1,1,2,2-TETRACHLOROETHANE1,1,2,2-Tetrachloroethane 3 Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected

This report contains the collective views of an international group of experts and does notnecessarily represent the decisions or the stated policy of the United Nations EnvironmentProgramme, the International Labour Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 3

1,1,2,2-TETRACHLOROETHANE

First draft prepared by Ms K. Hughes and Ms M.E. Meek,Environmental Health Directorate,Health Canada

Please note that the layout and pagination of this pdf filea re not identical to the printedCICAD

Published under the joint sponsorship of the United Nations Environment Programme, theInternational Labour Organisation, and the World Health Organization, and produced within theframework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health OrganizationGeneva, 1998

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO),and the World Health Organization (WHO). The overall objectives of the IPCS are to establish thescientific basis for assessment of the risk to human health and the environment from exposure tochemicals, through international peer review processes, as a prerequisite for the promotion of chemicalsafety, and to provide technical assistance in strengthening national capacities for the sound managementof chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,the United Nations Industrial Development Organization, and the Organisation for Economic Co-operationand Development (Participating Organizations), following recommendations made by the 1992 UNConference on Environment and Development to strengthen cooperation and increase coordination in thefield of chemical safety. The purpose of the IOMC is to promote coordination of the policies andactivities pursued by the Participating Organizations, jointly or separately, to achieve the soundmanagement of chemicals in relation to human health and the environment.

WHO Library Cataloguing in Publication Data

1,1,2,2-Tetrachloroethane.

(Concise international chemical assessment document ; 3)

1.Tetrachloroethylene – toxicity 2.Environmental exposureI.International Programme on Chemical Safety II.Series

ISBN 92 4 153003 0 (NLM Classification: QV 253) ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate itspublications, in part or in full. Applications and enquiries should be addressed to the Office ofPublications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latestinformation on any changes made to the text, plans for new editions, and reprints and translations alreadyavailable.

©World Health Organization 1998

Publications of the World Health Organization enjoy copyright protection in accordance with theprovisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the Secretariat of the World Health Organizationconcerning the legal status of any country, territory, city, or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.

The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany,provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

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TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . 5

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . 7

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.4 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

8.4.1 Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.4.2 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

8.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . 13

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

10.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

11.1.2 Criteria for setting guidance values for 1,1,2,2-tetrachloroethane . . . . . . . . . . . . . . . . . . . . . 14 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15


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13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

13.1 Advice to physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513.2 Health surveillance advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513.3 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513.4 Spillage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

1,1,2,2-Tetrachloroethane

1

FOREWORD

Concise International Chemical AssessmentDocuments (CICADs) are the latest in a family ofpublications from the International Programme onChemical Safety (IPCS) — a cooperative programme ofthe World Health Organization (WHO), the InternationalLabour Organisation (ILO), and the United NationsEnvironment Programme (UNEP). CICADs join theEnvironmental Health Criteria documents (EHCs) asauthoritative documents on the risk assessment ofchemicals.

CICADs are concise documents that providesummaries of the relevant scientific informationconcerning the potential effects of chemicals uponhuman health and/or the environment. They are basedon selected national or regional evaluation documents oron existing EHCs. Before acceptance for publication asCICADs by IPCS, these documents have undergoneextensive peer review by internationally selected expertsto ensure their completeness, accuracy in the way inwhich the original data are represented, and the validityof the conclusions drawn.

The primary objective of CICADs is character-ization of hazard and dose–response from exposure to achemical. CICADs are not a summary of all availabledata on a particular chemical; rather, they include onlythat information considered critical for characterizationof the risk posed by the chemical. The critical studiesare, however, presented in sufficient detail to supportthe conclusions drawn. For additional information, thereader should consult the identified source documentsupon which the CICAD has been based.

Risks to human health and the environment will

vary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered asrepresenting all possible exposure situations, but areprovided as guidance only. The reader is referred toEHC 1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwisestated, CICADs are based on a search of the scientificliterature to the date shown in the executive summary. Inthe event that a reader becomes aware of new infor-mation that would change the conclusions drawn in aCICAD, the reader is requested to contact the IPCS toinform it of the new information.

Procedures

The flow chart shows the procedures followed toproduce a CICAD. These procedures are designed totake advantage of the expertise that exists around theworld — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and otherdata that are necessary for assessing risks to humanhealth and/or the environment.

The first draft is based on an existing national,regional, or international review. Authors of the firstdraft are usually, but not necessarily, from the institutionthat developed the original review. A standard outlinehas been developed to encourage consistency in form. The first draft undergoes primary review by IPCS andone or more experienced authors of criteria documents toensure that it meets the specified criteria for CICADs.

The second stage involves international peerreview by scientists known for their particular expertiseand by scientists selected from an international rostercompiled by IPCS through recommendations from IPCSnational Contact Points and from IPCS ParticipatingInstitutions. Adequate time is allowed for the selectedexperts to undertake a thorough review. Authors arerequired to take reviewers’ comments into account andrevise their draft, if necessary. The resulting seconddraft is submitted to a Final Review Board together withthe reviewers’ comments.

The CICAD Final Review Board has severalimportant functions:

– to ensure that each CICAD has been subjected toan appropriate and thorough peer review;

– to verify that the peer reviewers’ comments havebeen addressed appropriately;

– to provide guidance to those responsible for thepreparation of CICADs on how to resolve anyremaining issues if, in the opinion of the Board, the author has not adequately addressed allcomments of the reviewers; and

– to approve CICADs as international assessments.

1 International Programme on Chemical Safety (1994)Assessing human health risks of chemicals: derivationof guidance values for health-based exposure limits.Geneva, World Health Organization (EnvironmentalHealth Criteria 170).


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S E L E C T I O N O F H I G H Q U A L I T YN A T I O N A L / R E G I O N A L

A S S E S S M E N T D O C U M E N T ( S )

CICAD PREPARATION FLOW CHART

F I R S T D R A F TP R E P A R E D

P R I M A R Y R E V I E W A T P R O D U C E R L E V E L(1-2 OTHER DOCUMENT PRODUCERS) 1

P R O D U C E R

REVIEW BY IPCS CONTACT POINTS

FINAL REVIEW BOARD 3

FINAL DRAFT 4

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

R E S P O N S I B L E O F F I C E R

( R O )

SELECTION OF PRIORITY CHEMICAL

1 Revision as necessary.2 Taking into account the comments from reviewers.3 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments (6-10 CICADs are usually reviewed atthe Final Review Board). In the case of pesticides the role of the Final Review Board is fulfilled by a joint meeting on pesticides.4 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RO),PREPARATION

OF SECOND DRAFT 2


3

Board members serve in their personal capacity, not asrepresentatives of any organization, government, orindustry. They are selected because of their expertise inhuman and environmental toxicology or because of theirexperience in the regulation of chemicals. Boards arechosen according to the range of expertise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,and advisers who participate in the preparation of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion at any stage of the process. Representativesof nongovernmental organizations may be invited toobserve the proceedings of the Final Review Board. Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may notparticipate in the final decision-making process.


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1. EXECUTIVE SUMMARY

This CICAD on 1,1,2,2-tetrachloroethane wasprepared by the Environmental Health Directorate ofHealth Canada and was based principally on a reviewprepared by the Government of Canada (1993) to assessthe potential effects on human health of indirect expo-sure to 1,1,2,2-tetrachloroethane in the general environ-ment and the chemical’s environmental effects, as well asa review prepared by the Agency for Toxic Substancesand Disease Registry (ATSDR, 1994) intended tocharacterize information on adverse health effects andpublic exposure. Data identified as of September 1992were considered in the Government of Canada (1993)review. A comprehensive literature search of several on-line databases was conducted in August 1995 to identifyany references published subsequent to those incorpo-rated in this review. Information on the nature of thepeer review and the availability of the source documentsis presented in Appendix 1. Information on the peerreview of this CICAD is presented in Appendix 2. ThisCICAD was approved for publication at a meeting of theFinal Review Board, held in Brussels, Belgium, on 18–20November 1996. Participants at the Final Review Boardmeeting are listed in Appendix 3. The InternationalChemical Safety Card (ICSC 0332) for 1,1,2,2-tetrachloroethane, produced by the InternationalProgramme on Chemical Safety (IPCS, 1993), has alsobeen reproduced in this document.

1,1,2,2-Tetrachloroethane (CAS no. 79-34-5) is avolatile synthetic chemical that is used principally as anintermediate in the synthesis of other chlorinated hydro-carbons, although use of this substance has declinedsignificantly. Releases to the environment are primarilyin emissions to ambient air, where the chemical is likelyto remain for several weeks. 1,1,2,2-Tetrachloroethane isnot expected to contribute to the depletion of strato-spheric ozone or to global warming. It is rapidlyremoved from aquatic systems and is unlikely tobioaccumulate. Human exposure to 1,1,2,2-tetra-chloroethane is principally via inhalation.

Very few data are available on the effects ofexposure to 1,1,2,2-tetrachloroethane in humans. Thetoxicological profile of 1,1,2,2-tetrachloroethane has alsonot been well characterized; because of the chemical’sdeclining use, available data are confined primarily toearly limited studies. The acute toxicity of 1,1,2,2-tetrachloroethane in experimental animals is slight tomoderate. Based on the results of principally limitedshort-term and subchronic studies, the liver appears tobe the most sensitive target organ. Although most ofthe available studies are inadequate to allow a no- or

lowest-observed-(adverse)-effect level [NO(A)EL orLO(A)EL] for hepatotoxicity to be determined withconfidence, minimal effects on the liver (reversibleincrease in lipid content) and other end-points (anincrease in levels of adrenocorticotropic hormone andreversible alterations in haematological parameters) havebeen observed in rats exposed to 13.3 mg/m3 for up to 9months. Based on limited, primarily range-findingstudies and early investigations, reproductive and devel-opmental effects have been observed in experimentalanimals only at doses that caused reductions in bodyweight.

Long-term ingestion of 1,1,2,2-tetrachloroethaneresulted in an increased incidence of liver tumours inboth male and female B6C3F1 mice. However, similarexposure was not associated with a significant increasein tumours at any site in Osborne-Mendel rats, althoughboth species were exposed only for up to 78 weeks. Based on the results of available in vivo and in vitroassays, 1,1,2,2-tetrachloroethane has, at most, weakgenotoxic potential. 1,1,2,2-Tetrachloroethane was apotent promoter, but not an initiator, of (-glutamyltrans-peptidase-positive foci in the liver of rats. The profile fortumour induction by 1,1,2,2-tetrachloroethane is similarto that of dichloroacetic acid, its primary metabolite. Information on the mechanism of tumour induction by1,1,2,2-tetrachloroethane is incomplete; for several of itsmetabolites, it has been suggested that tumours arelikely induced by mechanisms for which there is athreshold.

Exposure to 1,1,2,2-tetrachloroethane has beendemonstrated to inhibit the activities of environmentalbacteria (the lowest reported IC50 was 1.4 mg/litre) andcause immobilization in Daphnia magna (48-hour EC50

values of 23 mg/litre and above). In freshwater fishspecies, the lowest reported LC50 (96 hours) was 18.5mg/litre in flagfish (Jordanella floridae), whereas thelowest-observed-effect concentration (LOEC) for longer-term exposure was 7.2 mg/litre, which resulted in reducedlarval survival in the same species. No data wereidentified on the effects of this substance on terrestrialorganisms.

In order to provide guidance to relevant authori-ties, sample guidance values have been determined onthe basis of the potency of 1,1,2,2-tetrachloroethane toinduce liver tumours in mice, as this is the toxicologicalend-point for which the dose–response relationship isbest characterized. It is noted, however, that observedincreases in tumour incidence are currently restricted toone species and that there are suggestive but incompletedata indicating that tumours may be induced by a non-genotoxic mechanism. The potency, expressed as the


5

dose associated with a 5% increase in tumours, rangedfrom 5.8 to 28 mg/kg body weight per day. Sampleguidance values for air (the principal source of humanexposure), calculated on the basis of division of thispotency range by 5000 or 50 000, are 3.4–16 :g/m3 and0.34–1.6 :g/m3. These values correspond to thoseconsidered by some agencies to represent “essentiallynegligible” risk (i.e. 10–5 to 10–6) for a genotoxic carci-nogen; it should be noted, however, that a smallermargin may also be appropriate in view of the suggestivebut incomplete evidence for an epigenetic mechanism oftumour induction. Corresponding values for ingestionare 1.2–5.6 :g/kg body weight per day and 0.12–0.56:g/kg body weight per day. Based on a sample estimateof exposure, indirect exposure in the general environ-ment is less than these values, which are considered tobe conservative in view of the suggestive butincomplete evidence that 1,1,2,2-tetrachloroethane mayinduce tumours through a threshold mechanism.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

1,1,2,2-Tetrachloroethane (CAS no. 79-34-5;Cl2CHCHCl2; acetylene tetrachloride, sym-tetrachlor-ethane; see structural diagram below) is a syntheticchemical that is a colourless, non-flammable liquid atroom temperature. It is highly volatile, with a vapourpressure of 0.65 kPa at 20°C and water solubility of 2900mg/litre at 20°C. The log octanol/water partitioncoefficient for 1,1,2,2-tetrachloroethane is about 2.5,whereas its Henry’s law constant was determined torange from 0.0003 to 0.0009 m3•atm/mol (Tse et al., 1992;Government of Canada, 1993; Nichols et al., 1993). Additional physical/chemical properties are presented inthe International Chemical Safety Card (ICSC 0332)reproduced in this document.

Cl Cl * * Cl ) C ) C ) Cl * * H H

3. ANALYTICAL METHODS

Analysis of 1,1,2,2-tetrachloroethane in air usuallyinvolves preconcentration on a sorbent tube followed bythermal or solvent desorption or collection in a cryogen-ically cooled trap followed by gas chromatography

(flame ionization or electron capture detection). Detection limits range from 0.7 ng/m3 to 0.3 mg/m3

(ATSDR, 1994). Purge and trap methods followed bygas chromatography (flame ionization, electron captureelectrolytic conductivity, or microcoulometric detection)are generally used for water as well as sediment, soil, orother solid samples. Reported detection limits rangefrom 0.001 to 5 :g/litre for water and from 1 to 5 :g/kgfor soil and sediment samples (ATSDR, 1994). Detectionlimits of 0.01 :g/litre and 0.06 ppbv (0.4 :g/m3) havebeen reported for solid-phase microextraction coupledwith gas chromatography/ion trap mass spectrometryanalysis for water and air samples, respectively (Arthuret al., 1992; Chai & Pawliszyn, 1995). Gaschromatography, often in combination with massspectrometry, is commonly used for quantifying 1,1,2,2-tetrachloroethane in biological samples, with detectionlimits of 400 :g/kg in tissues and 5–500 ng/litre in blood(ATSDR, 1994).

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

There are no known natural sources of 1,1,2,2-tetrachloroethane. The principal use of 1,1,2,2-tetra-chloroethane is as an intermediate in the manufacture ofother chlorinated hydrocarbons, such as vinyl chloride,1,2-dichloroethane, trichloroethylene, and tetrachloro-ethylene; in the past, it was also used as an industrialsolvent and as a pesticide. Use, and hence production,of 1,1,2,2-tetrachloroethane has declined significantly;no recent data on production were identified. Releasesto the atmosphere through its use as a chemical interme-diate in Canada in 1990 were estimated to be approxi-mately 246 kg (Government of Canada, 1993), whereas64 251 pounds (29 144 kg) were estimated to be emittedto air from reporting industries in the USA in 1991(ATSDR, 1994). In 1991, 953 kg of 1,1,2,2-tetrachloro-ethane were discharged to water from reporting facilitiesin the USA (ATSDR, 1994).

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

1,1,2,2-Tetrachloroethane is released to theenvironment primarily in emissions to ambient air. Basedon its vapour pressure, it is not likely to be transferred toother compartments. The atmospheric lifetime for 1,1,2,2-tetrachloroethane reacting with hydroxyl radicals frommoderately polluted areas is estimated to be between 43


6

and 100 days, based on estimated and measured reactionrates, respectively (Government of Canada, 1993). Thehalf-life in the troposphere is estimated to be in excess of800 days, and diffusion into the stratosphere is expectedto be slow.1 Based on these estimates, there issignificant potential for long-range transport of 1,1,2,2-tetrachloroethane. In the stratosphere, 1,1,2,2-tetrachloroethane undergoes photolysis to producechlorine radicals, which may subsequently react withozone; however, the ozone depletion potential for1,1,2,2-tetrachloroethane is very much less than 0.001relative to the standard CFC-11 (trichlorofluoromethane),based on the method developed by Nimitz & Skaggs(1992).

1,1,2,2-Tetrachloroethane released to the aquaticenvironment is rapidly removed via volatilization, with anestimated half-life of 6.2 hours from running water and3.5 days from still water.1 Hydrolysis and biodegra-dation are the principal routes of removal fromgroundwater. The hydrolysis half-life in subsurfacesediment at 25°C was determined to be 29 days (Haag &Mill, 1988). Neutral and base-catalysed hydrolyses of1,1,2,2-tetrachloroethane in pure water yielded tri-chloroethylene as essentially the sole degradationproduct (Haag & Mill, 1988). The products of anaerobicbiodegradation of 1,1,2,2-tetrachloroethane were deter-mined in a 6-week study to be (in decreasing order) cis-1,2-dichloroethylene, trans-1,2-dichloroethylene,trichloroethylene, 1,1,2-trichloroethane, 1,1-dichloroethylene, and vinyl chloride (Hallen et al., 1986).

1,1,2,2-Tetrachloroethane is not expected to bio-accumulate in aquatic species, based on low measuredand calculated bioconcentration factors in fish (Govern-ment of Canada, 1993).

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

Data considered to be most representative ofcurrent levels of 1,1,2,2-tetrachloroethane in environ-mental media are presented in Table 1. Mean concen-trations of 1,1,2,2-tetrachloroethane in recent surveys ofambient air in cities in Canada ranged from <0.1 to 0.25

:g/m3. Maximum concentrations of up to 79 :g/m3 havebeen detected in the vicinity of waste sites in the USA(ATSDR, 1994).

Although data are limited, levels of 1,1,2,2-tetra-chloroethane in surface waters in Canada, the USA, andGermany generally range from <0.005 to 4 :g/litre, from<10 :g/litre to a maximum reported value of 180 :g/litre,and from <0.03 to 10 :g/litre, respectively; the chemicalwas not detected (detection limits 0.001–0.05 :g/litre) insurface waters in Japan.

1,1,2,2-Tetrachloroethane was not detected insediment in Japan in 1976 (detection limits ranged from0.05 to 1 :g/g dry weight).

6.2 Human exposure

Exposure of the general population to 1,1,2,2-tetrachloroethane in environmental media may beestimated based on concentrations determined in variousmedia and reference values for body weight and con-sumption patterns. Owing to the paucity of relevantdata from other countries, particularly for recent years,exposure has been estimated here based primarily ondata from North America, as an example. However,countries are encouraged to estimate total exposure onthe basis of local data, possibly in a manner similar tothat outlined here.

Mean levels in residential indoor air in Canada andthe USA are generally below the limits of detection (i.e.<0.1 :g/m3; see Table 1). Based on a daily inhalationvolume for adults of 22 m3, a mean body weight for malesand females of 64 kg, the assumption that 4 of 24 hoursare spent outdoors (IPCS, 1994), and the range of meanlevels of 1,1,2,2-tetrachloroethane in ambient air in recentsurveys in Canada of <0.1–0.25 :g/m3, the mean intakeof 1,1,2,2-tetrachloroethane from ambient air for thegeneral population is estimated to range from <0.006 to0.01 :g/kg body weight per day. Average intake of1,1,2,2-tetrachloroethane from indoor air, based on theassumption that 20 of 24 hours are spent indoors (IPCS,1994) and the mean concentration in residential indoorair in Canada and the USA of <0.1 :g/m3, is estimated tobe <0.03 :g/kg body weight per day.

In a survey of 1159 household products in theUSA, 1,1,2,2-tetrachloroethane was not detected abovethe limit of detection of 0.1% (see Table 1).

1,1,2,2-Tetrachloroethane has not been detected inrecent surveys of drinking-water in Canada and has beenonly extremely rarely detected (<0.03%) in recent surveysin the USA (detection limits 0.05–1.0 :g/litre; see Table1), although it was detected in groundwater near landfillsites in Finland at levels ranging from <0.1 to 2.5 :g/litre

1 Source: Hazardous Substances Data Bank, NationalLibrary of Medicine, Bethesda, MD, 1996.

1 Source: Hazardous Substances Data Bank, NationalLibrary of Medicine, Bethesda, MD, 1996.


7

Table 1: Levels of 1,1,2,2-tetrachloroethane in various media.

Medium Location Year Concentrations Reference

Ambient air Canada 1989–1990 <0.1–0.25 :g/m3 (means) Environment Canada,unpublished data, 1992

Ambient air USA pre-1987 0.7 :g/m3 (mean) Shah & Heyerdahl, 1988

Indoor air Canada 1991 <0.1 :g/m3 (mean) Fellin et al., 1992

Indoor air USA pre-1987 0.098 :g/m3 (mean) Shah & Heyerdahl, 1988

Drinking-water Canada 1988–1991

1990

<0.05 :g/litre

<1.0 :g/litre

P. Lachmaniuk, personalcommunication, 1991Ecobichon & Allen, 1990

Drinking-water USA pre-19861984–1992

<0.5 :g/litreNDa–5.8 :g/litre

ATSDR, 1994Storm, 1994

Surface water Canada 19851981

<1.0–4.0 :g/litre<0.005–0.06 :g/litre

COARGLWQ, 1986Kaiser & Comba, 1983

Surface water USA 1980–1988 <10–180 :g/litre ATSDR, 1994

Surface water Japan 1976 <0.001, <0.002, <0.05 :g/litre Environment Agency Japan,1976

Surface water Germany 1989–1990 <0.03–10 :g/litre Wittsiepe, 1990Food (34 groups) Canada 1991

1992

<50 :g/kg (solids), <1 :g/litre(liquids)<5 :g/kg (solids), <1 :g/litre(liquids)

Enviro-Test Laboratories, 1991

Enviro-Test Laboratories, 1992

Food (231 items) USA <13 :g/kg, <20 :g/kg Daft, 1988

Consumer products(1159 items)

USA <0.1% Sack et al., 1992

Sediment Japan 1976 <0.05 :g/g, <1 :g/g Environment Agency Japan,1976

a Detection limit not specified.

(Assmuth & Strandberg, 1993). Similarly, it has not beendetected in three surveys of foodstuffs in Canada andthe USA (detection limits were 1 :g/litre for liquids and5–50 :g/kg for solids; see Table 1). No data wereidentified on levels of 1,1,2,2-tetrachloroethane in humanbreast milk. Drinking-water and food probably do notrepresent significant sources of exposure to 1,1,2,2-tetrachloroethane, based on its volatility and lowpotential for bioaccumulation.(Assmuth & Strandberg, 1993). Similarly, it has not beendetected in three surveys of foodstuffs in Canada andthe USA (detection limits were 1 :g/litre for liquids and5–50 :g/kg for solids; see Table 1). No data wereidentified on levels of 1,1,2,2-tetrachloroethane in humanbreast milk. Drinking-water and food probably do notrepresent significant sources of exposure to 1,1,2,2-tetrachloroethane, based on its volatility and lowpotential for bioaccumulation.

Therefore, the principal media of exposure to1,1,2,2-tetrachloroethane for the general population arelikely indoor and outdoor air, with negligible amountsbeing contributed by food and drinking-water.

Although data on levels of 1,1,2,2-tetrachloro-ethane in the workplace were not identified, workers maybe exposed to the substance via inhalation or dermalcontact in “business services” (not further specified) aswell as the chemical and allied products industries(ATSDR, 1994).

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

1,1,2,2-Tetrachloroethane is readily absorbedfollowing inhalation, ingestion, and dermal exposure andis likely distributed throughout the body, althoughrelevant data are limited. Based on data on the metabo-lism of 1,1,2,2-tetrachloroethane in mice, Yllner (1971)suggested that the principal pathway of degradationinvolves stagewise hydrolytic cleavage of the carbon–chlorine bonds and oxidation to dichloroacetaldehydehydrate, dichloroacetic acid (the major metabolite), andeventually glyoxylic acid. The glyoxylic acid is thenmetabolized to oxalic acid, glycine, formic acid, andcarbon dioxide. A small proportion of the parentcompound is probably non-enzymatically dehydro-chlorinated to trichloroethylene, which is furtherconverted to trichloroacetic acid and trichloroethanol. Inaddition, a minor amount of 1,1,2,2-tetrachloroethanemay be oxidized to tetrachloroethylene, which, in turn, ismetabolized to trichloroacetic acid and oxalic acid. It hasalso been proposed that 1,1,2,2-tetrachloroethane may bemetabolized via cytochrome P-450 to dichloroacetylchloride, which is hydrolysed to dichloroacetic acid(Halpert, 1982). In addition to the liver, metabolism mayalso occur in the epithelia of the respiratory tract andupper alimentary tract (Eriksson & Brittebo, 1991). The


8

metabolites of 1,1,2,2-tetrachloroethane are eliminated inthe urine, faeces, skin, and expired air.

8. EFFECTS ON LABORATORY MAMMALSAND IN VITRO TEST SYSTEMS

8.1 Single exposure

The acute toxicity of 1,1,2,2-tetrachloroethane inexperimental animals is slight to moderate. Exposure toconcentrations of around 1000 ppm (6980 mg/m3) for 4 or6 hours or about 5000–6000 ppm (34 900–41 880 mg/m3)(duration not specified) caused deaths in rats and mice,respectively. Oral LD50s of 250–330 and 1000 mg/kgbody weight for 1,1,2,2-tetrachloroethane in rats havebeen reported. The dermal LD50 (24 hours) in rabbits was6360 mg/kg body weight (Kennedy & Graepel, 1991;ATSDR, 1994).

8.2 Irritation and sensitization

Epidermal and dermal changes were reported inrabbits following cutaneous exposure to 1,1,2,2-tetra-chloroethane (Smyth et al., 1969). Exposure to 580 ppm(4050 mg/m3) 1,1,2,2-tetrachloroethane caused ocularirritation in guinea-pigs (Price et al., 1978). No infor-mation on the sensitization potential of this substancewas identified.

8.3 Short-term exposure

In general, dose–response relationships have notbeen well characterized in available short-term studies inexperimental animals owing to limitations of the studies,including use of only one level of exposure or inade-quate description of protocol or results. Hepatic effects,including increased organ weight, congestion, fattydegeneration, histological changes, alterations in levelsof enzymes, and elevated DNA synthesis (the degree ofwhich increased with dose), have been observed inrodents following short-term inhalation of 1,1,2,2-tetra-chloroethane at concentrations as low as 13.3 mg/m3 (for2–10 days) and ingestion of the chemical at doses as lowas 75 mg/kg body weight per day (for 4 days) in the fewavailable, principally limited, studies (Horiuchi et al.,1962; Gohlke & Schmidt, 1972; Schmidt et al., 1972;Hanley et al., 1988; NTP, 1996). In a limited account of astudy in rats, Ulanova et al. (1984) reported effects onthe nervous system and kidneys to be similar followingcontinuous or intermittent exposure for 4–27 days tocomparable time-weighted-average concentrations of1,1,2,2-tetrachloroethane (235 and 250 mg/m3).

8.4 Long-term exposure

8.4.1 Subchronic exposure

Only a few limited studies have been identified onthe effects in experimental animals following subchronicexposure to 1,1,2,2-tetrachloroethane (see Table 2).1 Ingestion of up to 316 mg/kg body weight per day hadno effects on body weight gain or mortality in groups offive male or female B6C3F1 mice, whereas doses of 100(females) or 178 (males) mg/kg body weight per day andabove resulted in decreased body weight gain in groupsof five male or female Osborne-Mendel rats in sub-chronic studies preliminary to longer-term bioassays (noother end-points appear to have been examined) (NCI,1978). Histopathological damage (including chronicinflammation, necrosis, or atrophy) was observed in theliver, kidney, testicles, and thyroid gland of rats (n = 10per group) administered oral 1,1,2,2-tetrachloroethanedoses of 3.2–50 mg/kg body weight per day for periodsranging from 2 to 150 days (Gohlke et al., 1977), althoughthe limited documentation of results in this studyprecludes validation of an effect level.

Exposure to 1,1,2,2-tetrachloroethane at 50 mg/m3

for approximately 5 weeks resulted in alterations in bio-chemical parameters and organ weights in male rats(strain and number not specified), although no “morpho-logical changes” were noted upon examination (thenature and extent of the histopathological examinationwere unspecified) (Schmidt et al., 1975). Depressedagglutinin formation was observed in rabbits exposed to100 mg/m3, 3–4 hours/day, for 4–6 weeks (Navrotskiy etal., 1971) (no other effects were noted in this study, forwhich only secondary accounts were available). Hepaticeffects, including a transient increase in DNA synthesis,reversible histopathological changes (cytoplasmicvacuolization and hyperplasia), and an increase inrelative liver weight, were observed in female Sprague-Dawley rats (n = 55) exposed for 15 weeks to 560 ml/m3

(reported by ATSDR [1994] to be equivalent to 130 ppm[907 mg/m3], although information on the exposure levelpresented in the original paper was unclear) (Truffert etal., 1977).

1 Subchronic studies have been completed for theNational Toxicology Program (NTP) in which groups of10 male or female F344 rats and B6C3F1 mice wereadministered microencapsulated 1,1,2,2-tetrachloroethane in feed at doses equivalent to 18–300mg/kg body weight per day and 88–1400 mg/kg bodyweight per day, respectively, for 13 weeks. The resultsof these studies are currently being reviewed by theNTP’s Pathology Working Group.


9

Table 2: Investigations of non-neoplastic effects of 1,1,2,2-tetrachloroethane.

Study design Effects Effect level Comments Reference

INHALATION

Male rats exposed to 50 mg/m3, 4hours/day, 5 days/week, for 5 weeks;or to 130 mg/m3 for 15 minutes, 5times/day, separated by 40-minuteintervals, for 5 weeks

Neurological effects; alterations inbiochemical parameters and organweights (although within rangesobserved in controls); no“morphological changes”

Effects at 50mg/m3

Strain and number of rats notspecified; nature and extent ofhistopathological examination notspecified

Schmidt et al.,1975

Fifty-five female Sprague-Dawley ratsexposed to 560 ml/m3 for 5 or 6hours/day, 5 days/week, for 15 weeks;liver, kidneys, lungs, ovaries, uterus,and adrenal glands histopathologicallyexamined

Transient increase in hepatic DNAsynthesis, reversible histopatho-logical changes in the liver; increasein relative liver weight

Effects at 560ml/m3

(equivalent to130 ppm or907 mg/m3,based onATSDR [1994]conversion)

One exposure group only;uncertainty concerning exposurelevel based on unclearinformation in article (note:concentration more thanapproximately 10-fold higher thanthat at which effects werereported in other studies, nomatter how converted)

Truffert et al.,1977

Male rats exposed to 13.3 mg/m3

(probably for 4 hours/day) for 110 or265 days; one group exposed for 265days and allowed to recover until day325; seven rats sacrificed after eachinterval

Increased adrenocorticotropichormone activity in the hypophysisgreatest at 4 months and lessenedtowards the end of the study;reversible decrease in body weight;reversible increase in lipid content ofliver and reversible alterations inhaematological parameters, whichwere significantly different fromcontrols only at one point in timeduring the study

Minimaleffects at13.3 mg/m3

Exposure pattern (e.g. number ofexposed days per week) notclearly specified; histopatho-logical effects not described inpublished account of study

Schmidt et al.,1972

Rabbits exposed to 100 mg/m3 3–4hours/day for 4–6 weeks or exposed for7–11 months (different protocols notedin two secondary accounts)

Depressed agglutinin formation after4–6 weeks; early signs of liverdegeneration after 7–11 months

Effects at 100mg/m3

Secondary accounts availableonly; strain, number, and sex notspecified; may be only oneexposure level; no other effectsnoted

Navrotskiy etal., 1971

Chinchilla rabbits exposed to 0, 2, 10, or100 mg/m3, 3 hours/day, 6 days/ week,for 8 months (n = 50 for controls)

Decrease in titres of typhoidantibodies, an increase in theelectrophoretic mobility of antibodiestowards $- and "-globulin fractions,and a decrease in the level of“normal” haemolysins to theForsman’s antigen of sheeperythrocytes

Effects at 10mg/m3; noeffects at 2mg/m3

Sex and number of animals perexposed group not specified

Shmuter, 1977

Six rabbits were exposed to 10 mg/m3, 3hours/day, for approximately 8 months;15 rabbits were used as controls;animals were immunized at 1.5 and 4.5months with typhoid vaccine

Decreased levels of acetylcholineand acetylcholinesterase in theblood

Effects at 10mg/m3

Isomer not specified; no end-points other than cholinergicindices were investigated

Kulinskaya &Verlinskaya,1972

INGESTION

Groups of 10 rats administered 3.2,8.0, 20, or 50 mg/kg body weightper day by gavage for 2–150 days

Damage to liver, kidney,testicles, and thyroid gland(determined by histological,enzyme histochemical, andhistoautoradiographictechniques)

Effects at 3.2mg/kg bodyweight perday

Inadequate documentation ofprotocol and results; noquantitative data; notreported in which dose groupseffects were observed (somegroups were alsoconcomitantly exposed tohigh temperatures); notpossible to verify effect level

Gohlke etal., 1977

Five male or female B6C3F1 miceadministered 0, 32, 56, 100, 178, or316 mg/kg body weight per day bygavage, 5 days/week, for 6 weeks,followed by 2 weeks of observation

No effects on body weight gainor mortality

No effects athighest doseof 316 mg/kgbody weightper day

No end-points other thanbody weight and mortalityappear to have beenexamined

NCI, 1978

Five male or female Osborne-Mendel rats administered 0, 56,100, 178, 316, or 562 mg/kg bodyweight per day by gavage, 5days/week, for 6 weeks, followed by2 weeks of observation

Decrease in body weight gain inmales at 178 mg/kg body weightper day and in females at 100and 178 mg/kg body weight perday; all females exposed to 316mg/kg body weight per day died;one male exposed to 100 mg/kgbody weight per day died

Effects at100 mg/kgbody weightper day; noeffects at 56mg/kg bodyweight perday

No end-points other thanbody weight and mortalityappear to have beenexamined; no data presentedon effects on body weightgain at two highest doses oron mortality for other dosegroups

NCI, 1978


Table 2: Continued

Study design Effects Effect level Comments Reference

10

Fifty male or female B6C3F1 mice(n = 20 in controls) administeredtime-weighted-average doses of 0,142, or 284 mg/kg body weight perday by gavage, 5 days/week, for 78weeks, followed by 12 weeks ofobservation

Slight dose-related decreases inbody weight gain; dose-relatedincreases in mortality; noincreases in incidences of non-neoplastic lesions

Significance of decrease inbody weight gain notpresented; no end-pointsother than body weight,mortality, or histopathologywere examined

NCI, 1978

Fifty male or female Osborne-Mendel rats (n = 20 in controls)administered time-weighted-average doses of 0, 62, or 108mg/kg body weight per day (male)or 0, 43, or 76 mg/kg body weightper day (female) by gavage, 5days/week, for 78 weeks, followed by32 weeks of observation

Reversible dose-relateddecreases in body weight gain;increased mortality at higherdose; no increases in incidencesof non-neoplastic lesions

Significance of decrease inbody weight gain notpresented; no end-pointsother than body weight,mortality, or histopathologywere examined

NCI, 1978

8.4.2 Chronic exposure and carcinogenicity

The chronic toxicity of 1,1,2,2-tetrachloroethane has notbeen extensively investigated; available studies are notadequate to allow the confident determination of an“effect level” for non-neoplastic effects. A reversibledecrease in body weight and a reversible increase in lipidcontent of the liver were observed in male rats exposedto 1,1,2,2-tetrachloroethane by inhalation at 13.3 mg/m3

for 110 or 265 days or for 265 days with a 60-dayrecovery period (seven rats were killed at each interval);there were also reversible alterations in haematologicalparameters, which were statistically significantlydifferent from controls only at one point in time duringthe study, and increased adrenocorticotropic hormoneactivity in the hypophysis (Schmidt et al., 1972). However, histopathological effects were not described inthe published account of the investigation. In a studyfor which only secondary accounts were available, earlysigns of liver degeneration were observed in rabbitsexposed to 100 mg/m3 for 7–11 months (Navrotskiy et al.,1971) (no further details were provided).

An increase in the incidence of hepatocellularcarcinomas was observed in groups of 50 (n = 20 incontrols) male and female B6C3F1 mice administeredtechnical-grade 1,1,2,2-tetrachloroethane in corn oil bygavage at time-weighted-average daily doses of 142 or284 mg/kg body weight for 78 weeks (1/18, 13/50, and44/49 in males, and 0/20, 30/48, and 43/47 in females, inthe vehicle controls, low-dose group, and high-dosegroup, respectively). These tumours also appearedearlier in mice administered the higher dose. Slightlydecreased body weight gain and increased mortalitywere also observed in exposed mice; there were noincreases in the incidences of non-neoplastic lesions (NCI, 1978).

There were no significant increases in theincidence of any type of neoplastic or non-neoplasticlesion in groups of 50 (n = 20 in controls) male or femaleOsborne-Mendel rats similarly administered technical-

grade 1,1,2,2-tetrachloroethane in corn oil by gavage attime-weighted-average doses of 62 or 108 mg/kg bodyweight per day (males) and 43 or 76 mg/kg body weightper day (females) for 78 weeks, although there were twomales with hepatocellular carcinomas and one with ahepatic neoplastic nodule in the high-dose group. Therewere also reversible dose-related decreases in bodyweight gain and increased mortality in exposed rats (NCI,1978).

In a limited bioassay designed to investigate thepotential of 1,1,2,2-tetrachloroethane to induce pulmo-nary adenomas in a sensitive strain of mice, there was noincrease in the number of these tumours in a group of 20strain A mice intraperitoneally administered the chemicalfor 24 weeks; however, mortality was high in this study(Theiss et al., 1977; Stoner, 1991).

In an initiation/promotion assay, 1,1,2,2-tetra-chloroethane did not initiate formation of (-glutamyl-transpeptidase-positive foci in the liver (a putativepreneoplastic indicator) in groups of 10 male Osborne-Mendel rats administered an oral dose of 100 mg/kgbody weight followed by exposure to phenobarbital for 7weeks, although it acted as a potent promoter in ratsinitiated with a single dose of diethylnitrosaminefollowed by exposure to 1,1,2,2-tetrachloroethane bygavage for 7 weeks at 100 mg/kg body weight per day(Story et al., 1986; Milman et al., 1988).

Little information on the mechanism(s) of livertumour induction in mice exposed to 1,1,2,2-tetrachloro-ethane has been identified. Several of the metabolites of1,1,2,2-tetrachloroethane, including trichloroethylene,tetrachloroethylene, trichloroacetic acid, and dichloro-acetic acid, have been hepatocarcinogenic in experimen-tal animals (e.g. NCI, 1977; Maltoni et al., 1986, 1988;NTP, 1986, 1990; Herren-Freund et al., 1987; Bull et al.,1990; DeAngelo et al., 1991). Indeed, the toxicologicalprofile for 1,1,2,2-tetrachloroethane is very similar to thatfor dichloroacetic acid, the principal metabolite.


11

8.5 Genotoxicity and related end-points

Results of identified in vitro studies are summar-ized in Table 3. Predominantly negative results havebeen reported for the induction of gene mutation inprokaryotic systems with and without metabolicactivation, whereas both positive and negative resultshave been observed for gene conversions in yeast andfungi. 1,1,2,2-Tetrachloroethane induced sisterchromatid exchange but not chromosomal aberrations,

DNA repair, or unscheduled synthesis of DNA inmammalian cells in vitro.

Exposure to 1,1,2,2-tetrachloroethane at 349 mg/m3

for 5 days did not induce dominant lethal mutations inrats, and results for chromosomal aberrations in rat bonemarrow cells were equivocal; however, thisconcentration did not induce cytotoxicity (McGregor,1980). 1,1,2,2-Tetrachloroethane did not induceunscheduled DNA synthesis in hepatocytes of miceexposed to doses of up to 1000 mg/kg body weight by

Table 3: Genotoxicity of 1,1,2,2-tetrachloroethane in vitro.

Result

Species (test system) End-pointWith

activationWithout

activation Reference

Saccharomyces cerevisiae D7 Mitotic gene conversionRecombination

ntnt

++

Callen et al., 1980

Saccharomyces cerevisiae D7XV185-14C

Gene conversion and reversionntnt

––

Nestmann and Lee, 1983

Salmonella typhimurium

TA1530TA1535TA1538

Reverse mutationsntntnt

++–

Brem et al., 1974


TA1535TA100TA1537TA1538TA98

Reverse mutations–––––

–––––

Nestmann et al., 1980


TA1535 TA1537 TA98 TA100

Reverse mutations––––

––––

Milman et al., 1988


TA1535 TA1537 TA98 TA100

Reverse mutations––––

––––

Haworth et al., 1983

Salmonella typhimurium TA100 Reverse mutations – – Warner et al., 1988


TA97 TA98 TA100 TA102

Reverse mutations++––

––––

Mersch-Sundermann et al.,1989a


BA13/BAL13Forward mutations – – Roldan-Arjona et al., 1991

Escherichia coli (polymerasedeficient pol A+/pol A–)

DNA damage nt + Brem et al., 1974

Escherichia coli PQ37 Gene mutation – – Mersch-Sundermann et al.,1989b

Escherichia coli Induction of prophage lambda + – DeMarini & Brooks, 1992

Aspergillus nidulans Mitotic malsegregation nt + Crebelli et al., 1988

Chinese hamster ovary cells Chromosomal aberrations – – Galloway et al., 1987

Chinese hamster ovary cells Sister chromatid exchange + + Galloway et al., 1987

BALB/c3T3 cells (mouse) Sister chromatid exchange + + Colacci et al., 1992

Mouse hepatocytes DNA growth, repair, or synthesis nt – Williams, 1983

Mouse hepatocytes DNA repair nt – Milman et al., 1988

Rat hepatocytes DNA growth, repair, or synthesis nt – Williams, 1983

Rat hepatocytes DNA repair nt – Milman et al., 1988

Human embryonic intestinal cells Unscheduled DNA synthesis – – McGregor, 1980

nt = not tested


12

gavage, whereas results for the induction of S-phasesynthesis were negative and equivocal (Mirsalis et al.,1989).

1,1,2,2-Tetrachloroethane has also been reportedto bind to cellular macromolecules, including DNA,RNA, and proteins of several organs in rodents,following in vivo exposure (Mitoma et al., 1985; Colacciet al., 1987; Eriksson & Brittebo, 1991). Results for celltransformation in mammalian cells have been mixed, withpositive results being reported by only one of fourinvestigators (Little, 1983; Tu et al., 1985; Milman et al.,1988; Colacci et al., 1990, 1992, 1993).

1,1,2,2-Tetrachloroethane did not induce sex-linkedrecessive lethal mutations or mitotic recombination inDrosophila melanogaster in three studies (McGregor,1980; Woodruff et al., 1985; Vogel & Nivard, 1993).

With the possible exception of the equivocalresults for chromosomal aberrations observed in femalerats following inhalation (McGregor, 1980), the weight ofevidence overall indicates that 1,1,2,2-tetrachloroethaneis not genotoxic or that it is only weakly genotoxic,acting through a mechanism that results in geneconversion and induction of sister chromatid exchange.

8.6 Reproductive and developmentaltoxicity

Although available data are limited, reproductiveand developmental effects have been observed only inexperimental animals exposed orally or by inhalation tolevels of 1,1,2,2-tetrachloroethane that are also associ-ated with decreases in body weight. Effects on repro-ductive parameters, including decreases in testicular,epididymal, and caudal weights, decreased epididymalsperm motility, and altered estrous cycles, wereobserved in pilot studies in rats and mice orally exposedfor 90 days to doses that also caused significantdecreases in body weight (NTP, 1993). Althoughhistological changes in the testes have been observed inrats administered 1,1,2,2-tetrachloroethane doses of 8mg/kg body weight per day in peanut oil by gavage for150 days (Gohlke et al., 1977), no effects on reproductiveorgans were reported in the long-term studies in whichrats and mice were administered much higher doses for78 weeks (NCI, 1978) (see section 8.4.2) or in inhalationstudies in rats (Gohlke & Schmidt, 1972; Schmidt et al.,1972) or a single monkey (Horiuchi et al., 1962). Noeffect on male fertility or viability and no macroscopicchanges in offspring were observed in male rats exposedto 13.3 mg/m3 for 258 days (Schmidt et al., 1972). Small,but statistically significant, increases in one type ofsperm abnormality were observed in rats exposed to 349mg/m3 for 5 days, although the authors considered thiseffect to be of questionable biological significance(McGregor, 1980). Decreased fetal body weight and/or

increased resorptions were observed in range-findingstudies in rats and mice exposed to 1,1,2,2-tetrachloroethane in the feed during gestation at dosesgreater than those that induced maternal toxicity(increased mortality or decreased body weight gain)(NTP, 1991a,b).

8.7 Immunological and neurologicaleffects

Immunological effects have been observed in

limited studies in rabbits exposed to 1,1,2,2-tetrachloro-ethane by inhalation. For example, Shmuter (1977)reported a decrease in the titres of typhoid antibodies,an increase in the electrophoretic mobility of antibodiestowards $- and "-globulin fractions, and a decrease inthe level of “normal” haemolysins to the Forsman’santigen of sheep erythrocytes in animals exposed to1,1,2,2-tetrachloroethane at 10 mg/m3 and above for 8 months, whereas alterations in levels of acetylcholineand acetylcholinesterase in the blood have beenobserved at 10 mg/m3 (Kulinskaya & Verlinskaya, 1972).

Neurological effects have been observed in severalspecies following acute or short-term exposure to 1,1,2,2-tetrachloroethane (e.g. at concentrations as low as 200ppm [1396 mg/m3] for 6 hours [Horvath & Frantik, 1973]or 50 mg/m3 for approximately 5 weeks [Schmidt et al.,1975]). A single oral dose of 50 mg/kg body weightincreased levels of several neurotransmitters in the brainof rats (Kanada et al., 1994).

9. EFFECTS ON HUMANS

Death has been reported following suicidal inges-tion of doses of 1,1,2,2-tetrachloroethane estimated torange from 285 to 6000 mg/kg body weight (ATSDR,1994). Hepatic effects and death have also been reportedfollowing accidental poisoning with 1,1,2,2-tetra-chloroethane. Other effects noted in earlier reports ofworkers or volunteers exposed to 1,1,2,2-tetrachloro-ethane concentrations ranging up to 1800 mg/m3 includerespiratory failure, mucosal irritation, unconsciousness,gastrointestinal and neurological distress, jaundice, liverenlargement or degeneration, headache, tremors, dizzi-ness, numbness, and drowsiness (ATSDR, 1994).

No statistically significant increase in mortalitydue to any specific cause was noted in a limited epidemi-ological investigation in a population of 1099 menexposed to unknown concentrations of “tetrachloro-ethane” (Norman et al., 1981). The prevalence ofnervous symptoms, including tremors, headaches, and


13

vertigo, was reported to increase with airborne concen-tration of 1,1,2,2-tetrachloroethane (up to 98 ppm [684mg/m3]) in a group of 380 workers in India exposed forvarying durations, although no information waspresented on the prevalence of these signs in an unex-posed group. Exposed workers also reported loss ofappetite, nausea, vomiting, and abdominal pain (Lobo-Mendonca, 1963). Similar symptoms (i.e. loss ofappetite, bad taste in the mouth, epigastric pain, sensa-tion of pressure in the liver area, headaches, generaldebility, lack of stamina, loss of body weight, and occa-sional painful prurigo) were observed in employees of apenicillin plant exposed to concentrations of 1,1,2,2-tetrachloroethane ranging from 10 to 1700 mg/m3. Theprevalence of symptoms decreased with the implemen-tation of improvements in working conditions, and mostworkers were reported to be free of symptoms whenmaximum levels were below 250 mg/m3 (Jeney et al.,1957).

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

10.1 Aquatic environment

Bioassays were conducted by Blum & Speece(1991) on three groups of bacteria: methanogens(anaerobes from an enrichment culture maintained for>10 years), aerobic heterotrophic bacteria, and Nitroso-monas obtained from the mixed liquor of an activatedsludge wastewater treatment plant. Inhibition of gasproduction by methanogens, inhibition of oxygen uptakeby aerobic heterotrophic bacteria, and inhibition ofammonia oxidation by Nitrosomonas were the end-points used in this study to evaluate toxicity. Varyingdegrees of sensitivities were exhibited; however,Nitrosomonas, with an IC50 value of 1.4 mg/litre, wasmore sensitive than methanogens (IC50 value of 4.1mg/litre) and significantly more sensitive than aerobicheterotrophs (IC50 value of 130 mg/litre).

Based on bioluminescence, the 5-minute LC50 for1,1,2,2-tetrachloroethane was 5.4 mg/litre in a Microtoxtest using Photobacterium phosphoreum (Blum &Speece, 1991).

Unfed and fed Daphnia magna (first instar, <24hours old) had similar measured 48-hour LC50 values of62 and 57 mg/litre, respectively, under static test condi-tions (Richter et al., 1983). With complete immobilization

as the end-point, the 48-hour EC50 values were 23 and 25mg/litre for unfed and fed D. magna, respectively. LeBlanc (1980) conducted a similar test with D. magna at22°C and reported nominal 24-hour and 48-hour LC50

values of 18 and 9.3 mg/litre, respectively. Pawlisz &Peters (1995) reported that prior exposure of D. magna tosublethal concentrations of 1,1,2,2-tetrachloroethane(6.3–50% of the 48-hour LC50 of 0.095 mmol/litre) for 24hours did not influence the body burden required tonarcoticize the animals upon subsequent exposure to thechemical at the LC50.

The measured 28-day LOEC and no-observed-effect concentration (NOEC) for reproductive impairmentin D. magna were 14.4 and 6.9 mg/litre, respectively,under flow-through conditions (Richter et al., 1983).

Numerous acute toxicity studies have been con-ducted on a variety of freshwater fish species; in gener-al, 96-hour LC50 values were very similar. Under flow-through conditions, the measured 96-hour LC50s for 30-day-old fathead minnows (Pimephales promelas) were20.3 and 20.4 mg/litre (Veith et al., 1983; Walbridge et al.,1983). In juvenile (2- to 4-month-old) flagfish, themeasured 96-hour LC50 for 1,1,2,2-tetrachloroethane inthe flow-through toxicity test was 18.5 mg/litre; thenominal LC50 value in a static-renewal 96-hour toxicitytest was 26.8 mg/litre (ATRG, 1988; Smith et al., 1991). Noadequate acute toxicity studies of marine fish wereidentified.

Chronic toxicity studies under flow-through testconditions were conducted on the early life stages offlagfish by ATRG (1988) and Smith et al. (1991). Egghatchability was unaffected at a measured 1,1,2,2-tetra-chloroethane concentration of 22.0 mg/litre, the highestconcentration tested in both studies. The measuredLOECs for reduced 10-day larval survival were 10.6 and7.2 mg/litre, whereas the LOECs for 28-day juvenilesurvival were 11.7 and 8.5 mg/litre (ATRG, 1988; Smith etal., 1991). There were no statistically significant effectson the growth of 1-week-old fry over a 28-day exposureperiod, even at the highest concentration of 1,1,2,2-tetrachloroethane tested (11.7 mg/litre).

Ninety-day carcinogenicity studies were con-ducted under flow-through conditions on 2-day-oldguppy (Poecilia reticulata) and 6-day-old Japanesemedaka (Oryzias latipes) exposed continuously to1,1,2,2-tetrachloroethane at 4 mg/litre, exposed once perweek (24 hours) to 8 mg/litre, or exposed once per week(24 hours) to 15 mg/litre. Histopathological examination


14

of all exposed groups at 90 days did not reveal anyevidence of carcinogenicity (Hawkins, 1991).

10.2 Terrestrial environment

No studies were identified on the effects of 1,1,2,2-tetrachloroethane on terrestrial organisms.

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–responseassessment

Owing to the significant decline in the use of thissubstance, the toxicological profile of 1,1,2,2-tetrachloro-ethane has not been well characterized, with theavailable data being confined primarily to early limitedstudies.

Based on the results of studies in experimentalanimals, the acute toxicity of 1,1,2,2-tetrachloroethane isslight to moderate. The chemical may induce skin, eye,and mucosal irritation. Owing to the limitations of theavailable data in humans on effects associated withlonger-term exposure to 1,1,2,2-tetrachloroethane, it isnecessary to rely on information obtained from thelimited studies in animals for determination of the criticaleffects and associated effect levels.

The results of available studies on the non-neoplastic effects of 1,1,2,2-tetrachloroethane in experi-mental animals exposed by ingestion or inhalationindicate that the liver is the principal target organ. However, the majority of subchronic and chronic studiesare too limited to allow a confident determination of aNO(A)EL or LO(A)EL for hepatic or other effects,because of either the lack of information presented in thepublished accounts or the limitations of the studydesigns (e.g. small numbers of animals per experimentalgroup, lack of histopathological examination, etc.).

Long-term exposure to 1,1,2,2-tetrachloroethaneresulted in a significantly increased incidence ofhepatocellular carcinomas in both male and female mice. However, no significant increases in tumours wereobserved in similarly exposed rats, although there was anon-statistically significant increase at the highest dosetested (which was lower, on a time-weighted-averagebasis, than the lowest dose to which mice were exposed),and both species were exposed only for up to 78 weeks.

1,1,2,2-Tetrachloroethane was a potent promoter, but didnot act as an initiator, in an initiation/promotion assay. The weight of evidence of available in vitro and in vivoassays suggests that this substance is not genotoxic orthat it is, at most, weakly genotoxic. Although availabledata are incomplete, it has been proposed that the livertumours may be induced by mechanisms that may not berelevant to humans, for which humans are lesssusceptible, or for which there may be a threshold ofexposure. In addition, it has been hypothesized that thecarcinogenicity of 1,1,2,2-tetrachloroethane may beassociated with the formation of free radicals, lipidperoxidation, or hepatic damage (such as focal necrosisassociated with intense cellular proliferation) (Hanley etal., 1988; Larson & Bull, 1992; Paolini et al., 1992). Therefore, on the basis of data currently available, it isnot possible to draw any firm conclusions with respectto the potential carcinogenicity of 1,1,2,2-tetrachloro-ethane in humans.

Owing to the limitations of available studies on thepotential toxicological effects associated with exposureto 1,1,2,2-tetrachloroethane, it is not possible to confi-dently determine a NO(A)EL or LO(A)EL for non-neoplastic effects. The toxicological end-point for whichthe dose–response relationship is best characterized isthe increase in hepatocellular carcinomas observed inthe long-term bioassay in mice (NCI, 1978). It is noted,however, that the observed increases in tumourincidence are restricted to one species and that theweight of available data indicates that 1,1,2,2-tetrachloroethane is, at most, weakly genotoxic.

Based on multistage modelling of the incidence ofhepatocellular carcinomas in male or female mice exposedto time-weighted-average doses of 0, 142, or 284 mg/kgbody weight per day for up to 78 weeks, adjusted forcontinuous exposure for a standard duration of 104weeks and corrected for the expected rate of increase intumour formation in rodents in a standard bioassay of104 weeks, the doses associated with a 5% increase intumour incidence (TD0.05) range from 5.8 to 28 mg/kgbody weight per day.

11.1.2 Criteria for setting guidance values for1,1,2,2-tetrachloroethane

As noted in section 11.1.1, the toxicological end-point for which the dose–response relationship is bestcharacterized, and which might provide the basis forderivation of limits of exposure or for judgement of thequality of environmental media by relevant authorities, isthe increase in hepatocellular carcinomas observed inthe long-term bioassay in mice (NCI, 1978).


15

A value, for example, 5000 or 50 000 times less thanthe TD0.05s derived above might be consideredconservative as a guidance value. This margin (5000–50 000) affords protection similar to that associated withthe range for low-dose risk estimates generally consid-ered by various agencies to be “essentially negligible”(i.e. 10–5 to 10–6). As, on the basis of available data,1,1,2,2-tetrachloroethane is, at most, weakly genotoxic, asmaller margin (e.g. 1000) might also be consideredappropriate. As available data indicate that air is theprincipal medium of human exposure, the most conserva-tive of these approaches result in, for example, a range ofairborne concentrations of 3.4–16 :g/m3 or 0.34–1.6:g/m3, respectively. Corresponding values for ingestionare 1.2–5.6 :g/kg body weight per day or 0.12–0.56:g/kg body weight per day. It should be noted, how-ever, that these possible guidance values for air havebeen extrapolated directly from a study in which thechemical was administered orally to experimental animals. Although there may be substantial variations intoxicokinetics following exposure to 1,1,2,2-tetrachloro-ethane by different routes, available data are inadequateto quantitatively account for these differences in thederivation of guidance values.

It is noteworthy that a provisional tolerable con-centration derived on the basis of the minimal non-neoplastic effects observed in rats exposed to 13.3 mg/m3

(Schmidt et al., 1972) would fall within the range of thevalues presented here.

11.1.3 Sample risk characterization

Although data are insufficient to allow the confi-dent determination of a LO(A)EL or NO(A)EL for 1,1,2,2-tetrachloroethane, minimal effects in rodents have beenobserved only at levels more than 50 000 times greaterthan those in the principal medium of exposure (air) inthe general environment.

Based on a sample estimate of exposure, indirectexposure in the general environment is 14 to >160 or 1.4to >16 times less than guidance values that might bederived on the basis of available data on the dose–response relationship for liver tumour induction in mice(i.e. the TD0.05s divided by 5000 or 50 000, or 3.4–16:g/m3 or 0.34–1.6 :g/m3, respectively). It should also benoted, however, that indirect exposure in the generalenvironment is likely overestimated here, as it is basedon the range of mean concentrations for detected values,although 1,1,2,2-tetrachloroethane was detected in onlyapproximately 50% of samples.

11.2 Evaluation of environmental effects

1,1,2,2-Tetrachloroethane is released to theenvironment principally in emissions to ambient air,where it is moderately persistent. Because of itsvolatility, rapid photo-oxidation in the atmosphere, andan atmospheric ozone-depleting potential of less than0.001 relative to CFC-11, 1,1,2,2-tetrachloroethane is notexpected to contribute significantly either to thedepletion of the stratospheric ozone layer or to globalwarming.

Terrestrial organisms have the greatest potentialfor exposure to 1,1,2,2-tetrachloroethane in ambient air inthe environment. However, no data were identified onthe effects of 1,1,2,2-tetrachloroethane in terrestrialspecies. Therefore, it is not possible to characterize therisk to these organisms associated with levels of 1,1,2,2-tetrachloroethane present in the environment.

Although 1,1,2,2-tetrachloroethane may bereleased to surface waters in industrial effluents, it israpidly removed by volatilization. Based on the resultsof several studies in aquatic bacteria, invertebrates, andfish, effect levels are generally greater than 1 mg/litre. Although data are limited, concentrations of 1,1,2,2-tetrachloroethane in surface waters are generally muchless than this value (at least two orders of magnitude). Therefore, it is likely that 1,1,2,2-tetrachloroethane doesnot pose significant risk to aquatic organisms.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

The International Agency for Research on Cancer

(IARC, 1987) has classified 1,1,2,2-tetrachloroethane ingroup 3 (not classifiable as to its carcinogenicity tohumans), based on inadequate evidence of carcinogen-icity in humans and limited evidence in animals.

Information on international hazard classificationand labelling is included in the International ChemicalSafety Card reproduced in this document.


16

13. HUMAN HEALTH PROTECTION ANDEMERGENCY ACTION

Human health hazards, together with preventativeand protective measures and first aid recommendations,are presented in the International Chemical Safety Card(ICSC 0332) reproduced in this document.

13.1 Advice to physicians

In case of emergency, it is important to wash skinwith soap and water after removing contaminatedclothing. Like others of this class, 1,1,2,2-tetrachloro-ethane could generate some hyperexcitability of theheart. The prognosis following intoxication with thischemical is that rapid progression of jaundice indicates apoor outcome. In some instances, mild symptoms willpersist up to 3 months and then progress to acute yellowatrophy and death. Anuria may persist for as long as 2weeks and still be followed by complete recovery.

13.2 Health surveillance advice

Annual blood counts and monitoring of both liverand kidney function should be included in a healthsurveillance programme of individuals exposed to 1,1,2,2-tetrachloroethane.

13.3 Prevention

Because 1,1,2,2-tetrachloroethane decomposes onburning, maintenance workers must wait until all liquidand vapour have been cleared from the container orpiping before performing any duty that generates heat.

Fire-fighters need to wear chemical-resistant clothingand positive self-contained breathing apparatus.

13.4 Spillage

It is very important in the case of spillage to usefull protection, including respiratory protection, because1,1,2,2-tetrachloroethane passes through the skin and,under the influence of air, moisture, and ultraviolet light,will decompose, producing toxic and corrosive gases,such as hydrogen chloride and phosgene.

The IDLH (Immediately Dangerous to Life or Health)value for this substance is very low, at 100 ppm (698mg/m3) (NIOSH, 1994).

14. CURRENT REGULATIONS,GUIDELINES, AND STANDARDS

Information on national regulations, guidelines,and standards is available from the International Registerof Potentially Toxic Chemicals (IRPTC) legal file.

The reader should be aware that regulatorydecisions about chemicals taken in a certain country canbe fully understood only in the framework of thelegislation of that country. The regulations andguidelines of all countries are subject to change andshould always be verified with appropriate regulatoryauthorities before application.

Prepared in the context of cooperation between the InternationalProgramme on Chemical Safety and the European Commission

© IPCS 1999

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

1,1,2,2-TETRACHLOROETHANE 0332March 1995

CAS No: 79-34-5RTECS No: KI8575000UN No: 1702EC No: 602-015-00-3

Acetylene tetrachlorideSymmetrical-tetrachloroethaneS-tetrachloroethaneCHCl2CHCl2Molecular mass: 167.9

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Not flammable. Gives off irritatingor toxic fumes (or gases) in a fire.

NO open flames. In case of fire in the surroundings:all extinguishing agents allowed.

EXPLOSION In case of fire: keep drums, etc.,cool by spraying with water.

EXPOSURE STRICT HYGIENE!

Inhalation Abdominal pain. Cough.Dizziness. Headache. Nausea.Sore throat. Vomiting.

Ventilation, local exhaust, orbreathing protection.

Fresh air, rest. Artificial respirationif indicated. Refer for medicalattention.

Skin MAY BE ABSORBED! Dry skin.Tremors (further see Inhalation).

Protective gloves. Protectiveclothing.

Remove contaminated clothes.Rinse skin with plenty of water orshower. Refer for medical attention.

Eyes Redness. Pain. Face shield or eye protection incombination with breathingprotection.

First rinse with plenty of water forseveral minutes (remove contactlenses if easily possible), then taketo a doctor.

Ingestion Abdominal pain. Nausea. Vomiting(further see Inhalation).

Do not eat, drink, or smoke duringwork.

Do NOT induce vomiting. Rest.Refer for medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Ventilation. Collect leaking and spilled liquid insealable containers as far as possible. Absorbremaining liquid in sand or inert absorbent andremove to safe place. Do NOT let this chemicalenter the environment (extra personal protection:complete protective clothing includingself-contained breathing apparatus).

T+ SymbolR: 26/27-51/53S: (1/2-)38-45-61UN Hazard Class: 6.1UN Pack Group: II

Airtight. Do not transport with foodand feedstuffs. Marine pollutant.

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-719NFPA Code: H3; F0; R1

Separated from strong bases, food and feedstuffs. Cool. Keep in the dark.Well closed. Keep in a well-ventilated room.

Boiling point: 146�CMelting point: -44�CRelative density (water = 1): 1.6Solubility in water, g/100 ml at 20�C: 0.29

Vapour pressure, Pa at 25�C: 780Relative vapour density (air = 1): 5.8Relative density of the vapour/air-mixture at 20�C (air = 1): 1.031Octanol/water partition coefficient as log Pow: 2.39

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

© IPCS 1999

0332 1,1,2,2-TETRACHLOROETHANE

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR.

Physical DangersThe vapour is heavier than air.

Chemical DangersThe substance decomposes on burning under influence of air,moisture and UV light, producing toxic and corrosive gasesincluding hydrogen chloride and phosgene. Reacts violentlywith alkali metals, strong bases and many powdered metalsproducing toxic and explosive gases. Attacks plastic andrubber.

Occupational Exposure LimitsTLV: 1 ppm; 6.9 mg/m3 (as TWA) (skin) (ACGIH 1994-1995).MAK: 1 ppm; 7 mg/m3; skin, B (1992).

Routes of ExposureThe substance can be absorbed into the body by inhalation ofits vapour, through the skin and by ingestion.

Inhalation RiskA harmful contamination of the air can be reached ratherquickly on evaporation of this substance at 20�C.

Effects of Short-term ExposureThe substance irritates the eyes and the respiratory tract. Thesubstance may cause effects on the central nervous system,kidneys and liver, resulting in depression of the central nervoussystem, kidney impairment and liver impairment. Exposuremay result in unconsciousness. Exposure may result in death.

Effects of Long-term or Repeated ExposureThe liquid defats the skin. The substance may have effects onthe central nervous system and liver, resulting in impairedfunctions.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

The substance is toxic to aquatic organisms. This substance may be hazardous to the environment; special attention should begiven to its impact on the ozone layer.

NOTES

Use of alcoholic beverages enhances the harmful effect. The odour warning when the exposure limit value is exceeded isinsufficient. Do NOT use in the vicinity of a fire or a hot surface, or during welding.

ADDITIONAL INFORMATION


19

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APPENDIX 1 — SOURCE DOCUMENTS

Government of Canada (1993)

Copies of the Canadian Environmental Protection Act

(CEPA) Priority Substances List Assessment Report for 1,1,2,2-tetrachloroethane (Government of Canada, 1993) may beobtained from the:

Commercial Chemicals BranchEnvironment Canada14th Floor, Place Vincent Massey351 St. Joseph Blvd.Hull, QuebecCanada K1A 0H3

Environmental Health CentreHealth CanadaAddress Locator: 0801ATunney’s PastureOttawa, OntarioCanada K1A 0L2

Copies of the unpublished Supporting Documentationrelated to human health effects that formed the basis forpreparation of the above-mentioned report may be obtainedfrom the Environmental Health Centre at the address notedabove.

Initial drafts of the Supporting Documentation andAssessment Report for 1,1,2,2-tetrachloroethane were preparedby staff of Health Canada and Environment Canada. Theenvironmental sections were reviewed externally by Dr P.Cammer (Cammer and Associates), Dr D. Muir (Department ofFisheries and Oceans), Dr D. Singleton (National ResearchCouncil of Canada), and Dr K. Woodburn (Dow ChemicalCanada Inc.). Sections related to the assessment of humanexposure and health effects were peer reviewed by Dr J.Domoradzki (Dow Chemical Company, USA, SupportingDocumentation only), Dr R. Bull (Washington State University,USA), and the Information Department of BIBRA ToxicologyInternational, UK, and subsequently approved by the Standardsand Guidelines Rulings Committee of the Bureau of ChemicalHazards of Health Canada. The final Assessment Report wasreviewed and approved by the Environment Canada/HealthCanada CEPA Management Committee.

Agency for Toxic Substances and DiseaseRegistry (ATSDR, 1994)

Copies of the draft ATSDR profile for 1,1,2,2-tetrachloroethane (ATSDR, 1994) may be obtained from:

Agency for Toxic Substances and Disease RegistryDivision of Toxicology/Toxicology Information Branch1600 Clifton Road, NE, E-29Atlanta, Georgia 30333USA

The profile has undergone the following ATSDR internalreviews: Green Border Review, Health Effects Review, MinimalRisk Level Review, and Quality Assurance Review. In addition,a peer review panel, which included Dr Martin Alexander(Cornell University, USA), Mr Lyman Skory (private consultant,USA), and Dr James Withey (Health Canada), was assembled.

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on 1,1,2,2-tetrachloroethane was sent forreview to institutions and organizations identified by IPCS aftercontact with IPCS national Contact Points and ParticipatingInstitutions, as well as to identified experts. Comments werereceived from:

Department of Health, London, United Kingdom

Department of Public Health, Albert Szent-GyorgyiUniversity Medical School, Szeged, Hungary

Direccion General de Salud Ambiental, Subsecretario deRegulacion y Fomento Sanitario, San Luis Potosi,Mexico

Finnish Institute for Occupational Health, Helsinki,Finland

International Agency for Research on Cancer, Lyon,France

Ministry of Health and Welfare, International AffairsDivision, Government of Japan, Tokyo, Japan

National Institute for Working Life, Solna, Sweden

United States Department of Health and Human Services(Agency for Toxic Substances and Disease Registry;National Institute of Environmental Health Sciences)

United States Environmental Protection Agency (Office ofPollution Prevention and Toxics; National Center forEnvironmental Assessment, Office of Research andDevelopment; Office of Drinking Water)


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APPENDIX 3 — CICAD FINAL REVIEWBOARD

Brussels, Belgium, 18–20 November 1996

Members

Dr A. Aitio, Institute of Occupational Health, Helsinki, Finland

Dr K. Bentley, Director, Environment Policy Section,Commonwealth Department of Human Services and Health,Canberra, Australia

Mr R. Cary, Toxicology and Existing Substances RegulationUnit, Health and Safety Executive, Merseyside, United Kingdom

Dr J. de Fouw, National Institute of Public Health andEnvironmental Protection, Bilthoven, The Netherlands

Dr C. DeRosa, Director, Division of Toxicology, Agency for ToxicSubstances and Disease Registry, Atlanta, GA, USA

Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom

Dr W. Farland, Director, National Center for EnvironmentalAssessment, Office of Research and Development, USEnvironmental Protection Agency, Washington, DC, USA(Chairperson)

Dr T.I. Fortoul, Depto. Biologia Celular y Tisular, NationalUniversity of Mexico and Environmental Health Directorate ofthe Health Ministry, Mexico D.F., Mexico

Dr H. Gibb, National Center for Environmental Assessment, USEnvironmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection ofConsumers & Veterinary Medicine, Berlin, Germany

Mr J.R. Hickman, Environmental Health Directorate, HealthCanada, Ottawa, Ontario, Canada

Dr T. Lakhanisky, Head, Division of Toxicology, Institute ofHygiene and Epidemiology, Brussels, Belgium (Vice-

Chairperson)

Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,Fraunhofer Institute for Toxicology and Aerosol Sciences,Hanover, Germany

Ms E. Meek, Head, Priority Substances Section, EnvironmentalHealth Directorate, Health Canada, Ottawa, Ontario, Canada

Dr K. Paksy, National Institute of Occupational Health, Budapest,Hungary

Mr D. Renshaw, Department of Health, London, United Kingdom

Dr J. Sekizawa, Division of Chemo-Bio Informatics, NationalInstitute of Hygienic Sciences, Tokyo, Japan

Dr H. Sterzl-Eckert, GSF-Forschungszentrum für Umwelt undGesundheit GmbH, Institut für Toxikologie, Oberschleissheim,Germany

Professor S. Tarkowski, Department of Environmental HealthHazards, The Nofer Institute of Occupational Medicine, Lodz,Poland

Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna,Sweden

Observers

Professor F.M.C. Carpanini,1 Director, Centre for Ecotoxicologyand Toxicology of Chemicals (ECETOC), Brussels, Belgium

Mr R. Haigh,1 Head of Unit, Health and Safety Directorate, European Commission, Luxembourg

Mr B.U. Hildebrandt, Federal Ministry for the Environment,Nature Conservation and Nuclear Safety, Bonn, Germany

Mr P. Hurst,1 Chemical and Consumer Policy Officer,Conservation Policy Division, World Wide Fund for Nature,Gland, Switzerland

Dr A. Lombard (Representative of CEFIC), ELF-ATOCHEM,Paris, France

Dr P. McCutcheon,1 Environment, Consumer Protection andNuclear Safety, European Commission, Brussels, Belgium

Dr R. Montaigne, Counsellor, Technical Affairs Department,European Chemical Industry Council (CEFIC), Brussels, Belgium

Dr M. Pemberton, ICI Acrylics, Lancashire, United Kingdom

Dr A. Smith, Organisation for Economic Co-operation andDevelopment, Environment Division, Paris, France

Secretariat

Dr M. Baril, International Programme on Chemical Safety, WorldHealth Organization, Geneva, Switzerland

Dr L. Harrison, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Dr M. Mercier, Director, International Programme on ChemicalSafety, World Health Organization, Geneva, Switzerland

Dr P. Toft, Associate Director, International Programme onChemical Safety, World Health Organization, Geneva,Switzerland

1 Invited but unable to attend.


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RÉSUMÉ D’ORIENTATION

La Direction de l’Hygiène du Milieu de SantéCanada a rédigé ce CICAD (document internationalsuccinct sur l’évaluation des risques chimiques) sur le1,1,2,2-tétrachloréthane en s’inspirant d’un document duGouvernement du Canada (1993) qui évaluait lesconséquences potentielles pour la santé humaine d’uneexposition indirecte au 1,1,2,2-tétrachloréthane et leseffets de cette substance sur l’environnement, ainsi qued’une étude entreprise par l’Agence pour les substancestoxiques et l’enregistrement des maladies (ATSDR, 1994)en vue de caractériser les informations disponibles surses effets sanitaires indésirables et l’exposition dupublic. L’examen du Gouvernement canadien a pris enconsidération les données disponibles en septembre1992. Une recherche bibliographique détaillée a étéeffectuée en août 1995 dans plusieurs bases de donnéesen ligne pour identifier les références publiées postéri-eurement. L’appendice 1 donne des informations sur lanature du processus d’évaluation par les pairs et sur ladisponibilité des sources documentaires. Les informa-tions concernant l’examen par les pairs du présentCICAD figurent à l’appendice 2. La publication de ceCICAD a été approuvée à une réunion du Comitéd’évaluation finale qui s’est tenue à Bruxelles (Belgique)du 18 au 20 novembre 1996. La liste des participants àcette réunion figure à l’appendice 3. La ficheinternationale de sécurité chimique (ICSC 0332)concernant le 1,1,2,2-tétrachloréthane, établie par leProgramme international sur la sécurité chimique (IPCS,1993) est également reproduite dans le présent docu-ment.

Le 1,1,2,2-tétrachloréthane (CAS n/ 79-34-5) estun produit synthétique volatil utilisé principalementcomme intermédiaire dans la synthèse d’autres hydro-carbures chlorés, bien que cette utilisation ait diminuéconsidérablement. Sa présence dans l’environnementrésulte principalement d’émissions dans l’atmosphère,où il persiste probablement plusieurs semaines. Il nesemble pas que le 1,1,2,2-tétrachloréthane contribue à ladestruction de l’ozone atmosphérique ni au réchauffe-ment mondial. Il est rapidement éliminé des systèmesaquatiques et son potentiel de bioaccumulation estfaible. L’inhalation est la principale voie d’expositionpour l’homme.

On dispose de très peu de données concernantles effets sur l’homme de l’exposition au 1,1,2,2-tétra-chloréthane. Son profil toxicologique n’a pas non plusété caractérisé de façon précise. Étant donné qu’il est demoins en moins utilisé, la majorité des données disponi-bles proviennent d’études limitées relativement anci-ennes. La toxicité aiguë du 1,1,2,2-tétrachloréthane chez

les animaux de laboratoire est considérée comme légère àmodérée. D’après les résultats d’études de toxicité àcourt terme et subchronique, pour la plupart limitées, lefoie semble être l’organe cible le plus sensible. La plupartdes études disponibles ne permettent pas d’établir deNO(A)EL [dose sans effet (indésirable) observé] ni deLO(A)EL [dose minimale suivie d’un effet (indésirable)observé] fiable pour ce qui est de l’hépatotoxicité. Cependant, des effets minimes sur le foie (augmentationréversible de la teneur en lipides), ainsi que d’autreseffets (augmentation de la concentrationd’adrénocorticotropine et altérations réversibles desparamètres hématologiques), ont été observés chez desrats exposés à 13,3 mg/m3 pendant 9 mois. D’après lesrésultats d’études limitées et pour la plupart anciennes,des effets n’ont été observés sur la reproduction et ledéveloppement des animaux de laboratoire qu’à desdoses qui provoquaient une diminution de poids.

L’ingestion sur une longue période de 1,1,2,2-tétrachloréthane a provoqué une augmentation de l’inci-dence des tumeurs du foie chez des souris B6C3F1 mâleset femelles. Toutefois, une exposition analogue n’a pasété suivie d’une augmentation significative du nombredes tumeurs, quel que soit leur site, chez des ratsOsborne-Mendel, mais l’exposition a été limitée à78 semaines pour les deux espèces. D’après les résultatsdisponibles in vivo et in vitro, le 1,1,2,2-tétrachloréthaneaurait tout au plus une faible activité génotoxique. Il nedéclenche pas la formation de foyers positifs à la (-glutamyltranspeptidase dans le foie des rats, mais il lafavorise fortement. Le profil d’induction des tumeurs parle 1,1,2,2-tétrachloréthane est semblable à celui de l’acidedichloracétique, son principal métabolite. Le mécanismed’induction des tumeurs par le 1,1,2,2-tétrachloréthaneest encore mal connu; pour plusieurs de ses métabolites,on a émis l’hypothèse qu’il existerait un seuil.

Il a été démontré que l’exposition au 1,1,2,2-tétrachloréthane inhibe l’activité de certaines bactériesprésentes dans l’environnement (la CI50 la plus faibleétait de 1,4 mg/litre) et qu’il provoque l’immobilisation deDaphnia magna (CE50 à 48 heures $ 23 mg/litre). Chezles poissons d’eau douce, la CL50 la plus faible qui ait étésignalée (96 heures) était de 18,5 mg/litre (Jordanellafloridae), tandis que la concentration minimale suivied’effet (LOEC) à plus long terme (réduction de la surviedes larves chez la même espèce) était de 7,2 mg/litre. Aucun renseignement n’a été découvert concernant leseffets de cette substance sur les organismes terrestres.

Des valeurs guides à l’intention des autoritéscompétentes ont été établies sur la base de la capacité du1,1,2,2-tétrachloréthane à induire la formation de tumeursdu foie chez la souris, étant donné qu’il s’agit du critèretoxicologique pour lequel la relation dose-réponse est la


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mieux établie. Il faut cependant noter quel’augmentation observée de l’incidence des tumeurs selimite actuellement à une espèce et qu’il existe desdonnées qui, bien qu’incomplètes, laissent supposer queles tumeurs pourraient être induites par un mécanismenon génotoxique. Les doses associées à une augmen-tation de 5 % de l’incidence des tumeurs se situent entre5,8 et 28 mg/kg de poids corporel par jour. Dans le casde l’air (principale source d’exposition pour l’homme), sil’on divise ces doses par 5000 ou 50 000, on obtient desvaleurs guides de 3,4–16 :g/m3 et 0,34–1,6 :g/m3

respectivement. Ces valeurs correspondent à ce quecertains organismes considèrent comme un risque«pratiquement négligeable» (c’est-à-dire 10–5 à 10–6) pourun cancérogène génotoxique; il faut cependant noterqu’une marge plus faible serait peut-être appropriéecompte tenu des arguments en faveur d’un mécanismeépigénétique d’induction des tumeurs. Les valeurscorrespondantes pour l’ingestion sont respectivementde 1,2–5,6 et 0,12–0,56 :g/kg de poids corporel par jour. D’après une des estimations qui ont été faites,l’exposition indirecte dans un environnement normal estinférieure à ces valeurs, qui apportent déjà une marge desécurité considérable, compte tenu des arguments selonlesquels le mécanisme d’induction des tumeurs par letétrachloréthane pourrait impliquer un seuil.


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RESUMEN DE ORIENTACIÓN

Esta reseña de la evaluación química inter-nacional del 1,1,2,2-tetracloroetano ha sido preparadapor la Dirección de Higiene del Medio de Health Canadá,principalmente sobre la base de un informe preparadopor el Gobierno del Canadá (1993) para evaluar losefectos potenciales en la salud humana de la exposicióndirecta al 1,1,2,2-tetracloroetano en el medio ambientegeneral y los efectos ambientales de esta sustancia, asícomo un estudio preparado por la Agencia para elRegistro de Sustancias Tóxicas y Enfermedades(ATSDR, 1994) con objeto de caracterizar informaciónsobre los efectos adversos en la salud y la exposicióndel público. En el estudio del Gobierno del Canadá(1993) se examinaron datos identificados hastaseptiembre de 1992. En agosto de 1995 se hizo unabúsqueda exhaustiva de la bibliografía existente envarias bases de datos en línea con objeto de identificartoda referencia publicada con posterioridad a lostrabajos incorporados en este estudio. En el apéndice 1se presenta información sobre la naturaleza de la revisióncientífica y la disponibilidad de las fuentesdocumentales. En el apéndice 2 se presenta informaciónsobre la revisión científica de esta reseña. La presentereseña fue aprobada para publicación en una reunión dela Junta de Revisión Final, celebrada en Bruselas(Bélgica), del 18 al 20 de noviembre de 1996. Losparticipantes en la reunión de la Junta de Revisión Finalfiguran en el apéndice 3. En el presente documentotambién se reproduce la ficha internacional de seguridadquímica (ICSC 0332) del 1,1,2,2-tetracloroetano,producida por el Programa Internacional de Seguridad delas Sustancias Químicas (IPCS, 1993).

El 1,1,2,2-tetracloroetano (No CAS 79-34-5) es

una sustancia química sintética volátil que se utilizaprincipalmente como precursor en la síntesis de otroshidrocarburos clorados, aunque la utilización de estasustancia ha disminuido significativamente. La libera-ción en el medio ambiente ocurre principalmente enforma de emisiones en el aire ambiente, donde lasustancia química probablemente permanezca durantevarias semanas. No se prevé que el 1,1,2,2-tetracloro-etano contribuya al agotamiento del ozono estratosfériconi al calentamiento de la atmósfera. Se elimina rápida-mente de los sistemas acuáticos y probablemente no seaobjeto de bioacumulación. La exposición humana al1,1,2,2-tetracloroetano se hace principalmente porinhalación.

Se dispone de muy pocos datos sobre losefectos de la exposición al 1,1,2,2-tetracloroetano en elser humano. El perfil toxicológico del 1,1,2,2-tetracloro-etano tampoco se ha caracterizado bien; como la utiliz-

ación de la sustancia química se halla en disminución,los datos disponibles se limitan principalmente aestudios iniciales limitados. La toxicidad aguda del1,1,2,2-tetracloroetano en animales de laboratorio es deleve a moderada. Sobre la base de los resultados deestudios principalmente limitados a corto plazo ysubcrónicos, parece que el hígado es el órgano dianamás sensible. Si bien la mayor parte de los estudiosdisponibles son insuficientes para determinar conconfianza un nivel sin efectos (adversos) observados[NO(A)EL] o el nivel más bajo con efectos (adversos)observados [LO(A)EL] de hepatotoxicidad, se hanobservado efectos mínimos en el hígado (aumentoreversible del contenido de lípidos) y otros parámetros(aumento de los niveles de hormona adrenocortico-trópica y alteraciones reversibles en los parámetroshematológicos) en ratas expuestas a 13,3 mg/m3 duranteno más de nueve meses. Sobre la base de estudioslimitados, principalmente de determinación de la dosis einvestigaciones iniciales, se han observado efectos en lareproducción y en el desarrollo en animales experimen-tales solamente con dosis que ocasionaban reduccióndel peso corporal.

La ingestión prolongada de 1,1,2,2-tetracloro-etano hizo aumentar la incidencia de tumores del hígadoen ratones B6C3F1, tanto machos como hembras. Sinembargo, una exposición semejante no estuvo asociadaa un aumento significativo de tumores en ningún lugaren ratas Osborne-Mendel, aunque ambas especies sóloestuvieron expuestas durante un máximo de 78 semanas. Sobre la base de los resultados de valoraciones dispon-ibles in vivo e in vitro el 1,1,2,2-tetracloroetano tiene,como máximo, un potencial genotóxico débil. El 1,1,2,2-tetracloroetano fue un potente promotor, pero no uniniciador, de focos positivos a la (-glutamiltrans-peptidasa en el hígado de ratas. El perfil de inducción detumores por el 1,1,2,2-tetracloroetano es semejante al delácido dicloroacético, su metabolito principal. Lainformación existente sobre el mecanismo de inducciónde tumores por el 1,1,2,2-tetracloroetano es incompleta;con respecto a varios de sus metabolitos, se ha sugeridoque los tumores probablemente estén inducidos pormecanismos para los cuales existe un umbral.

Se ha demostrado que la exposición al 1,1,2,2-tetracloroetano inhibe la actividad de las bacteriasambientales (la CI50 más baja comunicada ha sido de 1,4mg/litro) y ocasiona inmovilización en Daphnia magna(valores de CE50 a las 48 horas de 23 mg/litro y superi-ores). En las especies ictícolas de agua dulce, la CL50

más baja comunicada (a las 96 horas) ha sido de 18,5mg/litro en Jordanella floridae, mientras que la concen-tración más baja con efectos observados (LOEC) tras laexposición a más largo plazo ha sido de 7,2 mg/litro; éstadio lugar a una reducción de la supervivencia de las


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larvas en las mismas especies mencionadas más arriba. No se identificaron datos sobre los efectos de estasustancia en organismos terrestres.

A fin de facilitar orientación a las autoridadespertinentes, se han determinado valores de orientaciónde muestra sobre la base del potencial del 1,1,2,2-tetracloroetano para inducir tumores hepáticos enratones, porque éste es el parámetro toxicológico conrespecto al cual se caracteriza mejor la relación derespuesta a la dosis. Sin embargo, es de señalar que losaumentos observados en la incidencia de tumores selimitan actualmente a una especie y hay datos, si bienincompletos, que sugieren que los tumores tal vez esténinducidos por un mecanismo no genotóxico. Elpotencial, expresado como la dosis asociada a unaumento del 5% en la incidencia de tumores, oscilabaentre 5,8 y 28 mg/kg de peso corporal por día. Losvalores de orientación de muestra correspondientes alaire (la principal fuente de exposición humana), que sehan calculado dividiendo esos márgenes de variación delpotencial por 5000 ó 50 000, son de 3,4–16 :g/m3 y0,34–1,6 :g/m3. Estos valores corresponden a losconsiderados por algunas autoridades como indicativosde riesgo «esencialmente insignificante» (es decir 10–5 a10–6) para un carcinógeno genotóxico; sin embargo, esde señalar que tal vez sea apropiado considerar unmargen más estrecho en vista de las indicaciones, si bienincompletas, que sugieren un mecanismo epigenético deinducción de tumores. Los valores correspondientespara la ingestión son de 1,2–5,6 :g/kg de peso corporalpor día y 0,12–0,56 :g/kg de peso corporal por día. Laexposición indirecta en el medio ambiente general,calculada sobre la base de una estimación de muestra dela exposición, es inferior a esos valores, que se consid-eran moderados en vista de los indicios, si bien incom-pletos, que sugieren que el 1,1,2,2-tetracloroetano tal vezinduzca tumores por un mecanismo de umbral.