Set of rules before REACH Regulation REACH …docenti.unicam.it/tmp/3956.pdf · REACH REGULATION REGISTRATION EVALUATION AUTHORISATION RESTRICTION ... stability and any impurity deriving

Index Set of rules before REACH Regulation REACH REGULATION REGISTRATION EVALUATION AUTHORISATION RESTRICTION Classification and Labelling Shared-Information-Down Stream Users

Regulation EC 1272/2008 for classification,

labelling and packaging of substance and mixture:

Classification

Labelling and

Packaging of substances and mixtures

•Harmonized system of criteria and application principles, came in force on 20th of

January 2009

•Replace/will replace

− Directive 67/548/CEE (hazard substances)

− Directive 1999/45/CE (hazard mixtures)

•During the transition period 2010 – 2015 will be used both systems of classification

What is CLP Regulation?

• It applies to the production and use of chemical substances and mixtures, regardless of quantity produced per year. • it is not about the rules of transportation, but ensures the compliance with them

Title 1. Art.1 Application field

Exeptions − radioactive substances and mixtures, substances and mixtures which are subject to customs supervision, non-isolated intermediates, substances and mixtures for scientific research and development, which are not placed on the market and wastes. − medicinal products, veterinary medicinal products, food and feeding stuffs, cosmetic products.

• Substance: a chemical element and its compounds

in the natural state or obtained by any manufacturing

process, including any additive necessary to preserve its

stability and any impurity deriving from the process used,

but excluding any solvent which may be separated

without affecting the stability of the substance or

changing its composition

• Mixture: mixture or solution composed of two or

more substances

HAZARD RISK

HAZARD Intrinsic property of a dangerous substance or physical state that can cause damage to humans and/or the environment RISK probability that a particular event will occur in a given period or in specified circumstances

Risk = EFFECTS X EXPOSURE

The hazard classes are divided into categories that specify the severity and are defined

in Parts 2 to 5 of Annex I

Title 1. Art.3

«Hazardous substances and mixtures and

specification of hazard classes»

Hazard type physical health environmental

Hazard classes 16 classes

of physical

hazard

9 classes

of health

hazard

2 classes

of environmental

hazard

2.1 Explosives (Unstable explosives, Divisions 1.1, 1.2, 1.3, 1.4, 1.5, e 1.6 )

2.2 Flammable gases (Categories 1 and 2)

2.3 Flammable aerosol (Categories 1 and 2)

2.4 Oxidising gases (Category 1)

2.5 Gases under pressure (compressed gases, liquefied gases, dissolved

gases or refrigerated liquefied gases)

2.6 Flammable liquids (Categories 1, 2 and 3)

2.7 Flammable solids (Categories 1 and 2)

2.8 Self-reactive substances and mixtures (Types A, B, C, D, E, F, and G)

2.9 Pyrophoric liquids (Category 1)

2.10 Pyrophoric solids (Category 1)

2.11 Self-heating substances and mixtures (Categories 1 and 2)

2.12 Substances and mixtures which in contact with water emit flammable

gases (Categories 1, 2 and 3)

2.13 Oxidising liquids (Categories 1, 2 and 3)

2.14 Oxidising solids (Categories 1, 2 and 3)

2.15 Organic peroxides (Types A, B, C, D, E, F and G)

2.16 Corrosive to metals (Category 1)

Classes/categories of PHYSICAL HAZARD

Acute toxicity, (Categories 1, 2, 3 and 4)

Skin corrosion/irritation, (Categories 1A, 1B, 1C and 2)

Serious eye damage/eye irritation, (Categories 1 and 2)

Respiratory or skin sensitisation (Category 1)

Classes/categories of HEALTH HAZARDS

Germ cell mutagenicity, (Category 1A, 1B and 2)

Carcinogenicity, (Category 1A, 1B and 2)

Reproductive toxicity (Category 1A, 1B and 2) plus 1 hazard

category for lactation effects

Specific target organ toxicity (STOT) — single exposure

(Categories 1, 2 and Category 3 that only includes narcotic effects

and respiratory tract irritation)

Specific target organ toxicity (STOT) — repeated exposure

(Categories 1 and 2) Aspiration hazard (Category 1)

Hazardous to the aquatic environment

− acute aquatic hazard Category 1

− long-term aquatic hazard

Categories 1, 2, 3, and 4

Classes/categories of ENVIRONMENTAL HAZARD

Hazardous to the ozone layer

Different system of classification

Substance X: acute oral toxicity LD50=257 mg/Kg

CAN: Toxic

USA:Toxic

Corea: Toxic

China: NON HAZARD

Japan: Toxic

India: Non Toxic

New Zeland: Hazard

Malaysia: Harmful

AUS: Harmful

GHS Hazard Toxic Category 3

Comparison between the classification systems most

relevant:

ONU Recommendations on the Transport

European Directives on substances and mixtures

U.S. and Canadian regulations on the workplace, consumer

products, biocides and plant protection

Elimination of differences with the definition of a system

to be used as a common denominator for other systems

or countries:

Global Harmonization System of Classification and Labelling of

Chemicals (GHS) published in 2003 and developed in the

United States since 1992

Principles of classification Harmonization Process

Principle “building block approach”:

allows you to exclude certain classes or hazard categories "less serious “

and preserve other not present in GHS.

The CLP takes all GHS hazard classes, but

excludes some categories not present in the

current EU regulations:

• Flammable liquids, Category 4

• Acute toxicity, category 5

• Corrosion / irritation category 3

• Aspiration Hazard Category 2

• Acute aquatic toxicity category 2 and 3

Transposition from GHS to CLP

Purpose and scope

The purpose of this Regulation is to ensure a high level of protection of

human health and the environment

• Harmonising the criteria for classification of substances and mixtures, and the rules on

labelling and packaging for hazardous substances and mixtures

• providing an obligation for:

i) manufacturers, importers and downstream users to classify substances and mixtures

placed on the market;

(ii) suppliers to label and package substances and mixture placed on the market;

(iii) manufacturers, producers of articles and importers to classify those substances not

placed on the market that are subject to registration or notification under REACH

• providing an obligation for manufacturers and importers of substances to notify the Agency

of such classifications and label elements

• establishing a list of substances with their harmonised classifications and labelling

elements

• establishing a classification and labelling inventory of substances

Title 1: General issues

The "body" of the Regulation on the general rules and principles is made

up of seven titles and seven technical annexes.

CLP Regulation stucture

Title I General issues

Title II Hazard identification, evaluation and classification

Title III

Hazard communication in the form of label

Title IV Packaging

Title V

Harmonisation of classification and labelling of substances and the classification and labelling inventory

Title VI

Competent authorities and enforcement

Title VII Common and final provision

Annex I Classification and labelling requirement for hazardous substances and mixture

Annex II Special rules for labelling and packaging of certain substances and mixture

Annex III

List of Hazard Statements and supplement hazard information and supplemental label elements

Annex IV List of Precautionary Statements

Annex V

Hazard pictograms

Annex VI

Harmonised classification and labelling for certain hazardous substances

Annex VII Translation table from classification under Directive 67/548/EEC to classification under this Regulation

CLP Regulation stucture Technical annex

• 1° ATP Regulation 790/2009/EC in force since 5th of September 2009

Applied since 1st December 2010

• 2° ATP: Regulation 286/2011/EC in force since19th of April 2011

Applied since 1st of December 2012 to substances

since 1st of June 2015 to mixtures.

• 3° ATP: Regulation 618/2012/EC in force since10th of July 2012 (updates the list of substances with

harmonised classification and labelling)

Applied since 1st of December 2013

• 4° ATP: Regulation 487/2013/EC in force since 8th of May 2013 (brings CLP into line with

the 4th revised edition of GHS)

Applied since 1st of December 2014 to substances

since 1st of June 2015 to mixtures.

• 5° ATP: Regulation 944/2013/EC in force since 2nd of October 2013 (brings CLP into line with

the 5th revised edition of GHS)

Adaptation to Technical and scientific Progresses (ATPs)

Definition based on Reach:

•article: an object which during production is given a special shape, surface or design

which determines its function to a greater degree than does its chemical composition;

•manifacturer: any natural or legal person established within the Community who

manufactures a substance within the Community;

•importer: any natural or legal person established within the Community who is

responsible for import;

•down stream user: any natural or legal person established within the Community, other

than the manufacturer or the importer, who uses a substance, either on its own or in a

mixture, in the course of his industrial or professional activities. A distributor or a

consumer is not a downstream user. A re-importer exempted pursuant to Article 2(7)(c) of

Regulation (EC) No 1907/2006 shall be regarded as a downstream user;

•distributor: any natural or legal person established within the Community, including a

retailer, who only stores and places on the market a substance, on its own or in a mixture, for third parties;

Title 1. Art.2 Definition

or

•on Self-classification applying the criteria

established by the CLP Regulation if not present in Annex VI or

properties other than those harmonized in Annex VI

Classification Substances are classified

•on the base of Harmonised Classification

reported in Annex VI of CLP Regulation,

Mixture are always classified

• on Self-classification applying the criteria

established by the CLP Regulation

• Classify, package and label according to CLP for placing on the

market

• Classify to register or notify under REACH

• Notify the C & L to ECHA for the Inventory

• Update the C & L in the case of new scientific and technical

informations

• Submit a proposal for the updating of harmonized C & L the

Competent Authorities of the Member States (MSCA), in the

event of new information,

• Keep all the details used for C & L available for at least 10 years

Art.4: What are the obligations for companies?

• epidemiological data

• cases and experience on humans

• any other scientific information adequate,

reliable and scientifically valid

Title II: Article 5 Identification and examination of available information

on substances

a) Test results for the physical-chemical properties

(if missing, new tests has to be done)

b) Results of assays for toxicological and ecotoxicological if available

(except for CMR properties and biodegradability),

or

- By analogy (bridging principles) with a mixture of similar

composition for which you have data, or

- Based on the properties of the components (that must be known) by

calculation

Title II: Article 6 Identification and examination of available information

on mixtures

•further experiments on animals, if necessary, according to Directive

86/609/EEC, shall be undertaken only if there are no alternatives that

provide adequate reliability and quality of data.

•are prohibited tests on non-human primates

•no tests on humans. The data obtained from other sources, such as

clinical trials, however, can be used for the purposes of this Regulation.

Title II Art. 7: Animal and human testing

Regulation on methods EC 440/2008 of 30th of May 2008 published on Official Journal L 142 of 31st of May 2008 and modified from Regulation 761/2009

• Where new tests for physical hazards are carried out for

the purposes of this Regulation, they shall be carried out, at

the latest from 1 January 2014, in compliance with a

relevant recognised quality system or by laboratories

complying with a relevant recognised standard.

• The new ecotoxicological or toxicological tests shall be in

conformity with Article 13, paragraph 4 of Regulation (EC)

No. 1907/2006 which provides for the implementation under the Good Laboratory Practice (GLP)

Title II Art 8(5): Generating new information for substances and mixtures

Application CLP: timeline

Harmonized classification : Methanol

Physico-chemical properties:

Flammability, explosivity, oxidising

(as obtained from laboratory tests)

Toxic effects on humans and animals

acute toxicity, irritation, corrosivity, sensitization, repeated dose toxicity,

mutagenicity, carcinogenicity, reproductive toxicity

(inferred from epidemiological studies or test on laboratory animals)

Toxic effects on environment

(deduced from physico-chemical properties and essays on

environmental indicators)

Hazard classification

on the base of

▼ Tests according to the methods of Regulation 440/2008

or in accordance with the Manual of Tests and Criteria used for

the transport sector:

www.unece.org/trans/ danger/publi/manual_e. html

▼ If data are available from tests different from that in the

previous point, a prior judgment of an expert is necessary

stating that quality and suitability for the type of hazard in

question is assured

▼ In some cases, the experience can prove properties

different from those shown by tests, which must be considered

for classifying (example: ammonium nitrate is explosive, but

test for explosivity is negative; volatile substances mixed with

halogenated hydrocarbons, but test

negative) Flammable liquids can be classified for calculation (Annex 1 2.6.4.2 e 2.6.4.3)

Classification for physical hazards

Tests according to the methods of Regulation 440/2008 or in accordance

with the OECD guidelines

How to evaluate the toxicity of a substance?

Qualitative evaluation:

the toxic action depends on the interaction of the molecular structure of the

substance with the biological mechanisms of receptor

Quantitative evaluation:

the toxic action occurs ONLY after a certain dose (in the environment or

in some organs) in proportion to the dose called “Dose-Response

Relationship”: measure of how many individuals within a relatively large

group show to suffer toxic effects at a given dose (eg. concentration per unit weight) of the substance.

Classification for hazards to human health

Toxicity_single exposure

LD50/LC50 = Median lethal dose- single dose, or

concentration that causes the death of 50% of

treated animals

Toxicity_repeated dose exposure

NOEL = NO EFFECT LEVEL , concentration or

dose at which an individual may be exposed

during the whole life without adverse effects on health

Toxicological parameters

• Ethyl alcohol 10.000

• Sodium chloride 4.000

• Ferrous sulphate1.500

• Morphine sulfate 900

• DDT 100

• Strychnine sulphate 2

• Nicotine 1

• Tetrodotoxin 0,1

• Dioxin 0,001 • Botulinum toxin 0,00001

LD50 Acute (mg/kg/body weight) for some substances

Chemicals absorbed can act both as a systemic

toxic for the whole body, or they can attack specific

organs:

Corrosion/Irritation

Sensitisation

Aspiration hazard

Specific target organ toxicity single and repeated

exposure

Cancerogenicity

Mutagenicity

Toxic for reproduction

Other effects

Health Effects: Acute oral toxicity classification criteria

When the inhalation toxicity is due to the corrosiveness you add the EU

H701: "corrosive to the respiratory tract" and you can add the pictogram of the

corrosion

Very toxic LD50 < 25 mg/Kg

Toxic 25 < LD50 < 200mg/Kg

Harmful 200 < LD50 < 2000mg/Kg

Category 1 LD50/ATE<5

mg/Kg

Category 2 5 < LD50/ATE >50

mg/Kg


mg/Kg


mg/Kg

200-300

EU

CLP

If the total concentration of the

components of unknown acute toxicity

is 10%

If the total concentration of

the components of

unknown acute toxicity is

> 10%,

Acute toxicity: Classification of mixtures from component (additivity formula)

The components devoid of information are not considered significant if

<1% even for the purposes of application of the second formula

ATE: Acute Toxicity Estimate

Sperimental value of LD50 or LC50

or

The converted value (estimate) of the acute

toxicity (Table 3.1.2 in Annex) for a test result as a range or a set of classification

Acute toxicity

ATE: Acute Toxicity Estimate

Exposure routes Toxicity range or category

ATE

Oral (mg/Kg/body

weight)

0 < Category 1 ≤ 5 5 < Category 2 ≤ 50

50 < Category 3 ≤ 300 300 < Category 4 ≤ 2000

2000 < Category 5 ≤ 5000

0,5 5

100 500

2500

Table 3.1.2 ATE conversion of the classification categories or ranges of

experimentally obtained acute toxicity

ATE (Acute Toxicity Estimate)

Example of classification of a mixture for acute toxicity

Classifed components Conc (%) Data

Component 1 8 Oral rat LD50: 200 mg/Kg

Component 2 20 Oral rat Cat. 4 (ATE=500)

Component 3 40 Oral rat LD50: 1050 mg/Kg

Result: ATE mixture = 847.5 mg/kg.

Based on data on the components the mixture is classified as a category 4

for the acute oral toxicity.

Health effects_criteria for classification Corrosion / irritation

«Causes severe skin burns and eye damage» Category 1 H314

«Causes severe burns» R35

«Causes burns» R34

«Irritating to skin» R38

Category 1 A

Category 1B

Category 1C

«Causes skin irritation. » H315

EU 67/548

CLP

Esposure (corrosion)

Observation period

Change the scores from >2 to

2.3÷ 4 on 2/3 of the treated animals

Corrosive Corrosive Irritant

Category 2

Skin corrosion/irritation

• Use existing data on humans or animals

• Avoid as much as possible in vivo testing for skin

corrosion / irritation

• Use, if possible, in vitro alternatives

• Consider the extreme value of pH (≤ 2 and ≥ 11.5) for

corrosion (to take into account the buffering capacity)

Does the alkali/acid reserve indicate that mixture may be corrosive?

Skin corrosive cat. 1A

Test in vitro available Skin corrosive cat. 1A

Test in vitro for corrosion Skin corrosive cat. 1A/1B/1C. If not possible cat. 1

Test in vitro for irritation Irritant

Non irritant

yes

no

no

positive

positive

yes

negative

negative

Mixture: effects on skin; extreme value of pH pH ≤ 2 o ≥ 11.5

Example for skin irritation

Skin Irritant Cat 2 because the average erythema is > 2.3 in 2 of three

animals as the average of 24, 48 and 72 hours

May cause sensitisation by inhalation

R42

May cause sensitisation by skin contact

R43

May cause allergy or asthma symptoms or breathing difficulties if inhaled

H334 Category 1

May cause an allergic skin reaction

H317 Category 1

EU 67/548

CLP

Effects

Sensitization by skin contact in a substantial number of persons or

positive results in appropriate tests on animals

Harmful Irritant

There is a good correspondence with Xi R42 and Xn R43

Health effects_criteria for classification respiratory or skin sensitisation

Specific hypersensitivity of the respiratory tract of man and/or positive data from animal studies

Data from human experience (*)

epidemiological studies

reported cases

The respiratory sensitisation can be induced either by

inhalation and for dermal contact

There are no validated animal tests for respiratory

sensitisation

measurements of Immunoglobulin E (IgE) and other

specific immunological parameters in mice; and specific

pulmonary responses in guinea pigs may indicate a potential sensitiser

Respiratory sensitisation

(*) When considering the human evidence, to decide on the

classification must also be taken into account: the size of the exposed population and the extent of exposure.

Updating of the criteria for skin and respiratory

sensitisation: two sub-categories 1A and 1B to

distinguish between strong and weak sensitiser when

the data permit ( level of positive responses frequency

in animal studies or human cases)

Information for protecting already sensitised

individuals who may exhibit an allergic response at low doses.

Regolation 286/2011 (2°ATP) 10th of March 2011

Test Criteria for 1A Criteria for 1B

LLNA (local lymph node assay)

EC3 ≤ 2 % EC3> 2 %

GPMT (the guinea pig maximisation test )

≥ 30 % respond to ≤ 0,1 % of the intradermal induction dose or ≥ 60 % respond to 0,1 % < conc. ≤ 1 % of the intradermal induction dose

From ≥ 30 % to < 60 % respond to 0,1% < dose ≤ 1 % of the intradermal induction dose or From ≥ 30 % respond to > 1 % of the intradermal induction dose

Test of Buehler ≥15 % respond to ≤ 0,2 % of the topic induction dose or ≥ 60 % respond to 0,2 %< dose ≤ 20 % of the topic induction dose

From ≥ 15 % to < 60 % respond to 0,2 % < dose ≤ 20 % of the topic induction dose or ≥ 15 % respond to > 20 % of the topic induction dose

Results of animal tests to distinguish between the two subcategories

Skin sensitisation CLP Criteria 67/548 Criteria

Beuhler test: 4/20 (80% subst. A) ie 20% positive 0/10 (control tests)

>15% positive ≥15% positive Dose >20%

≥15% positive

GPMT: 15/20 (1% subst. A) ie 75% positive 0/10 (control tests)

>60% positive 1A: ≥60% positive to 0,1%<conc >1%

≥30% positive

Example skin sensitisation

75% positive in GPMT justify the classification as cat.1A

Components classified as:

Limit concentrations for the classification of a mixture as:

Skin sensitiser Respiratory sensitiser

Solids/liquids Gas

Skin sensitiser 1 and 1B

≥0,1% (note 1) ≥ 1%

Respiratory Sensitiser 1 and 1B

≥0,1% (note 1) ≥ 1%

≥0,1% (note 1) ≥ 0,2%

Skin sensitiser 1A

≥0,01% (note 1) ≥ 0,11%

Respiratory sensitiser 1A

≥0,01% (note 1) ≥ 0,1%

Note 1: notation on the label and SDS required

Criteria 1272/2008 in black/ new criteria added with II ATP in violet

Mixture: Respiratory or Skin Sensitisation

Health effects_criteria for classification for Cancerogenicity/Mutagenicity/ Toxicity for

Reproduction (CMR)

Category 1 R45 (R49)/ R46/R60-61

Category 2 R45 (R49)/ R46/R60-61

Category 3 R40/R68/R62-63

Category 1 H350/H340/H360

Category 1A Category 1B

Category 2

H351/H341/H361

CLP

Substances recognized as known C/M/R for

humans

Substances to be considered C/M/R for

humans

Concern due to the possible effects C/M/R

EU 67/548

Component classified as:

Category 1 A M/C

Category 1 B M/C

Category 2 M/C

Category 1 A ≥ 0,1%

Category 1 B ≥ 0,1%

Category 2 ≥ 0,1% [Note 1]

Note:

The concentration limits in the table apply to solids and liquids (w/w

units) and to gas (v/v units)

Note 1:

If a Category 2 carcinogen is present in the mixture as an ingredient at

a concentration ≥ 0,1% a SDS shall be available for the mixture upon

request.

The transposition of the old into the new classification is

practically a direct

Mixture: Mutagenics and Cancerogenics (non additive)


Category 1 A Category 1 B

Category 2

Category 1 A ≥ 0,3%

Category 1 B ≥ 0,3%

Category 2 ≥ 3,0% [Note 1]

Additional category for effects on or via lactation

≥ 0,3% [Note 1]

Note:

The concentration limits in the table apply to solids and liquids (w/w units) and to gas

(v/v units)

Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects

on or via lactation is present in the mixture as an ingredient at a concentration at or

above 0,1 %, a SDS shall be available for the mixture upon request.

Mixture: Reproductive toxicity (non additive)

(0.5% according to 67/548)

(5% according to 67/548)

For mixtures do not change the limits for C and M but change to R

Repro cat 1, cat 2 Conc. >0,5%

Repro cat 3 Conc > 5%

Cat 1 A,B Conc>0,3%

Cat 2 Conc> 3%

Mixture CMR: Differences between 67/548 and CLP

“Danger of very serious irreversible effects”

R39

“Possible risk of irreversible effects”

R68

“Irritating to respiratory system”

R37

“Causes damage to organs”

H370 Category 1

“May cause damage to organs ”

H371 Category 2

“May cause respiratory irritation” H335

“May cause drowsiness or dizziness” H336

Category 3

CLP

Strong evidence of very serious injuries, non-lethal,

reversible or irreversible

Strong evidence of damage, non-lethal, reversible or

irreversible

Organ-specific effects

often transient

EU 67/548

Effects

Very Toxic/Toxic

Harmful Irritant

Health effects_criteria for classification for Specific target organ toxicity (STOT) —

single exposure (SE)

Human data from epidemiological studies or reported

cases

Data from observations during acute toxicity studies on

animals (clinical findings, effects on target organs and tissues)

Difficult to infer from older studies that detected only the

lethality

If the lethality is a consequence of a certain effect, this does

not imply classification as STOT-SE

Are not available in vitro tests


single exposure (SE)

Specific target organ toxicity (STOT) Single Exposure (SE)

Route of exposure

Cat. 1 Cat. 2 Cat. 3

Oral (rat) mg/Kg body weight

C ≤ 300 300 < C ≤ 2000 Transient target organ effects. This category only includes narcotic effects and respiratory tract irritation. The effects are reversible and values guide does not apply

Dermal (rat or rabbit) mg/Kg body weight

C ≤ 1000

1000 < C ≤ 2000

Inhalation (rat) Gas ppmV/4h

C ≤ 2500

2500 < C ≤ 5000

Inhalation (rat) vapour mg/l/4h

C ≤ 10

10 < C ≤ 20

Inhalation (rat) dust/mist/fume mg/l/4h

C ≤ 1,0 1,0 < C ≤ 5,0

• The hazard must contain the main organs affected by the toxic

effects (not more than three). When the organs are so many you use

the generic phrase "organ damage". The organs are not deducible

from the old classifications

• The route of exposure can be specified only if you can prove that

there is no danger for the remaining routes.

• Category 3 is assigned regardless of cat1 and 2

• If lethality is a consequence of an effect, this does not imply

classification as STOT-SE. Acute Toxicity and STOT classes are

independent, but should not be considered twice for the same effect

• If the serious effects are present at lower values, at least an order of

magnitude, in respect of the lowest guideline value (300 mg / kg, oral) apply specific limits (SCLS)

STOT SE

“Danger of serious damage to health by prolonged exposure”

R48

“Danger of serious damage to health by prolonged exposure”

R48

“Causes damage to organs through prolonged or repeated exposure”

H372 Category 1

“May cause damage to organs through prolonged or repeated exposure”

H373 Category 2

EU 67/548

CLP

Effects Adverse effects in humans based on animal data

Harmful

Severe toxicity or deemed capable of causing severe toxicity to humans

Toxic


repeated exposure (RE)

Specific target organ toxicity (STOT)

Repeated Exposure (RE)

Route of exposure

Cat. 1 Warning: HAZARD

Cat. 2 Warning: ATTENTION

Oral (rat) mg/Kg body weight

C ≤ 10 10 < C ≤ 100

Dermal (rat or rabbit) mg/Kg body weight

C ≤ 20

20 < C ≤ 200

Inhalation (rat) Gas ppmV/4h

C ≤ 50

50 < C ≤ 250

Inhalation (rat) vapour mg/l/4h

C ≤ 0,2

0,2 < C ≤ 1,0

Inhalation (rat) dust/mist/fume mg/l/4h

C ≤ 0,02 0,02 < C ≤ 0,2

C= Guide values for dose/conc. that cause effects

Human data from epidemiological studies or reported

cases

Data from repeated dose toxicity tests on animals (rat and

mouse) for 28 days, 90 days, 2 years

Has to be considered also:

Studies on other species if available

Studies of carcinogenicity, neurotoxicity, reproductive

toxicity if available

Are not available in vitro tests

is necessary to identify the major organs involved in the toxic effects , and not include side effects



We consider the significant effects and severe toxicity, ie,

morphological and functional disorders of toxicological

relevance

The effects should be relevant to humans

Guideline values are reported in studies with exposure to

90 days

To derive the guideline values at 28 days and two years

applies Haber's rule, namely that the product of dose and

exposure must remain the same.

Then for 28 days to multiply by 3 and for two years divide

to 4 Are fixed specific limits in the same way STOT SE




Generic limit for the classification of the mixture:

Cat. 1 Cat. 2

STOT Cat. 1 ≥ 10% 1%≤ C ≤ 10%

STOT Cat. 2 ≥ 10%

If a Category 2 specific target organ toxicant is present in the mixture as an ingredient at a concentration ≥ 1.0% a SDS shall be available for the mixture upon request.

Mixture:STOT SE and STOT RE (non additive)

Acute aquatic toxicity

Degradation (biotic or abiotic for organic

substances)

potential bioaccumulation

Chronic aquatic toxicity

Classification for environment– Basic elements

The parameters for estimating the aquatic toxicity (LC50)

and degradation (BOD / COD) are unchanged

Chronic toxicity is still based on the parameters of acute

toxicity in combination with the persistence parameters

The criteria for assessing the bioaccumulation change

The limit of log Kow goes from 3 to 4 and the limit of the

BCF (bioconcentration factor) from 100 to 500

(The values according to 65/548/EC were more restrictive)

Regulation CLP_ classification criteria:

What changes for the effects on the environment?

Substances hazardous to the aquatic environment : Acute toxicity

Category 1

Warning: ATTENTION Risk phrases Very toxic to aquatic life

96 h LC50 (fish) 48 h EC50 (crustacea) 72 h o 96 h (algae or other acquatic plants)

≤ 1 mg/l and/or ≤ 1 mg/l and/or ≤ 1 mg/l

Substances hazardous to the aquatic environment : Chronic toxicity

Category 1

Warning: ATTENTION Hazard statement Very toxic to aquatic life with long lasting effects

96 h LC50 (fish) 48 h EC50 (crustacea) 72 h o 96 h (algae or other acquatic plants) and the substance is not rapidly degradable and/or the

experimentally determined BCF ≥ 500 (or, if absent, the log Kow ≥ 4)

≤ 1 mg/l and/or ≤ 1 mg/l and/or ≤ 1 mg/l

Category 2

No warning Hazard statement Toxic to aquatic life with long lasting effects

96 h LC50 (fish) 48 h EC50( crustacea) 72 h o 96 h (algae or other acquatic plants) and the substance is not rapidly degradable and/or the experimentally determined BCF ≥ 500 (or, if absent, the log Kow ≥ 4)

1 < conc ≤ 10 mg/l and/or 1 < conc ≤ 10 mg/l and/or 1 < conc ≤ 10 mg/l

Category 3

No pictogram Hazard statement Harmful to aquatic life with long lasting effects

96 h LC50 (fish) 48 h EC50 (crustacea) 72 h o 96 h (algae or other acquatic plants) and the substance is not rapidly degradable and/or the experimentally determined BCF ≥ 500 (or, if absent, the log Kow ≥ 4)

10 < conc ≤ 100 mg/l and/or 10 < conc ≤ 100 mg/l and/or 10 < conc ≤ 100 mg/l

Category 4

No symbol and no warnings. Poorly soluble substances for which no acute toxicity is recorded at levels up to the water solubility, and which are not rapidly degradable and Kow ≥ 4 except if BCF <500 or NOEC> 1 mg / l, or evidence of rapid degradation in the environment

Mixture classification for enviromental hazard

Additive method (only for acute toxicity)

Ci = concentration of the component i (%

by weight)

L(E) C50i = LC50 or EC50 of the component i

n= number of components

L(E)C50m= L(E)C50 the part of the mixture

for which data assay are available

Only to be used for components when there is no harmonised classification,

but it has the data for acute toxicity. In fact, expert judgment is required to

select high quality data and the most appropriate of an entire set of data for

aquatic toxicity

When a substance classified in Category 1

acute or chronic it is necessary to indicate an

appropriate multiplying factor M

Sum of components classified as Mixture classification

Acute 1 (Chronic 1) x M 25% Acute 1 (Chronic 1)

We use the M-factor indicated for substances in

Annex VI. If not specified it must be obtained from

LC 50 value in order to apply the formulas of the summation method

Factor M

Factor M

L(E)C50 M (multiplying factor)

0,1 < L(E)C50 ≤ 1 1

0,01 < L(E)C50 ≤ 0,1 10

0,001 < L(E)C50 ≤ 0,01 100

0,0001 < L(E)C50 ≤ 0,001 1000

0,00001 < L(E)C50 ≤ 0,0001 10000

Continue in factor 10 intervals Continue in factor 10 intervals

Chronic 1 x M ≥25% Chronic 1

(M x 10 x Chronic 1) + Chronic 2 ≥25% Chronic 2

(M x 100 x Chronic 1) + (Mx10xChronic 2)+ Chronic 3 ≥25% Chronic 3

Chronic 1+ Chronic 2+ Chronic 3+ Chronic 4 ≥25% Chronic 4

This method including the calculation for

acute toxicity is used when the classifications

and M are known, but not the LC50 (as you use the ATE in the case of acute toxicity)

Mixture classification for environmental hazard on the base of the sum of components (%) classified for chronic toxicity

M also serves to establish the values of cut-

off values different from those generic.

Cut-off/M = 0,1% / M

Example:

Substance A with M= 100 The component is relevant from 0.001 %

Factor M and Cut Off

Ci = concentration of component i (% by weight)

Cj = concentration of component j (% by weight)

NOECi = NOEC( or other chronic parameters) of the component i

including the rapidly degradable components

NOECj = NOEC(or other chronic parameters) of the component j

including the rapidly degradable components

n= number of components

eqNOECm= NOEC equivalent the part of the mixture for which data

assay are available

Mixture classification for environmental hazard_Additive method for

Chronic toxicity

When a substance is classified in Category 1 acute or chronic it

is necessary to indicate an appropriate multiplication factor M

are used specific limits and M-factors listed in

Annex VI, if present, otherwise those notified to

the Classification Inventory, including those

relating to harmonized classifications without M-

factors listed in Annex VI

But if they are not listed in Annex VI should not

mean that M = 1?

Not for now, because all were not evaluated but

the new substances included and classified for the environment will have M factor.

SCL and Factor M

Acute toxicity for health hazard

Acute and chronic toxicity for environmental

hazard

Skin and eye corrosion/irritation

STOT SE cat 3 (ex R37)

STOT RE cat 3 (ex R67)

Additivity

Skin and eye sensitiser

Mutagenesis

Carcinogenesis

Reproductive toxicity

STOT SE e RE cat. 1 and 2

Risk for aspiration (ex R65)

Skin and eye corrosion/irritation in particular cases

Non-additivity

Classification by physical aspects: the results of tests

Classification for aspects of human health and the

environment :

Test results, if available

Bridging principle, if applicable

Quali quantitative composition

Component classification

If you get a mixture from one or more mixtures the

mentioned data are required for each of the component

mixtures

Only for acute toxicity on human health computing

system can be applied directly if the ATE of the

component mixtures are known, considering them as if they were substances

Summary of the minimum information necessary to classify the mixtures

QUESTION : Skin Corrosion/Irritation

N

animal

Erithema grade after….. Edema grade after…. Erithema

average

Edema

average

1h 24h 48h 72h 7gg 14gg 1h 24h 48h 72h 7gg 14g

g

1 3 3 2 1 0 1 3 2 2 0

2 2 2 1 1 0 1 1 1 0 0

3 2 2 2 1 0 0 1 3 2 2 0

How the substance is classifed?

QUESTION A mixture is composed by:

Substance

%

w/w

Classification

according to CLP

ATE /DL50(oral)

mg/Kg

Substance 1 10 Acute toxicity C.4, H302 500

Substance 2 10 Acute toxicity C.3, oral,

H301

unknown

Substance 3 2 TAcute toxicity 2, H300 50

Substance 4 78 No > 5000

How it is classified and labelled the mixture?

Parathion

Butyl benzyl

phthalate

(BBP)

Nonylphenol

ECO-TOXICOLOGICAL DATA

EC50 Daphnia magna, 48 h = 0,37 µg/L

LC50 Fish, Lepomis macrochirus, 96 h = 18 µg/L

log Kow= 3,15

BCF = 400

Non rapidly degradable

ErC50 Algae (Selenastrum capricornutum), 72 h = 0,2 mg/L

EC50 Daphnia magna, 48 h = 2,2 mg/L

log Kow= 4.7

BCF = 663 – 772

Rapidly degradable

EC50 Crustacea, 48 h = 0,0207 mg/L

LC50 Fish, Lepomis macrochirus, 96 h = 0,128 mg/l

log Kow= 4.5

BCF = 1300

Non rapidly degradable

SUBSTANCE % w/w

Parathion 0,002

Butyl benzyl phthalate (BBP)

1

Nonylphenol 0,02

How the mixture has to be classified according to CLP?

Documents

Set of rules before REACH Regulation REACH …docenti.unicam.it/tmp/3956.pdf · REACH REGULATION REGISTRATION EVALUATION AUTHORISATION RESTRICTION ... stability and any impurity deriving