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

3.4. Respiratory or skin sensitisation

3.4.1. Definitions and general considerations

3.4.1.1. Respiratory sensitiser means a substance that will lead to hypersensitivity of the airways following inhalation of the substance.

3.4.1.2. Skin sensitiser means a substance that will lead to an allergic response following skin contact.

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.

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.

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 at section 3.4.4.

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

• Respiratory Sensitisation;

• Skin Sensitisation.

3.4.2. Classification criteria for substances

3.4.2.1. Respiratory sensitisers

Substances shall be classified as respiratory sensitisers (Category 1) in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category for respiratory sensitisers

Category	Criteria
Category 1	Substances shall be classified as respiratory sensitisers (Category 1) 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.

3.4.2.1.1 Human evidence

3.4.2.1.1.1. Evidence that a 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/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.

3.4.2.1.1.2. 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:

(a)

the size of the population exposed;

(b)

the extent of exposure.

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

3.4.2.1.1.3. The evidence referred to above could be

(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.

3.4.2.1.1.4. 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.

3.4.2.1.1.5. 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.

3.4.2.1.2. Animal studies

3.4.2.1.2.1. 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:

(i)

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

(ii)

specific pulmonary responses in guinea pigs.

3.4.2.2. Skin sensitisers

3.4.2.2.1. Substances shall be classified as skin sensitisers (Category 1) in accordance with the criteria in Table 3.4.2:

Table 3.4.2
Hazard category for skin sensitisers
Category	Criteria
Category 1	Substances shall be classified as skin sensitisers (Category 1) in accordance with the following criteria: (i) if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons, or (ii) if there are positive results from an appropriate animal test (see specific criteria in paragraph 3.4.2.2.4.1).

3.4.2.2.2. Specific considerations

3.4.2.2.2.1. For classification of a substance as a skin sensitiser, evidence shall include any or all of the following:

(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 on humans (see Article 7(3));

(e)

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

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

3.4.2.2.2.2. Positive effects seen in either humans or animals will normally justify classification. Evidence from animal studies (see section 3.4.2.2.4) 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 intrinsic properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data can not normally be used to negate positive results from animal studies.

3.4.2.2.2.3. If none of the above mentioned 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, which shall be considered on a case-by-case basis:

(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 paragraph 3.4.2.2.4.1, 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.

3.4.2.2.3. Immunological contact urticaria

3.4.2.2.3.1. Some substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration shall be given to classifying these substances also as skin sensitisers and including information concerning contact urticaria on the label or in the SDS using appropriate warning information.

3.4.2.2.3.2. For substances which produce signs of immunological contact urticaria but which do not fulfil the criteria as a respiratory sensitiser, consideration shall be given to classification as a skin sensitiser. 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.

3.4.2.2.4. Animal studies

3.4.2.2.4.1. When an adjuvant type guinea pig 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. Test methods for skin sensitisation described in Regulation (EC) No 440/2008 adopted in accordance with Article 13(3) of Regulation (EC) No 1907/2006 (‘Test Method Regulation’) shall be used, or other methods provided that they are well-validated and scientific justification is given.

3.4.3. Classification criteria for mixtures

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

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.

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

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.

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

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 Table 3.4.3 for solid/liquid and gas respectively.

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 Table 3.4.1, in individuals who are already sensitised to the substance or mixture (see Note 1 to Table 3.4.3).

Table 3.4.3

Generic concentration limits of ingredients of a mixture classified as either skin sensitisers or respiratory sensitisers that trigger classification of the mixture

Ingredient classified as:	Concentration triggering classification of a mixture as:
	Skin Sensitiser	Respiratory Sensitiser
	All physical states	Solid/Liquid	Gas
Skin Sensitiser	≥ 0,1 % (Note 1)	—	—
	≥ 1,0 % (Note 2)	—	—
Respiratory Sensitiser	—	≥ 0,1 % (Note 1)	≥ 0,1 % (Note 1)
	—	≥ 1,0 % (Note 3)	≥ 0,2 % (Note 3)

Note 1

This concentration limit is generally used for the application of the special labelling requirements of Annex II section 2.8 to protect already sensitised individuals. A SDS is required for the mixture containing an ingredient above this concentration.

Note 2

This concentration limit is used to trigger classification of a mixture as a skin sensitiser.

Note 3

This concentration limit is used to trigger classification of a mixture as a respiratory sensitiser.

3.4.4. Hazard communication

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 3.4.4.

Table 3.4.4
Respiratory or skin sensitisation label elements.
Classification	Respiratory sensitisation	Skin sensitisation
	Category 1	Category 1
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 P285	P261 P272 P280
Precautionary Statement Response	P304 + P341 P342+ P311	P302 + P352 P333 + P313 P321 P363
Precautionary Statement Storage
Precautionary Statement Disposal	P501	P501

(1)

At present recognised animal models for the testing of respiratory hypersensitivity are not available.

(2)

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 should not be considered as respiratory sensitisers.