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

3.4. Respiratory or skin sensitisation U.K.

3.4.1. Definitions and general considerations U.K.

[F1 3.4.1.1. Respiratory sensitisation means hypersensitivity of the airways occurring after inhalation of a substance or a mixture.] U.K.

Textual Amendments

F1 Substituted by Commission Regulation (EU) 2019/521 of 27 March 2019 amending, for the purposes of its adaptation to technical and scientific progress Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance).

[F1 3.4.1.2. Skin sensitisation means an allergic response occurring after skin contact with a substance or a mixture.] U.K.

3.4.1.3. For the purpose of section 3.4, sensitisation includes two phases: the first phase is induction of specialised immunological memory in an individual by exposure to an allergen. The second phase is elicitation, i.e. production of a cell-mediated or antibody-mediated allergic response by exposure of a sensitised individual to an allergen. U.K.

3.4.1.4. For respiratory sensitisation, the pattern of induction followed by elicitation phases is shared in common with skin sensitisation. For skin sensitisation, an induction phase is required in which the immune system learns to react; clinical symptoms can then arise when subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a consequence, predictive tests usually follow this pattern in which there is an induction phase, the response to which is measured by a standardised elicitation phase, typically involving a patch test. The local lymph node assay is the exception, directly measuring the induction response. Evidence of skin sensitisation in humans normally is assessed by a diagnostic patch test. U.K.

3.4.1.5. Usually, for both skin and respiratory sensitisation, lower levels are necessary for elicitation than are required for induction. Provisions for alerting sensitised individuals to the presence of a particular sensitiser in a mixture can be found [F2 in Annex II, section 2.8.]. U.K.

Textual Amendments

F2 Substituted by Commission Regulation (EU) No 286/2011 of 10 March 2011 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance).

3.4.1.6. The hazard class Respiratory or Skin Sensitisation is differentiated into: U.K.

• Respiratory Sensitisation [F3 and];

• Skin Sensitisation.

Textual Amendments

F3 Inserted by Commission Regulation (EU) No 286/2011 of 10 March 2011 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance).

[F2 3.4.2. Classification criteria for substances U.K.

3.4.2.1. Respiratory sensitisers U.K.

3.4.2.1.1. Hazard categories U.K.

3.4.2.1.1.1. Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation. U.K.

3.4.2.1.1.2. Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers. U.K.

3.4.2.1.1.3. Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals. U.K.

3.4.2.1.1.4. Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1: U.K.

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

a At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.
Category	Criteria
Category 1	Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria: (a) if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or (b) if there are positive results from an appropriate animal test.
Sub-category 1A:	Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests a . Severity of reaction may also be considered.
Sub-category 1B:	Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests a . Severity of reaction may also be considered.

3.4.2.1.2. Human evidence U.K.

3.4.2.1.2.1. Evidence that a substance can lead to 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/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated. U.K.

3.4.2.1.2.2. When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases: U.K.

(a)

the size of the population exposed;

(b)

the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.1.2.3. The evidence referred to above could be: U.K.

(a)

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i)

in vivo immunological test (e.g. skin prick test);

(ii)

in vitro immunological test (e.g. serological analysis);

(iii)

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv)

a chemical structure related to substances known to cause respiratory hypersensitivity;

(b)

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

3.4.2.1.2.4. Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance 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 shall also include a note of other allergic or airway disorders from childhood, and smoking history. U.K.

3.4.2.1.2.5. The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out. U.K.

3.4.2.1.3. Animal studies U.K.

[F1 3.4.2.1.3.1. Data from appropriate animal studies (1) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans (2) may include: U.K.

(a)

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(b)

specific pulmonary responses in guinea pigs.]

3.4.2.2. Skin sensitisers U.K.

3.4.2.2.1. Hazard categories U.K.

3.4.2.2.1.1. Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation. U.K.

3.4.2.2.1.2. Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers. U.K.

3.4.2.2.1.3. Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B. U.K.

3.4.2.2.1.4. Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2: U.K.

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category	Criteria
Category 1	Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria: (a) if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or (b) if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).
Sub-category 1A:	Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.
Sub-category 1B:	Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

3.4.2.2.2. Human evidence U.K.

3.4.2.2.2.1. Human evidence for sub-category 1A can include: U.K.

(a)

positive responses at ≤ 500 μg/cm ² (HRIPT, HMT — induction threshold);

(b)

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c)

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

3.4.2.2.2.2. Human evidence for sub-category 1B can include: U.K.

(a)

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b)

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c)

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.2.3. Animal studies U.K.

3.4.2.2.3.1. For Category 1, when an adjuvant type test method for skin sensitisation is used, a response of at least 30 % of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15 % of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. Test methods for skin sensitisation are described in the OECD Guideline 406 (the Guinea Pig Maximisation test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are well-validated and scientific justification is given. For example, the mouse ear swelling test (MEST) could be a reliable screening test to detect moderate to strong sensitisers, and could be used as a first stage in the assessment of skin sensitisation potential. U.K.

3.4.2.2.3.2. Animal test results for sub-category 1A can include data with values indicated in Table 3.4.3 U.K.

Table 3.4.3

Animal test results for sub-category 1A

Assay	Criteria
Local lymph node assay	EC3 value ≤ 2 %
Guinea pig maximisation test	≥ 30 % responding at ≤ 0,1 % intradermal induction dose or ≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose
Buehler assay	≥ 15 % responding at ≤ 0,2 % topical induction dose or ≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

3.4.2.2.3.3. Animal test results for sub-category 1B can include data with values indicated in Table 3.4.4 below: U.K.

Table 3.4.4

Animal test results for sub-category 1B

Assay	Criteria
Local lymph node assay	EC3 value > 2 %
Guinea pig maximisation test	≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or ≥ 30 % responding at > 1 % intradermal induction dose
Buehler assay	≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or ≥ 15 % responding at > 20 % topical induction dose

3.4.2.2.4. Specific considerations U.K.

3.4.2.2.4.1. For classification of a substance, evidence should include any or all of the following using a weight of evidence approach: U.K.

(a)

positive data from patch testing, normally obtained in more than one dermatology clinic;

(b)

epidemiological studies showing allergic contact dermatitis caused by the substance. 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;

(c)

positive data from appropriate animal studies;

(d)

positive data from experimental studies in man (see section 1.3.2.4.7);

(e)

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f)

severity of reaction may also be considered.

3.4.2.2.4.2. Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle. U.K.

3.4.2.2.4.3. If none of the abovementioned conditions are met, the substance need not be classified as a skin sensitiser. However, a combination of two or more indicators of skin sensitisation as listed below may alter the decision. This shall be considered on a case-by-case basis. U.K.

(a)

Isolated episodes of allergic contact dermatitis;

(b)

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c)

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d)

positive data from non-standard methods;

(e)

positive results from close structural analogues.

3.4.2.2.4.4. Immunological contact urticaria U.K.

Substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration should be given to classifying these substances also as skin sensitisers. Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitisers should also be considered for classification as skin sensitisers.

There is no recognised animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence which will be similar to that for skin sensitisation.]

3.4.3. Classification criteria for mixtures U.K.

3.4.3.1. Classification of mixtures when data are available for the complete mixture U.K.

3.4.3.1.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture can be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose used does not render the results inconclusive. U.K.

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

3.4.3.2.1. Where the mixture itself has not been tested to determine its sensitising properties, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in section 1.1.3. U.K.

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

3.4.3.3.1. The mixture shall be classified as a respiratory or skin sensitiser when at least one ingredient has been classified as a respiratory or skin sensitiser and is present at or above the appropriate generic concentration limit as shown in [F2 Table 3.4.5 ] for solid/liquid and gas respectively. U.K.

3.4.3.3.2. Some substances that are classified as sensitisers may elicit a response, when present in a mixture in quantities below the concentrations established in [F2 Table 3.4.5], in individuals who are already sensitised to the substance or mixture (see Note 1 to [F2 Table 3.4.6]). U.K.

[F2 Table 3.4.5
Generic concentration limits of components of a mixture classified as either respiratory sensitisers or skin sensitisers that trigger classification of the mixture
Component classified as:	Generic concentration limits triggering classification of a mixture as:
	Respiratory sensitiser Category 1		Skin sensitiser Category 1
	Solid/liquid	Gas	All physical states
Respiratory sensitiser Category 1	≥ 1,0 %	≥ 0,2 %
Respiratory sensitiser Sub-category 1A	≥ 0,1 %	≥ 0,1 %
Respiratory sensitiser Sub-category 1B	≥ 1,0 %	≥ 0,2 %
Skin sensitiser Category 1			≥ 1,0 %
Skin sensitiser Sub-category 1A			≥ 0,1 %
Skin sensitiser Sub-category 1B			≥ 1,0 %]

[F3 Table 3.4.6

Concentration limits for elicitation of components of a mixture

Component classified as:	Concentration limits for elicitation
	Respiratory sensitiser Category 1		Skin sensitiser Category 1
	Solid/liquid	Gas	All physical states
Respiratory sensitiser Category 1	≥ 0,1 % (Note 1)	≥ 0,1 % (Note 1)
Respiratory sensitiser Sub-category 1A	≥ 0,01 % (Note 1)	≥ 0,01 % (Note 1)
Respiratory sensitiser Sub-category 1B	≥ 0,1 % (Note 1)	≥ 0,1 % (Note 1)
Skin sensitiser Category 1			≥ 0,1 % (Note 1)
Skin sensitiser Sub-category 1A			≥ 0,01 % (Note 1)
Skin sensitiser Sub-category 1B			≥ 0,1 % (Note 1)

[F1 Note 1: U.K.

This concentration limit for elicitation is used for the application of the special labelling requirements of section 2.8 of Annex II to protect already sensitised individuals. A SDS is required for the mixture containing a component at or above this concentration. For sensitising substances with a specific concentration limit, the concentration limit for elicitation shall be set at a tenth of the specific concentration limit.] ]

3.4.4. Hazard communication U.K.

[F2 3.4.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.4.7. U.K.

[F4 Table 3.4.7
Respiratory or skin sensitisation label elements
Classification	Respiratory sensitisation	Skin sensitisation
	Category 1 and subcategories 1A and 1B	Category 1 and subcategories 1A and 1B
GHS Pictograms
Signal Word	Danger	Warning
Hazard Statement	H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled	H317: May cause an allergic skin reaction
Precautionary Statement Prevention	P261 P284	P261 P272 P280
Precautionary Statement Response	P304 + P340 P342 + P311	P302 + P352 P333 + P313 P321 P362 + P364
Precautionary Statement Storage
Precautionary Statement Disposal	P501	P501] ]

Textual Amendments

F4 Substituted by Commission Regulation (EU) No 487/2013 of 8 May 2013 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance).

(1)

[F2 [F1 At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.] ]

(2)

[F2 [F1 The mechanisms by which substances induce symptoms of asthma are not yet fully known. For preventative measures, these substances are considered respiratory sensitisers. However, if on the basis of the evidence, it can be demonstrated that these substances induce symptoms of asthma by irritation only in people with bronchial hyper-reactivity, they shall not be considered as respiratory sensitisers .] ]

Textual Amendments

F1 Substituted by Commission Regulation (EU) 2019/521 of 27 March 2019 amending, for the purposes of its adaptation to technical and scientific progress Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance).

F2 Substituted by Commission Regulation (EU) No 286/2011 of 10 March 2011 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance).