European Communities (Classification, Packaging and Labelling of Plant Protection Products and Biocide Products) Regulations, 2001
Statutory Instruments
Source: Statutory Instruments

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paragraphs: 1
Introduction
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paragraphs: 2
Criteria for classification, choice of symbols, indication of danger, choice of risk phrases
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paragraphs: 2.1
Explosive
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paragraphs: 2.2
Oxidising
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paragraphs: 2.3
Extremely flammable
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paragraphs: 2.4
Highly flammable
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paragraphs: 2.5
Flammable
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paragraphs: 2.6
Other physico-chemical properties
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paragraphs: CLASSIFICATION ON THE BASIS OF TOXICOLOGICAL PROPERTIES
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paragraphs: 1
Introduction
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paragraphs: 2
Criteria for classification, choice of symbols, indication of danger, choice of risk phrases
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paragraphs: 2.1
Very toxic
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paragraphs: 2.2
Toxic
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paragraphs: 2.3
Harmful
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paragraphs: 2.4
Comments regarding the use of R48
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paragraphs: 2.5
Corrosive
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paragraphs: 2.6
Irritant
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paragraphs: 2.7
Sensitisation
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paragraphs: 2.8
Other toxicological properties
4
CLASSIFICATION ON THE BASIS OF SPECIFIC EFFECTS ON HUMAN HEALTH
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paragraphs: 1
Introduction
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paragraphs: 2
Criteria for classification, indication of danger, choice of risk phrases
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paragraphs: 2.1
Carcinogenic substances
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paragraphs: 2.2
Mutagenic substances
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paragraphs: 2.3
Substances toxic to reproduction
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paragraphs: 2.4
Procedure for the classification of preparations concerning specific effects on health
5
CLASSIFICATION ON THE BASIS OF ENVIRONMENTAL EFFECTS
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paragraphs: 1
Introduction
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paragraphs: 2
Criteria for classification, indication of danger, choice of risk phrases
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paragraphs: 2.1
Aquatic environment
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paragraphs: 2.2
Non-aquatic environment
6
CHOICE OF SAFETY ADVICE PHRASES
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paragraphs: 1
Introduction
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paragraphs: 2
Safety phrases for substances and preparations
7
LABELLING
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SPECIAL CASES: Substances
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paragraphs: 1
Mobile gas cylinders
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paragraphs: 2
Gas containers intended for propane, butane or liquefied petroleum gas (LPG)
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paragraphs: 3
Metals in massive form
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paragraphs: 4
Substances classified with R65
9
SPECIAL CASES: Preparations
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paragraphs: 1
Gaseous preparations (gas mixtures)
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paragraphs: 2
Gas containers intended for preparations containing stenched propane, butane or liquefied petroleum gas (LPG)
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paragraphs: 3
Alloys, preparations containing polymers, preparations containing elastomers
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paragraphs: 4
Preparations classified with R65
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paragraphs: 5
Organic peroxides
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paragraphs: 6
Additional labelling requirements for certain preparations
1 GENERAL INTRODUCTION
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paragraphs: 1 The object of classification is to identify all the physico-chemical, toxicological and ecotoxicological properties of substances and preparations that may constitute a risk during normal handling or use. Having identified any hazardous properties the substance or preparation must then be labelled to indicate the hazard(s) in order to protect the user, the general public and the environment.
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paragraphs: 2 This Annex sets out the general principles governing the classification and labelling of substances and preparations. It is addressed to all those concerned with methods of classifying and labelling dangerous substances and preparations (manufacturers, importers, and national authorities).
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paragraphs: 3 The provisions of the Directive of 1967 and of these Regulations are intended to provide the primary means by which the general public and persons at work are given essential information concerning dangerous plant protection products and biocide products. The label draws the attention of persons handling or using such substances and preparations to the inherent danger of certain such materials. The label may also serve to draw attention to more comprehensive product information on safety and use available in other forms.
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paragraphs: 4 The label takes account of all potential hazards that are likely to be faced in the normal handling and use of dangerous substances and preparations when in the form in which they are placed on the market, but not necessarily in any different form in which they may finally be used, e.g. diluted. The most severe hazards are highlighted using symbols. Such hazards and those arising from other dangerous properties are specified using standard risk phrases. Safety phrases provide advice on necessary precautions.
In the case of substances, the information provided is completed using the name of the substance using an internationally recognised chemical nomenclature, the preferred name being the one used in the European Inventory of Existing Commercial Chemical Substances (EINECS), the European List of Notified Chemical Substances (ELINCS), the EC number and the name, address and telephone number of the person established in the Community who is responsible for placing the substance on the market.
In the case of preparations, the information provided is augmented by the:
- designation or trade name of the preparation,
- chemical name of the active substance(s) and dangerous substances present in the preparation in accordance Regulation 13, and
- name, address and telephone number of the person established in the European Union who is responsible for placing the preparation on the market.
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paragraphs: 5 Article 6 of Directive of 1967 provides that manufacturers, distributors and importers of dangerous substances that appear in EINECS but which have not yet been introduced into Annex 1 are obliged to carry out an investigation to make themselves aware of the relevant and accessible data that exist concerning the properties of such substances. On the basis of that information, they must package and provisionally label such substances in accordance with the provisions of these Regulations and the criteria specified in this Annex.
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paragraphs: 6 Data required for classification and labelling
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paragraphs: 6.1 For substances the data required for classification and labelling may be obtained:
(a) as regards substances for which the information specified in Annex VII of the Directive of 1967 is required, most of the necessary data for classification and labelling appear in the ‘base set’. This classification and labelling must be reviewed, if necessary, when further information is available (Annex VIII of the Directive of 1967, Annex II and Annex III of the Directive of 1991 and Annex II, Annex III and Annex IV of the Directive of 1998);
(b) as regards other substances (e.g. those referred to in paragraph 1.5 above), the data required for classification and labelling may, if necessary, be obtained from a number of different sources, for example the results of previous tests, information required by international rules on the transport of dangerous substances, information taken from reference works and literature or information derived from practical experience. The results of validated structure-activity relationships and expert judgement may also be taken into account where appropriate.
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paragraphs: 6.2 For preparations, the data required for classification and labelling may be obtained:
(a) if it concerns physico-chemical data, by the application of the test methods specified in Annex V, unless in the case of plant protection products other internationally recognised methods are acceptable in accordance with Annex II and Annex III of the Directive of 1991. For gaseous preparations a calculation method may be used for flammable and oxidising properties (see Chapter 9 of this Annex). For non-gaseous preparations containing organic peroxides a calculation method may be used for oxidising properties (see paragraph 2.2.2.1 of this Annex);
(b) if it concerns data on health effects:
- by the application of the test methods specified in Annex V unless in the case of plant protection products other internationally recognised methods are acceptable in accordance with Annex II and Annex III of the Directive of 1991,
- and / or by the application of the conventional method referred to in Regulation 9, details of which are provided in Annex IX, or,
- in the case of R65, by the application of the rules provided in paragraph 3.2.3,
- however, if it concerns the evaluation of the carcinogenic, mutagenic and reproductive properties, by the application of the conventional method referred to in Regulation 9, details of which are provided in Annex IX;
(c) if it concerns data on ecotoxicological properties:
(i) for aquatic toxicity only:
- by the application of the test methods specified in Annex V, subject to the conditions specified in Part C of Annex X, unless in the case of plant protection products other internationally recognised methods are acceptable in accordance with Annex II and Annex III of the Directive of 1991,
- and / or by the application of the conventional method referred to in Regulation 10, details of which are provided in Annex X.;
(ii) for the calculation of the potential for (or actual) bioaccumulation through the determination of log Pow (or BCF), or the evaluation of degradability, by application of the conventional method referred to in Regulation 10, details of which are provided in Annex X;
(iii) for dangers to the ozone layer by the application of the conventional method referred to in Regulation 10, details of which are provided in Annex X.
Note concerning the performance of animal tests
The performance of animal tests to generate experimental data is subject to the provisions of Directive 86/609/EEC regarding the protection of animals used for experimental purposes 35.
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paragraphs: 7 Application of the criteria
Classification must cover the physico-chemical, toxicological and ecotoxicological properties of substances and preparations.
Classification of substances and preparations is made on the basis of the criteria in Chapters 2 to 5 of this Annex. All types of hazard must be considered. For instance, classification in accordance with paragraph 3.2.1 does not imply that the paragraphs such as 3.2.2 or 3.2.4 can be ignored.
The choice of symbol(s) and risk phrase(s) must be made on the basis of the classification to ensure that the specific nature of the potential dangers identified in classification is expressed on the label.
Notwithstanding the criteria specified in paragraphs 2.2.3, 2.2.4 and 2.2.5, substances and preparations in the form of aerosols shall be subject to the provisions of Directive 75/324/EEC33 as amended and adapted to technical progress.
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paragraphs: 7.1. Definitions
“Substances” means chemical elements and their compounds in the natural state or obtained by any production process, including any additive necessary to preserve the stability of the product, and any impurity deriving from the production process used, but excluding any solvent which may be separated without affecting the stability of the substance or changing its composition.
A substance may be chemically very well defined (e.g. acetone) or a complex mixture of constituents of variable composition (e.g. aromatic distillates). For certain complex substances, some individual constituents have been identified.
“Preparations” means mixtures or solutions composed of two or more substances.
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paragraphs: 7.2 Application of the criteria for substances
The criteria set out in this Annex are directly applicable when the data in question have been obtained using test methods comparable with those described in Annex V. In other cases, the available data must be evaluated by comparing the test methods employed with those specified in Annex V, following which where appropriate the rules specified in this Annex for determining the appropriate classification and labelling may be applicable.
In some cases there may be doubt over the application of the relevant criteria, especially where these require the use of expert judgement. In such cases the manufacturer, distributor or importer should provisionally classify and label the substance on the basis of an assessment of the evidence by a competent person.
Without prejudice to Article 6 of the Directive of 1967, where the above procedure has been followed and there is concern over possible inconsistencies then a proposal may be submitted for the entry of the provisional classification into Annex I. The proposal should be made to one of the Member States and should be accompanied by appropriate scientific data (see also paragraph 4.1).
A similar procedure may be followed when information is identified which gives cause for concern over the accuracy of an existing entry in Annex I.
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paragraphs: 7.2.1 Classification of substances containing impurities, additives or individual constituents
Where impurities, additives or individual constituents of substances have been identified, they shall be taken into account if their concentration is greater than or equal to the limits specified:
- 0.1 % for substances classified as very toxic, toxic, carcinogenic (category 1 or 2), mutagenic (category 1 or 2) or toxic to reproduction (category 1 or 2), or dangerous for the environment (assigned the symbol “N” for the aquatic environment, dangerous for the ozone layer),
- 1% for substances classified as harmful, corrosive, irritant sensitising, carcinogenic (category 3), mutagenic (category 3), or toxic to reproduction (category 3), or dangerous for the environment (not assigned the symbol “N”, i.e. harmful to aquatic organisms, may cause long-term adverse effects),
unless lower values have been specified in Annex I.
With the exception of substances listed specifically in Annex I, classification should be carried out according to the requirements of Regulations 8, 9 and 10 and labelled according to the requirements of Regulation 13.
In the case of asbestos (650-013-00-6) this general rule does not apply until a concentration limit has been fixed in Annex I. Substances in which asbestos is present must be classified and labelled according to the principles laid down in Article 6 of the Directive of 1967.
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paragraphs: 7.3 Application of the criteria for preparations
The criteria set out in this Annex are directly applicable when the data in question have been obtained using test methods comparable with those described in Annex V. In the case of the criteria specified in Chapter 4, the conventional method referred to in Regulation 9 must be applied. In the case of the criteria specified in Chapter 5, a conventional method referred to in Regulation 10 is also applicable, except in the case of aquatic toxicity subject to the conditions specified in Part C of Annex X. For plant protection products, data generated in accordance with the methods specified in Annexes II and III to the Directive of 1991 may be used. In other cases, the available data must be evaluated by comparing the test methods employed with those indicated in Annex V and where appropriate applying the rules specified in this Annex for determining the appropriate classification and labelling.
If the health and environmental hazards are assessed by applying the conventional methods referred to in Regulations 9 and 10, details of which are provided in Annexes IX and X, the individual concentration limits to be used are those set out either:
- in Annex I, or
- in accordance with Annexes IX and X where the substance or substances do not appear in Annex I, or appear in it without concentration limits.
In the case of preparations containing mixtures of gases, classification with respect to health and environmental effects must be established using the calculation method on the basis of the individual concentration limits from Annex I or, when these limits are not in Annex I on the basis of the criteria specified in Annexes IX and X.
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paragraphs: 7.3.1 Preparations or substances described in paragraph 1.7.2.1 used as constituents of another preparation
The labelling of such preparations must be in conformity with the provisions of Regulation 13.
In certain cases, the information on the label of the preparation or substance described in paragraph 1.7.2.1 is insufficient to enable other manufacturers who wish to use it as a constituent of their own preparation(s) to carry out the classification and labelling of their preparation(s) correctly. In these cases, the person established within the Community responsible for placing the original preparation or substance described in paragraph 1.7.2.1 on the market whether it be the manufacturer, the importer or the distributor shall supply upon justified request and as soon as possible all necessary data concerning the dangerous substances present to enable correct classification and labelling of the new preparation. This data is also necessary to enable the person responsible for placing the new preparation on the market to comply with other provisions of these Regulations.
2 CLASSIFICATION ON THE BASIS OF PHYSICO-CHEMICAL PROPERTIES
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paragraphs: 1 Introduction
The test methods relating to explosive, oxidizing and flammable properties included in Annex V serve to give specific meaning to the general definitions provided in paragraph (1) of Regulation 2. Criteria follow directly from the test methods in Annex V as far as they are mentioned.
If adequate information is available to demonstrate in practice that the physico-chemical properties of substances and preparations (apart from organic peroxides) are different from those revealed by the test methods specified in Annex V, then such substances and preparations must be classified according to the hazard they present, if any, to those handling the substances and preparations or to other persons.
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paragraphs: 2 Criteria for classification, choice of symbols, indication of danger and choice of risk phrases
In the case of preparations, the criteria referred to in Regulation 8 must be taken into consideration.
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paragraphs: 2.1 Explosive
Substances and preparations shall be classified as explosive and assigned the symbol “E” and the indication of danger “explosive” in accordance with the results of the tests specified in Annex V and in so far as the substances and preparations are explosive as placed on the market. One risk phrase is obligatory, it is to be specified on the basis of the following:
R2 Risk of explosion by shock, friction, fire or other sources of ignition
- substances and preparations except those set out below
R3 Extreme risk of explosion by shock, friction, fire or other source of ignition
- substances and preparations which are particularly sensitive such as picric acid salts or PETN
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paragraphs: 2.2 Oxidizing
Substances and preparations shall be classified as oxidizing and assigned the symbol “O” and the indication of danger “oxidizing” in accordance with the results of the tests specified in Annex V. One risk phrase is obligatory, it is to be specified on the basis of the test results but subject to the following:
R7 May cause fire
- organic peroxides which have flammable properties even when not in contact with other combustible material
R8 Contact with combustible material may cause fire
- other oxidizing substances and preparations, including inorganic peroxides, which may cause fire or enhance the risk of fire when in contact with combustible material
R9 Explosive when mixed with combustible material
- other substances and preparations, including inorganic peroxides, which become explosive when mixed with combustible materials, e.g. certain chlorates
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paragraphs: 2.2.1 Remarks concerning peroxides
In relation to explosive properties, an organic peroxide or preparation thereof in the form in which it is placed on the market must be classified according to the criteria in paragraph 2.2.1 on the basis of tests carried out in accordance with the methods specified in Annex V.
In relation to oxidising properties, the methods currently included in Annex V cannot be applied to organic peroxides.
Substances that are organic peroxides and not already classified as explosive are classified as dangerous on the basis of their structure (e.g. R-0-0-H; R1-0-0-R2).
Preparations not already classified as explosive must be classified using the calculation method based on the percentage of active oxygen shown in paragraph 9.5.
Any organic peroxide or preparation thereof not already classified as explosive is classified as oxidising, if the peroxide or its formulation contains:
- more than 5% of organic peroxides, or
- more than 0.5% available oxygen from organic peroxides, and more than 5% hydrogen peroxide
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paragraphs: 2.3 Extremely flammable
Substances and preparations shall be classified as extremely flammable and assigned the symbol “F+” and the indication of danger “extremely flammable” in accordance with the results of the tests specified in Annex V. The risk phrase R12 shall be assigned in accordance with the following criteria:
R12 Extremely flammable
- liquid substances and preparations which have a flash point lower than 0°C and a boiling point (or in case of a boiling range the initial boiling point) lower than or equal to 35°C
- gaseous substances and preparations which are flammable in contact with air at ambient temperature and pressure
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paragraphs: 2.4 Highly flammable
Substances and preparations shall be classified as highly flammable and assigned the symbol “F” and the indication of danger “highly flammable” in accordance with the results of the tests specified in Annex V. Risk phrases shall be assigned in accordance with the following criteria:
R11 Highly flammable
- solid substances and preparations which may readily catch fire after brief contact with a source of ignition and which continue to burn or to be consumed after removal of the source of ignition
- liquid substances and preparations having a flash point below 21°C but which are not extremely flammable.
R15 Contact with water liberates extremely flammable gases
- substances and preparations which, in contact with water or damp air, evolve extremely flammable gases in dangerous quantities, at a minimum rate of one litre per kilogram per hour
R17 Spontaneously flammable in air
- substances and preparations which may become hot and finally catch fire in contact with air at ambient temperature without any input of energy
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paragraphs: 2.5 Flammable
Substances and preparations shall be classified as flammable in accordance with the results of the tests specified in Annex V. The risk phrase shall be assigned in accordance with the criteria mentioned below.
R10 Flammable
- liquid substances and preparations having a flash point equal to or greater than 21 °C, and less than or equal to 55 °C.
However, in practice it has been shown that a preparation having a flash point equal to or greater than 21 °C and less than or equal to 55 °C need not be classified as flammable if the preparation could not in any way support combustion, subject to there being no reason to fear risks to those handling these preparations or to other persons.
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paragraphs: 2.6 Other physico-chemical properties
Additional risk phrases shall be assigned to substances and preparations which have been classified in accordance with paragraphs 2.2.1 to 2.2.5 above, or in accordance with Chapters 3, 4 and 5 below, in accordance with the following criteria (based on experience obtained during compilation of Annex I):
R1 Explosive when dry
for explosive substances and preparations put on the market in solution or in a wetted form; e.g. nitro-cellulose with more than 12.6% nitrogen
R4 Forms very sensitive explosive metallic compounds
for substances and preparations which may form sensitive explosive metallic derivatives, e.g. picric acid, styphnic acid
R5 Heating may cause an explosion
for thermally unstable substances and preparations not classified as explosive, e.g. perchloric acid > 50%
R6 Explosive with or without contact with air
for substances and preparations which are unstable at ambient temperatures, e.g. acetylene
R7 May cause fire
for reactive substances and preparations: e.g. fluorine, sodium hydrosulphite.
R14 Reacts violently with water
for substances and preparations which react violently with water, e.g. acetyl chloride, alkali metals, titanium tetrachloride
R16 Explosive when mixed with oxidizing substances
for substances and preparations which react explosively with an oxidizing agent, e.g. red phosphorus
R18 In use, may form flammable / explosive vapour-air mixture
for preparations not in themselves classified as flammable, which contain volatile components that are flammable in air
R19 May form explosive peroxides
for substances and preparations which may form explosive peroxides during storage, e.g. diethyl ether, 1,4-dioxan
R30 Can become highly flammable in use
for preparations not in themselves classified as flammable, which may become flammable due to the loss of non-flammable volatile components
R44 Risk of explosion if heated under confinement
for substances and preparations not in themselves classified as explosive in accordance with paragraph 2.2.1 but which may nevertheless display explosive properties in practice if heated under sufficient confinement. For example, certain substances that would decompose explosively if heated in a steel drum do not show this effect if heated in less-strong containers
For other additional risk phrases see paragraph 3.2.8.
3 CLASSIFICATION ON THE BASIS OF TOXICOLOGICAL PROPERTIES
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paragraphs: 1 Introduction
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paragraphs: 1.1 Classification is concerned with both the acute and long-term effects of substances and preparations, whether resulting from a single instance of exposure or repeated or prolonged exposure.
If adequate evidence is available to demonstrate that in practice the toxic effect of substances and preparations on man is, or is likely to be, different from that suggested by the experimental results obtained in animal tests or by the application of the conventional method referred to in Regulation 9, details of which are provided in Annex IX, then such substances and preparations should be classified according to their toxicity in man. The evidence referred to includes epidemiological studies, scientifically valid case studies as specified in this Annex, and statistically backed experience such as the assessment of data from poison information units or concerning occupational diseases. However, tests on man are discouraged and should not normally be used to negate positive animal data.
Directive 86/609/EEC35 serves to protect animal used for experimental and other scientific purposes. For several endpoints there are validated in vitro test methods in Annex V and these should be used where appropriate.
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paragraphs: 1.2 The classification of substances must be made on the basis of the experimental data available in accordance with the following criteria, which take into account the magnitude of these effects:
(a) for acute toxicity (lethal and irreversible effects after a single exposure), the criteria specified in paragraphs 3.2.1 to 3.2.3 are to be used;
(b) for subacute, subchronic or chronic toxicity the criteria specified in paragraphs 3.2.2 to 3.2.4 are to be used;
(c) for corrosive and irritant effects the criteria specified in paragraphs 3.2.5 and 3.2.6 are to be used;
(d) for sensitising effects the criteria specified in paragraph 3.2.7 are to be used;
(e) for specific effects on health (carcinogenicity, mutagenicity and reproductive toxicity), the criteria specified in Chapter 4 are to be used.
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paragraphs: 1.3. For preparations, classification in relation to danger for health must be carried out:
(a) on the basis of the conventional method referred to in Regulation 9, details of which are provided in Annex IX, in the absence of experimental data. Where the conventional method is used, the classification must be based on the individual concentration limits taken from:
- either Annex I,
- or provided for in Annex IX, where the substance or substances do not appear in Annex I, or appear in it without concentration limits; or
(b) when experimental data are available, in accordance with the criteria described in paragraph 3.1.2 - however carcinogenic, mutagenic and toxic to reproduction properties referred to under 3.1.2 (e) must be evaluated using the conventional method specified in Annex IX.
Whichever method is used for the evaluation of the danger of a preparation, all the dangerous effects addressed in Annex IX must be taken into consideration.
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paragraphs: 1.4 When the classification is to be established on the basis of experimental results obtained in animal tests the results should have validity for man in that the tests reflect, in an appropriate way, the risks to man.
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paragraphs: 1.5 The acute oral toxicity of substances or preparations placed on the market may be established through use of a method permitting assessment of the LD50 value, by determining the discriminating dose (the fixed dose procedure) or by determining the range of exposure where lethality may be expected (the acute toxic class method).
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paragraphs: 1.5.1 The discriminating dose is the dose that causes evident toxicity but not mortality and must be one of the four dosage levels specified in Annex V (5, 50, 500 or 2,000 mg per kg body weight).
The concept “evident toxicity” is used to designate toxic effects, after exposure to the substance tested, which are so severe that exposure to the next highest fixed dose would probably lead to mortality.
The results of testing at a particular dose following the fixed dose method may be either:
- less than 100 % survival,
- 100 % survival, but evident toxicity,
- 100 % survival, but no evident toxicity.
The criteria in paragraphs 3.2.1, 3.2.2 and 3.2.3 only include the final test result. The 2,000 mg/kg dose should be used primarily to obtain information on the toxic effects of substances which are of low acute toxicity and which are not classified on the basis of acute toxicity.
The test method requires in some cases testing at higher or lower doses, if not already tested at the relevant dose level. Refer also to the evaluation table in test method B.1 bis of Annex V.
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paragraphs: 1.5.2 The range of exposure where lethality may be expected is derived from the observed absence or presence of substance related mortality where the acute toxic class method has been used. For initial testing one of three fixed starting doses (25, 200 or 2,000 mg/kg body weight) should be used.
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paragraphs: 2 Criteria for classification, choice of symbols, indication of danger, choice of risk phrases
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paragraphs: 2.1 Very toxic
Substances and preparations shall be classified as very toxic, and assigned the symbol “T +” and the indication of danger “very toxic” in accordance with the criteria specified below.
Risk phrases shall be assigned in accordance with the following criteria:
R28 Very toxic if swallowed
acute toxicity results:
- LD50 oral, rat [not less than or equal to] 25 mg/kg
- less than 100% survival at 5 mg/kg oral, rat using the fixed dose procedure, or
- high mortality at doses [not less than or equal to] 25 mg/kg oral, rat, using the acute toxic class method (for test result interpretation see the flow charts in Appendix 2 to test method B.1 ter of Annex V)
R27 Very toxic in contact with skin
acute toxicity results:
- LD50 dermal, rat or rabbit: [not less than or equal to] 50 mg/kg
R26 Very toxic by inhalation
acute toxicity results:
- LC50 inhalation, rat, for aerosols or particulates: [not less than or equal to] 0.25 mg/litre/4hr
- LC50 inhalation, rat, for gases and vapours: [not less than or equal to] 0.5 mg/litre/4hr.
R39 Danger of very serious irreversible effects
- strong evidence that irreversible damage other than the effects referred to in Chapter 4 is likely to be caused by a single exposure by an appropriate route, generally in the above mentioned dose range.
In order to indicate the route of administration/exposure one of the following combinations shall be used: R39/26, R39/27, R39/28, R39/26/27, R39/26/28, R39/27/28, R39/26/27/28.
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paragraphs: 2.2 Toxic
Substances and preparations shall be classified as toxic and assigned the symbol “T” and the indication of danger “toxic” in accordance with the criteria specified below. Risk phrases shall be assigned in accordance with the following criteria.
R25 Toxic if swallowed
acute toxicity results:
- LD50 oral, rat: 25 < LD50 [not less than or equal to] 200 mg/kg
- discriminating dose, oral, rat, 5 mg/kg: 100% survival but evident toxicity, or
- high mortality at doses < 25 to [not less than or equal to] 200 mg/kg oral, rat, using the acute toxic class method (for test result interpretation see the flow charts in Appendix 2 to test method B.1 ter of Annex V)
R24 Toxic in contact with skin
acute toxicity results:
- LD50 dermal, rat or rabbit: 50 < LD50 [not less than or equal to] 400 mg/kg.
R23 Toxic by inhalation
acute toxicity results:
- LC50 inhalation, rat for aerosols or particulates: 0.25 < LC50 [not less than or equal to] 1 mg/litre/4hr
- LC50 inhalation, rat, for gases and vapours: 0.5 < LC50 [not less than or equal to] 2 mg/litre/4hr
R39 Danger of very serious irreversible effects
- strong evidence that irreversible damage other than the effects referred to in Chapter 4 is likely to be caused by a single exposure by an appropriate route, generally in the above mentioned dose range
In order to indicate the route of administration/exposure one of the following combinations shall be used: R39/23, R39/24, R39/25, R39/23/24, R39/23/25, R39/24/25, R39/23/24/25.
R48 Danger of serious damage to health by prolonged exposure
- serious damage (clear functional disturbance or morphological change which has toxicological significance) is likely to be caused by repeated or prolonged exposure by an appropriate route
Substances and preparations are classified at least as Toxic when these effects are observed at levels of one order of magnitude lower (i.e. 10-fold) than those set out for R48 in paragraph 3.2.3.
In order to indicate the route of administration/exposure one of the following combinations shall be used: R48/23, R48/24, R48/25, R48/23/24, R48/23/25, R48/24/25, R48/23/24/25.
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paragraphs: 2.3 Harmful
Substances and preparations shall be classified as harmful and assigned the symbol “Xn” and the indication of danger “harmful” in accordance with the criteria specified below. Risk phrases shall be assigned in accordance with the following criteria:
R22 Harmful if swallowed
acute toxicity results:
- LD50 oral, rat: 200 < LD50 [not less than or equal to] 2,000 mg/kg
- discriminating dose, oral, rat, 50 mg/kg: 100% survival but evident toxicity
- less than 100 % survival at 500 mg/kg, rat oral by the fixed dose procedure. Refer to the evaluation table in the test method B1 (a) of Annex V, or
- high mortality at doses <200 to [not less than or equal to] 2,000 mg/kg oral, rat, using the acute toxic class method (for test result interpretation see the flow charts in Appendix 2 to test method B.1 ter of Annex V).
R21 Harmful in contact with skin
acute toxicity results:
- LD50 dermal, rat or rabbit: 400 < LD50 [not less than or equal to] 2,000 mg/kg
R20 Harmful by inhalation
acute toxicity results:
- LC50 inhalation, rat, for aerosols or particulates: 1 < LC50 [not less than or equal to] 5 mg/litre/4hr
- LC50 inhalation, rat, for gases or vapours: 2 < LC50 [not less than or equal to] 20 mg/litre/4hr.
R65 Harmful: may cause lung damage if swallowed
liquid substances and preparations presenting an aspiration hazard in humans because of their low viscosity:
(a) for substances and preparations containing aliphatic, alicyclic and aromatic hydrocarbons in a total concentration equal to or greater than 10% and having either
- a flow time of less than 30 sec in a 3 mm ISO cup according to ISO 2431 (April 1996 / July 1999 edition) relating to “Paints and varnishes - Determination of flow time by use of flow cups”, or
- a kinematic viscosity measured by a calibrated glass capillary viscometer in accordance with ISO 3104/3105 of less than 7 × 10-6 m2 / sec at 40°C (ISO 3104, 1994 edition, relating to “Petroleum products - Transparent and opaque liquids - Determination of kinematic viscosity and calculation of dynamic viscosity”: ISO 3105, 1994 edition, relating to “Glass capillary kinematic viscometers - Specifications and operating instructions”), or
- a kinematic viscosity derived from measurements of rotational viscometry in accordance with ISO 3219 of less than 7 × 10-6 m2 / sec at 40 °C (ISO 3219, 1993 edition, relating to “Plastics - Polymers / resins in the liquid state or as emulsions or dispersions - Determination of viscosity using a rotational viscometer with defined shear rate”);
Note: substances and preparations meeting these criteria need not be classified if they have a mean surface tension greater than 33mN/m at 25 °C as measured by the du Nouy tensiometer or by the test methods shown in Annex V Part A.5
(b) for substances and preparations, based on practical experience in humans.
R68 Possible risk of irreversible effects
- strong evidence that irreversible damage other than the effects referred to in Chapter 4 is likely to be caused by a single exposure by an appropriate route, generally in the above mentioned dose range
In order to indicate route of administration/exposure one of the following combinations shall be used: R68/20, R68/21, R68/22, R68/20/21, R68/20/22, R68/21/22, R68/20/21/22.
R48 Danger of serious damage to health by prolonged exposure
- serious damage (clear functional disturbance or morphological change which has toxicological significance) is likely to be caused by repeated or prolonged exposure by an appropriate route
Substances and preparations are classified at least as harmful when these effects are observed at levels of the order of.
- oral, rat [not less than or equal to] 50 mg/kg (body weight)/day,
- dermal, rat or rabbit [not less than or equal to] 100mg/kg (body weight)/day,
- inhalation, rat [not less than or equal to] 0.25 mg/1, 6h/day.
These guide values can apply directly when severe lesions have been observed in a subchronic (90-day) toxicity test. When interpreting the results of a sub-acute (28-day) toxicity test these figures should be increased approximately three fold. If a chronic (2-year) toxicity test is available it should be evaluated on a case-by-case basis. If results of studies of more than one duration are available, then those from the study of the longest duration should normally be used.
In order to indicate route of administration/exposure one of the following combinations shall be used: R48/20, R48/21, R48/22, R48/20/21, R48/20/22, R48/21/22, R48/20/21/22.
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paragraphs: 2.3.1 Comments regarding volatile substances
For certain substances with a high saturated vapour concentration evidence may be available to indicate effects that give cause for concern. Such substances may not be classified under the criteria for health effects in this Annex (paragraph 3.2.3) or not covered by the criteria in paragraph 3.2.8. However, where there is appropriate evidence that such substances may present a risk in normal handling and use then classification on a case-by-case basis in Annex I may be necessary.
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paragraphs: 2.4 Comments regarding the use of R48
Use of this risk phrase refers to the specific range of biological effects as outlined hereunder. For application of this risk phrase serious damage to health is to be considered to include death, clear functional disturbance and morphological changes which are toxicologically significant. It is particularly important when these changes are irreversible. It is also important to consider not only specific severe changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs, or severe changes in general health status.
When assessing whether there is evidence of such effects reference should be made to the following guidelines:
1 evidence indicating that R48 should be applied:
(a) substance-related deaths:
(b) (i) major functional changes in the central or peripheral nervous systems, including sight, hearing and the sense of smell, assessed by clinical observations or other appropriate methods (e.g. electrophysiology),
(ii) major functional changes in other organ systems (for example the lung);
(c) any consistent changes in clinical biochemistry, haematology or urinalysis parameters which indicate severe organ dysfunction. Haematological disturbances are considered to be particularly important if the evidence suggests that they are due to decreased bone marrow production of blood cells;
(d) severe organ damage noted on microscopic examination following autopsy.
(i) widespread or severe necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity (e.g. liver).
(ii) severe morphological changes that are potentially reversible but are clear evidence of marked organ dysfunction (e.g. severe fatty change in the liver, severe acute tubular nephrosis in the kidney, ulcerative gastritis), or
(iii) evidence of appreciable cell death in vital organs incapable of regeneration (e.g. fibrosis of the myocardium or dying back of a nerve) or in stem cell populations (e.g. aplasia or hypoplasia of the bone marrow).
The above evidence will most usually be obtained from animal experiments. When considering data derived from practical experience special attention should be given to exposure levels.
2 Evidence indicating that R48 should not be applied
The use of this risk phrase is restricted to “serious damage to health by prolonged exposure”. A number of substance-related effects may be observed in both humans and animals that would not justify the use of R48. These effects are relevant when attempting to determine a no-effect level for a chemical substance.
Examples of well documented changes which would not normally justify classification with R48, irrespective of their statistical significance, include:
(a) clinical observations or changes in bodyweight gain, food consumption or water intake, which may have some toxicological importance but which do not, by themselves, indicate “serious damage”;
(b) small changes in clinical biochemistry, haematology or urinalysis parameters which are of doubtful or minimal toxicological importance;
(c) changes in organ weights with no evidence of organ dysfunction;
(d) adaptative responses (e.g. macrophage migration in the lung, liver hypertrophy and enzyme induction, hyperplastic responses to irritants). Local effects on the skin produced by repeated dermal application of a substance which are more appropriately classified with R38 “irritating to skin”; or
(e) where a species-specific mechanism of toxicity (e.g. specific metabolic pathways) has been demonstrated.
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paragraphs: 2.5 Corrosive
Substances and preparations shall be classified as corrosive and assigned the symbol “C” and the indication of danger “Corrosive” in accordance with the following criteria:
- a substance or a preparation shall be considered corrosive if, when it is applied to healthy intact animal skin, it produces full thickness destruction of skin tissue on at least one animal during the test for skin irritation cited in Annex V or during an equivalent test,
- classification can be based on the results of a validated in vitro test such as that cited in Annex V (B.40 Skin corrosion: rat skin transcutaneous electrical resistance assay and human skin model assay).
- a substance or a preparation shall also be considered corrosive if the result can be predicted, for example from strongly acid or alkaline reactions indicated by a pH of 2 or less or 11.5 or greater. Where extreme pH is the basis for classification, alkaline / acidic reserve may also be taken into consideration (J.R. Young, M.J. How, A.P. Walker and W.M.H. Worth (1998), “Classification as corrosive or irritant to skin of preparations containing acidic or alkaline substances, without testing on animals”, Toxic. In Vitro 2(1): pp 19-26). If consideration of alkaline or acidic reserve suggests that the substance or preparation may not be corrosive then further testing should be carried out to confirm this, preferably using an appropriate validated in vitro test. Consideration of alkaline or acidic reserve should not be used alone to exonerate substances or preparations from classification as corrosive.
Risk phrases shall be assigned in accordance with the following criteria:
R35 Causes severe burns
- if, when applied to healthy intact animal skin, full thickness destruction of skin tissue occurs as a result of up to three minutes exposure, or if this result can be predicted.
R34 Causes burns
- if, when applied to healthy intact animal skin, full thickness destruction of skin tissue occurs as a result of up to four hours exposure, or if this result can be predicted
- organic hydroperoxides, except where evidence to the contrary is available.
Note: Where classification is based upon the results of a validated in vitro test, R35 or R34 should be applied in accordance with the capacity of the test method to discriminate between the suitability of the two phrases.
Where classification is based upon consideration of extreme pH alone, R35 should be applied
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paragraphs: 2.6 Irritant
Substances and preparations shall be classified as irritant and assigned the symbol “Xi” and the indication of danger “irritant” in accordance with the criteria specified hereunder.
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paragraphs: 2.6.1 Inflammation of the skin
The following risk phrase shall be assigned in accordance with the criteria specified:
R38 Irritating to skin
- substances and preparations which cause significant inflammation of the skin which persists for at least 24 hours after an exposure period of up to four hours determined on the rabbit according to the cutaneous irritation test method cited in Annex V
Inflammation of the skin is significant if:
(a) the mean value of the scores for either erythema and eschar formation or oedema formation, calculated over all the animals tested, is 2 or more, or
(b) in the case where the Annex V test has been completed using three animals, either erythema and eschar formation or oedema formation equivalent to a mean value of 2 or more calculated for each animal separately has been observed in two or more animals.
In both cases all scores at each of the reading times (24, 48 and 72 hours) for an effect should be used in calculating respective mean values.
Inflammation of the skin is also significant if it persists in at least two animals at the end of the observation time. Particular effects e.g. hyperplasia, scaling, discoloration, fissures, scabs and alopecia should be taken into account.
Relevant data may also be available from non-acute animal studies (see comments on R48). These are considered significant if the effects seen are comparable to those described above.
- substances and preparations that cause significant inflammation of the skin, based on practical observations in humans on immediate, prolonged or repeated contact
- Organic peroxides, except where evidence to the contrary is available.
Paresthesia:
Paresthesia caused in humans by skin contact with pyrethroid pesticides is not regarded as an irritant effect justifying classification as Xi; R38. The S-phrase S24 should however be applied for substances seen to cause this effect.
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paragraphs: 2.6.2 Ocular lesions
The following risk phrases shall also be assigned in accordance with the criteria specified hereunder:
R36 Irritating to eyes
- substances and preparations which, when applied to the eye of the animal, cause significant ocular lesions which occur within 72 hours after exposure and which persist for at least 24 hours
Ocular lesions are significant if the mean scores of the eye irritation test cited in Annex V have any of the following values:
- cornea opacity equal to or greater than 2 but less than 3
- iris lesion equal to or greater than 1 but not greater than 1.5
- redness of the conjunctivae equal to or greater than 2.5
- oedema of the conjunctivae (chemosis) equal to or greater than 2
or, in the case where the Annex V test has been completed using three animals if the lesions on two or more animals are equivalent to any of the above values, except that for iris lesion the value should be equal to or greater than 1 but less than 2 and for redness of the conjunctivae the value should be equal to or greater than 2.5
In both cases all scores at each of the reading times (24, 48 and 72 hours) for an effect should be used in calculating the respective mean values.
- substances or preparations which cause significant ocular lesions, based on practical experience in humans
- organic peroxides except where evidence to the contrary is available
R41 Risk of serious damage to eyes
- substances and preparations which, when applied to the eye of the animal cause severe ocular lesions which occur within 72 hours after exposure and which persist for at least 24 hours
Ocular lesions are severe if the means of the scores of the eye irritation test in Annex V have any of the values:
- cornea opacity equal to or greater than 3
- iris lesion greater than 1.5
The same shall be taken to be the case where the test has been completed using three animals if these lesions, on two or more animals, have any of the values:
- cornea opacity equal to or greater than 3
- iris lesion equal to 2
In both cases all scores at each of the reading times (24, 48 and 72 hours) for an effect should be used in calculating the respective mean values.
Ocular lesions are also severe when they are still present at the end of the observation time.
Ocular lesions are also severe if the substance or preparation causes irreversible coloration of the eyes.
- substances and preparations that cause severe ocular lesions, based on practical experience in humans
Note: When a substance or preparation is classified “corrosive” and assigned R34 or R35, the risk of severe damage to eyes is considered implicit and R41 is not included in the label.
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paragraphs: 2.6.3 Respiratory system irritation
The following risk phrase shall be assigned in accordance with the criteria specified:
R37 Irritating to respiratory system
- substances and preparations that cause serious irritation to the respiratory system based on:
- practical observation in humans.
- positive results from appropriate animal tests
Comments regarding the use of R37
In interpreting practical observations in humans, care should be taken to distinguish between effects which lead to classification with R48 (see paragraph 3.2.4) from those leading to classification with R37. Conditions normally leading to classification with R37 are reversible and usually limited to the upper airways.
Positive results from appropriate animal tests may include data obtained in a general toxicity test, including histopathological data relating to the respiratory system. Data from the measurement of experimental bradypnea may also be used to assess airway irritation.
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paragraphs: 2.7 Sensitisation
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paragraphs: 2.7.1 Sensitisation by inhalation
Substances and preparations shall be classified as sensitising and assigned the symbol “Xn”, the indication of danger “Harmful” and the risk phrase R42 in accordance with the criteria specified hereunder:
R42 May cause sensitisation by inhalation
- if there is evidence that the substance or preparation can induce specific respiratory hypersensitivity,
- where there are positive results from appropriate animal tests, or
- if the substance is an isocyanate, unless there is evidence that the substance does not cause respiratory hypersensitivity.
Comments regarding the use of R42
Human evidence
Evidence that the substance can induce specific respiratory hypersensitivity will normally be based on human experience. In this context hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis and alveolitis must also be considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms need not be demonstrated.
When considering the evidence following human exposure, it is necessary for a decision on classification to take into account in addition to the evidence from the cases:
- the size of the population exposed, and
- the extent of exposure.
The evidence referred to above could be clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence that may include:
- a chemical structure related to substances known to cause respiratory hypersensitivity;
- in vivo immunological test (e.g. skin prick test);
- in vitro immunological test (e.g. serological analysis);
- studies that may indicate other specific, but non-immunological mechanisms of action, e.g. repeated low level irritation, pharmacologically mediated effects; or
- data from a positive bronchial challenge test with the substance, conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.
Clinical history should include both medical and occupational history to determine a relationship between exposure to a specific substance or preparation and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history should also include a note of other allergic or airway disorders from childhood, and smoking history.
The results of positive bronchial challenge tests are considered to provide sufficient evidence on their own for classification. It is however recognised that in practice that many of the examinations listed above will already have been carried out.
Substances that elicit symptoms of asthma by irritation only in people with bronchial hyper-reactivity should not be assigned R42.
Animal Studies
Data from tests that may be indicative of the potential of a substance to cause sensitisation by inhalation in humans may include:
- IgE measurements (e.g. in mice), and
- specific pulmonary responses in guinea pigs.
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paragraphs: 2.7.2 Sensitisation by skin contact
Substances and preparations shall be classified as sensitising and assigned the symbol “Xi”, the indication of danger “Irritant” and the risk phrase R43 in accordance with the criteria given hereunder:
R43 May cause sensitisation by skin contact
- if practical experience shows the substance or preparation to be capable of inducing sensitisation by skin contact in a substantial number of persons,
- where there are positive results from an appropriate animal test
Comments regarding the use of R43
Human evidence
The following evidence (practical experience) is sufficient to classify a substance or preparation with R43:
- positive data from appropriate patch testing, normally in more than one dermatological clinic;
- epidemiological studies showing allergic contact dermatitis caused by the substance or preparation. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small; or
- positive data from experimental studies in man (see also paragraph 3.1.1).
The following is sufficient to classify a substance with R43 when there is supportive evidence:
- isolated episodes of allergic contact dermatitis; or
- epidemiological studies where chance, bias or confounders have not been ruled out fully with reasonable confidence.
Supportive evidence may include:
- data from animal tests performed according to existing guidelines, with a result that does not meet the criteria given in the section on animal studies but is sufficiently close to the limit to be considered significant:
- data from non-standard methods; or
- appropriate structure-activity relationships.
Animal studies
Positive results from appropriate animal tests are:
- in the case of the adjuvant type test method for skin sensitisation detailed in Annex V or in the case of other adjuvant-type test methods, a response of at least 30 % of the animals considered,
- for any other test method a response of at least 15 % of the animals is considered.
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paragraphs: 2.7.3 Immunological contact urticaria
Some substances or preparations that meet the criteria for R42 may in addition cause immunological contact urticaria. In these cases, information concerning contact urticaria should be included by the use of appropriate S-phrases, usually S24 and S36/37, and in the Safety Data Sheet.
For substances or preparations, which produce signs of immunological contact urticaria, which do not fulfil the criteria for R42, consideration should be given to classification with R43.
There is no recognised animal model available to identify substances that cause immunological contact urticaria. Therefore, classification is normally based on human evidence similar to that for skin sensitisation (R43).
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paragraphs: 2.8 Other toxicological properties
Additional risk phrases shall be assigned in accordance with the following criteria (based on experience obtained during compilation of Annex I) to substances and preparations classified by virtue of paragraphs 2.2.1 to 3.2.7 above and/or chapters 4 and 5:
R29 Contact with water liberates toxic gas
substances and preparations which in contact with water or damp air, evolve very toxic/toxic gases in potentially dangerous amounts, e.g. aluminium phosphide, phosphorus pentasulphide
R31 Contact with acids liberates toxic gas
substances and preparations which react with acids to evolve toxic gases in dangerous amounts, e.g. sodium hypochlorite, barium polysulphide. For substances used by members of the general public, the use of S50 (do not mix with ... (to be proposed by the manufacturer)) would be more suitable
R32 Contact with acids liberates very toxic gas
substances and preparations which react with acids to evolve very toxic gases in dangerous amounts; e.g. salts of hydrogen cyanide, sodium azide. For substances used by members of the general public, the use of S50 (do not mix with ... (to be proposed by the manufacturer)) would be more suitable
R33 Danger of cumulative effects
substances and preparations likely to accumulate in the human body and may cause some concern which, however, is not sufficient to justify the use of R48
For comments on use for substances of R33 see paragraph 4.2.3.3 and for preparations see paragraph 3 of Part of Annex XII
R64 May cause harm to breastfed babies
substances and preparations absorbed by women and that may interfere with lactation or that may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child
For comments on the use for substances of R64 (and in some cases R33) see paragraph 4.2.3.3 and for preparations see paragraph 4 of Part A of Annex XII.
R66 Repeated exposure may cause skin dryness or cracking
substances and preparations that may cause concern as a result of skin dryness, flaking or cracking but which do not meet the criteria for R38:
based on either:
- practical observation after normal handling and use, or
- relevant evidence concerning their predicted effects on the skin.
See also paragraphs 1.6 and 1.7.
R67 Vapours may cause drowsiness and dizziness
volatile substances and preparations containing such substances which cause clear symptoms of central nervous system depression by inhalation and which are not already classified with respect to acute inhalation toxicity (R20, R23, R26, R68/20, R39/23 or R39/26).
The following evidence may be used:
(a) data from animal studies showing clear signs of CNS depression such as narcotic effects, lethargy, lack of co-ordination (including loss of righting reflex) and ataxia either:
- at concentrations/exposure times not exceeding 20 mg/l/4h or,
- for which the ratio of the effect concentration at [not less than or equal to] 4 h to the saturated vapour concentration (SVC) at 20°C is [not less than or equal to] 1/10.
b) practical experience in humans (e.g. narcosis, drowsiness, reduced alertness, loss of reflexes, lack of co-ordination, vertigo) from well-documented reports under comparable exposure conditions to the effects specified above for animals.
See also paragraphs 1.6 and 1.7.
For other supplementary risk phrases see paragraph 2.2.6.
4 CLASSIFICATION ON THE BASIS OF SPECIFIC EFFECTS ON HUMAN HEALTH
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paragraphs: 1 Introduction
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paragraphs: 1.1 This chapter sets out the procedure to be followed for the classification of substances which may have the effects mentioned below. For preparations see paragraph 4.2.4.
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paragraphs: 1.2 If a manufacturer, distributor or importer has information available which indicates that a substance should be classified and labelled in accordance with the criteria in paragraphs 4.2.1, 4.2.2 or 4.2.3, he shall provisionally label the substance in accordance with these criteria, on the basis of the assessment of the evidence by a competent person.
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paragraphs: 1.3 The manufacturer, distributor or importer shall submit as soon as possible a document summarising all relevant information to one Member State in which the substance is placed on the market. Relevant information in this context comprises in particular all available published and unpublished information required for appropriate classification of the substance in question, on the basis of its intrinsic properties and the criteria specified in this Annex. This summary document submitted should include a bibliography containing all relevant references, including any relevant unpublished data.
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paragraphs: 1.4 Furthermore, a manufacturer, distributor or importer who has new data which are relevant to the classification and labelling of a substance in accordance with the criteria in paragraphs 4.2.1, 4.2.2 or 4.2.3, shall submit this data as soon as possible to one Member State in which the substance is placed on the market.
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paragraphs: 1.5 In order to obtain as quickly as possible a harmonised classification for the European Union by means of the procedure defined in Article 28 of the Directive of 1967, Member States which have relevant information available justifying the classification of a substance in one of these categories, whether submitted by the manufacturer or not, should forward such information together with suggestions for classification and labelling, to the European Commission as soon as possible.
The European Commission will forward to the other Member States classification and labelling proposals that it receives. Any Member State may ask the European Commission for the information it has received.
Any Member State that has good reason to believe that the suggested classification and labelling is inappropriate as far as carcinogenic, mutagenic or reproductive toxicity effects are concerned shall notify the European Commission thereof.
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paragraphs: 2 Criteria for classification, indication of danger, choice of risk phrases
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paragraphs: 2.1 Carcinogenic substances
For the purpose of classification and labelling, and having regard to the current state of knowledge, such substances are divided into three categories:
Category 1
Substances known to be carcinogenic to man.
There is sufficient evidence to establish a causal association between human exposure to a substance and the development of cancer.
Category 2
Substances that should be regarded as if they are carcinogenic to man.
There is sufficient evidence to provide a strong presumption that human exposure to a substance may result in the development of cancer, generally on the basis of:
- appropriate long-term animal studies,
- other relevant information.
Category 3
Substances that cause concern for man owing to possible carcinogenic effects but in respect of which the available information is not adequate to make a satisfactory assessment.
There is some evidence from appropriate animal studies, but this is insufficient to place the substance in Category 2.
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paragraphs: 2.1.1 The following symbols and specific risk phrases apply:
Categories 1 and 2:
T;
R45
May cause cancer
However for substances and preparations which present a carcinogenic risk only when inhaled, for example, as dust, vapour or fumes, (other routes of exposure e.g. by swallowing or in contact with skin do not present any carcinogenic risk), the following symbol and specific risk phrase should be used:
T;
R49
May cause cancer by inhalation
Category 3:
Xn;
R40
Limited evidence of a carcinogenic effect
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paragraphs: 2.1.2 Comments regarding the categorisation of carcinogenic substances
The placing of a substance into Category 1 is done on the basis of epidemiological data; placing into Categories 2 and 3 is based primarily on animal experiments.
For classification as a Category 2 carcinogen either positive results in two animal species should be available or clear positive evidence in one species, together with supporting evidence such as genotoxicity data, metabolic or biochemical studies, induction of benign tumours, structural relationship with other known carcinogens, or data from epidemiological studies suggesting an association.
Category 3 actually comprises 2 sub-categories:
(a) substances which are well investigated but for which the evidence of a tumour-inducing effect is insufficient for classification in Category 2. Additional experiments would not be expected to yield further relevant information with respect to classification;
(b) substances which are insufficiently investigated. The available data are inadequate, but they raise concern for man. This classification is provisional; further experiments are necessary before a final decision can be made.
For a distinction between Categories 2 and 3 the arguments listed below are relevant which reduce the significance of experimental tumour induction in view of possible human exposure. These arguments, especially in combination, would lead in most cases to classification in Category 3, even though tumours have been induced in animals:
- carcinogenic effects observed only at very high dose levels exceeding the “maximal tolerated dose”. The maximal tolerated dose is characterized by toxic effects which, although not yet reducing lifespan, go along with physical changes such as about 10 % retardation in weight gain;
- appearance of tumours, especially at high dose levels, only in particular organs of certain species known to be susceptible to a high spontaneous tumour formation;
- appearance of tumours, only at the site of application, in very sensitive test systems (e.g. ip or sc application of certain locally active compounds), if the particular target is not relevant to man;
- lack of genotoxicity in short-term tests in vivo and in vitro;
- existence of a secondary mechanism of action with the implication of a practical threshold above a certain dose level (e.g. hormonal effects on target organs or on mechanisms of physiological regulation, chronic stimulation of cell proliferation);
- existence of a species-specific mechanism of tumour formation (e.g. by specific metabolic pathways) irrelevant for man.
For a distinction between Category 3 and no classification the following arguments are relevant which exclude a concern for man:
- a substance should not be classified in any of the categories if the mechanism of experimental tumour formation is clearly identified, with good evidence that this process cannot be extrapolated to man;
- if the only available tumour data are liver tumours in certain sensitive strains of mice, without any other supplementary evidence, the substance may not be classified in any of the categories;
- particular attention should be paid to cases where the only available tumour data are the occurrence of neoplasms at sites and in strains where they are well known to occur spontaneously with a high incidence.
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paragraphs: 2.2 Mutagenic substances
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paragraphs: 2.2.1 For the purposes of classification and labelling, and having regard to the current state of knowledge, such substances are divided into three categories:
Category 1
Substances known to be mutagenic to man.
There is sufficient evidence to establish a causal association between human exposure to a substance and heritable genetic damage.
Category 2
Substances which should be regarded as if they are mutagenic to man.
There is sufficient evidence to provide a strong presumption that human exposure to the substance may result in the development of heritable genetic damage, generally on the basis of:
- appropriate animal studies,
- other relevant information.
Category 3
Substances that cause concern for man owing to possible mutagenic effects.
There is evidence from appropriate mutagenicity studies, but this is insufficient to place the substance in Category 2.
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paragraphs: 2.2.2 The following symbols and specific risk phrases apply:
Category 1:
T;
R46
May cause heritable genetic damage
Category 2:
T;
R46
May cause heritable genetic damage
Category 3:
Xn;
R68
Possible risk of irreversible effects
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paragraphs: 2.2.3 Comments regarding the categorisation of mutagenic substances
Definition of terms:
A mutation is a permanent change in the amount or structure of the genetic material in an organism, resulting in a change of the phenotypic characteristics of the organism. The alterations may involve a single gene, a block of genes, or a whole chromosome. Effects involving single genes may be a consequence of effects on single DNA bases (point mutations) or of large changes, including deletions, within the gene. Effects on whole chromosomes may involve structural or numerical changes. A mutation in the germ cells in sexually reproducing organisms may be transmitted to the offspring. A mutagen is an agent that gives rise to an enhanced occurrence of mutations.
It should be noted that substances are classified as mutagens with specific reference to inherited genetic damage. However, the type of results leading to classification of chemicals in Category 3: “induction of genetically relevant events in somatic cells”, is generally also regarded as an alert for possible carcinogenic activity.
Method development for mutagenicity testing is an ongoing process. For many new tests no standardised protocols and evaluation criteria are presently available. For the evaluation of mutagenicity data the quality of the test performance and the degree of validation of the test method have to be considered.
Category 1
To place a substance in Category 1, positive evidence from human mutation epidemiology studies will be needed. Examples of such substances are not known to date. It is recognised that it is extremely difficult to obtain reliable information from studies on the incidence of mutations in human populations, or on possible increases in their frequencies.
Category 2
To place a substance in Category 2, positive results are needed from assays showing (a) mutagenic effects, or (b) other cellular interactions relevant to mutagenicity, in germ cells of mammals in vivo, or (c) mutagenic effects in somatic cells of mammals in vivo in combination with clear evidence that the substance or a relevant metabolite reaches the germ cells.
With respect to placement in Category 2, at present the following methods are appropriate:
(a) in vivo germ cell mutagenicity assays:
- specific locus mutation test,
- heritable translocation test,
- dominant lethal mutation test.
These assays demonstrate the appearance of affected progeny or a defect in the developing embryo.
(b) in vivo assays showing relevant interaction with germ cells (usually DNA):
- assays for chromosomal abnormalities, as detected by cytogenetic analysis, including aneuploidy, caused by malsegregation of chromosomes,
- test for sister chromatid exchanges (SCEs),