Regulation (EC) No 1272/2008 of the European Parliament and of the CouncilDangos y teitl llawn

3.6. Carcinogenicity

3.6.1. Definition

3.6.1.1. Carcinogen means a substance or a mixture of substances which induce cancer or increase its incidence. Substances which have induced benign and malignant tumours in well performed experimental studies on animals are considered also to be presumed or suspected human carcinogens unless there is strong evidence that the mechanism of tumour formation is not relevant for humans.

3.6.2. Classification criteria for substances

3.6.2.1. For the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on strength of evidence and additional considerations (weight of evidence). In certain instances, route-specific classification may be warranted, if it can be conclusively proved that no other route of exposure exhibits the hazard.

Table 3.6.1
Hazard categories for carcinogens
a Note: See 3.6.2.2.4.
Categories	Criteria
CATEGORY 1:	Known or presumed human carcinogens A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:
Category 1A:	Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or
Category 1B:	Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.
	The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from: human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or animal experiments for which there is sufficienta evidence to demonstrate animal carcinogenicity (presumed human carcinogen).
	In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.
CATEGORY 2:	Suspected human carcinogens The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limiteda evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

3.6.2.2. Specific considerations for classification of substances as carcinogens

3.6.2.2.1. Classification as a carcinogen is made on the basis of evidence from reliable and acceptable studies and is intended to be used for substances which have an intrinsic property to cause cancer. The evaluations shall be based on all existing data, peer-reviewed published studies and additional acceptable data.

3.6.2.2.2. Classification of a substance as a carcinogen is a process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.

3.6.2.2.3. Strength of evidence involves the enumeration of tumours in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the substance and an increased incidence of tumours. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. The terms ‘sufficient’ and ‘limited’ have been used here as they have been defined by the International Agency for Research on Cancer (IARC) and read as follows:

(a)

Carcinogenicity in humans

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

• sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;

• limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.

(b)

Carcinogenicity in experimental animals

Carcinogenicity in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis. In the absence of data from conventional long-term bioassays or from assays with neoplasia as the end-point, consistently positive results in several models that address several stages in the multistage process of carcinogenesis should be considered in evaluating the degree of evidence of carcinogenicity in experimental animals. The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

• sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;

• limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.

3.6.2.2.4. Additional considerations (as part of the weight of evidence approach (see 1.1.1)). Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors need to be considered that influence the overall likelihood that a substance poses a carcinogenic hazard in humans. The full list of factors that influence this determination would be very lengthy, but some of the more important ones are considered here.

3.6.2.2.5. The factors can be viewed as either increasing or decreasing the level of concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon the amount and coherence of evidence bearing on each. Generally there is a requirement for more complete information to decrease than to increase the level of concern. Additional considerations should be used in evaluating the tumour findings and the other factors in a case-by-case manner.

3.6.2.2.6. Some important factors which may be taken into consideration, when assessing the overall level of concern are:

(a)

tumour type and background incidence;

(b)

multi-site responses;

(c)

progression of lesions to malignancy;

(d)

reduced tumour latency;

(e)

whether responses are in single or both sexes;

(f)

whether responses are in a single species or several species;

(g)

structural similarity to a substance(s) for which there is good evidence of carcinogenicity;

(h)

routes of exposure;

(i)

comparison of absorption, distribution, metabolism and excretion between test animals and humans;

(j)

the possibility of a confounding effect of excessive toxicity at test doses;

(k)

mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity.

Mutagenicity: it is recognised that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.

3.6.2.2.7. A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B or Category 2 based on tumour data from a structural analogue together with substantial support from consideration of other important factors such as formation of common significant metabolites, e.g. for benzidine congener dyes.

3.6.2.2.8. The classification shall take into consideration whether or not the substance is absorbed by a given route(s); or whether there are only local tumours at the site of administration for the tested route(s), and adequate testing by other major route(s) show lack of carcinogenicity.

3.6.2.2.9. It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic properties of the substances, as well as any available relevant information on chemical analogues, i.e. structure activity relationship, is taken into consideration when undertaking classification.

3.6.3. Classification criteria for mixtures

3.6.3.1. Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.6.3.1.1. The mixture will be classified as a carcinogen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 carcinogen and is present at or above the appropriate generic concentration limit as shown in Table 3.6.2 for Category 1A, Category 1B and Category 2 respectively.

Table 3.6.2

Generic concentration limits of ingredients of a mixture classified as carcinogen that trigger classification of the mixture

Ingredient classified as:	Generic concentration limits triggering classification of a mixture as:
	Category 1A carcinogen	Category 1B carcinogen	Category 2 carcinogen
Category 1A carcinogen	≥ 0,1 %	—	—
Category 1B carcinogen	—	≥ 0,1 %	—
Category 2 carcinogen	—	—	≥ 1,0 % [Note 1]

Note

The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (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.

3.6.3.2. Classification of mixtures when data are available for the complete mixture

3.6.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients classified as carcinogens. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual ingredients. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of carcinogenicity test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

3.6.3.3. Classification of mixtures when data are not available for the complete mixture: bridging principles

3.6.3.3.1. Where the mixture itself has not been tested to determine its carcinogenic hazard, but there are sufficient data on the individual ingredients and similar tested mixtures (subject to paragraph 3.6.3.2.1) to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.

3.6.4. Hazard Communication

3.6.4.1. Label elements shall be used in accordance with Table 3.6.3, for substances or mixtures meeting the criteria for classification in this hazard class.

Table 3.6.3
Label elements for carcinogenicity
Classification	Category 1A or Category 1B	Category 2
GHS Pictograms
Signal Word	Danger	Warning
Hazard Statement	H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)
Precautionary Statement Prevention	P201 P202 P281	P201 P202 P281
Precautionary Statement Response	P308 + P313	P308 + P313
Precautionary Statement Storage	P405	P405
Precautionary Statement Disposal	P501	P501