hexahydrate Nickel oxide Nickel subsulphide

0, 3.5, 7, 15, 30, or 60 mg nickel sulphate hexahydrate/m3 (equivalent to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg nickel/m3).

0, 1.2, 2.5, 5, 10, or 30 mg nickel oxide/m3 (equivalent to 0, 0.9, 2.0, 3.9, 7.9, or 23.6 mg nickel/m3)

0, 0.6, 1.2, 2.5, 5, or 10 mg nickel subsulphide/m3 (equivalent to 0, 0.44, 0.88, 1.83, 3.65, and 7.33 mg nickel/m3)

In the core study, two 60 mg/m3 males, one 30 mg/m3 female, and all 60 mg/m3 females died before the end of the study. Final mean body weights of all exposed groups of males and females were significantly lower than those of the controls, as were mean body weight gains of male rats. Clinical findings included increased rates of respiration and reduced activity levels in rats in all exposure groups, except those exposed to 3.5 mg/m3. Absolute lung weights of 60 mg/m3 males and of all exposed groups of females were significantly greater than those of the controls, as were the relative lung weights of all exposed groups of males and females. Inflammation (including degeneration and necrosis of the bronchiolar epithelium) occurred in the lungs of all exposed groups of males and females. Atrophy of the olfactory epithelium occurred in the nasal passages of all exposed groups of males (except 60 mg/m3) and in 15, 30, and 60 mg/m3 females. Lymphoid hyperplasia in the bronchial or mediastinal lymph nodes was observed in 30 mg/m3 males and in 60 mg/m3 males and females.

The concentration of nickel in the lungs of all exposed groups of males and females was greater than in control animals.

All core study rats survived until the end of the study, final mean body weights of exposed male and female rats were similar to those of the controls, and there were no clinical findings related to nickel oxide exposure. Absolute and relative lung weights of male and female rats exposed to 10 or 30 mg/m3 were significantly greater than those of the controls. Pigment particles in alveolar macrophages or within the alveolar spaces were observed in the lungs of exposed groups of males and females. Chronic-active inflammation and accumulation of macrophages in alveolar spaces of the lungs and hyperplasia in the respiratory tract lymph nodes were most severe in 10 and 30 mg/m3 males and females. Hyperplasia of bronchial lymph nodes occurred in 30 mg/m3 rats. Atrophy of the olfactory epithelium was observed in one male and one female exposed to 30 mg/m3.

The concentrations of nickel oxide in the lungs of exposed groups of rats were greater than those in the lungs of control groups (males, 42 to 267 µg nickel/g lung; females, 54 to 340 µg nickel/g lung).

One male exposed to 10 mg nickel subsulphide/m3 in the core study died on day 14; all other rats survived until the end of the study. Final mean body weights and mean body weight gains of males exposed to 5 or 10 mg nickel subsulphide/m3 and females exposed to 2.5, 5, or 10 mg/m3 were significantly lower than those of the controls. Clinical findings of toxicity on day 5 of the study included laboured respiration in 10 mg/m3 males and 5 and 10 mg/m3 females and dehydration in 5 and 10 mg/m3 females. Absolute and relative lung weights of 2.5, 5, and 10 mg/m3 males and all exposed groups of females were significantly greater than those of the controls, as was the absolute lung weight of 1.2 mg/m3 males. Inflammation of the lung and atrophy of the nasal olfactory epithelium occurred in all exposed groups. The concentrations of nickel in the lungs of exposed groups of rats increased with exposure concentration (males, 7 to 67 µg nickel/g lung; females, 9 to 77 µg nickel/g lung).

4.1.2.5.1.1.1.2 16-day mouse studies All three studies used inhalation exposure for 6 h/day, 5 d/week for a total of 12 exposure days during a 16-day period (core studies). The exposure concentrations were identical to the corresponding rat study, allowing a direct comparison between the two species. The group size was 5 males and 5 females. Additional groups of 5 male and 5 female mice were exposed for tissue burden studies; these studies are not described in the present section. Similar types of toxic effects, and a similar order of toxicity to that of the rat, based on mg nickel/m3, are indicated: Nickel sulphate hexahydrate>nickel subsulphide>nickel oxide. The mouse was more sensitive than the rat to the toxic effects of nickel sulphate.

Table 4.1.2.5.C: 16-day mouse studies


0, 3.5, 7, 15, 30, or 60 mg nickel sulphate hexahydrate/m3 (equivalent to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg nickel/m3).

0, 1.2, 2.5, 5, 10, or 30 mg nickel oxide/m3 (equivalent to 0, 0.9, 2.0, 3.9, 7.9, or 23.6 mg nickel/m3)

0, 0.6, 1.2, 2.5, 5, or 10 mg nickel subsulphide/m3 (equivalent to 0, 0.44, 0.88, 1.83, 3.65, and 7.33 mg nickel/m3)

All core study mice exposed to 7 mg/m3 or greater died before the end of the study; all control and 3.5 mg/m3 mice survived to the end of the study. Final mean body weights and

No exposure-related deaths occurred among core study mice, and final mean body weights of exposed male and female mice were similar to those of the controls. There were no chemical-

All male and female mice exposed to 10 mg nickel subsulphide/m3 in the core study died before the end of the study; the death of one female was accidental. One control male, one control female, and one 1.2 mg/m3 male


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weight gains of 7, 15, 30, and 60 mg/m3 males and females were significantly less than those of the controls, and clinical findings in these groups included emaciation, lethargy, and rapid respiration rates. Absolute and relative lung weights of male and female mice exposed to 7 mg/m3 or greater were significantly greater than those of the controls. Only tissues from mice exposed to 0, 3.5, or 7 mg/m3 were examined histopathologically. Inflammation occurred in the lungs of 3.5 and 7 mg/m3 males and females; necrosis of the alveolar and bronchiolar epithelium was a component of the inflammation in 7 mg/m3 males and females. In addition, atrophy of the olfactory epithelium of the nasal passages was observed in 3.5 mg/m3 males and females.

Nickel concentrations in the lungs of mice exposed to 3.5 mg/m3 were greater than those in the controls.

related clinical findings. Pigment particles were present in the lungs of mice exposed to 2.5 mg/m3 or greater. Accumulation of macrophages in alveolar spaces was observed in the lungs of 10 and 30 mg/m3 males and females.

The concentrations of nickel oxide in the lungs of exposed groups of mice were significantly greater than those in the lungs of control animals (males, 32 to 84 µg nickel/g lung; females, 31 to 71 µg nickel/g lung).

also died before the end of the study. Final mean body weights and mean body weight gains of 5 mg/m3 males were significantly lower than those of the controls. Clinical findings at day 5 included laboured respiration in 10 mg/m3 males and females. The absolute lung weight of 5 mg/m3 males, the absolute and relative lung weights of 10 mg/m3 males and 5 mg/m3 females, and the relative lung weight of 10 mg/m3 females were significantly greater than those of the controls. Inflammation of the lung occurred in 2.5, 5, and 10 mg/m3 male and female mice, fibrosis of the lung occurred in 5 mg/m3 males and females, and lymphoid hyperplasia of the bronchial lymph nodes and atrophy of the nasal olfactory epithelium occurred in 1.2, 2.5, 5, and 10 mg/m3 males and females.

Nickel concentrations in the lung of exposed male and female mice were greater than those of the controls (males, 10 to 20 µg nickel/g lung; females, 8 to 20 µg nickel/g lung).

4.1.2.5.1.1.1.3 13-week rat studies Group size 10 males and 10 females. Additional groups of rats were exposed for tissue burden studies; these studies are not described in the present section. The comparison of the three compounds shows effects similar to those identified in the 16-day studies, including atrophy of olfactory epithelium, lung tissue inflammation, and increased relative and absolute lung weights. Again, nickel oxide appears less toxic than the other two compounds based on mg nickel/m3.

Table 4.1.2.5.D: 13-week rat studies


0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulphate hexahydrate (equivalent to 0, 0.03, 0.06, 0.11, 0.22, or 0.44 mg nickel/m3)

0, 0.6, 1.2, 2.5, 5, or 10 mg nickel oxide/m3 (equivalent to 0, 0.4, 0.9, 2.0, 3.9, or 7.9 mg nickel/m3)

0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickel subsulphide/m3 (equivalent to 0, 0.11, 0.22, 0.44, 0.88, and 1.83 mg nickel/m3)

In the core study, one 2 mg/m3 male rat died before the end of the study; all other males and all females survived until the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no significant clinical findings noted during the study. Exposure-related increases in neutrophile and lymphocyte numbers occurred and were most pronounced in female rats. With the exception of 0.12 mg/m3 rats, absolute and relative lung weights of all exposed groups were generally significantly greater than those of the controls. Exposure-related increases in the incidence and severity of inflammatory lesions (alveolar macrophages, chronic inflammation, and interstitial infiltration) occurred in the lungs of all exposed groups of males and females. Lymphoid hyperplasia of the bronchial and/or mediastinal lymph nodes occurred in males exposed to 0.5 mg/m3 or greater. Atrophy of the olfactory epithelium occurred in males and females exposed to 0.5, 1, and 2 mg/m3 and in 0.25 mg/m3

females. The concentration of nickel in the lungs of 0.5 and 2 mg/m3 rats was greater than that in the lungs of control animals at 4, 9, and 13 weeks

No exposure-related deaths occurred among core study rats, final mean body weights of exposed male and female rats were similar to those of the controls, and no clinical findings in any group were related to nickel oxide exposure. Lymphocyte, neutrophile, monocyte, and erythrocyte counts; haematocrit values; and haemoglobin and mean cell haemoglobin concentrations in exposed rats were minimally to mildly greater than those of the controls; these differences were most pronounced in females. Mean cell volumes in exposed rats were generally less than those in the controls. Absolute and relative lung weights of exposed groups of males and females were generally significantly greater than those of controls.

Chemical-related non-neoplastic lesions were observed in the lungs of male and female rats exposed to concentrations of 2.5 mg/m3 or higher, and the severity of these lesions generally increased with exposure concentration. Accumulation of alveolar macrophages, many of which contained black, granular pigment, was generally observed in all exposed groups of males and females, and increased incidences of inflammation

All core study rats survived until the end of the study. Final mean body weights and mean body weight gains of 2.5 mg/m3 males were significantly lower than those of the controls; final mean body weights of all other exposure groups were similar to those of the controls. Chemical-related clinical findings included laboured respiration in 2.5 mg/m3 males and females during weeks 2 through 7. In general, neutrophile and erythrocyte counts, haematocrit values, and haemoglobin concentrations were minimally increased in exposed rats. Absolute and relative lung weights of all exposed groups were significantly greater than those of the controls.

Increases in the number of alveolar macrophages, interstitial infiltrates, or incidences of chronic inflammation of the lung occurred in all groups exposed to nickel subsulphide concentrations of 0.3 mg/m3 or greater; the severity of these lesions generally increased with increasing exposure concentration. Increases in the number of alveolar macrophages were observed in 0.15 mg/m3 males and females. Lymphoid hyperplasia of the bronchial and mediastinal lymph nodes was observed in rats exposed to 0.3 mg/m3 or greater. Most 0.6, 1.2, and 2.5 mg/m3 males and females had atrophy of the nasal olfactory epithelium, and the severity generally increased with increasing exposure concentration.


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for males and at 13 weeks for females.

occurred in males and females exposed to 2.5 mg/m3 or higher. In addition, lymphoid hyperplasia and pigment occurred in the bronchial and mediastinal lymph nodes of 2.5, 5, and 10 mg/m3 males and females.

The concentration of nickel oxide in the lungs of 0.6, 2.5, and 10 mg/m3 males was greater than in the lungs of controls at 4, 9, and 13 weeks, and nickel continued to accumulate in the lung at the end of the 13-week exposures (4 weeks, 33 to 263 µg nickel/g lung; 9 weeks, 53 to 400 µg nickel/g lung; 13 weeks, 80 to 524 µg nickel/g lung).

Nickel concentrations in the lung increased with exposure concentration and were greater than those in the controls in rats exposed for 13 weeks (males, 5 to 18 mg nickel/g lung; females, 5 to 17 mg/g lung).

In a recent 13-week inhalation toxicity study, groups of Wistar rats were exposed (whole body exposure) to metallic nickel powder 6h/d, 5 d/w for 13 weeks at exposure levels of 0, 1, 4, and 8 mg/m3 (WIL Research Laboratories, 2003). The histological and/or toxicological most prominent and significant findings in the lungs were described as: black pigment (nickel dust), alveolar proteinosis and granulomatous inflammation in all groups of nickel exposure; mucoid exudate, fibrosis and mononuclear infiltrate in the 4 and 8 mg/m3 groups; alveolar/bronchiolar hyperplasia at the highest dose levels in both sexes and at 4 mg/m3 in males. The lowest exposure level, 1 mg/ m3, was a LOAEC for changes in lung weight and relative lung weight, alveolar proteinosis and granulomatous inflammation, accumulation of nickel particles in the lung and increased nickel blood levels.

4.1.2.5.1.1.1.4 13-week mouse studies The exposure concentrations were identical to the corresponding rat study, allowing a direct comparison between the two species. Effects were similar to those identified in the 16-day studies, including atrophy of olfactory epithelium, lung tissue inflammation, and increased relative and absolute lung weights.

Table 4.1.2.5.E: 13-week mouse studies


0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulphate hexahydrate/m3 (equivalent to 0, 0.03, 0.06, 0.11, 0.22, or 0.44 mg nickel/m3)

0, 0.6, 1.2, 2.5, 5, or 10 mg nickel oxide/m3 (equivalent to 0, 0.4, 0.9, 2.0, 3.9, or 7.9 mg nickel/m3)

0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickel subsulphide/m3 (equivalent to 0, 0.11, 0.22, 0.44, 0.88, and 1.83 mg nickel/m3)

In the core study, four control males, three control females, and one 0.12 mg/m3 male died before the end of the study; the deaths were not considered to be chemical related, and all other mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no chemical-related clinical findings. Haematology changes similar to those reported in female rats occurred in female mice, but the mice were minimally affected. The absolute and relative lung weights of 1 mg/m3 males and 2 mg/m3 males and females were significantly greater than those of the controls. Increased numbers of alveolar macrophages occurred in all males and females exposed to 0.5 mg/m3 or greater. Chronic active inflammation and fibrosis occurred in 1 and 2 mg/m3 males and females. Lymphoid hyperplasia of the bronchial lymph node and atrophy of the olfactory epithelium in the nasal passages were observed in 2 mg/m3

males and females.

Nickel concentration in the lung of 2 mg/m3 females was significantly

No exposure-related deaths occurred among core study animals, final mean body weights of exposed male and female mice were similar to those of the controls, and no clinical findings in any group were related to nickel oxide exposure. Haematocrit values and erythrocyte counts in 5 and 10 mg/m3 females were minimally greater than those of the controls, as was the haemoglobin concentration in 5 mg/m3 females. Absolute and relative lung weights of 10 mg/m3 males and females were significantly greater than those of controls, and absolute and relative liver weights of 10 mg/m3 males were significantly less than those of controls.

Accumulation of alveolar macrophages, many of which contained pigment particles, occurred in all groups of mice exposed to nickel oxide. Inflammation (chronic active perivascular infiltrates or granulomatous) occurred in 2.5, 5, and 10 mg/m3 males and females. In addition, lymphoid hyperplasia and pigment occurred in the bronchial lymph nodes of males and females exposed to 2.5 mg/m3 or higher.

The concentration of nickel in the lung

Final mean body weights of all exposure groups were similar to those of the controls. No chemical-related clinical findings were observed. Lymphocyte counts in 1.2 and 2.5 mg/m3 males were minimally greater than that of the controls. Haemoglobin concentrations and erythrocyte counts in 0.3, 0.6, 1.2, and 2.5 mg/m3 females were minimally greater than those of the controls. Absolute and relative lung weights of 1.2 and 2.5 mg/m3 males and females were significantly greater than those of the controls. An increase in alveolar macrophages was present in mice from the 0.3 mg/m3 and higher exposure groups. Chronic inflammation and fibrosis were observed in the lung of 1.2 and 2.5 mg/m3 males and females. Interstitial infiltrates of lymphocytes were observed in mice exposed to 0.6, 1.2, or 2.5 mg/m3. Lymphoid hyperplasia of the bronchial lymph nodes was observed in groups exposed to 1.2 or 2.5 mg/m3.

Atrophy of the nasal olfactory epithelium occurred in 0.6, 1.2, and 2.5 mg/m3 males and females, and incidences and severity generally increased with increasing exposure concentration.

At 13 weeks, nickel concentrations in the lungs of exposed mice were greater than those of the controls (males, 3 to 17 µg


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greater than in control animals. was greater than that of controls in 0.6, 2.5, and 10 mg/m3 males at 13 weeks (42 to 736 µg nickel/g lung).

nickel/g lung; females, 6 to 23 µg nickel/g lung) and these concentrations increased with increasing exposure concentration.

4.1.2.5.1.1.1.5 2-year rat studies Groups of 63-65 male and 63-64 female F344/N rats were exposed by inhalation for 6h/day, 5d/week, for 104 weeks. Effects included lung tissue inflammation, and increased relative and absolute lung weights. The soluble sulphate and insoluble subsulphide both caused atrophy of the nasal epithelium.

Table 4.1.2.5.F: 2-year rat studies


0, 0.12, 0.25, or 0.5 mg/m3 (equivalent to 0, 0.03, 0.06, or 0.11 mg nickel/m3)

0, 0.62, 1.25, or 2.5 mg nickel oxide/m3 (equivalent to 0, 0.5, 1.0, or 2.0 mg nickel/m3)

0, 0.15, or 1 mg nickel subsulphide/m3 (equivalent to 0, 0.11, or 0.73 mg nickel/m3)

The survival rates of all exposed groups of males and females were similar to those of the controls. Mean body weights of 0.5 mg/m3 female rats were slightly lower (6% to 9%) than those of the controls throughout the second year of the study; final mean body weights of all exposed groups of males and 0.12 and 0.25 mg/m3 females were similar to those of the controls. There were no clinical findings or haematology differences that were considered to be related to nickel sulphate hexahydrate administration.

Increased incidences of inflammatory lung lesions were generally observed in all exposed groups of male and female rats at the end of the study. The incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis were markedly increased in male and female rats exposed to 0.25 or 0.5 mg/m3. Increased incidences of lymphoid hyperplasia in the bronchial lymph nodes occurred in 0.5 mg/m3

male and female rats at the end of the 2-year study. The incidences of atrophy of the olfactory epithelium in 0.5 mg/m3 males and females were significantly greater than those in controls at the end of the study.

Lung nickel burdens in exposed male and female rats were greater than those in the controls at the 7- and 15-month interim evaluations, and lung nickel burdens values increased with increasing exposure concentration.

Survival of exposed male and female rats was similar to that of the controls. Mean body weights of 1.25 mg/m3 females and 2.5 mg/m3 males and females were slightly lower than those of the controls during the second year of the study. No chemical-related clinical findings were observed in male or female rats during the 2-year study. No chemical-related differences in haematology parameters were observed in male or female rats at the 15-month interim evaluation.

Absolute and relative lung weights of 1.25 and 2.5 mg/m3 males and females were significantly greater than those of the controls at 7 and 15 months. Chronic inflammation of the lung was observed in most exposed rats at 7 and 15 months and at 2 years; the incidences in exposed males and females at 2 years were significantly greater than those in the controls, and the severity of the inflammation increased in exposed groups. The incidences of pigmentation in the alveolus of exposed groups of males and females were significantly greater than those of the controls at 7 and 15 months and at 2 years.

Pigmentation in the bronchial lymph nodes similar to that in the lungs was observed in all exposure groups with the exception of 0.62 mg/m3 males and females at 7 months. Lymphoid hyperplasia was observed in the bronchial lymph nodes of 1.25 and 2.5 mg/m3 males and females at 7 and 15 months, and the incidence at 2 years generally increased with exposure concentration.

Nickel concentrations in the lung of exposed rats were greater than those in the controls at 7 and 15 months (7 months, 173 to 713 µg nickel/g lung; 15 months, 262 to 1116 µg nickel/g lung), and nickel concentrations increased with increasing exposure concentration and with time.

Survival of exposed males and female rats was similar to that of the controls. Mean body weights of males and females exposed to 0.15 mg/m3 were similar to those of the controls. Mean body weights of rats exposed to 1 mg/m3 were lower than those of the controls throughout the second year of the study. Chemical-related clinical findings included rapid and shallow breathing following exposure periods. Haematocrit values and haemoglobin concentrations in 1 mg/m3 males and females and the erythrocyte count in 1 mg/m3 males were mildly greater than those in the controls.

In general, the absolute and relative lung weights of exposed males and females were significantly greater than those of the controls at 7 and 15 months. Non-neoplastic lung lesions generally observed in exposed males and females included fibrosis; chronic active inflammation; focal alveolar epithelial hyperplasia, macrophage hyperplasia, and proteinosis; bronchial lymphoid hyperplasia; and interstitial inflammation.

At 2 years, the incidences of chronic active inflammation of the nose in 1 mg/m3 females and of olfactory epithelial atrophy in 1 mg/m3 males and females were significantly greater than those of the controls.

The incidences of lymphoid hyperplasia of the bronchial lymph node in exposed males at 7 and 15 months and in exposed males and females at 2 years were significantly greater than those of the controls. Incidences of macrophage hyperplasia in the bronchial lymph node of exposed males at 15 months and exposed males and females at 2 years were greater than those of the controls.

Nickel concentrations in the lungs of exposed rats were greater than those of the controls at 7 months (males, 6 to 9 µg nickel/g lung; females, 6 to 9 µg nickel/g lung) and 15 months (males, 4 to 3 µg nickel/g lung; females, 4 to 7 µg nickel/g lung).

4.1.2.5.1.1.1.6 2-year mouse studies Groups of B6C3F1 mice were exposed by inhalation for 6h/day, 5d/week, for 104 weeks. For nickel sulphate and subsulphide, the group size was 80, and for nickel oxide, the group size was 74-79. Effects included lung tissue inflammation, and increased relative and absolute lung weights.

Table 4.1.2.5.G: 2-year mouse studies


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0, 0.25, 0.5, or 1 mg/m3 (equivalent to 0, 0.06, 0.11, or 0.22 mg nickel/m3).

0, 1.25, 2.5, or 5 mg nickel oxide/m3 (equivalent to 0, 1.0, 2.0 or 4.0 mg nickel/m3)

0, 0.6, or 1.2 mg nickel subsulphide/m3 (equivalent to 0, 0.44, or 0.88 mg nickel/m3)

The survival rates of all exposed groups of males and females were similar to those of the controls. The mean body weights of 1 mg/m3 males and of all exposed groups of females were lower than those of the controls during the second year of the study. There were no clinical findings or haematology differences considered to be related to chemical exposure. Inflammatory lesions of the lung generally occurred in all exposed groups of male and female mice at the end of the 2-year study. These lesions included macrophage hyperplasia, chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), alveolar proteinosis, and infiltrating cells in the interstitium. Incidences of macrophage hyperplasia and/or lymphoid hyperplasia occurred in the bronchial lymph nodes of most of the 1 mg/m3 males and females and in some 0.5 mg/m3 females at the end of the 2-year study. Atrophy of the olfactory epithelium was observed in 0.5 and 1 mg/m3 males and in all exposed groups of females at the end of the 2-year study.

At the 7- and 15-month interim evaluations, lung nickel burden parameters measured in control and exposed groups were below the limit of detection. Absolute lung weights of 0.5 and 1 mg/m3 lung burden study females were significantly greater than those of the controls at 15 months.

Survival of exposed male and female mice was similar to that of the controls. Mean body weights of 5 mg/m3 females were slightly lower than those of the controls during the second year of the study. No chemical-related clinical findings were observed in male or female mice during the 2-year study. No chemical-related differences in haematology parameters were observed in male or female mice at the 15-month interim evaluation.

Generally, incidences of chronic inflammation increased with exposure concentration in males and females at 7 and 15 months. Bronchialization of minimal severity in exposed animals and proteinosis were first observed at 15 months. At 2 years, the incidences of chronic inflammation, alveolar epithelial hyperplasia, and proteinosis in exposed groups of males and females were significantly greater than those of the controls. The severity of chronic inflammation increased with exposure concentration in females, and proteinosis was most severe in 5 mg/m3 males and females. Pigment occurred in the lungs of nearly all exposed mice at 7 and 15 months and at 2 years, and the severity increased with exposure concentration.

Lymphoid hyperplasia occurred in two animals after 7 months; at 15 months, lymphoid hyperplasia occurred in males exposed to 2.5 and 5 mg/m3 and in all exposed groups of females. At 2 years, lymphoid hyperplasia occurred in some control animals, but this lesion was still observed more often in exposed males and females and the incidence increased with exposure concentration. Pigmentation was observed in the bronchial lymph nodes of exposed males and females at 7 and 15 months and in nearly all exposed animals at 2 years.

Nickel concentrations in the lungs of exposed mice were greater than those in the controls at 7 and 15 months (7 months, 162 to 1034 µg nickel/g lung; 15 months, 331 to 2258 µg nickel/g lung), and nickel concentrations increased with increasing exposure concentration and with time.

Survival of exposed male and female mice was similar to that of the controls. Mean body weights of 0.6 and 1.2 mg/m3 males and females were less than those of the controls throughout the second year of the study. Chemical-related clinical findings in male and female mice included laboured respiration following exposure periods. The haematocrit value and the segmented neutrophile, monocyte, lymphocyte, and total leukocyte counts in 1.2 mg/m3 females were greater than those in the controls.

Absolute and relative lung weights of exposed males and females were generally significantly greater than those of the controls at 7 and 15 months. In general, the incidences of chronic active inflammation; bronchialization (alveolar epithelial hyperplasia), macrophage hyperplasia and proteinosis; interstitial infiltration; and fibrosis in exposed groups of males and females were greater than those of the controls at 7 and 15 months and at 2 years.

The incidences of atrophy of the nasal olfactory epithelium and inflammation of the nose in exposed mice were also generally greater than those of the controls. At 2 years, the incidences of degeneration of olfactory epithelium in exposed females were significantly less than that of the controls.

The incidences of lymphoid hyperplasia of the bronchial lymph node in 1.2 mg/m3

males at 15 months, in 0.6 and 1.2 mg/m3 females at 15 months, and in 0.6 and 1.2 mg/m3 males and females at 2 years were significantly greater than those of the controls. The incidences of macrophage hyperplasia in 1.2 mg/m3 males at 7 and 15 months, in 0.6 and 1.2 mg/m3 females at 15 months, and in 0.6 and 1.2 mg/m3 males and females at 2 years were significantly greater than those of the controls.

Nickel concentrations in the lungs of exposed mice were greater than those of the controls at 7 months (males, 10 to 11 µg nickel/g lung; females, 10 to 14 µg nickel/g lung) and 15 months (males, 12 to 20 µg nickel/g lung; females, 15 to 26 µg nickel/g lung).

4.1.2.5.1.1.2 Other inhalation studies A 78-week inhalation study of nickel subsulphide has been conducted in rats using groups of approximately 100 animals of each sex. The concentration of nickel subsulphide was 0.71 mg Ni/m3. The exposure schedule was 6 h/day, 5 d/week. Mortality was significantly higher, and body weight significantly lower in test animals. Inflammatory and hyperplastic responses due to inhalation of nickel subsulphide were seen in the lungs of treated animals. There was also a higher incidence of adrenal medullary hyperplasia in treated animals. (Ottolenghi et al. 1975, quoted from UK HSE, 1987) A number of studies have examined local effects of nickel chloride inhalation in the lung. The effect of inhalation for up to 8 months of low nickel chloride concentrations (0.2-0.6 mg Ni/m3) on lung macrophages have been studied in rabbits (Johansson et al., 1980, 1986, 1987 and 1988; Berghem et al., 1987; Lundborg &


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Camner, 1981-82,1984; Camner et al., 1984). The effects included nodular accumulation of macrophages, which appeared inactive, and decreased lysozyme content. Dunnick et al. (1989) investigated the relative toxicity of nickel oxide (NiO), nickel sulphate hexahydrate (NiSO4.6H2O), and nickel subsulphide (Ni3S2) in F344/N rats and B6C3F1 mice after inhalation exposure for 6 hr/day, 5 days/week, for 13 weeks. Exposure concentrations used (as mg Ni/m3) were 0.4-7.9 for NiO, 0.02-0.4 for NiSO4.6H2O, and 0.11-1.8 for Ni3S2. No exposure-related effects on mortality and only minor effects on body weight gain were seen in rats or mice. The most sensitive parameter for nickel toxicity was histopathologic change in the lungs of exposed animals were chronic active inflammation, fibrosis, and alveolar macrophage hyperplasia were associated with nickel exposure. There was an exposure-related increase in lung weight in rats and mice. Equilibrium levels of nickel in the lung were reached by 13 weeks of nickel sulphate and nickel subsulphide exposure, whereas lung levels of nickel continued to increase throughout exposure to nickel oxide. Additional exposure-related histopathological lesions in treated animals included atrophy of the olfactory epithelium after nickel sulphate and nickel subsulphide exposure. No nasal lesions were seen after nickel oxide exposure. Lymphoid hyperplasia of the bronchial lymph nodes developed in animals exposed to all three nickel compounds. The order of toxicity corresponded to the water solubility of the nickel compounds, with nickel sulphate being most toxic, followed by nickel subsulphide and nickel oxide (Dunnick et al. 1989). Dunnick et al. (1988) studied the relative toxicity of nickel oxide (NiO), nickel sulphate hexahydrate. (NiSO4.6H2O), and nickel subsulphide (Ni3S2) was studied in F344/N rats and B6C3F1 mice after exposure by inhalation for 6 h/day, 5 days/week for 12 exposure days. Exposure concentrations used (as mg Ni/m3) were 0.9-23.6 for NiO; 0.8-13.3 for NiSO4.6H2O, and 0.4-7.3 for Ni3S2. For each compound there were 5 exposure groups plus a control group. NiSO4.6H2O was the most toxic compound with exposure related mortality seen at exposure concentrations of 13.3 mg/m3 in rats and 1.6 mg/m3 and above in mice. For Ni3S2, mortality was seen in mice (but not in rats) at the highest exposure concentration (7.3 mg/m3). No mortality was seen after NiO exposure. Lesions of the lung and nasal cavity were seen in both rats and mice after exposure to NiSO4.6H2O and Ni3S2 at the 4 highest exposure concentrations. Lesions of the lung were seen primarily at the highest exposure concentrations after NiO exposure. The amount of nickel in the lungs at the end of exposure varied in relation to the water solubility of the compounds. Based on these 2-week studies, the toxicity ranking was NiSO4.6H2O > Ni3S2 > NiO. Haley et al. (1990) studied the immunotoxicity of three nickel compounds following 13-week inhalation exposure in the mouse. Groups of B6C3F1 mice were exposed to aerosols of nickel subsulphide (Ni3S2), nickel oxide (NiO), or nickel sulphate hexahydrate (NiSO4.6H2O) 6 hr/day, 5 days per week for 65 days to determine the immunotoxicity of these compounds. Exposure concentrations were 0.11, 0.45, and 1.8 mg Ni/m3 for Ni3S2, 0.47, 2.0, and 7.9 mg Ni/m3 for NiO; and 0.027, 0.11, and 0.45 mg Ni/m3 for NiSO4. Thymic weights were decreased only in mice exposed to 1.8 mg Ni/m3 Ni3S2. Increased numbers of lung-associated lymph nodes (LALN), but not spleen nucleated cells, were seen with all compounds. Nucleated cells in lavage samples were increased in mice exposed to the highest concentrations of NiSO4 and NiO and to 0.45 and 1.8 mg Ni/m3 Ni3S2. Increased antibody-forming cells (AFC) were seen in LALN of mice exposed to 2.0 and 7.9 mg Ni/m3 NiO and 1.8 mg Ni/m3 Ni3S2. Decreased AFC/10(6) spleen cells were observed in mice exposed to NiO, and decreased AFC/spleen were seen for mice exposed to 1.8 mg Ni/m3 Ni3S2. Only mice exposed to 1.8 mg Ni/m3 Ni3S2 had a decrease in mixed lymphocyte response. All concentrations of NiO resulted in decreases in alveolar macrophage phagocytic activity, as did 0.45 and 1.8 mg Ni/m3 Ni3S2. None of the nickel compounds affected the phagocytic activity of peritoneal macrophages. Only 1.8 mg Ni/m3 Ni3S2 caused a decrease in spleen natural killer cell activity. The results indicate that inhalation exposure of mice to nickel can result in varying effects on the immune system, depending on dose and physicochemical form of the nickel compound. These nickel-induced changes may contribute to significant immunodysfunction.

4.1.2.5.1.1.3 Supporting mechanistic data for lung effects In order to compare the in vitro cytotoxicity of different nickel compounds Benson et al. (1992) studied the cytotoxicity of different nickel compounds, among these nickel sulphate, nickel subsulphide and nickel oxide to alveolar macrophages (AMs) and rat lung epithelial cells (LECs) in-vitro. Species differences in AM sensitivity were studied as MAs from F344/N-rats, B6C3F1-mice, beagle-dogs, as well as from monkeys were used in the study. Generally ranking of species sensitivity of AM to nickel compounds was dog > rat > mouse, with some evidence suggesting that the sensitivity of monkey AMs lies between those of the dog and rat. Ranking of the nickel compounds of interest, in decreasing order of cytotoxicity to AMs was Ni3S2 > NiSO4 > NiO. Similarly the ranking of the same nickel compounds with regard to cytotoxicity to LECs was Ni3S2 > NiSO4 > NiO. In another publication Benson et al. (1986) compared the cytotoxicity of the four nickel compounds nickel subsulphide (Ni3S2), nickel sulphate (NiSO4), nickel chloride (NiCl2), and nickel oxide (NiO). These compounds were tested in vitro for their relative toxicity to beagle dog and F344/Crl rat alveolar macrophages. Dog alveolar


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macrophages were at least 10 times more sensitive to the effects of each of the four nickel compounds than were rat alveolar macrophages. Toxicity ranking of the four nickel compounds to macrophages from both species was Ni3S2 greater than NiCl2 which were approximately the same as NiSO4 , which again was greater than NiO. Benson et al. (1989) evaluated the biochemical responses of lungs of rats and mice exposed for 13 weeks to occupationally relevant aerosol concentrations of nickel subsulphide, nickel sulphate or nickel oxide. Biochemical responses were measured in bronchoalveolar lavage fluid (BALF) recovered from lungs of exposed animals. Parameters evaluated in BALF were lactate dehydrogenase (LDH), beta-glucuronidase (BG), and total protein (TP). Total and differential cell counts were performed on cells recovered in BALF. All compounds produced an increase in LDH, BG, TP, and total nucleated cells, and an influx of neutrophiles, indicating the presence of a cytotoxic and inflammatory response in the lungs of exposed rats and mice. Increases in BG were greater than increases in LDH and TP for both rats and mice. Chronic active inflammation, macrophage hyperplasia, and interstitial phagocytic cell infiltrates were observed histologically in rats and mice exposed to all compounds. Statistically significant increases in BG, TP, neutrophiles, and macrophages correlated well with the degree of chronic active inflammation. Results indicated a toxicity ranking of NiSO4 which was greater than Ni3S2 and greater than NiO, based on toxicities of the compounds at equivalent mg Ni/m3 exposure concentrations.

4.1.2.5.1.2 Oral Data for effects following oral exposure have been found for nickel sulphate, nickel acetate, nickel chloride, and nickel carbonate. For nickel sulphate, long-term studies of toxicity following oral exposure have been conducted in rats, mice and dogs. Mainly non-specific indications of toxicity, such as decreased body weight, have been observed. In addition, reduced survival, increased urinary albumin (indicator of diminished kidney function), mild tubular nephrosis, as well as immuno-suppressive effects have been observed. An oral LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality and a NOAEL of 2.2 mg Ni/kg bw/day has been identified in a 2 year gavage study CRL, 2005), although uncertainties remain whether this actually should be considered as a NOAEL as reduced body weight gain (both sexes) and increased mortality (females) occurred to a statistically non-significant extent.. Data from 3 drinking water studies with Ni-acetate in rats and mice have been found. The concentration was 0 or 5 ppm (for rats equivalent to 0.17 mg Ni/kg bw/day assuming a water intake of 100 ml/kg/day) and the study duration was lifetime. Effects in rats included a 10-13% reduction in body weight and a 13% increased incidence of myocardial fibrosis. In mice only body weigh reduction was found. The studies were limited in the number of animals and parameters examined. (Schroeder et al., 1964; Schroeder & Mitchener 1975; quoted from TERA 1999) Although several studies of repeated dose oral toxicity of nickel chloride have been found, none are considered adequate for the determination of a NOAEL. A LOAEL of 5 mg Ni/kg bw/day based on mortality was identified in a 91-day gavage study by American Biogenics Corporation, 1988. In the reviews by UK HSE (1987), NIPERA (1997) and TERA (1999), repeated dose toxicity of nickel nitrate are not discussed. No data have been found. Inadequate oral studies of nickel carbonate in calves and monkeys have been found (see Risk Assessment Report on nickel carbonate).

4.1.2.5.1.3 Dermal No relevant studies of repeated dose toxicity of nickel compounds via the dermal route have been found.

4.1.2.5.2 Conclusion

4.1.2.5.2.1 Inhalation Inhalation of the insoluble nickel compounds (metal, subsulphide, and oxide) results in lung inflammation and fibrosis. Inhalation of the soluble nickel sulphate and chloride also affects the lungs. For nickel sulphate lung inflammation and fibrosis has been found, while for chloride apparently less severe effects were seen. Thus, it appears that the effects following inhalation exposure to nickel compounds do not depend on the solubility characteristics. Chronic lung inflammation and lung fibrosis are serious and potentially irreversible effects. Classification as T; R48/23 is included in the 30th ATP for nickel sulphate, nickel chloride, nickel nitrate and


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nickel carbonate, with a specific concentration limit of > 1% for T; R28/23 and > 0.1% for Xn; R48/20 for the three soluble nickel salts. Since the two soluble nickel compounds (nickel sulphate and chloride) have not been tested in a parallel manner it is not possible to carry out a direct comparison of the potency. For the three compounds tested by NTP in a similar protocol, the following order of toxic potency, based on mg nickel/m3, could be determined: Nickel sulphate hexahydrate>nickel subsulphide>nickel oxide. For the two insoluble compounds inflammatory lung lesions were observed at all concentration levels in two-year studies. For the soluble nickel sulphate hexahydrate a LOAEC for chronic lung inflammation and fibrosis could be determined at 0.056 mg Ni/m3. A definitive NOAEC for these effects could not be defined from the data. In the absence of NOAECs for the other soluble and sparingly soluble nickel compounds, the LOAEC for nickel sulphate hexahydrate (LOAEC of 0.056 mg Ni/m3, lung inflammation and fibrosis in 2-year rat study, NTP, 1996a) is taken forward to the risk characterisation for repeated dose toxicity via inhalation for nickel chloride, nickel nitrate and nickel (hydroxy)carbonate. For metallic nickel, a LOAEC of 1 mg/m3 from the 13 week inhalation study with rats (WIL Research Laboratories, 2003) is taken forward to risk characterisation for repeated dose toxicity.

4.1.2.5.2.2 Oral Sufficient oral repeated dose toxicity data are only available for the soluble nickel sulphate and nickel chloride. Nickel sulphate ingestion via feed or drinking water was associated with weight loss, and increased urinary albumin. In a 2 year gavage study with rats, decreased survival and reduced body weight gain was found. Reduced survival was also found with gavage administration of nickel chloride. However, when nickel chloride was administered in feed or drinking water at comparable doses no effects were found. There are no data on effects following repeated oral exposure with insoluble nickel compounds. In the absence of data for the insoluble nickel compounds, the values for nickel sulphate (oral LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality and NOAEL of 2.2 mg Ni/kg bw/day) is taken forward to the risk characterisation for repeated dose oral toxicity for soluble as well as insoluble nickel compounds, although uncertainties remain whether this actually should be considered as a NOAEL as reduced body weight gain (both sexes) and increased mortality (females) occurred to a statistically non-significant extent.

4.1.2.5.2.3 Dermal Dermal repeated dose toxicity data are lacking for soluble as well as insoluble nickel compounds. Dermal absorption is expected to be very limited. Therefore, this endpoint is not considered in the risk characterisation.

4.1.2.6 Mutagenicity The genotoxicity of nickel and nickel compounds have been reviewed by several organisations including IPCS (1991), IARC (1990), UK HSE (1987), ECETOC (1989), US ATSDR (1997), NiPERA13 (1996) and TERA (1999). This section contains a summary of the data for the five individual nickel substances (nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate) reviewed in the individual risk assessment reports. This section also describes aspects of the mutagenicity and genotoxicity of some other nickel compounds.

4.1.2.6.1 Summary of mutagenicity test results for the five selected nickel compounds. The tables below show in summary (and in some cases, simplified) form the data presented in the five individual reports. The reader is referred to the individual reports for more detailed assessments of the five individual nickel substances. Absence of an entry indicates that the individual reports do not contain data for these endpoints.

4.1.2.6.1.1 Summary of mutagenicity test results in vitro.

4.1.2.6.1.1.1 DNA damage and repair. Most of the data in the five risk assessment reports comes from studies with nickel chloride. There are some studies in bacteria showing differential toxicity between repair deficient and normal strains. There are positive studies of gene conversion in yeast, and a series of studies showing induction of DNA single strand breaks in 13 NiPERA has pointed out that this review was produced by independent scientists for NiPERA and that the conclusions of the report do not necessarily reflect the current position of NiPERA.


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mammalian cells. There is also evidence of DNA synthesis inhibition, disturbance of DNA damage recognition and inhibition of DNA repair. Human cells appear to be more resistant to nickel induced strand breakage than hamster cells (quoted from NiPERA, 1996). Whilst there is very little data in the five reports on other than nickel chloride and nickel sulphate, the NiPERA (1996) review indicates that similar effects are seen with both soluble nickel compounds such as the sulphate and chloride and with other, less soluble compounds. The S-phase inhibition seen in CHO cells with metal dust is consistent with this. There is evidence indicating that nickel ions bind to DNA. Nickel ion also binds to chromatin more strongly than to naked DNA. There is evidence of nickel catalysed oxidative damage to DNA. (Quoted from NiPERA, 1996).

Table 4.1.2.6.1.1.A: Summary of results of in vitro tests for DNA damage and repair with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

Prokaryotes

E. coli, differential toxicity in repair deficient strain

positive negative

Fungi

Yeast, gene conversion positive positive

Mammalian cells

rat liver epithelial cells (inhibition of DNA synthesis)

positive

Hamster CHO cells (DNA damage) positive positive

SHE (Strand breaks) positive

Human bronchial epithelial cells (inhibition of DNA synthesis)

positive

Human diploid fibroblasts (DNA damage) negative negative

Human gastric mucosal cells (DNA damage)

negative

Human peripheral lymphocytes (DNA strand breaks)

equivocal

Human lung cells (inhibition of DNA repair)

positive

4.1.2.6.1.1.2 Gene mutation. Nickel chloride has been tested extensively in bacteria, and most of the available data in the five risk assessment reports comes from studies with this nickel compound. In general, the nickel compounds tested gave negative results in bacterial assays with S. typhimurium and E. coli. It has been shown with other metallic ions like cobalt(II) that the results in bacteria are greatly influenced by the choice of the tester strain and the test conditions used (Arlauskas 1985; Pagano & Zeiger 1992; Beyersmann 1994; Binderup 1999). In two studies, it was shown that cobalt(II) was only genotoxic in the Salmonella strain TA97 and considerable more genotoxic in the preincubation assay than in the standard plate assay (Pagano & Zeiger 1992; Binderup 1999). Both nickel chloride and nickel nitrate were tested in this strain with negative results. The overall evidence indicates that nickel compounds are not mutagenic in bacteria. Both nickel sulphate and nickel chloride have been tested in gene mutation studies with mammalian cell lines. Many of these studies showed positive results, although these were often weakly positive. In some cases, only certain loci were affected (e.g. a positive result at the tkslow locus, but not at the tknormal or hprt loci, Skopek, 1995). Whilst these results may indicate gene mutation, the positive results in at least some of these assays could possibly be due to other genetic events (chromosomal aberrations and DNA methylation) than point mutations. For instance, it has been shown that the increases in mutant frequency seen at the gpt gene of v79 cells (Christie et al., 1992) were due to changes in DNA methylation (Klein, 1994). DNA methylation seems to be related to the inhibition of tumour suppression genes (Costa & Klein, 1999).


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Table 4.1.2.6.1.1.B: Summary of results of in vitro tests for gene mutations with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

Prokaryotes

S. typhimurium negative negative (4) negative

E. coli negative negative

Corynebacterium positive

Host mediated assay

Salmonella in NMRI mice negative

Serratia marcescens in NMRI mice negative

Fungi

S. cerevisiae negative positive

Mammalian cells

CHO cells equivocal

Mouse lymphoma cells (TK+/-) positive (1) positive

SHE cells negative (2)

V79 cells positive (1) positive

Rat NRK cells positive

Rat 6m2 murine sarcoma virus infected cells positive

Rat liver epithelial cells positive

Human lymphoblasts positive (3) positive (3) 1) weakly positive 2) co-mutagenic with benzo(a)pyrene 3) for the tkslow locus only. 4) a fluctuation test gave a positive result

4.1.2.6.1.1.3 Chromosomal effects. This effect has been extensively studied with both nickel chloride and nickel sulphate. There are slightly more studies of chromosomal aberrations (CA) with nickel chloride than with nickel sulphate; the reverse is true for studies of sister chromatid exchange (SCE). Positive results were seen in almost all studies of CA and SCE. Positive effects have also been seen with nickel carbonate. Effects have also been seen on spindle function, suggesting that numerical changes might occur.

Table 4.1.2.6.1.1.C: Summary of results of in vitro tests for chromosomal effects with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

Chromosomal aberrations

Pisum positive

mouse mammary carcinoma cells (FM3A cells )

positive

Rat lung epithelial cells positive

CHO cells positive positive

SHE cells positive

Human lymphocytes positive

Human bronchial epithelial cells positive negative


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Sister chromatid exchanges

mouse mammary carcinoma cells (FM3A cells )

positive positive

CHO cells positive positive positive

SHE cells positive

Human lymphocytes positive positive

Spindle disturbance

rat embryo cells positive

human peripheral lymphocytes positive

Micronucleus test (kinetochore stained)

Human diploid fibroblasts weak positive

weak positive

4.1.2.6.1.1.4 Cell transformation. Most of the data on cell transformation comes from studies on nickel sulphate, although there are additional studies with nickel chloride and nickel metal. Many of these studies indicate an effect on cell transformation, anchorage independence and loss of cell communication. The significance of these effects is largely related to the ability of modelling carcinogenic pathways in vitro.

Table 4.1.2.6.1.1.D: Summary of results of in vitro tests for cell transformation and other effects with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

BHK 21 cells positive

SHE cells positive positive positive

mouse embryonic fibroblasts negative negative

Rat embryo cells positive

Hamster V79, loss of cell communication positive positive

Human foreskin cells (anchorage independence)

positive

4.1.2.6.1.2 Summary of mutagenicity test results in vivo.

4.1.2.6.1.2.1 DNA damage and repair. There is evidence that both soluble and insoluble nickel compounds can give rise to both DNA breaks and DNA-protein crosslinks in vivo (quoted from NiPERA, 1996). Recent studies by Benson et al. (2002) have shown DNA-strand breaks in the lung after high doses of nickel sulphate and nickel subsulphide (see 4.1.2.6.2) given by inhalation, and Danadevi et al. (2004) have shown that nickel chloride induced single and double stranded DNA breaks as measured by the Comet assay in leucocytes in mice after oral administration.

Table 4.1.2.6.1.2.A.: Summary of results of in vivo tests for DNA damage and repair with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

Rat, mouse, DNA strand breakage positive positive positive

Mouse, inhibition of DNA synthesis:

kidney epithelium negative

liver epithelium positive


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Hamster, suppression of DNA synthesis positive

4.1.2.6.1.2.2 Gene mutations. The only in vivo studies for gene mutations with soluble nickel compounds have been carried out in Drosophila. Weakly positive effects have been seen in one study. This is consistent with the data seen in vitro. Nickel subsulphide has been studied in a transgenic rodent mutation assay (see 4.1.2.6.2).

Table 4.1.2.6.1.2.B: Summary of results of in vivo tests for gene mutations with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

Drosophila

somatic eye colour test negative negative

wing spot mutation positive(1)

Mutation negative equivocal 1) weakly positive

4.1.2.6.1.2.3 Chromosomal effects. Data for the evaluation of chromosomal effects in vivo is mainly available for nickel sulphate, chloride and nitrate. It should be noted that in most cases, the same authors have studied more than one of the substances: concordance in the results is therefore not surprising. Chromosomal aberrations have been seen in vivo in a number of studies (Chorvatiovicova, 1983; Mohanty, 1987: Sharma et al., 1987; Dhir et al., 1991). This effect has been seen with the three soluble substances tested. The authors of a much older study in bone marrow and spermatogonial cells (Mathur et al, 1978) claim a negative effect, but without reporting any data in support of this conclusion. The review of the mutagenicity data carried out by NiPERA (2003a) concludes that the Dhir et al. (1991) and the Chorvatovicova (1983) studies are positive. There is also evidence, sometimes with mixed exposure, to show that this effect is also seen in humans, although NiPERA (2003a) does not consider that these studies can be used as evidence. The data from micronucleus tests is conflicting, and these studies are discussed in more detail in the individual risk assessment reports. One of the studies was carried out as part of an international collaborative study (Morita et al., 1997). This study found a negative result for both nickel sulphate and nickel chloride. A micronucleus study of nickel sulphate in rats after oral administration using the Annex V B12 (OECD 474) protocol was also negative (Covance 2003). Deknudt & Léonard (1982) also found no effect on micronucleus induction. A number of largely Indian studies (Dhir et al., 1991, Sharma et al. 1987, Sobti & Gill, 1989,) have all shown positive results. NiPERA (2003a) agrees that the Dhir et al. (1991) intraperitoneal study is positive, but considers the oral studies (Sharma et al. 1987, Sobti & Gill, 1989) equivocal. The data from dominant lethal tests (Deknudt & Léonard, 1982, Saichenko, 1985) suggests that there is no significant dominant lethal effect, although the soluble nickel compounds tested may reduce fertilisation rate after intraperitoneal administration. The study by Sobti & Gill (1989) showed a significant increase in sperm head anomalies. There is therefore in vivo data confirming the clastogenicity seen in vitro.

Table 4.1.2.6.1.2.C: Summary of results of in vivo tests for chromosomal effects with five nickel compounds.

nickel sulphate

nickel chloride

nickel nitrate

nickel carbonate

nickel metal

Plants

Vicia faba (mitotic effects) positive

Insects

Drosophila positive

Mammals – Chromosomal aberrations


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Mouse positive (1) positive (1) positive (1)

Rat negative ?

Hamster positive

Human positive (2) positive (2)

Mammals – Sister chromatid exchanges

Mouse

Rat ?

Human negative

Mammals – Micronucleus

Mouse conflicting data

conflicting data

conflicting data

Rat negative positive

Mammals – Dominant lethal test

Mouse negative negative

Rat negative For a detailed discussion of the results, see individual reports. 1) regarded as equivocal by NiPERA (2003a) 2) NiPERA (2003a) considers that these studies cannot be used as evidence that nickel exposure caused the effects seen.

4.1.2.6.2 Genotoxicity of other nickel compounds.

4.1.2.6.2.1 Other soluble nickel compounds. The only other soluble nickel compound studied significantly is nickel acetate. The IARC (1990) review lists a number of in vitro endpoints. Most of these studies (De Flora et al. 1984, Umeda & Nishimura 1979, Nishimura & Umeda, 1979, Beidermann & Landolph, 1987) are already included in the risk assessment reports for nickel sulphate or nickel chloride. The Umeda & Nishimura (1979) and Nishimura & Umeda (1979) studies both show chromosome aberrations in transformed cells in vitro. Nickel acetate induces DNA-strand breaks and DNA-protein crosslinks in the kidney in vivo (Misra et al., 1993, quoted from NiPERA, 1996). The Rapporteur has not carried out any specific search for additional in vivo mutagenicity studies, and no additional information on in vivo studies with other soluble nickel compounds has been supplied by NiPERA.

4.1.2.6.2.2 Insoluble compounds. The data for insoluble compounds has been reviewed by IARC (1990) and NiPERA (1996). In some cases, insoluble compounds include nickel (hydroxy)carbonate under “oxidic” nickel. The data for this substance is treated separately above. Most of the studies on insoluble nickel compounds (oxides and (sub)sulphides) in these reviews are in vitro studies. NiPERA (1996) in reviewing both soluble and less soluble nickel compounds finds no evidence of qualitative differences between the different types of nickel compounds. For instance, in the studies on the tk locus referred to in 4.1.2.6.1.1.2 above (Skopek, 1995), nickel sulphate, nickel sulphide (Ni2S3), nickel hydroxide (Ni(OH)2), nickel oxide (NiO, green) and nickel metal all gave positive results for the tkslow locus. Positive results with tests for CA have been seen with nickel oxides and sulphides, as well as other soluble nickel compounds (nickel acetate). The NiPERA (1996) review concludes that “both soluble and insoluble nickel compounds are clastogenic in mammalian and human cells in culture”. More recent information is also available. Schwerdtle et al. (2002) studied the effects of nickel chloride (included in 4.1.2.6.1.1.1 above) and the largely water-insoluble black nickel oxide. A difference was seen between the two compounds in their ability to inhibit BPDE (benzo[a]pyrene-7,8-diol 9,10-epoxide) induced adducts. With respect to adduct formation, nickel oxide but not nickel chloride reduced the generation of DNA lesions by about 30%. Both nickel chloride and nickel oxide reduced the removal of the adducts in a dose-


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dependant manner. The authors consider that the results show that the nucleotide excision repair pathway is affected in general by both insoluble and water soluble nickel compounds, and provides further evidence that DNA repair inhibition is a mechanism in nickel-induced carcinogenicity. The information on in vivo genotoxicity of insoluble nickel compounds is even more limited than for soluble nickel compounds. The only in vivo animal study with either nickel oxides or sulphides included in IARC (1990) is a study where heterocyclic abnormalities were seen in early-passage cultures of cells from crystalline nickel sulphide-induced, mouse rhabdomyosarcomas (Christie et al., 1988, quoted from IARC, 1990). The evidence for in vivo chromosome aberrations for oxidic and sulphidic compounds in the NiPERA (1996) review comes from human studies. These studies are either carried out in refinery workers (Boysen et al. 1980, Waksvik & Boysen. 1982) or retired refinery workers (Waksvik et al. 1984). There is also evidence from exposure to nickel oxide at a chemical plant (Senft et al., 1992). These studies have been described in the nickel sulphate and nickel chloride reports. IARC (1990) regards the Waksvik studies as “other relevant information” in their summary, whilst NiPERA (2003a) does not consider that either the Waksik or the Senft studies can be used as evidence that nickel exposure caused the effects seen. Two studies on in vivo micronucleus formation by Arrouijal et al., (1990, 1992) for nickel sulphides are shown as positive in NiPERA (1996). From the description of the study in NiPERA (1996) one of these studies (Arrouijal et al., 1992) appears to be in vitro. Treatment with α- Ni subsulphide (2.2 – 73 mg Ni/l) increased the number of micronuclei in lymphocytes from Ni-hypersensitised and unsensitised individuals (Arrouijal et al., 1992, quoted from NiPERA, 1996). Positive induction of micronuclei (2 to 3 fold) has been seen in OF1 mice exposed intraperitoneally to α-Ni subsulphide (183 mg Ni/kg) (Arrouijal et al., 1990, quoted from NiPERA, 1996). More recent information is also available. As well as the nickel chloride and nickel sulphate study reported above, Morita et al., (1997) also includes a study on nickel oxide tested by a different group (M. Takeuchi et al., at Yoshitomi Pharmaceutical Co. Ltd.). Nickel oxide was dissolved in 0.5% HPMC (hydroxypropylmethyl cellulose) before intraperitoneal administration to CD-1 mice (ddY mice were used for the study with the soluble nickel salts). The study was carried out using the same dose and sampling protocol as used for the studies with the soluble salts. The study concluded that “a negative response was also observed in CD-1 mouse bone marrow cells 24 hr after a second intraperitoneal treatment with nickel oxide at 18.1, 36.3, 72.5 and 145 mg/kg bw/day although the ratio of polychromatic erythrocytes to total erythrocytes decreased markedly and dose-dependently”. The study by Mayer et al. (1998) into the genotoxic potential of nickel subsulphide included in vitro and in vivo comet assays and transgenic rat and mouse mutation tests. The study clearly indicates that nickel subsulphide induces DNA damage as shown by the Comet assay in mouse lung and nasal mucosa cells in vitro. Following in vivo exposure of male CD2F1 mice and F344 rats high doses of nickel subsulphide for 2 hr (up to 95 mg Ni3S2 / m3 for mice and up to 63 mg Ni3S2 / m3 for rates) increases in the incidence of DNA damage as measured by the Comet assay was seen in the nasal mucosa, and to a lesser extent in the lung. The effect occurred at lower doses in mice than in rats, and was less in rats than in mice. This study provides some evidence that nickel subsulphide is able to produce pre-mutagenic damage in target cells for carcinogenesis. No significant increase in mutation frequency was evident in the nasal mucosa or lung cells of transgenic LacZ CD2F1 mice or lacI F344 rats following in vivo inhalational exposure for two hours to Ni3S2 at dose levels close to the MTD. The lack of effect on mutations in vivo is expected from the short exposure time, as this model needs 4-6 weeks of exposure for maximal expression of mutations. The results do not support any conclusion regarding the ability of nickel subsulphide to induce mutations in vivo. Benson et al. (2002) have performed a comprehensive in vivo study in rats in order to throw some light on the differences and similarities in the mechanism of cancer induction by insoluble and soluble nickel compounds in the lung, which is the target organ for cancer development after inhalation. Several endpoints were investigated after inhalation of insoluble nickel subsulphide and soluble nickel sulphate hexahydrate. The most important endpoints for the evaluation of genotoxicity / carcinogenicity are DNA damage measured as DNA strand breaks and oxidative DNA damage in the comet assay, DNA degradation, DNA methylation and cell proliferation. Both compounds induce DNA strand breaks in the comet assay at the highest exposure levels (0.22 mg Ni /m3

for nickel sulphate and 0.44 mg Ni /m3 for the subsulphide,). In this assay there were no indication of oxidative DNA damage. DNA strand breaks were induced earlier and at lower concentrations with nickel subsulphide than


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with nickel sulphate and persisted after a 13 weeks recovery period. These findings are in accordance with in vitro studies of nickel and other metals, and are presumably due to higher intercellular concentrations of insoluble than soluble metals due to phagocytosis. Irregular shaped black particles were observed in macrophages after nickel subsulphide inhalation only. DNA damage was also measured as DNA degradation/fragmentation and there was a modest degradation of DNA after nickel subsulphide exposure after 3 weeks to the highest concentrations. After 13 weeks the DNA degradation increased. However, large DNA fractions were still present in the samples. At the highest nickel sulphate concentration primarily small DNA fragments were found, which might have influenced the comet assay results. Inflammation was evident at the same exposures where DNA strand breaks were observed. This might lead to confounding of the comet assay by apoptosis. However, there seems to be only a few seriously damaged cells, since the median scores were all well below 800 at all exposure levels. Moreover, there was no indication that oxidative damage caused the strand breaks as would be expected if they were secondary to inflammation. The genotoxic damage is therefore most likely unrelated to inflammation or apoptosis. In addition, DNA degradation reported in the study was not measured in the cells used for the comet assay but in whole lung tissue homogenate, and therefore a correlation between DNA strand breaks in the comet assay and the DNA degradation cannot be made. Overall there were few differences between the effects of the two compounds studied. The most pronounced difference was the ability of nickel subsulphide but not nickel sulphate to induce cell proliferation and a somewhat higher genotoxicity of nickel subsulphide. The Benson et al. (2002) study is in accordance with the earlier reviewed studies in the nickel risk assessment reports showing that both soluble and insoluble nickel compounds primarily induce structural DNA damage, which in other studies are mainly expressed as chromosomal aberrations. In this in vivo study the most relevant exposure pathway (inhalation) and target organ (the lung) were studied at a reasonable range of exposure concentrations. The study gives a fair explanation of the differences in carcinogenic potency of nickel subsulphide and nickel sulphate but underlines the genotoxic potential of both compounds in the target organ. The human studies by Waksvik and co-workers reported in the nickel sulphate and nickel chloride risk assessments were carried out on workers exposed to roasting and smelting operations as well as to workers in the electrolysis plants. The exposure of roasting / smelting workers is primarily to insoluble (oxidic or sulphidic) nickel. These studies are regarded by IARC as relevant data. NiPERA (2003a) does not believe the Waksvik studies can be used as evidence that nickel exposure induces chromosomal aberrations in the exposed workers studied. The studies reviewed above suggest that qualitatively similar effects are seen with both insoluble nickel compounds and the soluble salts described above, although solubility may well affect the potency of these effects.

4.1.2.6.3 Conclusions on the mutagenicity of the five selected nickel compounds. There is considerable evidence for the in vitro genotoxicity of nickel compounds. Positive effects are generally seen in studies of chromosomal effects (chromosomal aberrations, sister chromatid exchanges), cell transformation tests and tests for DNA damage and repair. Whilst there are positive results for gene mutations, particularly with nickel chloride, the positive results in at least some of these assays could possibly be due to genetic events other than point mutations. Interpretation of the results of in vivo studies is more complicated. Most of the studies reviewed in these reports have been carried out with the three soluble nickel compounds under review: nickel chloride, nickel sulphate and nickel nitrate. There is little in vivo data on other soluble compounds, and data on sparingly soluble nickel compounds such as nickel carbonate, insoluble compounds such as nickel oxide and nickel sulphides as well as nickel metal is also very limited. Of the individual compounds reviewed here, the genotoxicity of nickel chloride has been the most extensively studied following intraperitoneal and oral administration. There is data from studies on DNA damage, chromosomal aberration studies as well as micronucleus tests. Whilst NiPERA (1996) and TERA (1999) consider that the studies reviewed by them showed in general a positive effect in vivo, NiPERA (2003a) considers the evidence from many of these studies as equivocal. There is a recent collaborative study (Morita et al., 1997) which shows a negative micronucleus test after intraperitoneal administration. However, the positive results for chromosomal aberrations seen after intraperitoneal administration (Dhir et al., 1991 and Chorvatovicova, 1983) are not disputed. The recent study by Danadevi et al. (2004) also shows positive results in vivo using the Comet assay with DNA damage in leucocytes after oral administration of nickel chloride. In addition, there is supporting evidence from studies of workers exposed by inhalation (Waksvik & co-workers


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and other studies) which is regarded by IARC (1990) as relevant, but which NiPERA (2003a) does not consider can be used in evidence. The data on intraperitoneal and oral exposure of nickel sulphate is rather more limited than for nickel chloride. Again, there is data from chromosomal aberration studies as well as from micronucleus tests. The positive evidence in these studies is less clear-cut. Nickel sulphate was also tested in the recent collaborative study (Morita et al., 1997) after intraperitoneal administration and in a study commissioned by NiPERA (Covance, 2003) after oral administration. Both these studies were negative. The evidence from human studies is also relevant to the evaluation of nickel sulphate, as the studies by Waksvik & co-workers, (see above) involved exposure to both nickel sulphate and nickel chloride. There is also human evidence from workers exposed in a chemicals plant (Senft et al., 1992). Nickel sulphate has been studied by Benson et al. (2002) after inhalational exposure, and this study is the most comprehensive part of the database on in vivo genotoxicity of Ni compounds. The study has been criticized because it cannot discriminate direct induction of DNA damage from indirect damage secondary to inflammation or apoptosis. The nickel compounds tested seem to induce inflammation and genotoxicity at approximately the same concentrations and further testing is not likely to overcome this dilemma unless more sensitive techniques can show that one of the effects is elicited by even lower exposure levels. The evidence for nickel nitrate is even more limited, and adds little new information, as many of the studies include either nickel sulphate and/or nickel chloride, and are the same as the studies discussed above. The data for nickel carbonate from both in vitro and in vivo studies is very limited. NiPERA (2003a) considers that the mutagenicity assessment for nickel carbonate could be derogated to the overall mutagenicity assessment for either soluble or insoluble nickel compounds. As for nickel carbonate, the data for metallic nickel from both in vitro and in vivo studies is very limited. In this case, there is little or no agreement on whether it is appropriate to extrapolate from the results from other nickel compounds. In addition to the evidence from the soluble salts, there is however evidence to regard both nickel carbonate and metallic nickel as being of concern for genotoxicity. There are no definitive tests of nickel compounds on the germ cells and evidence for a possible effect is limited. There is evidence that the nickel ion reaches the testis, so a possible effect cannot be excluded. There are two negative dominant lethal tests (Deknudt & Léonard, 1982, Saichenko, 1985), as well as a number of other studies which are relevant to an evaluation of the effects on germ cells. Whilst some effects are seen in males (e.g. sperm abnormalities) there is little evidence for inheritable effects on the germ cells. The opinion of the Specialised Experts has been sought at their meeting in April, 2004. The Specialised Experts concluded that nickel sulphate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R68. This conclusion is based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure. Hence the possibility that the germ cells are affected cannot be excluded (European Commission, 2004). Concerning the nickel carbonate, the Specialised Experts concluded that there was insufficient evidence for classification (European Commission, 2004). However, classification as Muta. Cat. 3; R68 is justified on the basis of the Industry derogation statement. In addition, the evidence for significant absorption of nickel carbonate after oral administration (see 4.1.2.1.1.2), and the acute toxicity (see 4.1.2.2.3.2) also indicates that the possibility that the germ cells are affected cannot be excluded. The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates as Muta. Cat. 3; R68 and these classifications are included in the 30th ATP. The Specialised Experts did not consider that further testing of effects on germ cells was practicable (European Commission, 2004). Further testing in an in vivo comet assay in lung cells after inhalational exposure is also considered to be unnecessary for the purposes of risk characterisation. A positive result would not alter the conclusions for the classification as a mutagen, and a negative result would not be regarded as sufficient evidence to justify the use of a threshold approach in the carcinogenicity risk characterisation. Hence, further testing for this effect would not produce additional information that would significantly change the outcome of this risk assessment.


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4.1.2.7 Carcinogenicity

4.1.2.7.1 Animal data

4.1.2.7.1.1 Inhalation The data on the carcinogenicity of nickel compounds in experimental animals following exposure by inhalation are limited. Below, the available data regarding carcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) following inhalation exposure or intratracheal instillation are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant for the conclusion on the carcinogenicity of nickel in experimental animals following inhalation of the five prioritised nickel compounds.

4.1.2.7.1.1.1 Nickel sulphate The National Toxicology Program (NTP) has performed a comprehensive investigation of the toxic effects in rats and mice after chronic inhalation of nickel sulphate hexahydrate (NTP 1996a). The data concerning the carcinogenic effects of nickel sulphate hexahydrate are summarised in Table 4.1.2.7.1.A. The results as concluded in the study seem reliable, i.e. neither rats (F344/N) nor mice (B6C3F1) developed exposure related neoplasms after being exposed to nickel sulphate hexahydrate (mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm) by inhalation at concentrations up to 0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively.

Table 4.1.2.7.1.A: Summary of inhalation carcinogenicity studies of nickel sulphate hexahydrate in experimental animals.

Route of administration

Species, group size and sex

Concentration, exposure duration

Results References

Inhalation F344/N rats

63-65 males, 63-64 females per group

0, 0.03, 0,06 or 0.11 mg Ni/m3

6 hours/day, 5 days/week,

2 years

No exposure related neoplasms observed

NTP (1996a)

Inhalation B6C3F1 mice 80 males,

80 females per group

0, 0,06, 0.11 or 0.22 mg Ni/m3

6 hours/day, 5 days/week,

2 years

No exposure related neoplasms observed

NTP (1996a)

4.1.2.7.1.1.2 Nickel metal A number of animal studies on the carcinogenicity of nickel metal following inhalation or intratracheal instillation have been performed; these studies are summarised in Table 4.1.2.7.1.B. Local neoplasms were observed in most of the studies; however, all the studies suffer from inadequacies and are considered inappropriate for the risk assessment of the carcinogenic potential of nickel metal following exposure by inhalation. According to information provided by the Industry (NiPERA (2002b)), “a two-year inhalation cancer bioassay with elemental nickel powder in male and female Wistar rats is currently underway and will be completed in 2004. NiPERA is overseeing the conduct of this study. An OECD-compliant protocol is being used in the study, with supplemental lung burden analyses to assure absence of impaired lung clearance. “ NiPERA (2003b) has subsequently pointed out that “the inhalation cancer bioassay in Wistar rats is expected to be completed in 2006. This is a 30-month exposure study that has not yet begun”.

Table 4.1.2.7.1.B: Summary of carcinogenicity studies of nickel metal by inhalation and intratracheal instillation in experimental animals.



Concentration/dose, exposure duration

Results References Remarks

Inhalation

Wistar rats

50 animals of each sex

15 mg/m3,

6 hours/day,

Numerous multicentric, adenomatoid alveolar lesions and bronchial proliferations that were

Hueper (1958 – quoted from IARC 1990, NiPERA

No control group, short duration,

one exposure level


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Nickel metal powder, particle size ≤ 4µm

Bethesda black rats

60 females

4-5 days/week 21 months Observed up to 84 weeks

considered (by the author) as being benign neoplasms

1996)

Inhalation

Nickel metal powder, particle size ≤ 4µm

C57B1 mouse

20 females

15 mg/m3,

6 hours/day,

4-5 days/week

21 months

No neoplasms observed Hueper (1958 – quoted from IARC 1990, NiPERA 1996)

High mortality,

no control group, only one sex,

short duration,

one exposure level

Inhalation

Nickel metal powder (particle size not stated)

Strain 13 guinea-pigs

32 males, 10 females

9 controls (gender not specified)

15 mg/m3,

6 hours/day,

4-5 days/week 21 months

Almost all exposed animals developed adenomatoid alveolar lesions and terminal bronchiolar proliferations.

One exposed animal had an anaplastic intra-alveolar carcinoma; another an apparent adenocarcinoma metastasis in an adrenal node.

Hueper (1958 – quoted from IARC 1990, NiPERA 1996)

High mortality, short duration,

one exposure level

Inhalation

Metallic nickel dust, 98% of particles less than 2 µm in diameter

Wistar rats

77 males

control group included

3.1 mg/m3,

6 hours/day,

5 days/week

21 months

2 exposed rats and 1 control rat developed lung tumours of a carcinoid pattern

Kim et al. (1969 – quoted from IPCS 1990)

Short duration,

one exposure level, one sex only

Intratracheal instillation

Nickel metal powder

Wistar rats females (group size not stated)

40 saline-treated controls

10 weekly instillations of 0.9 mg,

or 20 weekly injections of 0.3 mg in saline

Observed for almost 2.5 years

Lung tumour incidence: 8/32, 10/39 and 0/40 (controls), respectively.

Tumours: one adenoma, four adenocarcinomas, 12 squamous-cell carcinomas, one mixed tumour.

Pott et al. (1987 – quoted from IARC 1990, NiPERA 1996)

One sex only,

short duration,

few dose levels


Metallic nickel powder (particle diameter 3-8 µm)

Syrian golden hamsters

100 animals per group (sex not specified)

Vehicle control group

Single instillation of 10, 20, 40 mg, or four instillations of 20 mg every six months

Intrathoracic malignant neoplasms (fibrosarcomas, mesotheliomas, rhabdomyosarcomas) at up to 12% in the highest single dose group and about 10% in the repeated dose group

Ivankovic et al. (1987 – quoted from IARC 1990)

Reported in an abstract only,

short duration,

few dose levels


Metallic nickel powder (particle

Syrian golden hamsters (Cpb-ShGa 51)

60 males, females Vehicle control group,

12 instillations of 0.8 mg at two-week intervals Median lifespan 90-130 weeks

One adenocarcinoma in lung of treated group

Muhle et al. (1990 – quoted from IARC 1990)

No lung tumours in positive control group,

one dose level


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size 3.1 µm) positive control group

4.1.2.7.1.1.3 Nickel chloride, nickel nitrate, and nickel carbonate No studies regarding carcinogenicity of nickel chloride, nickel nitrate, and nickel carbonate following inhalation exposure or intratracheal instillation in experimental animals have been located.

4.1.2.7.1.1.4 Nickel oxide F344/N rats were exposed to nickel oxide (CAS No: 1313-99-1) (high temperature, green nickel oxide, mass median diameter 2.2 ± 2.6 µm, at least 99% pure) at concentrations of 0, 0.62, 1.25, or 2.5 mg/m3 (equivalent to 0, 0.5, 1.0, or 2.0 mg Ni/m3) and B6C3F1 mice at concentrations of 0, 1.25, 2.5, or 5 mg/m3 (equivalent to 0, 1.0, 2.0, or 3.9 mg Ni/m3) by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposed animals was similar to that of the controls. At 2 years, tumours were observed in the lungs of rats (males: alveolar/bronchiolar adenoma or carcinoma or squamous cell carcinoma (combined) 1/54, 1/53, 6/53, 4/52; females: alveolar/bronchiolar adenoma or carcinoma (combined) 1/53, 0/53, 6/53, 5/54) and female mice (alveolar/bronchiolar adenoma or carcinoma (combined) 6/64, 15/66, 12/63, 8/64) and in the adrenal medulla of rats (males: benign or malignant pheochromocytoma (combined) 27/54, 24/52, 27/53, 35/52; females: benign pheochromocytoma 4/51, 7/52, 6/53, 18/53). It was concluded that there was some evidence of carcinogenic activity of nickel oxide in rats based on the increased incidences of tumours in the lungs and of the adrenal medulla. There was equivocal evidence of carcinogenic activity of nickel oxide in female mice based on marginally increased incidences of lung tumours in the mid- and high-dose groups. There was no evidence of carcinogenic activity in male mice. (NTP 1996b).

4.1.2.7.1.1.5 Nickel subsulphide F344/N rats were exposed to nickel subsulphide (CAS No: 12035-72-2) (mean value for the mass median aerodynamic diameter 2.0-2.2 µm, at least 97% pure) at concentrations of 0, 0.15, or 1.0 mg/m3 (equivalent to 0, 0.11, or 0.73 mg Ni/m3) and B6C3F1 mice at concentrations of 0, 0.6 or 1.2 mg/m3 (equivalent to 0, 0.44, or 0.88 mg Ni/m3) by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposed animals was similar to that of the controls. At 2 years, tumours were observed in the lungs of rats (males: alveolar/bronchiolar adenoma or carcinoma (combined) 0/53, 6/53, 11/53; females: alveolar/bronchiolar adenoma or carcinoma or squamous cell carcinoma (combined) 2/53, 6/53, 9/53) and in the adrenal medulla of rats (males: benign or malignant pheochromocytoma (combined) 14/53, 30/52, 38/53; females: benign pheochromocytoma 2/53, 7/53, 36/53). No tumours were observed in mice. It was concluded that there was clear evidence of carcinogenic activity of nickel subsulphide in rats based on the increased incidences of tumours in the lungs and of the adrenal medulla. There was no evidence of carcinogenic activity in mice. (NTP 1996c). When F344 rats were exposed to nickel subsulphide (0.97 mg Ni/m3, 70% particles smaller than 1 µm) by halation for 6 hours a day, 5 days per week for 78 weeks, the overall incidence of lung tumours in treated animals was 14% (15 adenomas, 10 adenocarcinomas, 3 squamous-cell carcinomas, 1 fibrosarcoma) compared to 1% (1 adenoma and 1 adenocarcinoma) in control animals (241 animals) (Ottolenghi et al. 1974 – quoted from NiPERA 1996, IPCS 1991 and IARC 1990).

4.1.2.7.1.2 Oral With the exception of nickel sulphate, the data on the carcinogenicity of nickel compounds in experimental animals following exposure by oral administration are very limited. Below, the available data regarding carcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) following oral administration are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant for the conclusion on the carcinogenicity of nickel in experimental animals following oral administration of the five prioritised nickel compounds.

4.1.2.7.1.2.1 Nickel sulphate The carcinogenicity of nickel sulphate following oral administration has been studied in rats and dogs; these studies are summarised in Table 4.1.2.7.1.C. An oral (gavage) OECD 451 carcinogenicity study in rats did not show any treatment related increase in tumours related to the exposure (CRL 2005). Furthermore, no neoplasms were revealed in either rats or dogs in the older studies; however, these studies are limited because of the low


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number of animals (rats and dogs), the high mortality in all groups of rats (causes of death not reported) resulting in only a small number of animals being exposed for the total period of 2 years and being available for sacrifice and histopathology, and the limited reporting of the study design and results.

Table 4.1.2.7.1.C: Summary of oral carcinogenicity studies of nickel sulphate hexahydrate in experimental animals.




Results Reference

Oral, dietary Wistar rats

25 males and females per group

0, 100, 1000 or 2500 ppm Ni in feed

2 years

No treatment related neoplasms observed

Ambrose et al. (1976)

Oral, dietary Beagle dogs


0, 100, 1000 or 2500 ppm Ni in feed

2 years


Ambrose et al. (1976)

Oral, gavage Fischer rats


0, 2.2, 6.7, 11 mg Ni/kg bw/day

2 years


CRL (2005)

4.1.2.7.1.2.2 Nickel chloride, nickel nitrate, nickel carbonate, and nickel metal No data regarding carcinogenicity of nickel chloride, nickel nitrate, nickel carbonate, and nickel metal following oral administration in experimental animals have been located.

4.1.2.7.1.2.3 Nickel acetate The carcinogenicity of nickel acetate has been tested in three drinking water studies with rats and mice (Schroeder et al. 1964, 1974, Schroeder & Mitchener 1975 – all three quoted in TERA 1999) receiving 0 or 5 mg/l Ni as nickel acetate (hydration state not reported) from the time of weaning until natural death. Histological examinations were limited to the lungs, heart, liver, kidneys, and spleen. No exposure-related neoplasms was observed in either rats or mice. According to TERA, the findings are not conclusively negative due to limitations in the design of the studies (single dose level, unclear if a maximum tolerated dose was achieved, less than half of the mice were necropsied and even fewer were sectioned).

4.1.2.7.1.3 Dermal

4.1.2.7.1.3.1 Nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal No data regarding carcinogenicity following dermal contact to nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal in experimental animals have been located.

4.1.2.7.1.3.2 Other nickel compounds When male golden Syrian hamsters were painted on the mucosa of the buccal pouches with 1 or 2 mg α-nickel subsulphide in 0.1 ml glycerol three times a week for 18 weeks (6-7 animals; total doses 54 and 108 mg nickel subsulphide) or with 5 or 10 mg three times a week for 36 weeks (13-15 animals; total doses 540 and 1080 mg nickel subsulphide) and observed for more than 19 months, no tumours developed in the buccal pouch, oral cavity, or intestinal tract in the treated or control groups (Sunderman 1983 – quoted from IARC 1990).

4.1.2.7.1.4 Other routes of administration Several studies have investigated the carcinogenicity of nickel compounds in experimental animals following exposure by other routes of administration than inhalation, oral administration, and dermal contact. Below, the available data regarding carcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) following other routes of administration are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant for the conclusion on the carcinogenicity of the five prioritised nickel compounds in experimental animals following exposure by other routes of administration.

4.1.2.7.1.4.1 Nickel sulphate


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Studies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, or intraperitoneal injections have been performed in rats; these studies are summarised in Table 4.1.2.7.1.D. Tumours were observed following administration by intraperitoneal injections and by intramuscular implants, but not by intramuscular injections.

Table 4.1.2.7.1.D: Summary of carcinogenicity studies of nickel sulphate in experimental animals by other routes of administration than inhalation, oral administration, and dermal contact.




Results Reference

Intramuscular injections to one or both thigh muscles

Wistar rats,

32 males and females

No control group

Single dose of 5 mg of nickel sulphate hexahydrate

Observation for 603 days

No local tumours at the injection sites, no other treatment-related tumours

Gilman (1962 – quoted from IARC 1990, TERA 1999)

Intramuscular implants (in sheep fat pellets)

NIH black rats, 35 animals per group

Vehicle controls

3 implants (interval unspecified) of 7 mg of nickel sulphate (hydration not stated)

Observation for 18 months

Implantation-site sarcomas in 1/35

No tumours in controls (0/35)

Payne (1964 – quoted from IARC 1990, TERA 1999). Reported as an abstract.

Intramuscular injections

Wistar rats

20 males

Positive (nickel subsulphide) and negative (sodium sulphate) controls

15 injections of 0.26 mg of nickel as nickel sulphate (hydration not stated) every second day during one month

Observation for 2 years

No injection site tumours in treated animals or in negative controls

Local sarcomas in positive controls (16/20)

Kasprzak et al. (1983 – quoted from IARC 1990, TERA 1999)

Intraperitoneal injections

Wistar rats

30 females

Controls:

1 ml saline x 3

1 ml saline x 50

2 ml saline x 4

50 injections of 1 mg nickel as nickel sulphate heptahydrate twice weekly

Observation for 132 weeks

Abdominal tumours in 6/30 (p<0.05)

(1 mesothelioma, 5 sarcomas)

1/33 (sarcoma)

0/34

3/66 (1 mesothelioma, 3 sarcomas)

Pott et al.

(1989, 1992)

(Pott et al. 1992 is cited in IARC and TERA 1999 as Pott et al. 1990)

4.1.2.7.1.4.2 Nickel chloride Studies on the carcinogenicity of nickel chloride following intramuscular implants or intraperitoneal injections have been performed in rats; these studies are summarised in Table 4.1.2.7.1.E. Tumours were observed following administration by intraperitoneal injections but not by intramuscular implants.

Table 4.1.2.7.1.E: Summary of carcinogenicity studies of nickel chloride in experimental animals by other routes of administration than inhalation, oral administration, and dermal contact.




Results Reference



Vehicle controls

3 implants (interval unspecified) of 7 mg of nickel chloride (hydration not stated)

No implantation-site tumours

No tumours in



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Results Reference


controls (0/35)


Wistar rats

32 females

Controls:

1 ml saline x 3

1 ml saline x 50

2 ml saline x 4

50 injections of 1 mg nickel as nickel chloride hexahydrate twice weekly


Abdominal tumours in 4/32 (p<0.05)

(1 mesothelioma, 3 sarcomas)

1/33 (sarcoma)

0/34


Pott et al. (1989, 1992)

(Pott et al. 1992 is cited in IARC, 1990 and TERA 1999 as Pott et al. 1990)

4.1.2.7.1.4.3 Nickel nitrate No data regarding carcinogenicity following exposure by other routes of administration of nickel nitrate in experimental animals have been located.

4.1.2.7.1.4.4 Nickel carbonate Studies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitoneal injections have been performed in rats; these studies are summarised in Table 4.1.2.7.1.F. Tumours were observed following both routes of administration.

Table 4.1.2.7.1.F: Summary of carcinogenicity studies of nickel carbonate in experimental animals by other routes of administration than inhalation, oral administration, and dermal contact.




Results Reference



Vehicle controls

3 implants (interval unspecified) of 7 mg of nickel carbonate


Implantation-site sarcomas in 6/35 rats

No tumours in controls (0/35)



Wistar rats

35 females

Controls:

1 ml saline x 3

1 ml saline x 50

2 ml saline x 4

25 or 50 injections of 1 mg nickel as nickel carbonate twice weekly


Abdominal tumours in 1/35

(1 sarcoma) or 3/33 (2 mesothelioma, 1 sarcomas)

1/33 (sarcoma)

0/34


Pott et al. (1989, 1992)

(Pott et al. 1992 is cited in IARC and TERA 1999 as Pott et al. 1990)

4.1.2.7.1.4.5 Nickel metal One study on the carcinogenicity of nickel metal following subcutaneous implantation has been performed. Wistar rats (5 animals of each sex received four subcutaneous implants of pellets of metallic nickel or nickel-gallium alloy (60% nickel) used for dental prostheses and were observed for 27 months. Local sarcomas were noted in 5/10 rats that received the metallic nickel and in 9/10 rats that received the nickel-gallium alloy. No local tumours occurred in 10 groups of animals that received similar implants of other dental materials (Mitchell et al. 1960 – quoted from IARC 1990).


118

A number of studies have been performed in which nickel metal powder has been injected at various sites to experimental animals. Several studies in rats and one study in hamsters have shown sarcomas at the injection sites following intramuscular injection. Intravenous injection produced local sarcomas in rats, but not in mice and rabbits. Following injection into the femurs of rats and rabbits, local sarcomas were observed at the injection site. Intrathoracic injections produced mesotheliomas in rats. Following intraperitoneal injection to rats, tumours were observed. (IPCS, 1991).

4.1.2.7.1.4.6 Other nickel compounds Dose-effect relationships could be demonstrated for nickel subsulphide in rats following intramuscular and intrarenal injections and in hamsters following intramuscular and intratesticular injections. Following intramuscular injection, local tumours were mostly rhabdomyosarcomas, fibrosarcomas, and undifferentiated sarcomas; rats appeared more susceptible to the induction of sarcomas by nickel subsulphide than mice, hamsters, or rabbits. (IPCS, 1991, IARC, 1990). Nickel oxide produced local tumours (mainly rhabdomyosarcomas, fibrosarcomas, and undifferentiated sarcomas) at high incidence following intrapleural, intramuscular, and intraperitoneal injections (IARC, 1990, IPCS, 1991). No renal tumours were seen following intrarenal injections (IARC, 1990). Following intramuscular implants of sheep fat pellets (repeated three times) containing 0 or 7 mg of various nickel compounds and observation for up to 18 months following treatment, implantation-site sarcomas developed in 1/35, 4/35, and 12/35 rats treated with nickel acetate, nickel(II) oxide, and nickel subsulphide, respectively. No tumours were observed following implantation of anhydrous nickel acetate, nickel ammonium sulphate, or nickel(III) oxide. (Payne, 1964, abstract only, quoted from TERA, 1999, IARC, 1990). Nickel acetate injected subcutaneously once or twice a week for 5-8 weeks in Male F344 rats produced fibrosarcomas in 5/16 rats 22-66 weeks after injections. Controls treated with physiological saline showed no tumour growth (Teraki & Uchiumi, 1992). Other studies with nickel acetate given intraperitoneally to mice cited by IARC (1990) and TERA (1999) (Stoner et al., 1976, Poirier et al., 1984) suggest that water-soluble nickel salts may produce tumours in animals by this route of administration.

4.1.2.7.1.5 Initiator-Promoter studies Below, the available data regarding promoting effects of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on other nickel compounds are also summarised below when considered relevant.

4.1.2.7.1.5.1 Nickel sulphate Three studies evaluating the promoting effect of nickel sulphate in experimental animals have been located; these studies are summarised in Table 4.1.2.7.1.G. The studies may indicate a promoter effect of nickel sulphate if applied locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, the indications are rather weak. Based on these studies, it is not possible to draw any conclusion regarding a promoting potential of nickel sulphate.

Table 4.1.2.7.1.G: Summary of promoter studies of nickel sulphate in experimental animals.




Results Reference

1) Topical insertion into the nasopharynx

2) In drinking water

Rats

12 animals

Controls:

Initiated only or nickel sulphate only

Initiation: single s.c. injection of 9 mg/ml dinitrosopiperazine

1) 0.02 ml 0.5% nickel sulphate in 4% aqueous gelatin once a week (0.04 mg Ni/week), for 7 weeks

1) Two tumours in the nasopharynx (one papilloma, one early carcinoma)

2) Two tumours in the

Ou et al. (1980, quoted from IARC 1990, TERA 1999, IPCS 1991)


119




Results Reference

2) 1 ml of aqueous 1% nickel sulphate (3.8 mg Ni/day) for 6 weeks


nasopharynx (one squamous cell carcinoma, one fibrosarcoma)

No tumours in any of the controls

3) Topical insertion in the oral cavity

4) In drinking water

Rats

22 animals

Controls:

Initiated only or nickel sulphate only

Initiation: single s.c. injection of 9 mg/ml dinitrosopiperazine

3) 0.02 ml 0.5% nickel sulphate in 4% aqueous gelatin once a week (0.04 mg Ni/week), for 7 week

4) 1 ml of aqueous 1% nickel sulphate (3.8 mg Ni/day) for 6 weeks


3) 5/22 developed carcinomas (2 in the nasopharynx, 2 in the nasal cavity, 1 of the hard palate)

4) No tumour developed

No tumours in any of the controls

Liu et al. (1983, quoted from IARC 1990, TERA 1999, IPCS 1991).

Reported in an abstract.

Feed Rats

13 females

Initiation: single s.c. injection of 9 mg/ml dinitrosopiperazine on day 18 of gestation

Pups of treated dams fed 0.05 ml of 0.05% nickel sulphate (9.5 µg Ni/day) daily for one month increasing every month with 0.1 ml (19 µg Ni/day) for further 5 months

Controls:

Initiated dams

Untreated pups of treated dams

Untreated pups of uninitiated dams

5/21 pups (24%) developed carcinomas of the nasal cavity

No tumours (0/13)

3/11 pups (27%) developed tumours (one nasopharyngeal squamous-cell carcinoma, one neurofibrosarcoma of the peritoneal cavity, one granulosa-thecal-cell carcinoma of the ovary)

No tumours

Ou et al. (1983, quoted from IARC 1990, TERA 1999, IPCS 1991).

Reported in an abstract.

4.1.2.7.1.5.2 Nickel chloride


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A study evaluating the promoting effect of nickel chloride in male rats is summarised in Table 4.1.2.7.1.H. The study indicates a promoter effect of orally administered nickel chloride in renal carcinogenesis under the conditions of the study.

Table 4.1.2.7.1.H: Summary of promoter studies of nickel chloride in experimental animals.




Method Results Reference

Drinking water

Rats F344

15 males

Controls: Distilled water for 25 weeks

Initiation: 500 mg/l N-ethyl-N-hydroxyethyl-nitrosamine (EHEN) for 2 weeks

600 mg/l nickel chloride hexahydrate for 25 weeks

Kidneys were examined histologically for assessment of Dysplastic Foci (DF) and Renal Cell Tumours (RCT)

The number of DF was 170.

12 RCT’s (adenomas) identified in 8 rats.

Controls: The number of DF was 17; 2 rats with totally 3 RCT’s identified.

Kurokawa et al. (1985)

In a two-stage carcinogenesis assay, orally administered nickel chloride enhanced the renal carcinogenicity of N-ethyl-N-hydroxyethylnitrosamine in rats, but not the hepatocarcinogenicity in rats after initiation with N-nitrosodiethylamine, the gastric carcinogenicity in rats after initiation with of N-methyl-N-nitro-N-nitrosoguanidine, the pancreatic carcinogenicity in Syrian golden hamsters following initiation with N-nitrosobis(2-oxopropyl)amine, or the skin carcinogenicity in mice initiated with 7,12-dimethylbenzanthracene (Hayashi et al., 1984, Kurokawa et al., 1985, quoted from IARC, 1990, IPCS, 1991).

4.1.2.7.1.5.3 Nickel metal When female Wistar rats received intratracheal instillations of 20-methylcholanthrene with metallic nickel powder, nickel seemed to enhance the lung carcinogenicity of 20-methylcholanthrene (squamous-cell carcinomas) (Mukubo 1978 – quoted from IARC, 1990, IPCS, 1991).

4.1.2.7.1.5.4 Nickel nitrate, nickel carbonate No data regarding the promoting effect of nickel nitrate and nickel carbonate in experimental animals have been located.

4.1.2.7.1.5.5 Other nickel compounds No data regarding the promoting effect of other nickel compounds in experimental animals have been located. A two-stage carcinogenesis study has been performed in which nickel acetate (administered as the tetrahydrate, single intraperitoneal injection of 5.3 mg Ni/kg) was tested as a tumour initiator in male rats using sodium barbital (500 mg/l in the drinking water) as the promoter (Kasprzak et al. 1990). Incidences of renal cortical adenomas alone and combined adenomas and adenocarcinomas were significantly increased in the initiated/promoted rats compared to those administered nickel without subsequent sodium barbital promotion. Nickel acetate by itself resulted in one renal cortical adenoma. Sodium barbital by itself resulted in six renal cortical adenomas and 13 renal pelvic tumours (12 papillomas and 1 carcinoma). A transplacental carcinogenicity study (Diwan et al. 1992) has been performed in pregnant rats administered nickel acetate by intraperitoneal injection. Offspring were either untreated or treated with sodium barbital in the drinking water. The incidences of kidney tumours (adenomas or carcinomas) were significantly higher in male offspring that were treated with nickel acetate prenatally and sodium barbital postnatally than in control males. No kidney tumours developed in males given prenatal nickel acetate only, or in any of the female groups. Pituitary tumours (combined adenomas and carcinomas) were significantly increased in offspring of both sexes given nickel acetate prenatally compared to controls. Postnatal administration of sodium barbital had no influence on the development of the pituitary tumours. The authors conclude that “The results of this study indicate that nickel acetate is a transplacental initiator of kidney tumours and a complete transplacental carcinogen for pituitary tumors”. TERA (1999) concludes that: “Nickel acetate also shows evidence of carcinogenicity in initiation-promotion studies and demonstrates transplacental initiation (Diwan et al., 1992; Kasprazak et al., 1990; Tables 25 and


121

26) and of promotion of carcinogenesis (Kurokawa et al., 1985; Liu et al., 1980, 1983; Ou et al., 1980) (insoluble forms were not tested in the latter system)”.

4.1.2.7.1.6 Discussion and conclusions, carcinogenicity in experimental animals The following plausible mechanisms leading to the carcinogenic effects of nickel have been presented by MAK (2006). A number of biochemical studies suggest that the release of nickel ions is responsible for the genotoxic and carcinogenic effects of nickel compounds. Nickel ions from readily soluble nickel salts are slowly taken up into mammalian cells through plasma membrane ion channels. In contrast, nickel metal and the less soluble nickel sulphides and oxides are taken up by phagocytosis. Metallic nickel was phagocytized by alveolar macrophages of exposed rats (Johansson et al. 1980) and also in vitro by CHO cells (Costa & Mollenhauer 1980). Nickel subsulphide was also phagocytized by CHO cells (Lee et al. 1995). Inside mammalian cells, less soluble nickel compounds and nickel metal result in the release of nickel ions. A much higher intracellular bioavailability of poorly soluble nickel compounds as compared to that of readily soluble nickel salts may explain the higher potency of poorly soluble nickel salts. For example the concentration of intracellular nickel ions was more than two orders of magnitude higher after phagocytosis of less soluble nickel salts as compared to uptake of soluble nickel salts. And in CHO cells treated with a suspension of nickel sulphide (10 mg/l), binding of nickel ions to nucleic acids was 300 to 2 000 fold higher as compared to incubation with the same concentration of soluble nickel salts (Harnett et al. 1982). After the phagocytosis of nickel subsulphide, very stable ternary protein-nickel-DNA complexes were formed in the nuclei of CHO cells (Lee et al. 1982) and intracellular nickel ion concentrations in the mmol/l range were calculated for poorly soluble nickel compounds.

4.1.2.7.1.6.1 Inhalation Inhalation studies of nickel sulphate hexahydrate (mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm) have been performed in rats and mice (NTP 1996a); no exposure related neoplasms were observed in neither rats (F344/N) nor mice (B6C3F1) after exposure to nickel sulphate hexahydrate by inhalation in concentrations up to 0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively for 2 years. A number of animal studies on the carcinogenicity of nickel metal following inhalation or intratracheal instillation have been performed. Local neoplasms were observed in most of the studies; however, all the studies suffer from inadequacies and are considered inappropriate for the risk assessment of the carcinogenic potential of nickel metal following inhalation. No studies regarding carcinogenicity following inhalation exposure or intratracheal instillation of nickel chloride, nickel nitrate, and nickel carbonate in experimental animals have been located. NTP has also investigated the carcinogenic potential of nickel oxide and nickel subsulphide in 2-year inhalation studies in rats (F344/N) and mice (B6C3F1). There was some evidence of carcinogenic activity of nickel oxide (high temperature, green nickel oxide, mass median diameter 2.2 ± 2.6 µm) in rats (concentrations up to 2.0 mg Ni/m3) based on the increased incidences of tumours in the lungs and of the adrenal medulla. There was equivocal evidence of carcinogenic activity of nickel oxide in female mice (concentrations up to 3.9 mg Ni/m3) based on marginally increased incidences of lung tumours in the mid- and high-dose groups. There was no evidence of carcinogenic activity in male mice (concentrations up to 3.9 mg Ni/m3). (NTP 1996b). There was clear evidence of carcinogenic activity of nickel subsulphide (mean value for the mass median aerodynamic diameter 2.0-2.2 µm) in rats (concentrations up to 0.73 mg Ni/m3) based on the increased incidences of tumours in the lungs and of the adrenal medulla. There was no evidence of carcinogenic activity in mice (concentrations up to 0.88 mg Ni/m3). (NTP 1996c). In another inhalation study (78 weeks) of nickel subsulphide (0.97 mg Ni/m3, 70% particles smaller than 1 µm) in rats (F344/N), the incidence of lung tumours in treated animals was increased as well (Ottolenghi et al. 1974 – quoted from NiPERA 1996, IPCS 1991 and IARC 1990). According to TERA (1999), some arguments have been raised that the negative evidence from the NTP study (NTP 1996a) on nickel sulphate cannot be considered definitive. It has been questioned whether sufficiently high concentrations were tested in the rat study on nickel sulphate based on the observation of a somewhat higher incidence of lung lesions in rats exposed to 0.11 mg Ni/m3 as nickel subsulphide than in rats exposed to the same concentration as nickel sulphate. According to TERA, the NTP review panel has noted that slightly higher


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concentrations of nickel sulphate could have been tested, but overall the study was judged to be adequate. According to NTP (1996a), the high concentration (0.11 mg Ni/m3) in the nickel sulphate study was chosen based on the observation of chronic active inflammation in the lungs of rat in the 13-week study and this lesion was considered to be potentially life-threatening, because of the possibility of reduced lung function; the high nickel sulphate concentration in the 2-year rat study was just below the concentration at which mild chronic active inflammation was seen in the 13-week study. Sanner & Dybing (1996) have analysed the sensitivity of the NTP-studies on nickel subsulphide, nickel oxide and nickel sulphate hexahydrate. In the sensitivity analysis, it was addressed and discussed whether the lack of alveolar/bronchiolar neoplasms in rats exposed to nickel sulphate hexahydrate is related to the insignificant increases in lung weights and nickel lung burden, especially after 7 months of treatment, when compared to findings in the analogous studies performed on nickel subsulphide and nickel oxide, which induced lung tumours in rats of both sexes (nickel subsulphide: clear evidence of carcinogenic activity; nickel oxide: some evidence of carcinogenic activity). Furthermore it was discussed whether nickel sulphate hexahydrate would have been expected to induce tumours if the tumour inducing potency of the sulphate was the same as that of the subsulphide or oxide. According to the sensitivity analysis “the number of lung tumours in the three studies increased linearly with the observed increase in lung weight, which was assumed to be caused by inflammatory processes in the lung. Moreover, the number of tumours found for nickel sulphate and nickel subsulphide increased proportionally with the nickel lung burden.” It was concluded “that nickel sulphate may have the same tumour inducing potency as nickel subsulphide and nickel oxide when using concentrations giving the same increase in lung weight, and the same tumour inducing potency as nickel subsulphide when using concentrations giving the same nickel lung burden. Thus, it is likely that nickel sulphate would have shown carcinogenic activity if tested at a higher concentration.” Furthermore, “the members of the NTP Technical Report’s Review Subcommittee has noted that it could have been possible to use a higher exposure concentration of nickel sulphate hexahydrate than those used.” A response from Industry (NiPERA 2002a) has pointed out that “when the lung weights of male and female rats are compared after 15 months of exposure to the highest nickel sulphate concentration that was negative and the lowest nickel subsulphide and nickel oxide concentrations that were positive, similar values are found for all three compounds, with lung weights differing by just 10% (males) or 30% (females). These results indicate that although inflammatory processes may contribute to tumour induction they are not the primarily means by which tumours are induced by exposure to nickel subsulphide or nickel oxide.” Furthermore, Industry pointed out that “if a two-fold higher concentration was tested in the NTP studies (i.e., 0.22 mg Ni/m3 for rats) without increased mortality, the lung burdens of these animals would still be lower than those present in the nickel subsulphide-exposed animals based on curves for lung burdens as a function of nickel exposure levels. Nevertheless, the fact that nickel oxide was negative at 0.5 mg Ni/m3 with lung burdens much higher than those at which nickel subsulphide was positive (0.11 and 0.73 mg Ni/m3) cast serious doubt on the relevance of nickel lung burdens to predict risk of lung tumours from nickel exposures.” According to TERA (1999), the lack of evidence (nickel sulphate, nickel subsulphide, nickel oxide in males) or equivocal evidence (nickel oxide in females) for carcinogenic activity in mice following inhalation has raised the question of how informative the mouse studies are. TERA states that there are “two interpretations to the negative mouse data for nickel sulphate. One interpretation is that the mouse bioassay constitutes a valid test in a second species (in addition to the rat), and that the negative result in the mouse study (together with the negative result in the rat bioassay) suggests that soluble nickel is not carcinogenic. A second interpretation is that, based on the negative and equivocal results for nickel subsulphide and nickel oxide, respectively, in mice, the mouse is not a suitable species for studying nickel carcinogenesis. The mouse is, however, considered an appropriate model for inhalation carcinogenesis of metals.” The last statement is based on a search of the NTP bioassay results database, which found no tendency for mice to be less likely to develop lung tumours than rats, even when considering only inhalation studies or metals (cobalt sulphate, molybdenum trioxide, and selenium sulphide) (NTP 1998 – quoted from TERA 1999). The available data raises the question of whether soluble forms of nickel differ from insoluble forms of nickel in carcinogenic potential (i.e., qualitatively) or only in potency (i.e., quantitatively) in experimental animals following exposure by inhalation; however, the available data are not sufficient for an evaluation of this question. The suggestion of a difference in carcinogenic potential or potency between soluble and insoluble forms of nickel might be supported by data indicating that the cellular uptake of soluble and insoluble nickel compounds are different (see section 4.1.2.1.2) as insoluble nickel compounds enter the cell via phagocytosis, while soluble nickel compounds are not phagocytised, but enter the cell via metal ion transport systems or through membrane diffusion. The latter two processes are, according to TERA (1999), much less efficient implicating that the same extracellular levels of soluble and insoluble nickel compounds lead to lower nickel levels intracellularly for soluble nickel


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compounds. Soluble forms of nickel interact with the cell in a way that maximises cytotoxicity and minimises nickel delivery to the nucleus, while insoluble forms of nickel interact with cells in a way that decreases the cytotoxic potential while increasing the delivery of nickel to the nucleus. Overall, there is no evidence of carcinogenic activity following inhalation of nickel sulphate hexahydrate in rats and mice under the conditions of the available inhalation studies (NTP 1996a); however, it should be noted, as discussed above, that some arguments have been raised that the negative evidence from the NTP studies on nickel sulphate cannot be considered definitive. The studies in experimental animals on the carcinogenicity of nickel metal following inhalation or intratracheal instillation suffer from inadequacies and are considered inadequate for an evaluation of the carcinogenic activity of nickel metal following inhalation. No studies regarding carcinogenic activity following inhalation exposure or intratracheal instillation of nickel chloride, nickel nitrate, and nickel carbonate in experimental animals have been located. The inhalation studies on nickel oxide (NTP 1996b) and nickel subsulphide (NTP 1996c) showed some evidence and clear evidence, respectively, for carcinogenic activity following inhalation in rats, and there was equivocal evidence for nickel oxide in female mice. No other data considered as being relevant for the conclusion on the carcinogenicity of the five prioritised nickel compounds in experimental animals following inhalation have been located. In conclusion, the available data on carcinogenicity of various nickel compounds is considered as being insufficient for a conclusion on the carcinogenic potential of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) in experimental animals following inhalation. It should be noted that soluble forms of nickel might differ from insoluble forms of nickel in carcinogenic potential or in potency in experimental animals following exposure by inhalation; however, the available data are not sufficient for an evaluation of this suggestion.

4.1.2.7.1.6.2 Oral The carcinogenicity of nickel sulphate following oral administration has been studied in two old non-guideline studies with rats and dogs. No neoplasms were revealed in either rats or dogs in these studies . A 2-year carcinogenicity study with rats performed according to OECD 451 did not show any carcinogenic potential of exposure to nickel sulphate following oral (gavage) administration. No data regarding carcinogenicity of nickel chloride, nickel nitrate, nickel carbonate, and nickel metal in experimental animals following oral administration have been located. When nickel acetate was tested for carcinogenic effects in drinking water studies with rats and mice, no exposure-related neoplasms was observed in either rats or mice; however, the studies suffer from several limitations and are therefore not conclusively negative. In conclusion, based on the available data on nickel sulphate, the water soluble nickel compounds should be considered without carcinogenic concern as well. Data are too limited for a direct evaluation of the carcinogenic potential in experimental animals following oral administration of nickel carbonate and nickel metal as well as of other insoluble nickel compounds. However, given the lower solubility of these compounds, carcinogenic potential following this route of administration is considered unlikely.

4.1.2.7.1.6.3 Dermal No data regarding carcinogenicity following dermal contact to nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal in experimental animals have been located. No tumours developed in the buccal pouch, oral cavity, or intestinal tract of male hamsters painted on the mucosa of the buccal pouches with α-nickel subsulphide. In conclusion, although the available data are sparse, the lack of carcinogenic potential after oral exposure to nickel sulphate make carcinogenic effects following dermal exposure to nickel chloride, nickel nitrate, nickel carbonate, and nickel metal very unlikely.

4.1.2.7.1.6.4 Other routes of administration Studies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, or intraperitoneal injections have been performed in rats; tumours were observed following administration by intraperitoneal injections and by intramuscular implants but not by intramuscular injections.


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Studies on the carcinogenicity of nickel chloride following intramuscular implants or intraperitoneal injections have been performed in rats; tumours were observed following administration by intraperitoneal injections but not by intramuscular implants. No data regarding carcinogenicity following exposure by other routes of administration of nickel nitrate in experimental animals have been located. Studies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitoneal injections have been performed in rats; tumours were observed following both administration routes. One study on the carcinogenicity of nickel metal following subcutaneous implantation has been performed in rats; local tumours were observed. A number of studies have been performed in which nickel metal powder has been injected at various sites to experimental animals; with few exceptions these studies showed that nickel metal caused local tumours. A large number of studies have been performed in which nickel subsulphide or nickel oxide have been injected at various sites to experimental animals; with few exceptions these studies showed that these two nickel compounds caused local tumours. In conclusion, the available data show that nickel compounds, with a few exceptions, produce local tumours following injection at various sites to experimental animals. These routes of administration are not directly relevant for humans exposed via inhalation, oral intake or dermal contact. They are however relevant in evaluating exposure to nickel by implants of nickel metal or nickel-containing alloys (iatrogenic exposure). In addition, the results of these studies with animals exposed by these routes (injections, installations etc), is also of relevance in the evaluation of effects from other routes of exposure in humans, as they constitute examples of how mammalian cells may react under certain circumstances.

4.1.2.7.1.6.5 Initiator-Promoter studies Three studies evaluating the promoting effect of nickel sulphate in experimental animals have been located, which may indicate a promoter effect of nickel sulphate, if applied locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, the indications are rather weak. In a two-stage carcinogenesis assay, orally administered nickel chloride enhanced the renal carcinogenicity of N-ethyl-N-hydroxyethylnitrosamine in rats, but not the hepatocarcinogenicity in rats after initiation with N-nitrosodiethylamine, the gastric carcinogenicity in rats after initiation with of N-methyl-N-nitro-N-nitrosoguanidine, the pancreatic carcinogenicity in Syrian golden hamsters following initiation with N-nitrosobis(2-oxopropyl)amine, or the skin carcinogenicity in mice initiated with 7,12-dimethylbenzanthracene. When female Wistar rats received intratracheal instillations of 20-methylcholanthrene with nickel metal powder, nickel seemed to enhance the lung carcinogenicity of 20-methylcholanthrene (squamous-cell carcinomas). No data regarding the promoting effect of nickel nitrate and nickel carbonate in experimental animals have been located. No data regarding the promoting effect of other nickel compounds and considered as being relevant for the conclusion on the carcinogenicity of the five prioritised nickel compounds in experimental animals following inhalation have been located. In conclusion, the available data indicate that nickel sulphate, nickel chloride, and nickel metal may have a promoting effect in combination with selected initiators. The two soluble nickel compounds, nickel sulphate and nickel chloride, were tested for promoter activity after oral administration. The data for the soluble nickel salts suggests that these salts do not cause cancer following oral administration on their own, although the available data is limited. The study of nickel sulphate following oral administration currently being carried out will provide more reliable data. This study will not however provide any additional information on possible effects of soluble nickel salts as promoters. Nickel metal was tested as a promoter after intratracheal instillation. The significance of this study is not clear in the evaluation of the inhalational carcinogenicity of the metal.


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Nickel acetate administered intraperitoneally has been shown to initiate renal tumours in rats and rat offspring when administered to pregnant rats. In the latter situation, nickel acted as a complete carcinogen producing pituitary tumours.

4.1.2.7.1.6.6 Conclusions in reviews on nickel compounds

4.1.2.7.1.6.6.1 CSTEE (2001) The lack of evidence for carcinogenicity of nickel sulphate hexahydrate can be due to the relatively low lung burden that was tested, since the exposure levels had to be kept lower than for nickel oxide and nickel subsulphide due to respiratory toxicity of nickel sulphate hexahydrate. Thus, the lung burden (amount nickel per g of lung) from the highest exposure concentration of nickel sulphate hexahydrate was approximately 6 times lower than the lowest exposure concentrations to nickel subsulphide. In studies with parenteral administration, soluble nickel compounds induce local tumours, albeit with much lower potency than that seen with insoluble nickel compounds. Therefore, the CSTEE concludes that the lack of evidence of carcinogenicity of nickel sulphate hexahydrate in the NTP study cannot be taken as evidence of lack of carcinogenic potential for soluble nickel compounds. Nickel carcinogenicity will be dependent on the time-integrated intracellular concentration of nickel ions as the active entity, so that the relative potency of various nickel species will be related to their bioavailability and lung burden. In the rat experiments it is the insoluble nickel compounds that are most potent with respect to carcinogenicity.

4.1.2.7.1.6.6.2 TERA (1999) Standard animal bioassays of soluble nickel compounds administered to rats or mice by the oral or inhalation routes have not shown soluble nickel compounds to be carcinogenic. Studies of insoluble nickel compounds, nickel oxide (NTP 1996b) and nickel subsulphide (NTP 1996c), provided evidence for carcinogenicity of these compounds in rats, and there was equivocal evidence for nickel oxide carcinogenicity in female mice.

4.1.2.7.1.6.6.3 IARC (1999) There is sufficient evidence in experimental animals for the carcinogenicity of implants of metallic nickel and for nickel alloy powder containing approximately 66-67% nickel, 13-16% chromium and 7% iron. There is limited evidence in experimental animals for the carcinogenicity of implants of alloys containing nickel, other than the specific aforementioned alloy.

4.1.2.7.1.6.6.4 NiPERA (1996) Studies on inhalation of metallic nickel powder are essentially negative for carcinogenicity. Intratracheal instillation of nickel powder has been shown to produce malignant lung tumours in animals, but the relevance of such studies in the aetiology of lung cancer in humans is questionable. The review concludes that animal evidence of carcinogenicity for metallic nickel is lacking. The carcinogenicity of green nickel oxide via routes relevant to occupational exposures suggests that it is capable of inducing lung tumours in animals, although it does not appear to be a very strong carcinogen. Unlike NiO, the evidence for lung cancer in rats of nickel subsulphide is more definitive. Nickel subsulphide at the doses tested is not a particularly strong carcinogen. Exposure to nickel sulphate at the highest doses tested in the NTP study failed to produce any carcinogenic effects in the lung or elsewhere in rats and mice. Soluble nickel compounds via other relevant routes of exposure have also failed to produce tumours.

4.1.2.7.1.6.6.5 IPCS (1991) There is a lack of evidence of a carcinogenic risk from oral exposure to nickel, but the possibility that it acts as a promoter has been raised. There is evidence of a carcinogenic risk through the inhalation of nickel metal dusts and some nickel compounds.

4.1.2.7.1.6.6.6 IARC (1990) There is sufficient evidence in experimental animals for the carcinogenicity of metallic nickel, nickel monoxides, nickel hydroxides and crystalline nickel sulphides.


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There is limited evidence in experimental animals for the carcinogenicity of nickel alloys, nickelocene, nickel carbonyl, nickel salts, nickel arsenides, nickel antimonide, nickel selenides and nickel telluride. There is inadequate evidence in experimental animals for the carcinogenicity of nickel trioxide, amorphous nickel sulphide and nickel titanate.

4.1.2.7.1.7 Conclusion, carcinogenicity in experimental animals The data in experimental animals on nickel compounds as reported here give some evidence for the carcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) in experimental animals. There is evidence for carcinogenicity following inhalation for some nickel compounds. Based on the available oral data on nickel sulphate the water-soluble nickel compounds should be considered without carcinogenic concern as well. However, data are too limited for an evaluation of the carcinogenic potential in experimental animals following oral administration of nickel carbonate and nickel metal as well as of other nickel compounds. Although there is no data on carcinogenicity following dermal exposure, the lack of carcinogenic potential after oral exposure to nickel sulphate make carcinogenic effects following dermal exposure to nickel chloride, nickel nitrate, nickel carbonate, and nickel metal very unlikely. The available data show that some nickel compounds can produce local tumours following injection at various sites to experimental animals. It should be noted that these routes of administration are irrelevant for humans exposed via inhalation, oral intake or dermal contact. These studies are however relevant when evaluating exposure to nickel metal by implants of nickel metal or of nickel containing alloys (iatrogenic exposures). It should be noted that IARC (1999) for implants of nickel metal or nickel containing alloys has concluded that there is “sufficient evidence in experimental animals for the carcinogenicity of implants of metallic nickel and for nickel alloy powder containing approximately 66-67% nickel, 13-16% chromium and 7% iron.”

4.1.2.7.2 Human data

4.1.2.7.2.1 Epidemiology In the final report from the International Committee on Nickel Carcinogenesis in Man (ICNCM), quantitative exposure estimates were introduced for four forms of nickel (water-soluble, sulphidic, oxidic, and metallic nickel), with the aim to identify which form(s) of nickel that contributed to the cancer risk in exposed humans (Doll et al., 1990). The analyses were based on calculation of standardised mortality ratios from lung cancer and nasal cancer according to duration of work in different departments and to cumulative exposures to the four forms of nickel. The variables were used in a categorical form, and the workers were cross-classified according to dichotomised nickel exposure variables (low or high exposure). Multivariable regression analyses or continuous variables were not used. Although a standardized strategy of analysis was used, the uncertainty and variation in the exposure measures made it difficult to compare across cohorts. Somewhat more confidence was put in comparisons made between groups at the same refinery. The most informative cohorts of nickel exposed workers proved to be the Welsh, the Norwegian, and some of the Canadian cohorts. For exposure to water soluble nickel compounds, strong evidence of a dose related increase in lung cancer risk came from the electrolysis workers in the Norwegian cohort. These workers had only low exposure to less soluble forms of nickel. Some evidence, but slightly less convincing, was found in the Welsh cohort. Both the Norwegian and the Welsh cohorts gave evidence that water-soluble nickel increased the lung cancer risk associated with exposure to oxidic nickel, the Welsh also for the combination of water-soluble and sulphidic nickel. The lack of evidence of risk associated with water-soluble nickel among the Port Colborne electrolysis workers was explained by lower exposures to water-soluble as well as to less soluble forms. The results from Wales suggested a separate effect on lung cancer risk from sulphidic nickel, but no support was found for this view in the other cohorts. Some evidence from the Norwegian and Welsh cohort suggested a lung cancer risk from exposure to oxidic nickel, although a possible contribution from water-soluble nickel could not be excluded in the Welsh data. A potential effect from the concomitant exposure to copper oxides was also discussed. No evidence was found of increased lung cancer risk from exposure to metallic nickel. As an overall conclusion, much of the lung cancer was ascribed to high exposures to the combination of nickel oxides


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and nickel sulphides, or to high levels of oxidic nickel in the absence of sulphidic nickel. Water-soluble nickel was found to increase the risk of lung cancer alone or together with less soluble forms. The data suggested that water-soluble nickel compounds might increase lung cancer risk at exposure levels below those of less soluble forms of nickel (1 mg Ni/m3 versus 10 mg/m3). Since the ICNCM study, two of the cohorts have been analysed with more or less the same exposure estimates and with regression methods that allow a simultaneous estimation of the effect of the four forms of nickel. Easton et al., (1992). Compared to the Welsh contribution in the ICNCM study, the Easton et al., (1992) paper was based on an additional year of follow-up (through 1985). The same exposure matrix was used. Initially, the risk of lung (and nasal) cancer was estimated by duration of employment in the high-risk areas identified by Kaldor et al., (1986). Additionally, based on 172 lung cancer deaths before 1930, a model was fitted with each of the four types of nickel included in their continuous form. The strongest effect was suggested for water-soluble nickel, and the authors concluded that some of the risk was due to water-soluble nickel with contributions also from at least one insoluble form of nickel. Andersen et al., (1996). Andersen and co-workers analysed a cancer update of the Norwegian nickel workers using the exposure estimates and the cohort sample from the ICNCM study extended with workers who had 3 years service or more from the years before 1946. Standardized incidence ratios were calculated and internal comparisons performed in multivariable analyses with Poisson regression including cumulative exposure to water-soluble and oxidic nickel, age, observation period, and smoking habits. Based on 200 cases of lung cancer, there was an excess risk from cumulative exposure to water soluble and oxidic nickel. A strong dose related increase was seen for water-soluble nickel, not equally clear for oxidic nickel. The effect of the combination of smoking and nickel exposure seemed to fit into a multiplicative pattern. Anttila et al., (1998). Some workers from this Finnish refinery were considered in the ICNCM study, but only one case of lung cancer was found. The cohort was enlarged to include workers with a minimum of 3 months employment at a copper/nickel smelter and a nickel refinery, and analysed by Anttila and co-workers. Although the number of cases was small, with 6 lung cancers and 2 nasal cancers among the refinery workers, the risk was increased significantly at the 5% level among the workers who had mostly been exposed to water-soluble nickel. Another two nasal cancers had been detected in the same group of workers, one probably misclassified and one diagnosed after the end of follow-up. Grimsrud et al., (2002). In the Norwegian cohort of nickel workers, Grimsrud and co-workers performed a case-control study of lung cancer including 213 of the identified cases and their age-matched controls (94% participation rate). The historical nickel exposures had been reassessment in a study based on a large number of personal measurements and speciation analyses in the 1990s. Detailed information on smoking habits was collected through interviews with participants or next-of-kin. A strong dose-related effect from water-soluble nickel on the relative risk of lung cancer was found when adjustment was made for smoking, other exposures at the refinery, and occupational lung carcinogens outside the refinery. The effect from the insoluble forms of nickel was less clear. Grimsrud et al., (2003). An update of the cancer incidence in the Norwegian cohort confirmed the findings from the case-control study. The risk pattern in the nickel electrolysis was of the same size before and after the change from a nickel sulphate based process to a predominantly nickel chloride based electrolysis. Only minor differences were found when the smoking habits in the cohort and smoking data from the case-control study were compared with the national data. Some other small studies on nickel workers elsewhere also have been published, but due to the size and design of the studies the information that can be drawn from them is very limited.

4.1.2.7.2.2 Exposures During the 1990s, further studies on exposures in the nickel producing industries indicated that most nickel species were present wherever nickel was found, although in varying proportions. On the basis of these findings, some characteristics of the earlier exposure estimates can be questioned. Kiilunen et al., (1997).


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Kiilunen and co-workers studied the past and present exposures in the nickel refinery where the workers studied by Anttila et al., (1998). The predominating exposure at the refinery was water-soluble nickel, and the particle size was large enough to explain deposition in the upper respiratory tract, and the average nickel levels in the breathing zone were in the range 0.15 and 0.25 mg/m3. Andersen et al., (1998). Andersen and co-workers analysed airborne dust from the Norwegian refinery and identified between 4.6 and 35.3% by weight of water-soluble nickel in the roasting area. Thomassen et al., (1999). Thomassen and co-workers studied the exposures in a Russian nickel refinery in Monchegorsk at the Kola Peninsula. The results were of particular interest for the Norwegian studies as the electrolysis were of the same type (Hybinette method) as the one used in Norway until 1978. The rest of the process also followed much of the same principles. In line with reports from the Norwegian and Canadian refineries, the results from the Russian plant identified the highest levels of water-soluble nickel in the roasting areas, especially at the upper floors of the roaster building. Werner et al., (1999a). Werner and co-workers studied the distribution of the four forms of nickel in aerosols from four different departments at the Norwegian refinery. The results contrasted sharply with the estimates in ICNCM study, both with respect to the absolute levels and the distribution of species: In the matte grinding area, the ICNCM study took the levels to be 1.3 mg/m3 sulphidic, 0.3 mg/m3 metallic, and no water-soluble nickel until 1984, while the measurements taken in 1995 suggested levels of 0.4, 0.03, and 0.03 mg/m3, respectively (inhalable aerosol sampler). Werner et al., (1999b). In a study of particle size distribution in some departments at the Norwegian refinery, between 14 and 33% of the inhalable aerosols belonged to the fine fraction expected to pass beyond the larynx. When compared to ‘total’ aerosol samples, which is the type used in the new exposure estimates for the Norwegian refinery (Grimsrud et al., 2000), the fraction passing to the bronchi and lung would constitute an even greater proportion, as these samplers leave out some of the largest particles. Vincent et al., (2001). In a study of nickel species in works and departments where raw ore is handled, the four forms of nickel were found at all sites. The proportion of water-soluble nickel varied between 2 and 8%, while, in the ICNCM study, similar areas were assumed to have a zero level of water-soluble nickel.

4.1.2.7.3 Discussion A frequently stated criticism of the nickel-cancer epidemiology is directed towards the lack of good exposure measures and the lack of control for important confounders such as tobacco smoking and other occupational exposures. Another question is the apparent discrepancy between the epidemiological results and the ease with which less soluble forms can induce cancer in experimental research, and the difficulties of achieving similar results with water-soluble nickel. The following discussion is limited to these aspects. The most recent studies among the Norwegian refinery workers were based on an exposure matrix developed from personal measurements and speciation analyses of the four different forms of nickel in refinery dusts and aerosols. This approach led to some important changes in the exposure estimates: The previously assumed "negligible" exposure to water-soluble nickel in the Norwegian grinding, roasting, and smelting departments, taken to be zero in the ICNCM study, was replaced by some 10% of the total nickel in the new exposure matrix. The recent studies on nickel species in nickel production confirm the appropriateness of these changes in exposure estimates. They also suggest that the levels of water-soluble nickel may have been underestimated in the ICNCM report even for other nickel works. The recent results from the Norwegian and Welsh cohorts are very much in agreement with each other. Additionally, the recent study from the Finnish nickel-refinery cohort concluded that exposure to water-soluble nickel was the most likely explanation of the excess risk of lung and nasal cancer (Anttila et al., 1998). A study among Russian nickel workers reported the highest risk of lung cancer among electrolysis workers (Saknyn & Shabynina, 1973; quoted in IARC, 1990). The lung cancer mortality among electrolysis workers at the Canadian refinery in Port Colborne did not show any increased risk in the studies by Roberts and co-workers and the ICNCM (Roberts et al., 1984; Roberts et al.,


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1989; Doll et al., 1990) although the exposures were predominantly to water-soluble nickel. Loss to follow-up and the method of estimation of standardised mortality ratios in these studies probably led to an underestimation of the risk. The exposure estimates for the refinery were too imprecise to allow any formal comparison with the Norwegian refinery. Still, differences in the process do suggest that the exposures to water-soluble and even to the less soluble forms of nickel in the electrolysis were lower at Port Colborne than in the Norwegian refinery, as the Port Colborne electrolysis ran no copper leaching and a less intensive electrolyte purification, both activities known to involve high exposures to soluble and insoluble nickel. Until 1990, the increase in respiratory cancer risk in the pyrometallurgical areas, especially roasting or calcining, was ascribed to oxidic or to the combination of oxidic and sulphidic nickel (Doll et al., 1990; IARC, 1990), and the risk among hydrometallurgy workers was considered to be caused by water-soluble nickel, possibly in combination with less soluble forms (Doll et al., 1990; IARC, 1990). This traditional view is strongly supported by experimental results. It has been shown beyond dispute that sulphidic nickel compounds produce tumours in experimental animals after injection or inhalation (IARC, 1990). These results along with the abundance of the compounds in the furnace departments made it easy to assume that they played an important role for the cancer hazard. However, it is not self-evident that the most predominant nickel species constitute the predominant or only cancer cause. The strong carcinogenic effect in animals of the less soluble nickel forms has been explained by phagocytosis and a subsequent slow solubilisation in vacuoles inside the cells, leading to a steady delivery of nickel ions to the cell nucleus. It is, however, not certain that phagocytosis is involved in nickel carcinogenesis in human airway epithelium. In addition to phagocytosis (Abbracchio et al., 1982), there are a number of ways in which nickel as nickel ions has been shown to enter animal or human cells: Through calcium channels (Refsvik & Andreassen, 1995), as part of an active trans-cellular absorption (Tallkvist et al., 1998), transport within and between cells (Henriksson et al., 1997), and uptake of nickel bound to amino acids or proteins (Webb & Weinzierl, 1972). Inside the cell, nickel shows a low mutagenic activity in conventional assays (Denkhaus & Salnikow, 2002), but in vitro exposure of rodent and human cells may lead to transformation, i.e. changes in phenotype and growth pattern (Tveito et al., 1989; Patierno et al., 1993). In a comparative in vitro experiment, ionising radiation and nickel chloride produced immortalized cells more effectively than known mutagens (Trott et al., 1995). But mutation in the important TP53 tumour suppressor gene (coding for the p53 protein) has indeed been demonstrated after chronic exposure of human cells (Maehle et al., 1992), although similar mutations were not found in nickel exposed rats (Weghorst et al., 1994). Chromosomal damage is seen in the form of sister chromatid exchange (SCE), micronuclei, and DNA-protein cross-links (Denkhaus & Salnikow, 2002). For further discussion of the mutagenicity, see 4.1.2.6. Cell damage has been proposed to arise from the formation of reactive oxygen species, via the binding of nickel to the amino acid histidine, or binding to nuclear proteins like histones (Kasprzak et al., 2003). A possible effect from nickel on sperm DNA has been proposed, which, also suggested by the author, may have consequences for childhood cancer (Kasprzak et al., 2003). The effects may be genotoxic (damage of DNA) or epigenetic (changes in the regulation of genes). A number of important genes can be activated or silenced through epigenetic mechanisms via methylation or deacetylation mechanisms, thereby inducing permanent changes in cells, inheritable through cell division, even in the further absence of nickel (Bal & Kasprzak, 2002). Toxic effects can also be exerted through the binding of nickel to receptors on the surface of human cells (Martin et al., 2003), a mechanism that may have a relevance to lung cancer (Stabile et al., 2002). Effects on production of hormones have been seen in in vitro experiments with rat cells (Laskey & Phelps, 1991). Nickel exposure can influence the calcium balance of the cell possibly linked to altered expression of genes associated with cell growth, differentiation, and apoptosis (Rosen et al., 1995; Nicotera & Orrenius, 1998). Nickel has been shown to induce the expression of a specific gene via changes in the intracellular calcium level (Zhou et al., 1998). Nickel may activate hypoxic signalling pathways, producing changes in the metabolism of the cells and making them more resistant to lack of oxygen, a characteristic also seen in cancer cells (Salnikow & Costa, 2000). Another possible mechanism for nickel carcinogenicity may involve inhibition of DNA repair. Reconstruction of DNA is vital after environmental damage or spontaneous changes. Impaired repair function has been seen in vitro at low non-cytotoxic nickel doses (Hartwig & Schwerdtle, 2002). A large number of these effects can be exerted experimentally by water-soluble nickel as well as less soluble forms. Still, in animal experiments, water-soluble nickel tends to give negative results in a number of situations where less soluble compounds produce tumours (IARC, 1990). The negative results have been explained by the more rapid excretion of water-soluble nickel compared with the less soluble forms. This explanation may be especially relevant to studies based on exposure by a single injection. Repeated intraperitoneal or subcutaneous


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injections of water-soluble nickel compounds have, in some studies, produced malignant tumours in mice and rats (IARC, 1990; Pott et al., 1989, 1992; Teraki & Uchiumi, 1992). An important role of time or cumulative exposure was suggested in experiments with human monocytes in vitro, as adverse biological effects were observed for nickel ions after 3 to 4 weeks exposure to concentrations an order of magnitude lower than the level known to be cytotoxic in 24-hour experiments (Wataha et al., 2000). A single intraperitoneal injection of nickel acetate, a water-soluble salt, has been shown to initiate renal cancer in rats (Kasprzak et al., 1990), and in another study, nickel chloride administered to rats in the drinking water served as a promoter for renal cancer (Kurokawa et al., 1985). An aqueous solution of nickel acetate administered intraperitoneally to pregnant rats initiated epithelial tumours in foetal kidneys of male (only) pups and was a complete transplacental carcinogen for rat pituitary gland (Diwan et al., 1992). Much attention has been directed towards the well-conducted series of long-term inhalation experiments organized under the U.S. National Toxicology Programme (NTP, 1996a, 1996b, 1996c). Rats and mice were exposed to aerosols of nickel subsulphide, nickel oxide, or nickel sulphate hexahydrate for 2 years. In rats, tumours were found in a dose-dependent manner after exposure to the sulphidic compound, and some evidence of carcinogenicity was found even for nickel oxide. On the other hand, no evidence of carcinogenicity appeared in mice, except for an equivocal result for nickel oxide in female mice. For the water-soluble nickel sulphate, no carcinogenic activity was seen, either in mice or rats (Dunnick et al., 1995). The relevance of rodent inhalation experiments for assessment of human risk was recently reviewed by Mauderly (1997). Results of studies on different rodent species are often inconsistent. For substances classified as human carcinogens by IARC, mice tended to give false negative results with particulate exposures, while rats appeared to give falsely negative responses with gases and vapours. Hamsters were less susceptible to lung tumours than both rats and mice. Mauderly specifically commented on the NTP rodent experiments with nickel sulphate, since this was the only known case of a classified human lung carcinogen with negative high-quality inhalation experiments in rats and mice. Nickel sulphate was considered by Mauderly (1997) as particles in the NTP experiments, as the water evaporated from the droplets after generation of aerosol from an aqueous solution. The rodents therefore inhaled an aerosol of hydrated salts (NTP, 1996a), but to what extent these highly soluble crystals behaved as particles when they reached the airways was not discussed. The papers cited above constitute only a small part of the vast number of experimental studies and review articles on nickel toxicology and carcinogenesis. Although some possible mechanisms have been described, the understanding is far from complete. Nickel demonstrates not only species specific but also tissue specific differences in response (Salnikow & Costa, 2000). If long-term animal experiments do not match the results of epidemiological studies, mechanistic evidence as shown above may support the plausibility of biological effects relevant to carcinogenicity. The evidence from experimental studies suggest that any form of nickel that produce nickel ions inside or outside cells may affect the cell by a number of pathways, leading to profound effects on cell growth, mutations, inhibition of DNA repair, and changes in the expression of a number of genes, thereby altering the metabolism and regulatory systems in the cell. Still, the concomitant exposure in nickel refineries to more than one form of nickel makes it difficult to decide by epidemiological studies whether the effect of one type of nickel is independent of the others. In the ICNCM study, an important criterion for the evaluation was the degree of dose-dependent increase in risk associated with different forms of nickel (Doll et al., 1990). The studies from the Welsh, the Finnish, and the Norwegian cohorts that have been published after 1990 indicate that the water-soluble nickel species as a group satisfy the following criteria for causality to a higher degree than do the sulphidic, oxidic, and metallic species: The ‘strength of the association’, the ‘biological gradient’, and the ‘consistency’ across groups of nickel exposed workers (Hill, 1965). There are also some negative studies among nickel-exposed workers that have not been cited in the present report due to limitations in the information on nickel exposure, in study size, and in study design.

4.1.2.7.4 Overall Conclusion for carcinogenicity. Nickel compounds are considered as human carcinogens based on epidemiological studies, mechanistic information and evidence from animal studies. The overall findings indicate that nickel ions generated in target cells are determinants for the carcinogenic process. Based on the epidemiological results discussed above following inhalational exposure and the variety of effects demonstrated in a large number of experimental studies with different nickel species, it is reasonable to assume


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that all nickel compounds that can create nickel ions inside or outside the cell are carcinogenic to humans following exposure by inhalation. For metallic nickel there is sufficient evidence of carcinogenicity in experimental studies, but no conclusion can be drawn based on epidemiology. Whilst most nickel compounds are evaluated in terms of their (aqueous) solubility, metallic nickel is often treated separately. The C&L Health Effects Group have agreed that the current classification of Carc. Cat. 3; R40 should be maintained at the present time. Further studies of the inhalational carcinogenicity of metallic nickel in animals are currently in progress and the mutagenicity of metallic nickel following inhalation will also be studied. The classification of nickel metal will be reconsidered when further evidence becomes available from the studies currently in progress or being planned. There is also evidence for local carcinogenicity of some nickel compounds following direct injection. These studies are relevant when evaluating exposure to nickel metal by implants of nickel metal or of nickel containing alloys (iatrogenic exposures). The experimental evidence for carcinogenicity following oral exposure suggests that this effect does not occur with soluble nickel salts. A recent oral carcinogenicity study (CRL, 2005) using nickel sulphate administered to rats (OECD 451) did not find any indications for a carcinogenic potential.. At their meeting in April 2004, the Specialised Experts concluded that nickel sulphate and nickel chloride should be considered as human carcinogens (Carc. Cat. 1). The data was considered to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer. There was supporting evidence for this conclusion from more limited data on nasal cancer (European Commission, 2004). In drawing this conclusion regarding lung cancer, it was recognised that the epidemiological data showed a clear exposure response relationship for water soluble compounds, consistency across and within studies and time periods, and high strength of association. Improved exposure characterisation based on personal air sampling and improved analysis of the water soluble fractions added to the reliability of the findings. Confounding factors such as co-exposure to insoluble nickel compounds and smoking were adequately addressed, and did not lower the level of confidence in reaching the conclusion (European Commission, 2004). The Specialised Experts also agreed that nickel nitrate and nickel carbonate should be classified as Carc. Cat. 1. In reaching this conclusion for nickel nitrate the Specialised Experts recognised that the water solubility of this compound was sufficiently similar to that of nickel sulphate and nickel chloride to justify the same classification. Since both the water soluble nickel compounds considered at this meeting and the insoluble inorganic nickel compounds already classified in Annex I are considered as human carcinogens consequently also the nickel carbonate was considered to be a human carcinogen (European Commission, 2004). The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates as Carc. Cat. 1; R4914.

4.1.2.8 Toxicity for reproduction

4.1.2.8.1 Effects on fertility

4.1.2.8.1.1 Animal studies An oral 1-generation study with two successive gestation periods and an oral 2-generation reproduction study of nickel chloride are available (Smith et al. 1993, RTI 1988). No effects on fertility have been found in these studies at highest dose levels used, i.e. up to 42 mg Ni/kg bw/day. Effects on sperm and oestrus cyclicity were not investigated in these studies. An increase in abnormalities was observed in spermatozoa from mice treated orally with a single dose of nickel chloride (43 mg Ni/kg bw) (Sobti & Gill 1989). Dose related effects on sperm motility and count as well as decreased body weight gain were observed after repeated dosing with nickel chloride at 10 and 20 mg/kg bw/day, but not at a dose level of 5 mg/kg bw/day (Pandey & Srivastava 2000). However, due to the limited number of animals used in this study, the dose level of 5 mg/kg bw/day cannot be considered as a reliable NOAEL.

14 These classifications are included in the 30th ATP.


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Two oral multi-generation reproduction studies and a range-finding one-generation study of nickel sulphate are available (Ambrose et al. 1976, NiPERA 2000a, NiPERA 2000b). No effects on fertility have been found in these studies. The study by Ambrose et al. (1976) and the one-generation range-finding study (NiPERA 2000a) indicate NOAELs of 52-80 mg Ni/kg bw/day and 16.8 mg Ni/kg bw/day, respectively. However, the Ambrose et al. study has a limited reporting of data and the range-finding study uses only a limited number of animals (8 per group). Therefore, the most reliable NOAEL for fertility effects is from the recent OECD TG 416 two-generation study (NiPERA et al. 2000b) where the NOAEL is the highest dose investigated, i.e. 2.2 mg Ni/kg bw/day. Effects on male sex organs in rats and mice have been reported in limited studies after oral, inhalation or subcutaneous administration of nickel sulphate. These studies indicate a LOAEL for oral exposure of 5.6 mg Ni/kg bw/day and an inhalation LOAEC at 1.6 mg Ni/m3. A repeated dose toxicity study provides a NOAEC for effects on sperm and oestrus cyclicity of 0.45 mg Ni/m3 for inhalation exposure. No effects on male sex organs including sperm quality were found in the recent oral OECD TG 416 two-generation study (NiPERA 2000b) and the NOAEL is therefore the highest dose studied, i.e. is 2.2 mg Ni/kg bw/day. No relevant studies regarding nickel carbonate, nickel nitrate, nickel sulphide, nickel oxide or metallic nickel have been found.

4.1.2.8.1.2 Human data No relevant studies have been found.

4.1.2.8.2 Developmental toxicity

4.1.2.8.2.1 Animal studies

4.1.2.8.2.1.1 Oral exposure No standard prenatal developmental toxicity studies via either the oral or inhalation routes were located. For nickel chloride, a 1-generation study with two gestation periods, a 2-generation study and a one-generation study using a limited number of animals provide consistent evidence of developmental toxicity (postimplantation/perinatal death) in rats, but a reliable NOAEL cannot be set based on these studies. As all three measures of pup death were statistically significant or borderline significant at the low dose in the second generation in the Smith et al study (1993) an equivocal LOAEL for this study was 1.33 mg Ni/kg bw/day. For nickel sulphate, multi-generation studies and a one-generation range-finding study provide consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal death) in rats at dose levels not causing maternal toxicity. Based on the increased postimplantation/perinatal lethality in F1 generation in the OECD TG 416 two-generation study (NIPERA 2000b) at 2.2 mg Ni/kg bw/day, the NOAEL that is used for developmental toxicity for regulatory purposes is set to 1.1 mg Ni/kg bw/day. No relevant studies regarding nickel carbonate, nickel nitrate, nickel sulphide, nickel oxide or metallic nickel have been found. Schroeder & Mitchener (1971) conducted a 3-generation study of rats administered nickel as an unspecific salt at 5 ppm in drinking water (estimated at 0.43 mg Ni/kg bw/day), and observed significantly increased neonatal mortality and incidence of runts. This study is significantly limited, however, by the use of only 5 mated pairs/dose group. In addition, the matings were not randomised and the males were not rotated. This study was conducted in an environmentally controlled facility where rats had access to food and water containing minimal levels of essential trace metals. Because of the interactions of nickel with other trace metals (chromium was estimated as inadequate), the restricted exposure to trace metals may have contributed to the toxicity of nickel. Therefore, this study does not present a reliable estimate of nickel toxicity.

4.1.2.8.2.1.2 Inhalation In the only study located that evaluated developmental or reproductive effects after inhalation of nickel compounds, Weischer et al. (1980), groups of 10-13 pregnant Wistar rats were continuously exposed to NiO at 0.8, 1.6, or 3.2 mg/m3 NiO (0.6, 1.2, or 2.5 mg Ni/m3) for 21 days, beginning on gestation day 1. Maternal endpoints evaluated were body weight, organ weights, serum urea, and haematology. The only foetal endpoints evaluated were foetal weight, leukocytes, and serum urea. Maternal body weight gain was statistically significantly reduced in all exposed groups, and statistically significant decreases in foetal body weight were


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observed at the top two exposure levels. Other developmental effects, such as foetal survival, were apparently not evaluated.

4.1.2.8.2.1.3 Other routes Studies using intraperitoneal or intramuscular dosing of nickel chloride during pregnancy in mice and rats have reported reduced number of live pups, lower body weights in foetuses and offspring, or malformations (Sunderman et al. 1978b, Mas et al. 1985, Lu et al. 1979). These studies are not considered useful for risk assessment because of the route of exposure.

4.1.2.8.2.2 Human data A cross sectional study of female nickel hydrometallurgy workers in a Russian refinery plant suggesting increased incidences of spontaneous abortions and malformations during exposure to soluble nickel exposure levels around 0.2 mg/m3 is considered as inconclusive due to flaws in the study design and reporting (Chashschin et al. 1994). A subsequent study by Vaktskjold et al. (2006) investigated genital malformations in newborns of female nickel-refinery workers using a register-based cohort study design. No negative effects on genital malformations was seen, but, as is also stated by the authors, this result should be interpreted with caution since there were few cases in the higher exposure groups.

4.1.2.8.3 Conclusions There are no relevant studies in humans. Consequently, the risk assessment is based on experimental data. No relevant studies regarding nickel carbonate, nickel nitrate, nickel sulphide, nickel oxide or metallic nickel have been found. Data on nickel chloride and nickel sulphate are therefore used, as the basic assumption is made that after intake nickel compounds are changed and that it is the nickel ion that is the determining factor for the reproductive and developmental toxicity. No effects on fertility have been found in two-generation studies on nickel chloride or nickel sulphate using dose levels up to around 50 mg Ni/kg bw/day. Effects on male sex organs in rats and mice have been reported in limited studies after oral, inhalation or subcutaneous administration of nickel chloride or nickel sulphate. The NOAEC for effects on male sex organs of 0.45 mg Ni /m3 for inhalation exposure and the NOAEL of 2.2 mg Ni/kg bw/day for oral administration is taken forward to the risk characterization. The potential for effects on sex organs has not been sufficiently investigated, as sperm quality and oestrus cyclicity either was not investigated or the highest dose level did not induce any signs of toxicity in the adult animals. Therefore, to be able to draw clear conclusions regarding the potential for effects on sex organs further studies using higher dose levels and including these end points would be relevant. However, there is no reason to expect that such testing would lead to lower NOAELs than the ones already determined for effects on sex organs. Therefore, the results of such testing are unlikely to influence the outcome of the risk assessment. No standard prenatal developmental toxicity studies via either the oral or inhalation routes were located. The available studies on nickel chloride, nickel sulphate and an unspecified nickel salt provide consistent evidence of increased postimplantation/perinatal lethality in rats after oral exposure. Based on an OECD TG 416 two-generation study on nickel sulphate, a NOAEL of 1.1 mg Ni/kg bw/day was identified. As this NOAEL is below the equivocal LOAEL of 1.33 mg Ni/kg bw/day for nickel chloride, the NOAEL that is used for developmental toxicity for regulatory purposes is set to 1.1 mg Ni/kg bw/day. This value is taken forward to the risk characterisation. In the only study located that evaluated developmental effects after inhalation, pregnant rats were exposed to NiO at 0.8, 1.6, or 3.2 mg/m3 NiO (0.6, 1.2, or 2.5 mg Ni/m3). Maternal body weight gain was reduced in all exposed groups, and decreases in foetal body weight were observed at the top two exposure levels. As other developmental effects, especially foetal survival, apparently were not evaluated, a NOAEC for developmental effects cannot be established. Based on the consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal lethality) in rats at dose levels not causing maternal toxicity, soluble nickel compounds should be classified for developmental toxicity in Category 2 with R61. Classification of the nickel carbonates is justified on the evidence for significant absorption of nickel carbonate after oral administration (see 4.1.2.1.1.2), supported by the acute toxicity data (see 4.1.2.2.3.2). The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates as Repr. Cat. 2; R61 and these classifications are included in the 30th ATP.


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Although there is a lack of a standard prenatal developmental toxicity studies (OECD 414) via either the oral or inhalation routes, there is not considered to be urgent need for further testing for developmental toxicity if nickel compounds is classified for developmental toxicity.

4.1.3 Risk characterisation The risk characterisation of the production and use of metallic nickel, nickel sulphate, nickel chloride, nickel carbonate and nickel nitrate is described in the individual risk assessment reports on these substances. A risk characterisation of the production and use of other nickel compounds described in Chapter 2.1.1 is not covered here. The approach used in the risk assessments of the five nickel compounds listed above may prove helpful in preparing a risk characterisation for specific compounds. Risk characterisations of other scenarios described in Chapter 2.1.2 not directly related to the production and use of nickel and nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments.

4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES) Risk assessment concerning the properties listed in Annex IIA of Regulation 1488/94

4.2.1 Exposure assessment See section 4.1.1

4.2.2 Effects assessment: The physical-chemical data for nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate is shown in the individual risk assessment reports. Apart from water solubility, there is very limited physical-chemical data for other nickel compounds. In particular, there is very little physical-chemical data for these substances in IUCLID (2002).

4.2.2.1 Explosivity Nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate are not explosive. There is no data to indicate whether other nickel compounds have explosive properties.

4.2.2.2 Flammability Nickel metal, nickel sulphate, nickel chloride and nickel carbonate are not flammable. Nickel nitrate is a fire risk. There is no data to indicate whether other nickel compounds are flammable.

4.2.2.3 Oxidising potential Nickel nitrate is an oxidiser, and the TC C&L has agreed to classify nickel nitrate as O; R8, and this classification is included in the 30th ATP. Nickel metal, nickel sulphate, nickel chloride and nickel carbonate are not oxidisers. There is no data to indicate whether other nickel compounds are oxidisers.

4.2.3 Risk characterisation The risk characterisation for worker and consumer exposure to metallic nickel, nickel sulphate, nickel chloride, nickel carbonate and nickel nitrate is described in the individual risk assessment reports on these substances, whereas risk characterisation for human indirect exposure via environment and combined exposure for the substances is performed in the separate report: “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”. A risk characterisation of the production and use of other nickel compounds described in Chapter 2.1.1 is not covered here. The approach used in the risk assessments of the five nickel compounds listed above may prove helpful in preparing a risk characterisation for specific compounds. Risk characterisations of other scenarios described in Chapter 2.1.2 not directly related to the production and use of nickel and nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments.


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5. CONCLUSIONS/RESULTS The risk assessment for worker and consumer exposure to metallic nickel, nickel sulphate, nickel chloride, nickel carbonate and nickel nitrate is described in the individual risk assessment reports on these substances, whereas risk characterisation for human indirect exposure via environment and combined exposure for the substances is performed in the separate report: “Humans exposed indirectly via the environment and combined exposure - exposure assessment and risk characterisation”. A full risk assessment of the production and use of the other nickel compounds described in this report has not been attempted by the Rapporteur, as these other nickel compounds are not included in a priority list under the Existing Substances Regulation. However, the Rapporteur considers that the approach used in the risk assessments of the five nickel compounds listed above may prove helpful to others when preparing a risk assessment for specific nickel compounds. Risk characterisations of scenarios not directly related to the production and use of nickel and nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments.


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• Wilson HTH (1956): Nickel dermatitis. Practitioner 177: 303-. • Zhou D, Salnikow K, Costa M. (1998): Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res

58: 2182-2189. • Zissu D, Cavelier C, De Ceaurriz J (1987): Experimental sensitization of guinea pigs to nickel and patch testing

with metal samples. Food Chem Toxicol 25, 83-.


154

7. APPENDICES

7.1 WATER SOLUBILITY OF SELECTED NICKEL COMPOUNDS. Substance Structure CAS No. Solubility Reference

metallic nickel Ni 7440-02-0 insoluble IPCS, 1991

TERA, 1999 nickel oxide NiO 1313-99-1 insoluble IPCS, 1991

TERA, 1999 nickel sulfide NiS 16812-54-7 insoluble

0.00036 g/100 ml @ 18°C IPCS, 1991, TERA, 1999

nickel disulfide NiS2 ? nickel subsulfide Ni3S2 12035-72-2 insoluble IPCS, 1991

TERA, 1999 nickel carbonyl Ni(CO)4 13463-39-3 insoluble HSE, 1987 nickel arsenate Ni3(AsO4)2 insoluble IPCS, 1991 nickel carbonate 2NiCO3 3333-67-3

(EC No: 222-068-2) insoluble 0.0093 g/100ml @ 25°C

IPCS, 1991 TERA, 1999

nickel carbonate CH2O3.xNi 16337-48-1 (EC No: 240-408-8)

nickel hydroxide Ni (OH)2 12054-48-7 insoluble 0.013 g/100ml

IPCS, 1991 TERA, 1999

nickel hydroxy-carbonate, tetrahydrate

2NiCO3.3Ni (OH)2 .4H2O

insoluble

nickel phosphate Ni3(PO4)3 insoluble IPCS, 1991 nickel acetate Ni (OOCCH3)2 soluble

17 g/100ml @ 20°C IPCS, 1991 TERA, 1999

nickel acetate tetrahydrate

Ni (OOCCH3)2 .4H2O

6018-89-9 soluble TERA, 1999

nickel ammonium sulphate

Ni(NH3)2.SO4 .6H2O

7785-20-8 2.5 g/100ml @ 0°C TERA, 1999

nickel bromide NiBr2 soluble IPCS, 1991 nickel dichloride NiCl2 7718-54-9

(EC No: 231-743-0) soluble 64.2 g/100ml @ 20°C

IPCS, 1991 TERA, 1999

nickel dichloride hexahydrate

NiCl2.6H2O 7791-20-0 254 g/100ml @ 20°C TERA, 1999

nickel chloride NiCl2 37211-05-5 (EC No: 253-399-0)

nickel fluoroboride Ni(BF4)2.6H2O 14708-14-6 soluble TERA, 1999 nickel fluoride NiF2 10028-18-9 slightly soluble

4 g/100ml @ 0°C

IPCS, 1991 TERA, 1999

nickel formate Ni(CHO2)2.2H2O 3349-06-2 soluble TERA, 1999 nickel nitrate Ni (NO3)2.6H2O 13138-45-9

(EC No: 236-068-5) soluble 283.5 g/100ml @ 0°C

IPCS, 1991 TERA, 1999

nickel nitrate (nitric acid, nickel salt)

HNO3.xNi 14216-75-2 (EC No: 238-076-4)

nickel sulphamate Ni(SH2NO3)2 .4H2O 13770-89-3 soluble TERA, 1999 nickel sulphate NiSO4 7786-81-4 soluble

29.3 g/100ml @ 0°C IPCS, 1991 TERA, 1999

nickel sulphate hexahydrate

NiSO4.6H2O 10101-97-0 65.5 g/100ml @ 0°C TERA, 1999


155

7.2 NICKEL AND NICKEL COMPOUNDS IN EINECS

7.2.1 Nickel, nickel compounds, and complex substances containing nickel included in EINECS.

Nickel metal and metal compounds. EC Number CAS

Number Chemical Name HPVC / LPVC CUS

Number231-111-4 7440-02-0 Nickel- HPVC 11024 234-439-6 12003-78-0 Aluminum, compd. with nickel (1:1) 235-261-1 12142-92-6 Nickel, compd. with zirconium (1:2) 234-807-6 12034-55-8 Nickel, compd. with niobium (1:1) 235-034-7 12059-23-3 Nickel, compd. with tin (3:1) 234-827-5 12035-52-8 Antimony, compd. with nickel (1:1) 235-676-8 12503-49-0 Antimony, compd. with nickel (1:3) 235-372-5 12196-72-4 Lanthanum, compd. with nickel (1:5) 235-341-6 12175-27-8 Dysprosium, compd. with nickel (1:2) 235-773-5 12688-64-1 Bismuth, compd. with nickel (1:1) 257-510-3 51912-52-8 Copper, compd. with lanthanum and nickel (4:1:1) Inorganic nickel compounds. EC Number CAS


Number 215-215-7 1313-99-1 Nickel oxide (NiO) HPVC 20749 215-217-8 1314-06-3 Nickel oxide (Ni2-O3) 20765 234-323-5 11099-02-8 Nickel-oxide- 234-823-3 12035-36-8 Nickel oxide (NiO2) 234-454-8 12004-35-2 Aluminum nickel oxide (Al2-NiO4) 234-825-4 12035-39-1 Nickel titanium oxide (NiTiO3) 235-752-0 12653-76-8 Nickel-titanium-oxide- 257-970-5 52502-12-2 Nickel vanadium oxide (NiV2-O6) 234-636-7 12018-18-7 Chromium nickel oxide (Cr2-NiO4) 235-335-3 12168-54-6 Iron nickel oxide (Fe2-NiO4) 306-902-3 97435-21-7 Iron nickel zinc oxide (Fe2-NiZnO4) 261-346-8 58591-45-0 Cobalt nickel oxide (CoNiO2) 269-051-6 68186-89-0 Cobalt nickel gray periclase LPVC 268-169-5 68016-03-5 Cobalt molybdenum nickel oxide (CoMo2-NiO8) 274-755-1 70692-93-2 Nickel zirconium oxide (NiZrO3) 305-835-7 95046-47-2 Spinels, cobalt nickel zinc grey 238-034-5 14177-55-0 Molybdenum nickel oxide (MoNiO4) 234-824-9 12035-38-0 Nickel tin oxide (NiSnO3) 20760 238-032-4 14177-51-6 Nickel tungsten oxide (NiWO4) 239-876-6 15780-33-3 Nickel uranium oxide (NiU3-O10) 277-627-3 73892-02-1 Antimony oxide (Sb2-O3), solid soln. with nickel oxide (NiO)

and titanium oxide (TiO2)

232-353-3 8007-18-9 Antimony nickel titanium oxide yellow- LPVC 269-071-5 68187-10-0 Nickel ferrite brown spinel LPVC 271-112-7 68515-84-4 Olivine, nickel green 271-853-6 68610-24-2 Nickel barium titanium primrose priderite; C.I. No. 77900 271-892-9 68611-43-8 Nickel niobium titanium yellow rutile; C.I. No. 77895 275-738-1 71631-15-7 Nickel iron chromite black spinel; C.I. No. 77504 LPVC 309-018-6 99749-23-2 Cassiterite, cobalt manganese nickel grey 273-686-4 69011-05-8 Nickel titanium oxide tungstate (NiTi20-O35-(WO6)2) 269-047-4 68186-85-6 C.I.Pigment Green 50


156

234-348-1 11113-74-9 Nickel-hydroxide- 235-008-5 12054-48-7 Nickel hydroxide (Ni(OH)2) LPVC 20745


157

Inorganic nickel compounds (continued). 234-493-0 12007-00-0 Nickel boride (NiB) 234-494-6 12007-01-1 Nickel boride (Ni2-B) 234-495-1 12007-02-2 Nickel boride (Ni3-B) 235-723-2 12619-90-8 Nickel-boride-

235-033-1 12059-14-2 Nickel silicide (Ni2-Si) 235-379-3 12201-89-7 Nickel silicide (NiSi2) 234-828-0 12035-64-2 Nickel phosphide (Ni2-P) 234-349-7 11113-75-0 Nickel-sulfide- 234-829-6 12035-72-2 Nickel sulfide (Ni3-S2) 25517 240-841-2 16812-54-7 Nickel sulfide (NiS) LPVC 25516 235-103-1 12068-61-0 Nickel arsenide (NiAs2) 248-169-1 27016-75-7 Nickel arsenide (NiAs) 215-216-2 1314-05-2 Nickel selenide (NiSe) 233-263-7 10101-96-9 Selenious acid, nickel(2+) salt (1:1) 239-125-2 15060-62-5 Selenic acid, nickel(2+) salt (1:1) 20757 235-260-6 12142-88-0 Nickel telluride (NiTe) 20758 271-512-1 68583-44-8 Cadmium sulfide (CdS), solid soln. with zinc sulfide, nickel and

silver-doped

271-539-9 68584-42-9 Cadmium sulfide (CdS), solid soln. with zinc sulfide, copper and nickel-doped

270-961-0 68512-22-1 Zinc sulfide (ZnS), nickel and silver-doped 271-601-5 68585-93-3 Zinc sulfide (ZnS), copper and nickel-doped 272-277-8 68784-84-9 Zinc sulfide (ZnS), copper and nickel and silver-doped 236-669-2 13463-39-3 Nickel carbonyl (Ni(CO)4), (T-4)- 20730 209-160-8 557-19-7 Nickel cyanide (Ni(CN)2) 20734 254-261-2 39049-81-5 Nickelate(2-), tris(cyano-C)-, dipotassium 238-082-7 14220-17-8 Nickelate(2-), tetrakis(cyano-C)-, dipotassium, (SP-4-1)- 238-946-3 14874-78-3 Ferrate(4-), hexakis(cyano-C)-, nickel(2+) (1:2), (OC-6-11)- 20738 222-068-2 3333-67-3 Carbonic acid, nickel(2+) salt (1:1) HPVC 20729 240-408-8 16337-84-1 Carbonic acid, nickel salt 235-715-9 12607-70-4 Nickel, [carbonato(2-)]tetrahydroxytri- LPVC (25626)15

265-748-4 65405-96-1 Nickel, [mu-[carbonato(2-)-O:O’]]dihydroxydi- 233-071-3 10028-18-9 Nickel fluoride (NiF2) LPVC 20739 231-743-0 7718-54-9 Nickel chloride (NiCl2) HPVC 2073116 253-399-0 37211-05-5 Nickel-chloride- 267-897-0 67952-43-6 Chloric acid, nickel(2+) salt 237-124-1 13637-71-3 Perchloric acid, nickel(2+) salt 20754 236-665-0 13462-88-9 Nickel bromide (NiBr2) LPVC 20728 238-596-1 14550-87-9 Bromic acid, nickel(2+) salt 236-666-6 13462-90-3 Nickel iodide (NiI2) 20747 231-827-7 7757-95-1 Sulfurous acid, nickel(2+) salt (1:1) 232-104-9 7786-81-4 Sulfuric acid, nickel(2+) salt (1:1) HPVC 20762 237-563-9 13842-46-1 Sulfuric acid, nickel(2+) potassium salt (2:1:2) 20756 239-793-5 15699-18-0 Sulfuric acid, ammonium nickel(2+) salt (2:2:1) 11026 275-897-7 71720-48-4 Sulfuric acid, monoethyl ester, nickel(2+) salt 237-396-1 13770-89-3 Sulfamic acid, nickel(2+) salt (2:1) LPVC 20761 239-967-0 15851-52-2 Telluric acid (H2-TeO3), nickel(2+) salt (1:1) 239-974-9 15852-21-8 Telluric acid (H2-TeO4), nickel(2+) salt (1:1)

15 CUS Number for the tetrahydrate, CAS No. 39430-27-8. 16 Also nickel (II) chloride hexahydrate, CAS No.: 7791-20-0, CUS No.: 39096


158

Inorganic nickel compounds (continued). 236-068-5 13138-45-9 Nitric acid, nickel(2+) salt HPVC 2075017 238-076-4 14216-75-2 Nitric acid, nickel salt 238-278-2 14332-34-4 Phosphoric acid, nickel(2+) salt (1:1) 242-522-3 18718-11-1 Phosphoric acid, nickel(2+) salt (2:1) 233-844-5 10381-36-9 Phosphoric acid, nickel(2+) salt (2:3) 20751 268-585-7 68130-36-9 Molybdenum-nickel-hydroxide-oxide-phosphate- 238-426-6 14448-18-1 Diphosphoric acid, nickel(2+) salt (1:2) 238-511-8 14507-36-9 Phosphinic acid, nickel(2+) salt 20746 252-840-4 36026-88-7 Phosphinic acid, nickel salt 236-771-7 13477-70-8 Arsenic acid (H3-AsO4), nickel(2+) salt (2:3) 20724 244-578-4 21784-78-1 Silicic acid (H2-SiO3), nickel(2+) salt (1:1) 237-411-1 13775-54-7 Silicic acid (H4-SiO4), nickel(2+) salt (1:2) 20759 250-788-7 31748-25-1 Silicic acid (H2-SiO3), nickel(2+) salt (4:3) 253-461-7 37321-15-6 Silicic acid, nickel salt 235-688-3 12519-85-6 Nickel hydroxide silicate (Ni3-(OH)4-(Si2-O5)) 238-766-5 14721-18-7 Chromic acid (H2-CrO4), nickel(2+) salt (1:1) 20732 239-646-5 15586-38-6 Dichromic acid (H2-Cr2-O7), nickel(2+) salt (1:1) 237-595-3 13859-60-4 Nickelate(2-), tetrafluoro-, dipotassium, (T-4)- 308-989-3 99587-11-8 Nickelate(2-), tetrachloro-, diammonium, (T-4)- 246-378-2 24640-21-9 Nickelate(1-), trichloro-, ammonium 11021 237-597-4 13859-65-9 Nickel, tetrakis(phosphorous trifluoride)-, (T-4)- 238-753-4 14708-14-6 Borate(1-), tetrafluoro-, nickel(2+) (2:1) 20740 237-638-6 13877-20-8 Nickel(2+), hexaammine-, (OC-6-11)-, bis[tetrafluoroborate(1-)] 247-430-7 26043-11-8 Silicate(2-), hexafluoro-, nickel(2+) (1:1) 20741 250-370-4 30868-55-4 Zirconate(2-), hexafluoro-, nickel(2+) (1:1), (OC-6-11)- 235-531-9 12263-13-7 Molybdate(3-), tetracosa-mu-oxododecaoxo[mu12-[phosphato(3-

)-O:O:O:O':O':O':O'':O'':O'':O''':O''':O''']]dodeca-, nickel(2+) (2:3)

Organic nickel compounds. EC Number CAS

Number Chemical Name HPVC /

LPVC

222-101-0 3349-06-2 Formic acid, nickel(2+) salt 20742 239-946-6 15843-02-4 Formic acid, nickel salt 268-755-0 68134-59-8 Formic acid, copper nickel salt 272-149-1 68758-60-1 Nickel(2+), hexaammine-, (OC-6-11)-, diformate 237-205-1 13689-92-4 Thiocyanic acid, nickel(2+) salt 208-933-7 547-67-1 Ethanedioic acid, nickel(2+) salt (1:1) 20752 243-867-2 20543-06-0 Ethanedioic acid, nickel salt 206-761-7 373-02-4 Acetic acid, nickel(2+) salt LPVC 2072318 239-086-1 14998-37-9 Acetic acid, nickel salt LPVC 240-235-8 16083-14-0 Acetic acid, trifluoro-, nickel(2+) salt 262-383-2 60700-37-0 2-Propenoic acid, nickel(2+) salt 257-066-0 51222-18-5 2-Propenoic acid, nickel salt 267-961-8 67968-22-3 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)]-,

triammonium hydrogen, (T-4)-

264-338-2 63588-33-0 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)]-, tetrapotassium, (T-4)-

268-296-6 68052-00-6 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)-N,O,O'',O''']-, tetrasodium, (T-4)-

222-102-6 3349-08-4 Propanoic acid, nickel(2+) salt 267-923-0 67952-69-6 1,2,3-Propanetriol, mono(dihydrogen phosphate), nickel(2+) salt

(1:1)

269-946-1 68391-37-7 1,2,3-Propanetriol, 1-(dihydrogen phosphate), nickel(2+) salt (1:1) 264-136-4 63427-32-7 Copper(2+), bis(1,2-ethanediamine-N,N’)-, (SP-4-1)-

tetrakis(cyano-C)nickelate(2-) (1:1)

17 Also nickel(II) nitrate hexahydrate, CAS No.: 13478-00-7, CUS No. 39097. 18 Also nickel(II) acetate tetrahydrate, CAS No.: 6018-89-9, CUS No. 39093.


159

Organic nickel compounds (continued). 273-379-5 68958-89-4 Nickel(2+), bis(1,2-ethanediamine-N,N’)-, bis[bis(cyano-

C)aurate(1-)]

244-300-1 21264-77-7 Nickel(2+), bis(ethylenediamine)-, sulfate (1:1) 287-849-2 85586-46-5 Nickel, bis(1H-1,2,4-triazole-3-sulfonato-N(2)-,O(3))- 228-501-1 6283-67-6 2-Butenedioic acid (E)-, nickel(2+) salt (1:1) 237-618-7 13869-33-5 Nickel, [N-(carboxymethyl)glycinato(2-)-N,O,O(N)-]- 268-711-0 68133-84-6 Nickel, [(2-amino-2-oxoethoxy)acetato(2-)]- 268-195-7 68025-40-1 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]-,

triammonium, (T-4)-

264-360-2 63597-34-2 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]-, tripotassium, (T-4)-

268-196-2 68025-41-2 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]-, trisodium, (T-4)-

257-963-7 52496-91-0 2-Propenoic acid, 2-methyl-, nickel(2+) salt 304-466-9 94275-78-2 2-Propenoic acid, 2-methyl-, nickel salt 267-894-4 67952-41-4 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel(2+) salt

(2:1)

257-610-7 52022-10-3 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel salt 237-877-6 14038-85-8 Nickelate(2-), tetrakis(cyano-C)-, disodium, (SP-4-1)- 273-375-3 68958-86-1 Nickelate(6-), [[[1,2-

ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonato]](8-)]-, pentaammonium hydrogen, (OC-6-21)-

273-376-9 68958-87-2 Nickelate(6-), [[[1,2-ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonato]](8-)]-, pentapotassium hydrogen, (OC-6-21)-

273-377-4 68958-88-3 Nickelate(6-), [[[1,2-ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonato]](8-)]-, pentasodium hydrogen, (OC-6-21)-

257-953-2 52486-98-3 Nickel, bis[(2-hydroxyethyl)carbamodithioato-S,S’]-, (SP-4-1)- 239-560-8 15521-65-0 Nickel, bis(dimethylcarbamodithioato-S,S’)-, (SP-4-1)- 20737 252-235-5 34831-03-3 Nickelate(1-), [N,N-bis(carboxymethyl)glycinato(3-)-

N,O,O’,O’’]-, hydrogen, (T-4)-

264-377-5 63640-18-6 Nickelate(1-), [N,N-bis(carboxymethyl)glycinato(3-)-N,O,O’,O’’]-, potassium, (T-4)-

254-642-3 39819-65-3 Benzenesulfonic acid, nickel(2+) salt 303-972-7 94232-44-7 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, cobalt(2+) nickel(2+)

salt (2:1:2)

227-873-2 6018-92-4 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, nickel(2+) salt (2:3) 20733 304-013-5 94232-84-5 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, cobalt(2+) nickel(2+)

salt (2:2:1)

268-176-3 68025-13-8 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, ammonium nickel(2+) salt (2:2:1)

242-533-3 18721-51-2 Citric acid, nickel(2+) salt (1:1) 242-161-1 18283-82-4 Citric acid, ammonium nickel salt 245-119-0 22605-92-1 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, nickel salt 209-046-8 553-71-9 Benzoic acid, nickel(2+) salt 20726 254-210-4 38951-94-9 Nickel, bis[2-butene-2,3-dithiolato(2-)-S,S’]-, (SP-4-1)- 275-994-4 71767-12-9 Uranate(2-), tetrakis(acetato-O)dioxo-, nickel(2+) (1:1), (OC-6-

11)- 20766

236-782-7 13478-93-8 Nickel, bis[(2,3-butanedione dioximato)(1-)-N,N’]-, (SP-4-1)- 16135 224-699-9 4454-16-4 Hexanoic acid, 2-ethyl-, nickel(2+) salt 231-480-1 7580-31-6 Hexanoic acid, 2-ethyl-, nickel salt 301-323-2 93983-68-7 Hexanoic acid, dimethyl-, nickel salt 225-656-7 4995-91-9 Octanoic acid, nickel(2+) salt LPVC 249-555-2 29317-63-3 Isooctanoic acid, nickel(2+) salt 248-585-3 27637-46-3 Isooctanoic acid, nickel salt 284-349-6 84852-37-9 Isononanoic acid, nickel(2+) salt 300-094-6 93920-10-6 Neononanoic acid, nickel(2+) salt 215-039-0 1271-28-9 Nickelocene- 274-912-4 70824-02-1 Nickel, bis(5-oxo-L-prolinato-N(1)-,O(2))-


160

Organic nickel compounds (continued). 285-069-7 85026-81-9 Nickel, bis(5-oxo-DL-prolinto-N(1)-,O(2))- 247-019-2 25481-21-4 Nickelate(2-), [[N,N'-1,2-ethanediylbis[N-

(carboxymethyl)glycinato]](4-)-N,N',O,O',O(N)-,O(N')-]-, dihydrogen, (OC-6-21)-

267-686-3 67906-12-1 Nickelate(1-), [[N,N'-1,2-ethanediylbis[N-(carboxymethyl)glycinato]](4-)-N,N',O,O',O(N)-,O(N')-]-, potassium, (OC-6-21)-

221-875-7 3264-82-2 Nickel, bis(2,4-pentanedionato-O,O')-, (SP-4-1)- 223-463-2 3906-55-6 Cyclohexanebutanoic acid, nickel(2+) salt 20735 257-954-8 52486-99-4 Nickel, bis[bis(2-hydroxyethyl)carbamodithioato-S,S']-, (SP-4-1)- 278-504-7 76625-10-0 Nickel, bis[N-(2-hydroxyethyl)-N-methylglycinato-N,O,O(N)-]- 238-157-4 14267-17-5 Nickel, bis(diethylcarbamodithioato-S,S')-, (SP-4-1)- 258-044-3 52610-81-8 Nickel, bis(diethylcarbamodithioato-S,S')- 287-468-1 85508-43-6 Isodecanoic acid, nickel(2+) salt 287-469-7 85508-44-7 Neodecanoic acid, nickel(2+) salt 257-447-1 51818-56-5 Neodecanoic acid, nickel salt 239-028-5 14949-69-0 Nickel, bis(1,1,1,5,5,5-hexafluoro-2,4-pentanedionato-O,O')-, (SP-

4-1)-

300-093-0 93920-09-3 Neoundecanoic acid, nickel(2+) salt 235-339-5 12170-92-2 Nickel, di-mu-carbonylbis(eta(5)-2,4-cyclopentadien-1-yl)di-, (Ni-

Ni)

255-387-0 41476-75-9 Nickel, bis(1-piperidinecarbodithioato-S,S')- 20753 276-205-6 71957-07-8 Nickel, bis(D-gluconato-O(1)-,O(2))- 258-051-1 52625-25-9 Benzoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, nickel(2+)

salt (2:1)

215-072-0 1295-35-8 Nickel, bis[(1,2,5,6-eta)-1,5-cyclooctadiene]- 32526 238-536-4 14522-99-7 Nickel, bis(6-methyl-2,4-heptanedionato-O,O')- 284-350-1 84852-38-0 Nickel, (2-ethylhexanoato-O)(isooctanoato-O)- 237-138-8 13654-40-5 Hexadecanoic acid, nickel(2+) salt 274-916-6 70833-37-3 Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1-one

oximato-N(2)-,O(1))- LPVC

250-401-1 30947-30-9 Phosphonic acid, [[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-, monoethyl ester, nickel(2+) salt (2:1)

287-470-2 85508-45-8 Nickel, (2-ethylhexanoato-O)(isononanoato-O)- 287-471-8 85508-46-9 Nickel, (isononanoato-O)(isooctanoato-O)- 265-022-7 64696-98-6 Nickel, [2,3'-bis[[(2-hydroxyphenyl)methylene]amino]-2-

butenedinitrilato(2-)-N(2)-,N(3)-,O(2)-,O(3)-]-, (SP-4-2)-

237-950-2 14100-15-3 Nickel, bis(8-quinolinolato-N(1)-,O(8))- 239-841-5 15751-00-5 Nickel(2+), hexakis(1H-imidazole-N(3))-, dichloride, (OC-6-11)- 284-347-5 84852-35-7 Nickel, (isooctanoato-O)(neodecanoato-O)- 284-351-7 84852-39-1 Nickel, (2-ethylhexanoato-O)(isodecanoato-O)- 285-698-7 85135-77-9 Nickel, (2-ethylhexanoato-O)(neodecanoato-O)- 285-909-2 85166-19-4 Nickel, (isodecanoato-O)(isooctanoato-O)- 235-832-5 13001-15-5 9-Octadecenoic acid (Z)-, nickel(2+) salt 237-696-2 13927-77-0 Nickel, bis(dibutylcarbamodithioato-S,S')-, (SP-4-1)- LPVC 20736 239-354-8 15317-78-9 Nickel, bis[bis(2-methylpropyl)carbamodithioato-S,S']-, (SP-4-1)- 218-744-1 2223-95-2 Octadecanoic acid, nickel(2+) salt 27634 288-967-7 85958-80-1 Nickel, [2-hydroxybenzoic acid [3-[1-cyano-2-(methylamino)-2-

oxoethylidene]-2,3-dihydro-1H-isoindol-1-ylidene]hydrazidato(2-)]-

284-348-0 84852-36-8 Nickel, (isodecanoato-O)(isononanoato-O)- 287-592-6 85551-28-6 Nickel, (isononanoato-O)(neodecanoato-O)- 235-829-9 12794-26-2 Nickel, bis(1-nitroso-2-naphthalenolato)- 238-380-7 14406-66-7 Nickel, bis(1-nitroso-2-naphthalenolato-N(1)-,O(2))-, (T-4)- 249-503-9 29204-84-0 Nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-

,N(3)-]- LPVC

287-467-6 85508-42-5 Nickel, (isodecanoato-O)(neodecanoato-O)- 300-092-5 93920-08-2 Nickel, (neononanoato-O)(neoundecanoato-O)- 256-331-8 47726-62-5 Nickel, [[2,2'-(4,8-dichlorobenzo[1,2-d:4,5-d']bisoxazole-2,6-

diyl)bis[4,6-dichlorophenolato]](2-)]-


161

Organic nickel compounds (continued). 255-924-9 42739-61-7 Nickel, bis[2,3-bis(hydroxyimino)-N-(2-

methoxyphenyl)butanamidato]- LPVC

252-937-1 36259-37-7 Nickel, bis(dipentylcarbamodithioato-S,S')-, (SP-4-1)- 286-563-5 85269-39-2 Nickel, bis[N-(2,4-dimethoxyphenyl)-2,3-

bis(hydroxyimino)butanamidato-N(2)-,N(3)-]-, (SP-4-1)-

279-314-7 79817-91-7 Nickelate(3-), [5-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]-4-hydroxy-3-[(2-hydroxy-3-nitro-5-sulfophenyl)azo]-2,7-naphthalenedisulfonato(5-)]-, trisodium

243-820-6 20437-10-9 Nickel, [[1,1'-[1,2-phenylenebis(nitrilomethylidyne)]bis[2-naphthalenolato]](2-)-N,N',O,O']-

249-353-4 28984-20-5 Nickel, bis[1,2-diphenyl-1,2-ethenedithiolato(2-)-S,S']-, (SP-4-1)- 248-536-6 27574-34-1 Nickel, [[2,2'-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-

O,O',S]-

251-715-1 33882-09-6 Nickel, [[2,2'-thiobis[3-octylphenolato]](2-)-O,O',S]- 240-485-8 16432-37-4 Nickel, [[2,2'-sulfonylbis[4-(1,1,3,3-

tetramethylbutyl)phenolato]](2-)-O(1)-,O(1')-,O(2)-]-

262-703-0 61300-98-9 Nickelate(1-), [3,4-bis[[(2-hydroxy-1-naphthalenyl)methylene]amino]benzoato(3-)-N(3)-,N(4)-,O(3)-,O(4)-]-, hydrogen

255-965-2 42844-93-9 Nickel, [1,3-dihydro-5,6-bis[[(2-hydroxy-1-naphthalenyl)methylene]amino]-2H-benzimidazol-2-onato(2-)-N(5)-,N(6)-,O(5)-,O(6)-]-, (SP-4-2)-

257-521-3 51931-46-5 Nickel, bis[3-[(4-chlorophenyl)azo]-2,4(1H,3H)-quinolinedionato]-

267-045-8 67763-27-3 Nickel, (2-propanol)[[2,2'-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O',S]-

249-155-8 28680-76-4 Nickel, [29H,31H-phthalocyaninetetrasulfonyl tetrachloridato(2)-N(29)-,N(30)-,N(31)-,N(32)-]-

237-893-3 14055-02-8 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, (SP-4-1)-

LPVC

254-212-5 38951-97-2 Nickel, bis[1,2-bis(4-methoxyphenyl)-1,2-ethenedithiolato(2-)-S,S']-, (SP-4-1)-

253-958-9 38465-55-3 Nickel, bis[1-[4-(dimethylamino)phenyl]-2-phenyl-1,2-ethenedithiolato(2-)-S,S']-

238-523-3 14516-71-3 Nickel, (1-butanamine)[[2,2'-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O',S]-

LPVC

276-364-1 72139-08-3 Nickelate(8-), bis[3-[(2-amino-8-hydroxy-6-sulfo-1-naphthalenyl)azo]-2-hydroxy-5-sulfobenzoato(5-)]-, hexasodium dihydrogen

281-282-4 83898-70-8 Nickel, dimethoxy[29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, (OC-6-12)-

274-027-3 69524-96-5 Nickel, bis(4-benzoyl-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato-O,O')-

238-400-4 14428-08-1 Nickel, bis[bis(2-ethylhexyl)carbamodithioato-S,S']- 238-154-8 14264-16-5 Nickel, dichlorobis(triphenylphosphine)- 32583 279-060-7 79102-62-8 Nickelate(4-), [[[(3-amino-4-sulfophenyl)amino]sulfonyl]-

29H,31H-phthalocyaninetrisulfonato(6-)-N(29)-,N(30)-,N(31)-,N(32)-]-, tetrahydrogen

300-365-9 93939-76-5 Nickelate(4-), [[[(3-amino-4-sulfophenyl)amino]sulfonyl]-29H,31H-phthalocyaninetrisulfonato(6-)-N(29)-,N(30)-,N(31)-,N(32)-]-, tetrasodium

235-851-9 13007-90-4 Nickel, dicarbonylbis(triphenylphosphine)-, (T-4)- 32582 283-380-2 84604-95-5 Nickel, bis[bis(3,5,5-trimethylhexyl)carbamodithioato-S,S’]- 260-258-7 56557-00-7 Nickel, bis[2,4-dihydro-5-methyl-4-(1-oxodecyl)-2-phenyl-3H-

pyrazol-3-onato-O,O’]-

276-491-2 72229-81-3 Nickelate(3-), [[[[3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]amino]sulfonyl]tris(aminosulfonyl)-29H,31H-phthalocyaninetrisulfonato(5-)-N(29)-,N(30)-,N(31)-,N(32)-]-, trisodium


162

Organic nickel compounds (continued). 275-295-4 71243-96-4 Nickelate(3-), [22-[[[3-[(5-chloro-2,6-difluoro-4-

pyrimidinyl)amino]phenyl]amino]sulfonyl]-29H,31H-phthalocyanine-1,8,15-trisulfonato(5-)-N(29)-,N(30)-,N(31)-,N(32)-]-, trisodium, (SP-4-2)-

276-168-6 71889-22-0 Nickel, [mu-(piperazine-N(1)-:N(4))]bis[3-[1-[(4,5,6,7-tetrachloro-1-oxo-1H-isoindol-3-yl)hydrazono]ethyl]-2,4(1H,3H)-quinolinedionato(2-)]di-

239-949-2 15843-91-1 Nickel, bis[[2-hydroxy-4-(octyloxy)phenyl]phenylmethanonato]- 306-462-2 97280-68-7 Nickelate(4-), [bis[[[4-[[2-

(sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl]-29H,31H-phthalocyaninedisulfonato(6)-N(29)-,N(30)-,N(31)-,N(32)-]-, tetrasodium

245-028-6 22484-07-7 Nickel, [mu-[[1,1’,1’’,1’’’-[1,2,4,5-benzenetetrayltetrakis(nitrilomethylidyne)]tetrakis[2-naphthalenolato]](4-)]]di-

272-095-9 68698-80-6 Nickelate(6-), [4-[[5-[[(3,6-dichloro-4-pyridazinyl)carbonyl]amino]-2-sulfophenyl]azo]-4,5-dihydro-5-oxo-1-[5-[[(trisulfo-29H,31H-phthalocyaninyl)sulfonyl]amino]-2-sulfophenyl]-1H-pyrazole-3-carboxyla

299-467-3 93891-86-2 Nickelate(6-), [4-[[5-[[(3,6-dichloro-4-pyridazinyl)carbonyl]amino]-2-sulfophenyl]azo]-4,5-dihydro-5-oxo-1-[2-sulfo-5-[[(trisulfo-29H,31H-phthalocyaninyl)sulfonyl]amino]phenyl]-1H-pyrazole-3-carboxyla

272-799-6 68912-08-3 Nickel, bis(2-heptadecyl-1H-imidazole-N(3))bis(octanoato-O)- 279-067-5 79121-51-0 Nickel, bis(4-benzoyl-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-

3-onato-O,O’)(2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]heneicosan-21-one-O(21))-

276-399-2 72152-45-5 Nickelate(6-), [22-[[[3-[[4,5-dihydro-3-methyl-5-oxo-1-[3-sulfo-4-[2-[2-sulfo-4-[(2,5,6-trichloro-4-pyrimidinyl)amino]phenyl]ethenyl]phenyl]-1H-pyrazol-4-yl]azo]-4-sulfophenyl]amino]sulfonyl]-29H,31H-

306-784-3 97404-21-2 Nickel, [[N,N’,N’’-[29H,31H-phthalocyaninetriyltris(sulfonylimino-3,1-phenylene)]tris[3-oxobutanamidato]](2-)-N(29)-,N(30)-,N(31)-,N(32)-]-

269-684-8 68309-97-7 Nickel(2+), tris(4,7-diphenyl-1,10-phenanthroline-N(1)-,N(10))-, (OC-6-11)-, bis[tetrafluoroborate(1-)]

254-127-3 38780-90-4 Nickel(2+), tris(4,7-diphenyl-1,10-phenanthroline-N(1)-,N(10))-, (OC-6-11)-, dinitrate

277-174-1 72986-45-9 Nickel, [N,N’,N’’,N’’’-tetrakis[4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl]-29H,31H-phthalocyaninetetrasulfonamidato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-

306-785-9 97404-22-3 Nickel, [[N,N’,N’’,N’’’-[29H,31H-phthalocyaninetetrayltetrakis(sulfonylimino-3,1-phenylene)]tetrakis[3-oxobutanamidato]](2-)-N(29)-,N(30)-,N(31)-,N(32)-]-

252-777-2 35884-66-3 Nickel, tetrakis[tris(methylphenyl) phosphite-P]- 262-934-7 61725-51-7 Nickel, 3-[(4-chlorophenyl)azo]-4-hydroxy-2(1H)-quinolinone

complex; C.I. 12775

263-000-1 61788-71-4 Naphthenic acids, nickel salts 269-826-9 68334-36-1 Resin acids and Rosin acids, nickel salts 271-764-2 68607-31-8 Resin acids and Rosin acids, calcium nickel salts 270-174-2 68412-18-0 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-

,N(32)-]-, sulfo [[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs.

270-944-8 68511-62-6 Nickel, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes LPVC 276-877-0 72828-53-6 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-

,N(32)-]-, [[3-[(1,3-dioxobutyl)amino]phenyl]amino]sulfonyl derivs.

294-302-1 91697-41-5 Fatty acids, C6-C19-branched, nickel salts


163

Organic nickel compounds (continued). 283-972-0 84776-45-4 Fatty acids, C8-C18 and C18-unsatd., nickel salts 287-356-2 85480-75-7 Nickel, 2,2'-thiobis[4-nonylphenol] complexes 291-676-8 90459-33-9 Nickel, isooctanoate naphthenate complexes 287-801-0 85585-98-4 Nickel, isononanoate naphthenate complexes 287-800-5 85585-97-3 Nickel, isodecanoate naphthenate complexes 287-802-6 85585-99-5 Nickel, naphthenate neodecanoate complexes 291-673-1 90459-30-6 Nickel, acetate carbonate C8-C10-branched fatty acids C9-C11-

neofatty acids complexes LPVC

291-674-7 90459-31-7 Nickel, borate C8-C10-branched carboxylate complexes 291-675-2 90459-32-8 Nickel, C5-C23-branched carboxylate octanoate complexes 291-677-3 90459-34-0 Nickel, acetylacetone 6-methyl-2,4-heptanedione complexes 291-678-9 90459-35-1 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-

,N(32)-]-, [[3-[(5-chloro-2,6-difluoro-4-pyrimidinyl)amino]phenyl]amino]sulfonyl sulfo derivs., sodium salts

291-679-4 90459-36-2 Nickelate(4-), [bis[[[3-[[4,5-dihydro-3-methyl-5-oxo-1-[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]-1H-pyrazol-4-yl]azo]phenyl]amino]sulfonyl]-29H,31H-phthalocyaninedisulfonato(6-)-N(29)-,N(30)-,N(31)-,N(3

295-925-1 92200-98-1 Nickel, C5-C23-branched carboxylate naphthenate complexes 295-926-7 92200-99-2 Nickel, C5-C25-branched carboxylate naphthenate octanoate

complexes

296-343-0 92502-55-1 Nickel, borate neodecanoate complexes 297-548-8 93573-14-9 Nickel, C5-C23-branched carboxylate C4-C10-fatty acids

naphthenate complexes

297-549-3 93573-15-0 Nickel, C4-C10 fatty acids naphthenate complexes 297-550-9 93573-16-1 Nickel, C4-C10 fatty acids octanoate complexes 297-774-7 93762-59-5 Nickel, C5-C23-branched carboxylate C4-C10 fatty acids

complexes

297-551-4 93573-17-2 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, potassium sodium

305-643-3 94891-42-6 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, potassium salts

305-644-9 94891-43-7 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, sodium salts

Diverse Nickel compounds. EC Number CAS


Number 307-554-5 97660-42-9 Copper, bis(8-quinolinolato-N(1)-,O(8))-, reaction products with

C8-C10-branched fatty acids, tert-decanoic acid, nickel(2+) diacetate, nickel(2+) carbonate (1:1) and nickel hydroxide (Ni(OH)2)

283-945-3 84776-20-5 Bentonite, nickeloan 232-490-9 8052-42-4 Asphalt HPVC 266-046-0 65997-17-3 Glass, oxide, chemicals HPVC 266-047-6 65997-18-4 Frits, chemicals HPVC 266-048-1 65997-19-5 Steel manufacture, chemical 266-340-9 66402-68-4 Ceramic materials and wares, chemicals HPVC 266-965-7 67711-89-1 Calcines, copper roasting 266-967-8 67711-91-5 Matte, copper HPVC 266-968-3 67711-92-6 Slags, copper smelting HPVC 268-627-4 68131-74-8 Ashes, residues HPVC


164

273-700-9 69011-59-2 Lead alloy, base, dross LPVC 273-701-4 69011-60-5 Lead alloy, base, Pb,Sn, dross HPVC 273-704-0 69011-64-9 Babbitt, dross 273-720-8 69012-20-0 Waste solids, copper electrolyte purifn. cathodes HPVC 273-729-7 69012-29-9 Slags, ferronickel-manufg. HPVC 273-749-6 69012-50-6 Matte, nickel HPVC 273-795-7 69029-51-2 Lead, antimonial, dross 282-214-6 84144-92-3 Leach residues, nickel-vanadium ore 293-311-8 91053-46-2 Leach residues, zinc ore-calcine, cadmium-copper ppt. HPVC 293-312-3 91053-47-3 Leach residues, zinc ore-calcine, iron contg. HPVC 293-796-6 91082-81-4 Waste solids, chromium-nickel steel manuf. 293-799-2 91082-84-7 Waste solids, nickel-manuf. 295-859-3 92129-57-2 Slimes and Sludges, copper electrolyte refining, decopperised, Ni

sulfate HPVC

297-402-3 93571-76-7 Ashes (residues), heavy fuel oil fly LPVC 305-433-1 94551-87-8 Slimes and Sludges, copper electrolyte refining, decopperised LPVC 308-765-5 98246-91-4 Speiss, lead, nickel-contg. 310-050-8 102110-49-6 Residues, copper-iron-lead-nickel matte, sulfuric acid-insol. Note: EINECS entries that include a reference to nickel as e.g. a catalyst rather than as a constituent have not been included.

7.2.2 Nickel compounds included in Elincs EC Number CAS


Number

410-160-7 148732-74-5 Tetrasodium (c-(3-(1-(3-(e-6-dichloro-5-cyanopyrimidin-f-yl(methyl)amino)propyl)-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridylazo)-4-sulfonatophenylsulfamoyl) phtalocyanine-a,b,d-trisulfonato(6-))nickelato II, where a is 1 or 2 or 3 or 4,b is 8 or 9 or 10 or 11, c is 15 or 16 or 17 or 18, d is 22 or 23 or 24 or 25 and where e and f together are 2 and 4 or 4 and 2 respectively

407-110-1 - Trisodium (1-(3-carboxylato-2-oxido-5-sulfonatophenylazo)-5-hydroxy-7-sulfonatophthalen-2-amido)nickel(II)

417-250-5 151436-99-6 Hexasodium (di(N-(3-(4-[5-(5-amino-3-methyl-1-phenylpyrazol-4-yl-azo)-2,4-disulfo-anilino]-6-chloro-1,3,5-triazin-2-ylamino)phenyl)-sulfamoyl](disulfo)-phthalocyaninato)nickel


165

7.2.3 Additional Nickel compounds included in TSCA (through 08/2000) but not included in EINECS.

CAS Number Chemical Name 12031-65-1 Lithium nickel oxide (LiNiO2) 12645-50-0 Iron-nickel-zinc-oxide- 12673-58-4 Molybdenum-nickel-oxide- 12737-30-3 Cobalt-nickel-oxide- 14221-00-2 Nickel, tetrakis(triphenyl phosphite-kappaP)-, (T-4)- 14406-71-4 Nickel, [[2,2'-[1,2-phenylenebis[(nitrilo-kappaN)methylidyne]]bis[phenolato-

kappaO]](2-)]-

14434-67-4 Nickel, bis(hexahydro-1H-azepine-1-carbodithioato-kappaS,kappaS')-, (SP-4-1)-

17169-61-8 Phosphoric acid, calcium nickel salt 18824-79-8 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, nickel(2+) salt (1:1) 18972-69-5 Nickel(2+), bis(1,2-propanediamine-kappaN,kappaN')-, bis[bis(cyano-

kappaC)aurate(1-)]

19372-20-4 Diphosphoric acid, nickel(2+) salt 34109-80-3 Titanate(2-), hexafluoro-, nickel(2+), (1:1), (OC-6-11)- 36545-21-8 Nickel, bis[(phenyldiazenecarbothioic acid-kappaS) 2-phenylhydrazidato-

kappaN2]-

51449-18-4 Nickel, bis[1-[4-(diethylamino)phenyl]-2-phenyl-1,2-ethenedithiolato(2-)-kappaS,kappaS']-

53199-85-2 Nickel(1+), [1-[2-amino-4-(imino-kappaN)-5(4H)-thiazolylidene]-N-[1-[2-amino-4-(imino-kappaN)-5(4H)-thiazolylidene]-1H-isoindol-3-yl-kappaN]-1H-isoindol-3-aminato-kappaN2]-, chloride

54576-53-3 Antimony-nickel-titanium-oxide- 55868-93-4 Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, nickel(2+) salt

(2:1)

65229-23-4 Nickel-boron-phosphide- 68189-15-1 Nickel, bis[[2-(hydroxy-kappaO)-4-octylphenyl]phenylmethanonato-kappaO]- 68412-19-1 Nickel, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, [(3-

aminophenyl)amino]sulfonyl sulfo derivs.

68412-20-4 Nickel, dextrin complexes 68585-48-8 Sulfuric acid, nickel(2+) salt (1:1), reaction products with nickel and nickel

oxide (NiO)

69012-51-7 Copper cake, zinc-refining 70776-98-6 Nickel, (2-ethylhexanoato-kappaO)(trifluoroacetato-kappaO)- 71050-57-2 Acetic acid, nickel(2+) salt, polymer with formaldehyde and 4-(1,1,3,3-

tetramethylbutyl)phenol

71215-73-1 Nickel, [[2,2'-[methylenebis(thio-kappaS)]bis[acetato-kappaO]](2-)]- 71215-97-9 Nickel(2+), tris(1,2-ethanediamine-kappaN,kappaN')-, (OC-6-11)-, salt with

dimethylbenzenesulfonic acid (1:2)

71215-98-0 Nickel(2+), bis(1,2-ethanediamine-kappaN,kappaN')-, salt with dimethylbenzenesulfonic acid (1:2)

71605-83-9 Nickel, bis[N-hydroxy-3-(hydroxyimino-kappaN)-N'-(2-methoxyphenyl)butanimidamidato-kappaN']-

71889-20-8 Nickel, [N-(4-chlorophenyl)-3-[[[1-(4-chlorophenyl)-4,5-dihydro-3-methyl-5-(oxo-kappaO)-1H-pyrazol-4-yl]methylene]hydrazino-kappaN2]-alpha-cyano-1H-isoindole-3-acetamidato(2-)-kappaN2,kappaO3]-

72162-32-4 Sulfuric acid, nickel salt, reaction products with sulfurized calcium phenolate 72252-57-4 Nickel, [N,N',N''-tris[4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl]-

29H,31H-phthalocyanine-C,C,C-trisulfonamidato(2-)-kappaN29,kappaN30,kappaN31,kappaN32]-

72319-19-8 2,7-Naphthalenedisulfonic acid, nickel(2+) salt (1:1) 79357-65-6 Aluminum, triethyl-, reaction products with nickel(2+) bis(2-ethylhexanoate) 83864-02-2 Nickel, bis[(cyano-C)triphenylborato(1-)-N]bis(hexanedinitrile-N,N')- 91845-72-6 Fatty acids, C3-22, nickel salts, basic 106316-55-6 Nickel, aqua[2-[[4,5-dihydro-3-methyl-5-(oxo-kappaO)-1H-pyrazol-4-yl]azo-

kappaN1]benzoato(2-)-kappaO]-


166

Additional nickel compounds included in TSCA (through 08/2000) but not included in EINECS (continued).

108818-89-9 Nickel(2+), hexakis(1H-imidazole-kappaN3)-, (OC-6-11)-, 1,2-benzenedicarboxylate (1:1)

113894-88-5 Nickel, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, sulfo [[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs., potassium sodium salts

131866-99-4 Nickel, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, sulfo [[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs., sodium salts

7.2.4 Additional Nickel compounds listed in ECICS (European Customs Inventory of chemical substances), but not included in EINECS or the TSCA Inventory.

CAS No. Name CUS Number. 10471-42-8 nickel tartrate 20764 10534-88-0 hexaamminenickel dichloride 18196 12137-12-1 trinickel tetrasulfide 20763 12758-25-7 nickel metaborate 20727 13601-55-3 hexaamminenickel dibromide 11020 15651-35-1 tetraamminenickel dinitrate 11025 16039-61-5 nickel dilactate 20748 74195-78-1 diammonium nickel hexacyanoferrate 11023 74646-29-0 trinickel bis(arsenite) 20725

7.2.5 Additional Nickel compounds in Annex I to Directive 67/548/EEC but not in EINECS or TSCA.

CAS Number Chemical Name Part of Group

entry: 12256-33-6 nickel arsenide, Ni11As8 033-002-00-5 12255-80-0 nickel arsenide, Ni5As2 033-002-00-5 12255-10-6 nickel arsenide sulfide, NiAsS 033-002-00-5 12137-13-2 nickel selenide, Ni3Se2 034-002-00-8 71077-18-4 Rutile, antimony nickel yellow 051-003-00-9 68130-19-8 Silicic acid, lead nickel salt 082-001-00-6

7.2.6 Additional nickel compound found in the course of compiling the inventory of nickel compounds

EC No. CAS No. Name HPVC/ LPVC

CUS Number

11132-10-8 nickel potassium fluoride

391864-36-1 nickel potassium cyanide (NiK2(CN)4)

55465-44-6 potassium nickel cyanide

nickel calcium cyanide19

131344-56-4 cobalt lithium nickel oxide

162004-08-2 cobalt lithium nickel oxide (Co,Li,Ni)O2

510727-46-5 cobalt lithium nickel oxide (Co,Li)NiO2

19 Marketed without CAS No.


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7.2.7 Additional nickel hydroxycarbonate compounds not included in the lists above EC No. CAS No. Name, formula HPVC/

LPVC CUS Number

152008-07-6 4NiCO3.Ni(OH)2

128024-15-7 3NiCO3.Ni(OH)2

342774-56-5 Ni(CO3)0-1.5(OH)0-3

148522-90-1 3NiCO3.4Ni(OH)2

12122-15-5 pentanickel dicarbonate hexahydroxide, 2NiCO3.3Ni(OH)2

12274-86-1 NiCO3.3Ni(OH)2

404866-99-5 NiCO3.13Ni(OH)2

7.2.8 Nickel containing minerals (from IARC, 1990 and NiPERA, 1996). CAS Number Name Chemical composition

53809-86-2, 12174-14-0 1 Pentlandite (Fe,Ni)9S8 1

1314-04-1 Millerite NiS

12035-71-1 Heazlewoodite Ni3S2

Polydymite Ni3S4

Siegenite (Co,Ni)3S4

Violarite Ni2FeS4

12035-50-6 Vaesite NiS2 2

Pyrrhotite, nickeliferous (Fe,Ni)1-xS

1303-13-5 Niccolite, nickeline NiAs

12044-65-4 Maucherite Ni11As8

Rammelsbergite NiAs2

12255-11-7 Gersdorffite NiAsS

12201-85-3 Makinenite, Maekinenite NiSe

12125-61-0 Breithauptite NiSb

24270-51-7 Imgreite NiTe

Garnierite (Ni, Mg)SiO3.nH2O

Nickeliferous limonite (Fe,Ni)O(OH).nH2O

34492-97-2 Bunsenite NiO

39430-27-8 Zaratite (basic nickel carbonate, tetrahydrate) NiCO3.2Ni(OH)2.4H2O

Morenosite (nickel sulphate heptahydrate) NiSO4.7H2O 1) CAS No. 53809-86-2 corresponds to Fe9Ni9S16; CAS No. 12174-14-0 corresponds to (Fe0.4-0.6Ni0.4-0.6)9S8 (NiPERA, 1996). 2) IARC also lists pure nickel sulphide (NiS2), CAS No. 12035-51-7. Both compounds are in the +4 oxidation state. Minerals are exempted from registration under REACH. However, minerals should be classified if they fulfill the classification criteria.


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7.3 NICKEL CONTENT IN FOOD. Food μg Ni / g wet weight (1) μg Ni / kg (2) mean (range) Beverages Beer 0.004 Coffee 0.015 Cola 0.001 Juice 0.04 (0.01 – 0.17) Orange juice 0.015 Tea 0.052 Wine 0.028 Starches Wheat flour 0.135 0.13 (0.03 – 0.3) Rye flour 0.1 (0.03 – 0.3) Oat meal 1.76 (0.80 – 4.7) Bread, white 0.053 Bread, whole wheat Rice 0.21 (0.08 – 0.45) Rice cereal cooked 0.083 Pasta, plain, cooked 0.012 Pasta, canned 0.081 Biscuits 0.243 Cookies 1.273 Chocolate, Sugar and products thereof, Confectionary products. Sugar 0.05 (0.01 – 0.09) Sugar, white 0.003 Honey 0.012 Chocolate pudding 0.185 Doughnuts 0.178 Fruits, Vegetables and products thereof. Apples 0.042 0.01 (BLD (3) – 0.03) Pears 0.133 0.14…(0.07 – 0.42) Plums 0.12 (0.03 – 0.20) Plums, Prunes, dried, canned 0.284 Grapes 0.01 0.02 (0.01 – 0.04) Raisins 0.074 0.03 (0.02 – 0.04) Currants 0.06 (0.01 – 0.2) Strawberries 0.05 (0.03 – 0.08) Rhubarb 0.13 (0.01 – 0.22) Bananas 0.078 0.02 (0.01 – 0.03) Citrus fruit 0.062 0.03 (0.01 – 0.04) Pineapple 0.162 Canned fruits 0.31 (0.02 – 1.36) Asparagus 0.42 Cucumber 0.187 0.04 (0.01 – 0.11) Tomatoes 0.036 0.07 (0.01 – 0.25 Lettuce 0.097 0.36 (BLD – 1.4) Celery 0.058 Celery root 0.06 (0.04 – 0.1) Mushrooms 0.045 Mushrooms, canned 0.152 Beans, raw and canned, cooked 0.222 Broccoli 0.081 Cabbage 0.17 (0.01 – 0.63)


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Cabbage, cooked and coleslaw 0.027 Kale 0.20 (0.15 – 0.24) Cauliflower 0.3 (0.03 – 1.0) Cauliflower, raw and cooked 0.069 Peas 0.42 (0.13 – 0.8) Peas, raw and canned, cooked 0.225 Spinach 0.52 (0.02 – 2.99) Beetroot 0.12 (0.01 – 0.3) Carrots 0.056 0.04 (<0.01 – 0.16) Carrots, cooked, canned 0.006 Potatoes 0.14 (BLD – 0.44) Potato skins, cooked or boiled 0.982 Potatoes, peeled, cooked or boiled 0.042 Onions 0.06 Onions, cooked or boiled 0.044 Fats and Oils Cooking fats and salad oils 0.045 Butter 0.017 0.1 (0.03 – 0.2) Peanut butter & Peanuts 1.467 Margarine 0.185 0.34 (0.2 – 2.5) Animal products and Eggs Fish 0.04 (0.005 – 0.303) Marine fish, cooked or boiled 0.211 Freshwater fish, cooked or boiled 0.047 Fish, canned 0.101 Shellfish, fresh or frozen 0.118 Beef 0.047 – 2.521 0.02 (0.01 – 0.03) Veal, cooked or boiled 0.067 Pork 1.009 0.02 (<0.02 – 0.02) Pork, cooked or boiled 0.702 Lamb 0.02 (<0.02 – 0.02) Liver, kidney 0.11 (0 – 0.94) Chicken 0.11 (0.02 – 0.24) Chicken, cooked or boiled 0.283 Eggs 0.007 0.05 (0.01 – 0.35) Milk Products Milk 0.009 0.02 (BLD – 0.13) Cream 0.03 (0.01 – 0.04) Yogurt 0.014 0.01 (0.004 – 0.03) Cheese 0.066 0.10 (0.02 – 0.34 Cheese, cottage 0.019 Cheese, processed cheddar 0.100 Miscellaneous Ice cream 0.323 1) Council of Europe (2001). Reference to “The Essentiality of Nickel”, NiPERA, 1999. The original source is given as CEPA (1994). 2) Nickel content in foods in the average Danish diet. (Grandjean et. al., 1989), quoted in IARC (1990). 3) BLD: Below detection Limit

Education

Nickel Background EU Risk Assessment Report March 2008 Final Draft