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

3. PART 3: HEALTH HAZARDS

3.1. Acute toxicity

3.1.1. Definitions

3.1.1.1. Acute toxicity means those adverse effects occurring following oral or dermal administration of a single dose of a substance or a mixture, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours.

3.1.1.2. The hazard class Acute Toxicity is differentiated into:

• Acute oral toxicity;

• Acute dermal toxicity;

• Acute inhalation toxicity.

3.1.2. Criteria for classification of substances as acutely toxic

3.1.2.1. Substances can be allocated to one of four toxicity categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric criteria shown in Table 3.1.1. Acute toxicity values are expressed as (approximate) LD₅₀ (oral, dermal) or LC₅₀ (inhalation) values or as acute toxicity estimates (ATE). Explanatory notes are shown following Table 3.1.1.

Table 3.1.1
Acute toxicity hazard categories and acute toxicity estimates (ATE) defining the respective categories
a Gas concentrations are expressed in parts per million per volume (ppmV).
Exposure Route		Category 1	Category 2	Category 3	Category 4
Oral (mg/kg bodyweight) See Note (a)		ATE ≤ 5	5 < ATE ≤ 50	50 < ATE ≤ 300	300 < ATE ≤ 2 000
Dermal (mg/kg bodyweight) See Note (a)		ATE ≤ 50	50 < ATE ≤ 200	200 < ATE ≤ 1 000	1 000 < ATE ≤ 2 000
Gases (ppmVa
see:	Note (a) Note (b)	ATE ≤ 100	100 < ATE ≤ 500	500 < ATE ≤ 2 500	2 500 < ATE ≤ 20 000
Vapours (mg/l)
see:	Note (a) Note (b) Note (c)	ATE ≤ 0,5	0,5 < ATE ≤ 2,0	2,0 < ATE ≤ 10,0	10,0 < ATE ≤ 20,0
Dusts and Mists (mg/l)
see:	Note (a) Note (b)	ATE ≤ 0,05	0,05 < ATE ≤ 0,5	0,5 < ATE ≤ 1,0	1,0 < ATE ≤ 5,0

Notes to Table 3.1.1

(a)

The acute toxicity estimate (ATE) for the classification of a substance or ingredient in a mixture is derived using:

• the LD₅₀/LC₅₀ where available,

• the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or

• the appropriate conversion value from Table 3.1.2 that relates to a classification category.

(b)

Generic concentration limits for inhalation toxicity in the table are based on 4 hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1 hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

(c)

For some substances or mixtures the test atmosphere will not just be a vapour but will consist of a mixture of liquid and vapour phases. For other substances or mixtures the test atmosphere may consist of a vapour which is near the gaseous phase. In these latter cases, classification shall be based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2 500 ppmV), Category 4 (20 000 ppmV).

The terms ‘dust’, ‘mist’ and ‘vapour’ are defined as follows:

• Dust: solid particles of a substance or mixture suspended in a gas (usually air);

• Mist: liquid droplets of a substance or mixture suspended in a gas (usually air);

• Vapour: the gaseous form of a substance or mixture released from its liquid or solid state.

Dust is generally formed by mechanical processes. Mist is generally formed by condensation of supersaturated vapours or by physical shearing of liquids. Dusts and mists generally have sizes ranging from less than 1 to about 100 μm.

3.1.2.2. Specific considerations for classification of substances as acutely toxic

3.1.2.2.1. The preferred test species for evaluation of acute toxicity by the oral and inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal toxicity. When experimental data for acute toxicity are available in several animal species, scientific judgement shall be used in selecting the most appropriate LD₅₀ value from among valid, well-performed tests.

3.1.2.3. Specific considerations for classification of substances as acutely toxic by the inhalation route

3.1.2.3.1. Units for inhalation toxicity are a function of the form of the inhaled material. Values for dusts and mists are expressed in mg/l. Values for gases are expressed in ppmV. Acknowledging the difficulties in testing vapours, some of which consist of mixtures of liquid and vapour phases, the table provides values in units of mg/l. However, for those vapours which are near the gaseous phase, classification shall be based on ppmV.

3.1.2.3.2. Of particular importance in classifying for inhalation toxicity is the use of well articulated values in the high toxicity categories for dusts and mists. Inhaled particles between 1 and 4 microns mean mass aerodynamic diameter (MMAD) will deposit in all regions of the rat respiratory tract. This particle size range corresponds to a maximum dose of about 2 mg/l. In order to achieve applicability of animal experiments to human exposure, dusts and mists would ideally be tested in this range in rats.

3.1.2.3.3. In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity was corrosivity, the substance or mixture shall also be labelled as ‘corrosive to the respiratory tract’ (see note 1 in 3.1.4.1). Corrosion of the respiratory tract is defined by destruction of the respiratory tract tissue after a single, limited period of exposure analogous to skin corrosion; this includes destruction of the mucosa. The corrosivity evaluation can be based on expert judgment using such evidence as: human and animal experience, existing (in vitro) data, pH values, information from similar substances or any other pertinent data.

3.1.3. Criteria for classification of mixtures as acutely toxic

3.1.3.1. The criteria for classification of substances for acute toxicity as outlined in section 3.1.2 are based on lethal dose data (tested or derived). For mixtures, it is necessary to obtain or derive information that allows the criteria to be applied to the mixture for the purpose of classification. The approach to classification for acute toxicity is tiered, and is dependent upon the amount of information available for the mixture itself and for its ingredients. The flow chart of Figure 3.1.1 outlines the process to be followed.

3.1.3.2. For acute toxicity each route of exposure shall be considered for the classification of mixtures, but only one route of exposure is needed as long as this route is followed (estimated or tested) for all ingredients. If the acute toxicity is determined for more than one route of exposure, the more severe hazard category will be used for classification. All available information shall be considered and all relevant routes of exposure shall be identified for hazard communication.

3.1.3.3. In order to make use of all available data for purposes of classifying the hazards of the mixtures, certain assumptions have been made and are applied where appropriate in the tiered approach:

(a)

the ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a reason to suspect that an ingredient present at a concentration of less than 1 % is still relevant for classifying the mixture for acute toxicity (see Table 1.1).

(b)

where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture may be used, when calculating the classification of the new mixture using the formulas in section 3.1.3.6.1 and paragraph 3.1.3.6.2.3.

Figure 3.1.1

Tiered approach to classification of mixtures for acute toxicity

3.1.3.4. Classification of mixtures where acute toxicity data are available for the complete mixture

3.1.3.4.1. Where the mixture itself has been tested to determine its acute toxicity, it shall be classified according to the same criteria as those used for substances, presented in Table 3.1.1. If test data for the mixture are not available, the procedures presented under sections 3.1.3.5 and 3.1.3.6 shall be followed.

3.1.3.5. Classification of mixtures where acute toxicity data are available for the complete mixture: bridging principles

3.1.3.5.1. Where the mixture itself has not been tested to determine its acute toxicity, 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.

3.1.3.5.2. If a mixture is diluted with water or other totally non-toxic material, the toxicity of the mixture can be calculated from test data on the undiluted mixture.

3.1.3.6. Classification of mixtures based on ingredients of the mixture (Additivity formula)

3.1.3.6.1. Data available for all ingredients

In order to ensure that classification of the mixture is accurate, and that the calculation need only be performed once for all systems, sectors, and categories, the acute toxicity estimate (ATE) of ingredients shall be considered as follows:

(a)

include ingredients with a known acute toxicity, which fall into any of the acute toxicity categories shown in Table 3.1.1;

(b)

ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);

(c)

ignore ingredients if the oral limit test does not show acute toxicity at 2 000 mg/kg bodyweight.

Ingredients that fall within the scope of this paragraph are considered to be ingredients with a known acute toxicity estimate (ATE).

The ATE of the mixture is determined by calculation from the ATE values for all relevant ingredients according to the following formula for Oral, Dermal or Inhalation Toxicity:

where:

C_i

=

concentration of ingredient i ( % w/w or % v/v)

i

=

the individual ingredient from 1 to n

n

=

the number of ingredients

ATE_i

=

Acute Toxicity Estimate of ingredient i.

3.1.3.6.2. Classification of mixtures when data are not available for all components

3.1.3.6.2.1. Where an ATE is not available for an individual ingredient of the mixture, but available information, such as that listed below, can provide a derived conversion value such as those laid out in Table 3.1.2, the formula in section 3.1.3.6.1 shall be applied.

This includes evaluation of:

(a)

extrapolation between oral, dermal and inhalation acute toxicity estimates(1). Such an evaluation could require appropriate pharmacodynamic and pharmacokinetic data;

(b)

evidence from human exposure that indicates toxic effects but does not provide lethal dose data;

(c)

evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or

(d)

data from closely analogous substances using structure/activity relationships.

This approach generally requires substantial supplemental technical information, and a highly trained and experienced expert (expert judgement, see section 1.1.1), to reliably estimate acute toxicity. If such information is not available, proceed to paragraph 3.1.3.6.2.3.

3.1.3.6.2.2. In the event that an ingredient without any useable information at all is used in a mixture at a concentration of 1 % or greater, it is concluded that the mixture cannot be attributed a definitive acute toxicity estimate. In this situation the mixture shall be classified based on the known ingredients only, with the additional statement that x percent of the mixture consists of ingredient(s) of unknown toxicity.

3.1.3.6.2.3. If the total concentration of the ingredient(s) with unknown acute toxicity is ≤ 10 % then the formula presented in section 3.1.3.6.1 shall be used. If the total concentration of the ingredient(s) with unknown toxicity is > 10 %, the formula presented in section 3.1.3.6.1 shall be corrected to adjust for the total percentage of the unknown ingredient(s) as follows:

Table 3.1.2

Conversion from experimentally obtained acute toxicity range values (or acute toxicity hazard categories) to acute toxicity point estimates for classification for the respective routes of exposure

Exposure routes	Classification Category or experimentally obtained acute toxicity range estimate	Converted acute toxicity point estimate(see Note 1)
Oral (mg/kg bodyweight)	0 < Category 1 ≤ 5 5 < Category 2 ≤ 50 50 < Category 3 ≤ 300 300 < Category 4 ≤ 2 000	0,5 5 100 500
Dermal (mg/kg bodyweight)	0 < Category 1 ≤ 50 50 < Category 2 ≤ 200 200 < Category 3 ≤ 1 000 1 000 < Category 4 ≤ 2 000	5 50 300 1 100
Gases (ppmV)	0 < Category 1 ≤ 100 100 < Category 2 ≤ 500 500 < Category 3 ≤ 2 500 2 500 < Category 4 ≤ 20 000	10 100 700 4 500
Vapours (mg/l)	0 < Category 1 ≤ 0,5 0,5 < Category 2 ≤ 2,0 2,0 < Category 3 ≤ 10,0 10,0 < Category 4 ≤ 20,0	0,05 0,5 3 11
Dust/mist (mg/l)	0< Category 1 ≤ 0,05 0,05 < Category 2 ≤ 0,5 0,5 < Category 3 ≤ 1,0 1,0 < Category 4 ≤ 5,0	0,005 0,05 0,5 1,5

Note 1

These values are designed to be used in the calculation of the ATE for classification of a mixture based on its components and do not represent test results.

3.1.4. Hazard Communication

3.1.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.1.3.

Table 3.1.3
Acute toxicity label elements
Classification	Category 1	Category 2	Category 3	Category 4
GHS Pictograms
Signal Word	Danger	Danger	Danger	Warning
Hazard Statement: Oral	H300: Fatal if swallowed	H300: Fatal if swallowed	H301: Toxic if swallowed	H302: Harmful if swallowed
Dermal	H310:Fatal in contact with skin	H310:Fatal in contact with skin	H311: Toxic in contact with skin	H312: Harmful in contact with skin
Inhalation (see Note 1)	H330:Fatal if inhaled	H330: Fatal if inhaled	H331: Toxic if inhaled	H332: Harmful if inhaled
Precautionary Statement Prevention (oral)	P264 P270	P264 P270	P264 P270	P264 P270
Precautionary Statement Response (oral)	P301 + P310 P321 P330	P301 + P310 P321 P330	P301 + P310 P321 P330	P301 + P312 P330
Precautionary Statement Storage (oral)	P405	P405	P405
Precautionary Statement Disposal (oral)	P501	P501	P501	P501
Precautionary Statement Prevention (dermal)	P262 P264 P270 P280	P262 P264 P270 P280	P280	P280
Precautionary Statement Response (dermal)	P302 + P350 P310 P322 P361 P363	P302 + P350 P310 P322 P361 P363	P302 + P352 P312 P322 P361 P363	P302 + P352 P312 P322 P363
Precautionary Statement Storage (dermal)	P405	P405	P405
Precautionary Statement Disposal (dermal)	P501	P501	P501	P501
Precautionary Statement Prevention (inhalation)	P260 P271 P284	P260 P271 P284	P261 P271	P261 P271
Precautionary Statement Response (inhalation)	P304 + P340 P310 P320	P304 + P340 P310 P320	P304 + P340 P311 P321	P304 + P340 P312
Precautionary Statement Storage (inhalation)	P403 + P233 P405	P403 + P233 P405	P403 + P233 P405
Precautionary Statement Disposal (inhalation)	P501	P501	P501

Note 1

In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity is corrosivity, the substance or mixture shall also be labelled as EUH071: ‘corrosive to the respiratory tract’ — see advice at 3.1.2.3.3. In addition to an appropriate acute toxicity pictogram, a corrosivity pictogram (used for skin and eye corrosivity) may be added together with the statement ‘corrosive to the respiratory tract’.

Note 2

In the event that an ingredient without any useable information at all is used in a mixture at a concentration of 1 % or greater, the mixture shall be labelled with the additional statement that ‘x percent of the mixture consists of ingredient(s) of unknown toxicity’ — see advice at 3.1.3.6.2.2.

3.2. Skin corrosion/irritation

3.2.1. Definitions

3.2.1.1. Skin Corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis, following the application of a test substance for up to 4 hours. Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at 14 days, by discolouration due to blanching of the skin, complete areas of alopecia, and scars. Histopathology shall be considered to evaluate questionable lesions.

Skin Irritation means the production of reversible damage to the skin following the application of a test substance for up to 4 hours.

3.2.2. Classification criteria for substances

3.2.2.1. Several factors need to be considered in determining the corrosion and irritation potential of substances before testing is undertaken. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes. Existing human experience and animal data from single or repeated exposure shall be the first line of analysis, as they give information directly relevant to effects on the skin. In vitro alternatives that have been validated and accepted may also be used to help make classification decisions (see Article 5). In some cases enough information may be available from structurally related compounds to make classification decisions.

3.2.2.2. Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when buffering capacity is known, although the correlation is not perfect. Generally, such substances are expected to produce significant effects on the skin. If consideration of alkali/acid reserve suggests the substance may not be corrosive despite the low or high pH value, then further testing shall be carried out to confirm this, preferably by use of an appropriate validated in vitro test.

3.2.2.3. If a substance is highly toxic by the dermal route, a skin irritation/corrosion study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin irritation/corrosion in acute toxicity studies and are observed up through the limit dose, additional testing is not needed, provided that the dilutions used and species tested are equivalent.

3.2.2.4. All the above information that is available on a substance shall be used in determining the need for in vivo skin irritation testing.

Although information might be gained from the evaluation of single parameters within a tier (see paragraph 3.2.2.5), e.g. caustic alkalis with extreme pH shall be considered as skin corrosives, there is merit in considering the totality of existing information and making an overall weight of evidence determination. This is especially true when there is information available on some but not all parameters. Generally, primary emphasis shall be placed upon existing human experience and data, followed by animal experience and testing data, followed by other sources of information, but case-by-case determinations are necessary.

3.2.2.5. A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that all elements may not be relevant in certain cases.

3.2.2.6. Corrosion

3.2.2.6.1. On the basis of the results of animal testing a substance is classified as corrosive, as shown in Table 3.2.1. A corrosive substance is a substance that produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least 1 tested animal after exposure up to a 4 hour duration. Corrosive reactions are typified by ulcers, bleeding, bloody scabs and, by the end of observation at 14 days, by discoloration due to blanching of the skin, complete areas of alopecia and scars. Histopathology shall be considered to discern questionable lesions.

3.2.2.6.2. Three subcategories are provided within the corrosive category: subcategory 1A — where responses are noted following up to 3 minutes exposure and up to 1 hour observation; subcategory 1B — where responses are described following exposure between 3 minutes and 1 hour and observations up to 14 days; and subcategory 1C — where responses occur after exposures between 1 hour and 4 hours and observations up to 14 days.

3.2.2.6.3. The use of human data is discussed in paragraphs 3.2.2.1 and 3.2.2.4 and also in paragraphs 1.1.1.3, 1.1.1.4 and.1.1.1.5.

Table 3.2.1
Skin Corrosive category and subcategories
		Corrosive in > 1 of 3 animals
	Corrosive subcategories	Exposure	Observation
Category 1: Corrosive	1A	≤ 3 minutes	≤ 1 hour
	1B	> 3 minutes - ≤ 1 hour	≤ 14 days
	1C	> 1 hour - ≤ 4 hours	≤ 14 days

3.2.2.7. Irritation

3.2.2.7.1. Using the results of animal testing a single irritant category (Category 2) is presented in Table 3.2.2. The use of human data is discussed in paragraphs 3.2.2.1 and 3.2.2.4 and also in paragraphs 1.1.1.3, 1.1.1.4 and.1.1.1.5. The major criterion for the irritant category is that at least 2 of 3 tested animals have a mean score of ≥ 2,3 - ≤ 4,0.

Table 3.2.2
Skin irritation category
Category	Criteria
Category 2: Irritant	(1) Mean value of ≥ 2,3 - ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or (2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or (3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.

3.2.2.8. Comments on responses obtained in skin irritation tests in animals

3.2.2.8.1. Animal irritant responses within a test can be quite variable, as they are with corrosion. The major criterion for classification of a substance as irritant to skin, as shown in paragraph 3.2.2.7.1, is the mean value of the scores for either erythema/eschar or oedema calculated in at least 2 of 3 tested animals. A separate irritant criterion accommodates cases when there is a significant irritant response but less than the mean score criterion for a positive test. For example, a test material might be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score throughout the study, including lesions persisting at the end of an observation period of normally 14 days. Other responses could also fulfil this criterion. However, it should be ascertained that the responses are the result of chemical exposure.

3.2.2.8.2. Reversibility of skin lesions is another consideration in evaluating irritant responses. When inflammation persists to the end of the observation period in 2 or more test animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a material shall be considered to be an irritant.

3.2.3. Classification criteria for mixtures

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

3.2.3.1.1. The mixture will be classified using the criteria for substances, and taking into account the testing and evaluation strategies to develop data for these hazard classes.

3.2.3.1.2. Unlike other hazard classes, there are alternative tests available for skin corrosivity of certain types of substances and mixtures that can give an accurate result for classification purposes, as well as being simple and relatively inexpensive to perform. When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence strategy as included in the criteria for classification of substances for skin corrosion and irritation (paragraph 3.2.2.5), to help ensure an accurate classification as well as avoid unnecessary animal testing. A mixture is considered corrosive to skin (Skin Corrosive Category 1) if it has a pH of 2 or less or a pH of 11,5 or greater. If consideration of alkali/acid reserve suggests the substance or mixture may not be corrosive despite the low or high pH value, then further testing shall be carried out to confirm this, preferably by use of an appropriate validated in vitro test.

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

3.2.3.2.1. Where the mixture itself has not been tested to determine its skin irritation/corrosion hazards, 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.

3.2.3.3. Classification of mixtures when data are available for all components or only for some components of the mixture

3.2.3.3.1. In order to make use of all available data for purposes of classifying the skin irritation/corrosion hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

Assumption: the ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a presumption (e.g., in the case of corrosive ingredients) that an ingredient present at a concentration of less than 1 % can still be relevant for classifying the mixture for skin irritation/corrosion.

3.2.3.3.2. In general, the approach to classification of mixtures as irritant or corrosive to skin when data are available on the components, but not on the mixture as a whole, is based on the theory of additivity, such that each corrosive or irritant component contributes to the overall irritant or corrosive properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for corrosive components when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as an irritant. The mixture is classified as corrosive or irritant when the sum of the concentrations of such components exceeds a concentration limit.

3.2.3.3.3. Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be an irritant or a corrosive to the skin.

3.2.3.3.4.1. Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in paragraphs 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many of such substances are corrosive or irritant at concentrations < 1 %.

3.2.3.3.4.2. For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see paragraph 3.2.3.1.2) since pH is a better indicator of corrosion than the concentration limits of Table 3.2.3.

3.2.3.3.4.3. A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosive Category 1A, 1B or 1C if it contains ≥ 1 % of an ingredient classified in Category 1A, 1B or 1C respectively or as Category 2 when it contains ≥ 3 % of an irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

3.2.3.3.5. On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence strategy shall be applied, as described in paragraph 3.2.2.5.

3.2.3.3.6. If there are data showing that (an) ingredient(s) is/are corrosive or irritant at a concentration of < 1 % (corrosive) or < 3 % (irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified for skin corrosive/irritant hazard (Category 1 or 2) that trigger classification of the mixture as corrosive/irritant to skin

Sum of ingredients classified as:	Concentration triggering classification of a mixture as:
	Skin Corrosive	Skin Irritant
	Category 1(see note below)	Category 2
Skin Corrosive Categories 1A, 1B, 1C	≥ 5 %	≥ 1 % but < 5 %
Skin irritant Category 2		≥ 10 %
(10 × Skin Corrosive Category 1A, 1B, 1C) + Skin irritant Category 2		≥ 10 %

Note

The sum of all ingredients of a mixture classified as Skin Corrosive Category 1A, 1B or 1C respectively, shall each be ≥ 5 % respectively in order to classify the mixture as either Skin Corrosive Category 1A, 1B or 1C. If the sum of the Skin Corrosive Category 1A ingredients is < 5 % but the sum of Category 1A+1B ingredients is ≥ 5 %, the mixture shall be classified as Skin Corrosive Category 1B. Similarly, if the sum of Skin Corrosive Category 1A+1B ingredients is < 5 % but the sum of Category 1A+1B+1C ingredients is ≥ 5 % the mixture shall be classified as Skin Corrosive Category 1C.

Table 3.2.4

Generic concentration limits of ingredients of a mixture for which the additivity approach does not apply, that trigger classification of the mixture as corrosive/irritant to skin

Ingredient:	Concentration:	Mixture classified as: Skin
Acid with pH ≤ 2	≥ 1 %	Category 1
Base with pH ≥ 11,5	≥ 1 %	Category 1
Other corrosive (Categories 1A, 1B, 1C) ingredients for which additivity does not apply	≥ 1 %	Category 1
Other irritant (Category 2) ingredients for which additivity does not apply, including acids and bases	≥ 3 %	Category 2

3.2.4. Hazard Communication

3.2.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5
Label elements for skin corrosion/irritation
Classification	Category 1 A/1 B/1 C	Category 2
GHS Pictograms
Signal Word	Danger	Warning
Hazard Statement	H314: Causes severe skin burns and eye damage	H315: Causes skin irritation
Precautionary Statement Prevention	P260 P264 P280	P264 P280
Precautionary Statement Response	P301 + P330 + P331 P303 + P361 + P353 P363 P304 + P340 P310 P321 P305 + P351 + P338	P302 + P352 P321 P332 + P313 P362
Precautionary Statement Storage	P405
Precautionary Statement Disposal	P501

3.3. Serious eye damage/eye irritation

3.3.1. Definitions

3.3.1.1. Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, following application of a test substance to the anterior surface of the eye, which is not fully reversible within 21 days of application.

Eye irritation means the production of changes in the eye following the application of test substance to the anterior surface of the eye, which are fully reversible within 21 days of application.

3.3.2. Classification criteria for substances

3.3.2.1. The classification system for substances involves a tiered testing and evaluation scheme, combining pre-existing information on serious ocular tissue damage and on eye irritation (including data relating to historical human or animal experience) as well as considerations on (Q)SAR and the output of validated in vitro tests in order to avoid unnecessary animal testing.

3.3.2.2. Before any in vivo testing for serious eye damage/eye irritation is carried out, all existing information on a substance shall be reviewed. Preliminary decisions can often be made from existing data as to whether a substance causes serious (i.e. irreversible) damage to the eyes. If a substance can be classified on the basis of these data, no testing is required.

3.3.2.3. Several factors need to be considered in determining the serious eye damage or irritation potential of a substance before testing is undertaken. Accumulated human and animal experience shall be the first line of analysis, as it gives information directly relevant to effects on the eye. In some cases enough information may be available from structurally related compounds to make hazard decisions. Likewise, pH extremes like ≤ 2 and ≥ 11,5 may produce serious eye damage, especially when associated with significant buffering capacity. Such substances are expected to produce significant effects on the eyes. Possible skin corrosion has to be evaluated prior to consideration of serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious damage to the eyes as well (Category 1), while skin irritant substances may be considered as leading to eye irritation (Category 2). In vitro alternatives that have been validated and accepted can be used to make classification decisions (see Article 5).

3.3.2.4. All the above information that is available on a substance shall be used in determining the need for in vivo eye irritation testing. Although information may be gained from the evaluation of single parameters within a tier (e.g. caustic alkalis with extreme pH shall be considered as local corrosives), the totality of existing information shall be considered in making an overall weight of evidence determination, particularly when there is information available on some but not all parameters. Generally, primary emphasis shall be placed upon expert judgement, considering human experience with the substance, followed by the outcome of skin irritation testing and of well-validated alternative methods. Animal testing with corrosive substances or mixtures shall be avoided whenever possible.

3.3.2.5. A tiered approach to the evaluation of initial information shall be considered where applicable, while recognising that all elements may not be relevant in certain cases.

3.3.2.6. Irreversible effects on the eye/serious damage to eyes (Category 1)

3.3.2.6.1. Substances that have the potential to seriously damage the eyes are classified in Category 1 (irreversible effects on the eye). Substances are classified in this hazard category on the basis of the results of animal testing, in accordance with the criteria listed in Table 3.3.1. These observations include animals with grade 4 cornea lesions and other severe reactions (e.g., destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Substances are also classified in Category 1 if they fulfil the criteria of corneal opacity ≥ 3 or iritis > 1,5 detected in a Draize eye test with rabbits, recognising that such severe lesions usually do not reverse within a 21-day observation period.

Table 3.3.1
Category for irreversible eye effects
Category	Criteria
Irreversible effects on the eye (Category 1)	If, when applied to the eye of an animal, a substance produces: at least in one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or at least in 2 of 3 tested animals, a positive response of: corneal opacity ≥ 3 and/or iritis > 1,5 calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material.

3.3.2.6.2. The use of human data is discussed in paragraphs 3.3.2.1, 3.3.2.4, and also in paragraphs 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.3.2.7. Reversible effects on the eye (Category 2)

3.3.2.7.1. Substances that have the potential to induce reversible eye irritation are classified in Category 2 (irritating to eyes).

Table 3.3.2
Category for reversible eye effects
Category	Criteria
Irritating to eyes (Category 2)	if, when applied to the eye of an animal, a substance produces: at least in 2 of 3 tested animals, a positive response of: corneal opacity ≥ 1 and/or iritis ≥ 1, and/or conjunctival redness ≥ 2 and/or conjunctival oedema (chemosis) ≥ 2 calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material, and which fully reverses within an observation period of 21 days

3.3.2.7.2. For those substances where there is pronounced variability among animal responses, this information shall be taken into account in determining the classification.

3.3.3. Classification criteria for mixtures

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

3.3.3.1.1. The mixture will be classified using the criteria for substances, and taking into account the testing and evaluation strategies used to develop data for these hazard classes.

3.3.3.1.2. Unlike other hazard classes, there are alternative tests available for skin corrosivity of certain types of mixtures that give an accurate result for classification purposes, as well as being simple and relatively inexpensive to perform. When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence strategy as included in the criteria for classification of substances for skin corrosion and serious eye damage and eye irritation to help ensure an accurate classification, as well as avoid unnecessary animal testing. A mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2,0 or ≥ 11,5. If consideration of alkali/acid reserve suggests the mixture may not have the potential to cause serious eye damage despite the low or high pH value, then further testing needs to be carried out to confirm this, preferably by use of an appropriate validated in vitro test.

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

3.3.3.2.1. Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage or irritation, 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.

3.3.3.3. Classification of mixtures when data are available for all components or only for some components of the mixture

3.3.3.3.1. In order to make use of all available data for purposes of classifying the eye irritation/serious eye damaging properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

Assumption: The ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a presumption (e.g. in the case of corrosive ingredients) that an ingredient present at a concentration of less than 1 % is still relevant for classifying the mixture for eye irritation/serious eye damage.

3.3.3.3.2. In general, the approach to classification of mixtures as eye irritant or seriously damaging to the eye when data are available on the components, but not on the mixture as a whole, is based on the theory of additivity, such that each corrosive or irritant component contributes to the overall irritant or corrosive properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for corrosive components when they are present at a concentration below the generic concentration limit for classification in Category 1, but are at a concentration that will contribute to the classification of the mixture as an irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such components exceeds a concentration limit.

3.3.3.3.3. Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as irritant or as seriously damaging to the eye.

3.3.3.3.4.1. Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in paragraphs 3.3.3.3.1 and 3.3.3.3.2 might not work given that many of such substances are corrosive or irritant at concentrations < 1 %.

3.3.3.3.4.2. For mixtures containing strong acids or bases the pH shall be used as classification criteria (see paragraph 3.3.2.3) since pH will be a better indicator of serious eye damage than the generic concentration limits of Table 3.3.3.

3.3.3.3.4.3. A mixture containing corrosive or irritant ingredients that cannot be classified based on the additivity approach (Table 3.3.3), due to chemical characteristics that make this approach unworkable, shall be classified as Category 1 for effects on the eye if it contains ≥ 1 % of a corrosive ingredient and as Category 2 when it contains ≥ 3 % of an irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

3.3.3.3.5. On occasion, reliable data may show that the reversible/irreversible eye effects of an ingredient will not be evident when present at a level above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4. In these cases the mixture shall be classified according to those data. On other occasions, when it is expected that the skin corrosion/irritation hazards or the reversible/irreversible eye effects of an ingredient will not be evident when present at a level above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence strategy shall be applied.

3.3.3.3.6. If there are data showing that (an) ingredient(s) may be corrosive or irritant at a concentration of < 1 % (corrosive) or < 3 % (irritant), the mixture shall be classified accordingly.

Table 3.3.3

Generic concentration limits of ingredients of a mixture classified as Skin corrosive Category 1 and/or eye Category 1 or 2 for effects on the eye that trigger classification of the mixture for effects on the eye (Category 1 or 2)

Sum of ingredients classified as:	Concentration triggering classification of a mixture as:
	Irreversible Eye Effects	Reversible Eye Effects
	Category 1	Category 2
Eye Effects Category 1 or Skin Corrosive Category 1A, 1B, 1C	≥ 3 %	≥ 1 % but < 3 %
Eye Effects Category 2		≥ 10 %
(10 × Eye Effects Category 1) + Eye effects Category 2		≥ 10 %
Skin Corrosive Category 1A, 1B, 1C + Eye effects Category 1	≥ 3 %	≥ 1 % but < 3 %
10 × (Skin Corrosive Category 1A, 1B, 1C + Eye Effects Category 1) + Eye Effects Category 2		≥ 10 %

Table 3.3.4

Generic concentration limits of ingredients of a mixture for which the additivity approach does not apply, that trigger classification of the mixture as hazardous to the eye

Ingredient	Concentration	Mixture classified as: Eye
Acid with pH ≤ 2	≥ 1 %	Category 1
Base with pH ≥ 11,5	≥ 1 %	Category 1
Other corrosive (Category 1) ingredients for which additivity does not apply	≥ 1 %	Category 1
Other irritant (Category 2) ingredients for which additivity does not apply, including acids and bases	≥ 3 %	Category 2

3.3.4. Hazard Communication

3.3.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5
Label elements for serious eye damage/eye irritation
Classification	Category 1	Category 2
GHS Pictograms
Signal Word	Danger	Warning
Hazard Statement	H318: Causes serious eye damage	H319: Causes serious eye irritation
Precautionary Statement Prevention	P280	P264 P280
Precautionary Statement Response	P305 + P351 + P338 P310	P305 + P351 + P338 P337 + P313
Precautionary Statement Storage
Precautionary Statement Disposal

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(2) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans(3) 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

3.5. Germ cell mutagenicity

3.5.1. Definitions and general considerations

3.5.1.1. A mutation means a permanent change in the amount or structure of the genetic material in a cell. The term ‘mutation’ applies both to heritable genetic changes that may be manifested at the phenotypic level and to the underlying DNA modifications when known (including specific base pair changes and chromosomal translocations). The term ‘mutagenic’ and ‘mutagen’ will be used for agents giving rise to an increased occurrence of mutations in populations of cells and/or organisms.

3.5.1.2. The more general terms ‘genotoxic’ and ‘genotoxicity’ apply to agents or processes which alter the structure, information content, or segregation of DNA, including those which cause DNA damage by interfering with normal replication processes, or which in a non-physiological manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators for mutagenic effects.

3.5.2. Classification criteria for substances

3.5.2.1. This hazard class is primarily concerned with substances that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, the results from mutagenicity or genotoxicity tests in vitro and in mammalian somatic and germ cells in vivo are also considered in classifying substances and mixtures within this hazard class.

3.5.2.2. For the purpose of classification for germ cell mutagenicity, substances are allocated to one of two categories as shown in Table 3.5.1.

Table 3.5.1
Hazard categories for germ cell mutagens
Categories	Criteria
CATEGORY 1:	Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans. Substances known to induce heritable mutations in the germ cells of humans.
Category 1A:	The classification in Category 1A is based on positive evidence from human epidemiological studies. Substances to be regarded as if they induce heritable mutations in the germ cells of humans.
Category 1B:	The classification in Category 1B is based on: positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.
CATEGORY 2:	Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans The classification in Category 2 is based on: positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from: somatic cell mutagenicity tests in vivo, in mammals; or other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays. Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

3.5.2.3. Specific considerations for classification of substances as germ cell mutagens

3.5.2.3.1. To arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall also be considered.

3.5.2.3.2. The system is hazard based, classifying substances on the basis of their intrinsic ability to induce mutations in germ cells. The scheme is, therefore, not meant for the (quantitative) risk assessment of substances.

3.5.2.3.3. Classification for heritable effects in human germ cells is made on the basis of well conducted, sufficiently validated tests, preferably as described in Regulation (EC) No 440/2008 adopted in accordance with Article 13(3) of Regulation (EC) No 1907/2006 (‘Test Method Regulation’) such as those listed in the following paragraphs. Evaluation of the test results shall be done using expert judgement and all the available evidence shall be weighed in arriving at a classification.

3.5.2.3.4. In vivo heritable germ cell mutagenicity tests, such as:

• rodent dominant lethal mutation test;

• mouse heritable translocation assay.

3.5.2.3.5. In vivo somatic cell mutagenicicty tests, such as:

• mammalian bone marrow chromosome aberration test;

• mouse spot test;

• mammalian erythrocyte micronucleus test.

3.5.2.3.6. Mutagenicity/genotoxicity tests in germ cells, such as:

(a)

mutagenicity tests:

• mammalian spermatogonial chromosome aberration test;

• spermatid micronucleus assay;

(b)

Genotoxicity tests:

• sister chromatid exchange analysis in spermatogonia;

• unscheduled DNA synthesis test (UDS) in testicular cells.

3.5.2.3.7. Genotoxicity tests in somatic cells such as:

• liver Unscheduled synthesis test (UDS) in vivo;

• mammalian bone marrow Sister Chromatid Exchanges (SCE);

3.5.2.3.8. In vitro mutagenicity tests such as:

• in vitro mammalian chromosome aberration test;

• in vitro mammalian cell gene mutation test;

• bacterial reverse mutation tests.

3.5.2.3.9. The classification of individual substances shall be based on the total weight of evidence available, using expert judgement (See 1.1.1). In those instances where a single well-conducted test is used for classification, it shall provide clear and unambiguously positive results. If new, well validated, tests arise these may also be used in the total weight of evidence to be considered. The relevance of the route of exposure used in the study of the substance compared to the route of human exposure shall also be taken into account.

3.5.3. Classification criteria for mixtures

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

3.5.3.1.1. The mixture shall be classified as a mutagen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 mutagen and is present at or above the appropriate generic concentration limit as shown in Table 3.5.2 for Category 1A, Category 1B and Category 2 respectively.

Table 3.5.2

Generic concentration limits of ingredients of a mixture classified as germ cell mutagens that trigger classification of the mixture.

	Concentration limits triggering classification of a mixture as:
Ingredient classified as:	Category 1A mutagen	Category 1B mutagen	Category 2 mutagen
Category 1A mutagen	≥ 0,1 %	—	—
Category 1B mutagen	—	≥ 0,1 %	—
Category 2 mutagen	—	—	≥ 1,0 %

Note

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

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

3.5.3.2.1. 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 germ cell mutagens. 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 germ cell mutagenicity test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

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

3.5.3.3.1. Where the mixture itself has not been tested to determine its germ cell mutagenicity hazard, but there are sufficient data on the individual ingredients and similar tested mixtures (subject to paragraph 3.5.3.2.1), 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.

3.5.4. Hazard communication

3.5.4.1. Label elements shall be used in accordance with Table 3.5.3, for substances or mixtures meeting the criteria for classification in this hazard class.

Table 3.5.3
Label elements of germ cell mutagenicity
Classification	Category 1A or Category 1B	Category 2
GHS Pictograms
Signal Word	Danger	Warning
Hazard Statement	H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H341: Suspected of causing genetic defects (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

3.5.5. Additional classification considerations

It is increasingly accepted that the process of chemical-induced tumorigenesis in humans and animals involves genetic changes for example in proto-oncogenes and/or tumour suppresser genes of somatic cells. Therefore, the demonstration of mutagenic properties of substances in somatic and/or germ cells of mammals in vivo may have implications for the potential classification of these substances as carcinogens (see also Carcinogenicity, section 3.6, paragraph 3.6.2.2.6).

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

3.7. Reproductive toxicity

3.7.1. Definitions and general considerations

3.7.1.1. Reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring. The definitions presented below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Principles for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classification purposes, the known induction of genetically based heritable effects in the offspring is addressed in Germ Cell Mutagenicity (section 3.5), since in the present classification system it is considered more appropriate to address such effects under the separate hazard class of germ cell mutagenicity.

In this classification system, reproductive toxicity is subdivided under two main headings:

(a)

adverse effects on sexual function and fertility;

(b)

adverse effects on development of the offspring.

Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures containing them, shall be classified as reproductive toxicants.

3.7.1.2. For the purpose of classification the hazard class Reproductive Toxicity is differentiated into:

• adverse effects

  • on sexual function and fertility, or

  • on development;

• effects on or via lactation.

3.7.1.3. Adverse effects on sexual function and fertility

Any effect of substances that has the potential to interfere with sexual function and fertility. This includes, but is not limited to, alterations to the female and male reproductive system, adverse effects on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour, fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in other functions that are dependent on the integrity of the reproductive systems.

3.7.1.4. Adverse effects on development of the offspring

Developmental toxicity includes, in its widest sense, any effect which interferes with normal development of the conceptus, either before or after birth, and resulting from exposure of either parent prior to conception, or exposure of the developing offspring during prenatal development, or postnatally, to the time of sexual maturation. However, it is considered that classification under the heading of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification, developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of parental exposure. These effects can be manifested at any point in the life span of the organism. The major manifestations of developmental toxicity include (1) death of the developing organism, (2) structural abnormality, (3) altered growth, and (4) functional deficiency.

3.7.1.5. Adverse effects on or via lactation are also included in reproductive toxicity, but for classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is desirable to be able to classify substances specifically for an adverse effect on lactation so that a specific hazard warning about this effect can be provided for lactating mothers.

3.7.2. Classification criteria for substances

3.7.2.1. Hazard categories

3.7.2.1.1. For the purpose of classification for reproductive toxicity, substances are allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately. In addition, effects on lactation are allocated to a separate hazard category.

Table 3.7.1(a)
Hazard categories for reproductive toxicants
Categories	Criteria
CATEGORY 1	Known or presumed human reproductive toxicant Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).
Category 1A	Known human reproductive toxicant The classification of a substance in Category 1A is largely based on evidence from humans.
Category 1B	Presumed human reproductive toxicant The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.
CATEGORY 2	Suspected human reproductive toxicant Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification. Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

Table 3.7.1(b)
Hazard category for lactation effects
EFFECTS ON OR VIA LACTATION
Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the: (a) human evidence indicating a hazard to babies during the lactation period; and/or (b) results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

3.7.2.2. Basis of classification

3.7.2.2.1. Classification is made on the basis of the appropriate criteria, outlined above, and an assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances shall not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.

The classification of a substance is derived from the hazard categories in the following order of precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lactation. If a substance meets the criteria for classification into both of the main categories (for example Category 1B for effects on sexual function and fertility and also Category 2 for development) then both hazard differentiations shall be communicated by the respective hazard statements. Classification in the additional category for effects on or via lactation will be considered irrespective of a classification into Category 1A, Category 1B or Category 2.

3.7.2.2.2. In the evaluation of toxic effects on the developing offspring, it is important to consider the possible influence of maternal toxicity (see section 3.7.2.4).

3.7.2.2.3. For human evidence to provide the primary basis for a Category 1A classification there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classification shall ideally be from well conducted epidemiological studies which include the use of appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less rigorous data from studies in humans shall be supplemented with adequate data from studies in experimental animals and classification in Category 1B shall be considered.

3.7.2.3. Weight of evidence

3.7.2.3.1. Classification as a reproductive toxicant is made on the basis of an assessment of the total weight of evidence, see section 1.1.1. This means that all available information that bears on the determination of reproductive toxicity is considered together, such as epidemiological studies and case reports in humans and specific reproduction studies along with sub-chronic, chronic and special study results in animals that provide relevant information regarding toxicity to reproductive and related endocrine organs. Evaluation of substances chemically related to the substance under study may also be included, particularly when information on the substance is scarce. The weight given to the available evidence will be influenced by factors such as the quality of the studies, consistency of results, nature and severity of effects, the presence of maternal toxicity in experimental animal studies, level of statistical significance for inter-group differences, number of endpoints affected, relevance of route of administration to humans and freedom from bias. Both positive and negative results are assembled together into a weight of evidence determination. A single, positive study performed according to good scientific principles and with statistically or biologically significant positive results may justify classification (see also 3.7.2.2.3).

3.7.2.3.2. Toxicokinetic studies in animals and humans, site of action and mechanism or mode of action study results may provide relevant information which reduces or increases concerns about the hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified.

3.7.2.3.3. If, in some reproductive toxicity studies in experimental animals the only effects recorded are considered to be of low or minimal toxicological significance, classification may not necessarily be the outcome. These effects include small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments.

3.7.2.3.4. Data from animal studies ideally shall provide clear evidence of specific reproductive toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs together with other toxic effects in the dam, the potential influence of the generalised adverse effects shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely to have influenced these effects, as part of the weight of evidence. In general, developmental effects that are observed at maternally toxic doses shall not be automatically discounted. Discounting developmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis when a causal relationship is established or refuted.

3.7.2.3.5. If appropriate information is available it is important to try to determine whether developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of maternal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly demonstrated that the effects are secondary non-specific effects. This is especially the case when the effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In some situations it can be assumed that reproductive toxicity is due to a secondary consequence of maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.

3.7.2.4. Maternal toxicity

3.7.2.4.1. Development of the offspring throughout gestation and during the early postnatal stages can be influenced by toxic effects in the mother either through non-specific mechanisms related to stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In the interpretation of the developmental outcome to decide classification for developmental effects it is important to consider the possible influence of maternal toxicity. This is a complex issue because of uncertainties surrounding the relationship between maternal toxicity and developmental outcome. Expert judgement and a weight of evidence approach, using all available studies, shall be used to determine the degree of influence that shall be attributed to maternal toxicity when interpreting the criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be first considered, and then maternal toxicity, along with any other factors which are likely to have influenced these effects, as weight of evidence, to help reach a conclusion about classification.

3.7.2.4.2. Based on pragmatic observation, maternal toxicity may, depending on severity, influence development via non-specific secondary mechanisms, producing effects such as depressed foetal weight, retarded ossification, and possibly resorptions and certain malformations in some strains of certain species. However, the limited number of studies which have investigated the relationship between developmental effects and general maternal toxicity have failed to demonstrate a consistent, reproducible relationship across species. Developmental effects which occur even in the presence of maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivocally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, significant post-natal functional deficiencies.

3.7.2.4.3. Classification shall not automatically be discounted for substances that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. However, when a substance is so toxic that maternal death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects. Classification is not necessarily the outcome in the case of minor developmental changes, when there is only a small reduction in foetal/pup body weight or retardation of ossification when seen in association with maternal toxicity.

3.7.2.4.4. Some of the end points used to assess maternal effects are provided below. Data on these end points, if available, need to be evaluated in light of their statistical or biological significance and dose response relationship.

Maternal mortality:

an increased incidence of mortality among the treated dams over the controls shall be considered evidence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive and the data for that dose level shall not normally be considered for further evaluation.

Mating index

(no. animals with seminal plugs or sperm/no. mated × 100)(4)

Fertility index

(no. animals with implants/no. of matings × 100)

Gestation length

(if allowed to deliver)

Body weight and body weight change:

Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight shall be included in the evaluation of maternal toxicity whenever such data are available. The calculation of an adjusted (corrected) mean maternal body weight change, which is the difference between the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in body weight during pregnancy.

Food and water consumption (if relevant):

The observation of a significant decrease in the average food or water consumption in treated dams compared to the control group is useful in evaluating maternal toxicity, particularly when the test material is administered in the diet or drinking water. Changes in food or water consumption need to be evaluated in conjunction with maternal body weights when determining if the effects noted are reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.

Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):

The observation of increased incidence of significant clinical signs of toxicity in treated dams relative to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity, loss of righting reflex, ataxia, or laboured breathing.

Post-mortem data:

Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity. This can include gross or microscopic pathological findings or organ weight data, including absolute organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by findings of adverse histopathological effects in the affected organ(s), the observation of a significant change in the average weight of suspected target organ(s) of treated dams, compared to those in the control group, may be considered evidence of maternal toxicity.

3.7.2.5. Animal and experimental data

3.7.2.5.1. A number of internationally accepted test methods are available; these include methods for developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-generation toxicity testing (e.g. OECD Test Guidelines 415, 416).

3.7.2.5.2. Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with Reproduction/Development Toxicity Screening Test) can also be used to justify classification, although it is recognised that the quality of this evidence is less reliable than that obtained through full studies.

3.7.2.5.3. Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies, which are judged likely to impair reproductive function and which occur in the absence of significant generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the gonads.

3.7.2.5.4. Evidence from in vitro assays, or non-mammalian tests, and from analogous substances using structure-activity relationship (SAR), can contribute to the procedure for classification. In all cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate data shall not be used as a primary support for classification.

3.7.2.5.5. It is preferable that animal studies are conducted using appropriate routes of administration which relate to the potential route of human exposure. However, in practice, reproductive toxicity studies are commonly conducted using the oral route, and such studies will normally be suitable for evaluating the hazardous properties of the substance with respect to reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals shall not be classified.

3.7.2.5.6. Studies involving routes of administration such as intravenous or intraperitoneal injection, which result in exposure of the reproductive organs to unrealistically high levels of the test substance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with extreme caution and on their own are not normally the basis for classification.

3.7.2.5.7. There is general agreement about the concept of a limit dose, above which the production of an adverse effect is considered to be outside the criteria which lead to classification, but not regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guidelines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific limit dose may not be adequate for situations where humans are more sensitive than the animal model.

3.7.2.5.8. In principle, adverse effects on reproduction seen only at very high dose levels in animal studies (for example doses that induce prostration, severe inappetence, excessive mortality) would not normally lead to classification, unless other information is available, e.g. toxicokinetics information indicating that humans may be more susceptible than animals, to suggest that classification is appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this area.

3.7.2.5.9. However, specification of the actual ‘limit dose’ will depend upon the test method that has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose toxicity studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose, unless expected human response indicates the need for a higher dose level.

3.7.3. Classification criteria for mixtures

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

3.7.3.1.1. The mixture shall be classified as a reproductive toxicant when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Category 1B and Category 2 respectively.

3.7.3.1.2. The mixture shall be classified for effects on or via lactation when at least one ingredient has been classified for effects on or via lactation and is present at or above the appropriate generic concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.

Table 3.7.2

Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or for effects on or via lactation that trigger classification of the mixture

Ingredient classified as:	Generic concentration limits triggering classification of a mixture as:
	Category 1A reproductive toxicant	Category 1B reproductive toxicant	Category 2 reproductive toxicant	Additional category for effects on or via lactation
Category 1A reproductive toxicant	≥ 0,3 % [Note 1]
Category 1B reproductive toxicant		≥ 0,3 % [Note 1]
Category 2 reproductive toxicant			≥ 3,0 % [Note 1]
Additional category for effects on or via lactation				≥ 0,3 % [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 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture upon request.

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

3.7.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients of the mixture. 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 components. 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 reproduction test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

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

3.7.3.3.1. Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine its reproductive toxicity, 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 applicable bridging rules set out in section 1.1.3.

3.7.4. Hazard Communication

3.7.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.7.3

Table 3.7.3
Label elements for reproductive toxicity
Classification	Category 1A or Category 1B	Category 2	Additional category for effects on or via lactation
GHS Pictograms			No pictogram
Signal Word	Danger	Warning	No signal word
Hazard Statement	H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H362: May cause harm to breast-fed children.
Precautionary Statement Prevention	P201 P202 P281	P201 P202 P281	P201 P260 P263 P264 P270
Precautionary Statement Response	P308 + P313	P308 + P313	P308 + P313
Precautionary Statement Storage	P405	P405
Precautionary Statement Disposal	P501	P501

3.8. Specific target organ toxicity — single exposure

3.8.1. Definitions and general considerations

3.8.1.1. Specific target organ toxicity (single exposure) is defined as specific, non lethal target organ toxicity arising from a single exposure to a substance or mixture. All significant health effects that can impair function, both reversible and irreversible, immediate and/or delayed and not specifically addressed in sections 3.1 to 3.7 and 3.10 are included (see also 3.8.1.6).

3.8.1.2. Classification identifies the substance or mixture as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.

3.8.1.3. These adverse health effects produced by a single exposure include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism, and these changes are relevant for human health.

3.8.1.4. Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs.

3.8.1.5. Specific target organ toxicity can occur by any route that is relevant for humans, i.e. principally oral, dermal or inhalation.

3.8.1.6. Specific target organ toxicity following a repeated exposure is classified as described in Specific target organ toxicity — Repeated exposure (section 3.9) and is therefore excluded from section 3.8. Other specific toxic effects, listed below, are assessed separately and consequently are not included here:

(a)

Acute toxicity (section 3.1);

(b)

Skin corrosion/irritation (section 3.2);

(c)

Serious eye damage/eye irritation (section 3.3);

(d)

Respiratory or skin sensitisation (section 3.4);

(e)

Germ cell mutagenicity (section 3.5);

(f)

Carcinogenicity (section 3.6);

(g)

Reproductive toxicity (section 3.7); and

(h)

Aspiration toxicity (section 3.10).

3.8.1.7. The hazard class Specific Target Organ Toxicity — Single Exposure is differentiated into:

• Specific target organ toxicity — single exposure, Category 1 and 2;

• Specific target organ toxicity — single exposure, Category 3.

See Table 3.8.1.

Table 3.8.1
Categories for specific target organ toxicity-single exposure
Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).
Categories	Criteria
Category 1	Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of: (a) reliable and good quality evidence from human cases or epidemiological studies; or (b) observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.
Category 2	Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification. In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).
Category 3	Transient target organ effects This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

3.8.2. Classification criteria for substances

3.8.2.1. Substances of Category 1 and Category 2

3.8.2.1.1. Substances are classified for immediate or delayed effects separately, by the use of expert judgement (see 1.1.1) on the basis of the weight of all evidence available, including the use of recommended guidance values (see 3.8.2.1.9). Substances are then placed in Category 1 or 2, depending upon the nature and severity of the effect(s) observed (Table 3.8.1).

3.8.2.1.2. The relevant route or routes of exposure by which the classified substance produces damage shall be identified (see 3.8.1.5).

3.8.2.1.3. Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.

3.8.2.1.4. Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification.

3.8.2.1.5. The information required to evaluate specific target organ toxicity comes either from single exposure in humans, such as: exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are acute toxicity studies which can include clinical observations and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Results of acute toxicity studies conducted in other species may also provide relevant information.

3.8.2.1.6. In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of target organ toxicity in Category 2:

(a)

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or

(b)

based on the nature and severity of effects.

Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.

3.8.2.1.7. Effects considered to support classification for Category 1 and 2

3.8.2.1.7.1. Classification is supported by evidence associating single exposure to the substance with a consistent and identifiable toxic effect.

3.8.2.1.7.2. Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.

3.8.2.1.7.3. Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, must be taken into consideration in the classification process, including but not limited to the following effects in humans and/or animals:

(a)

morbidity resulting from single exposure;

(b)

significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (such as sight, hearing and sense of smell);

(c)

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

(d)

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(e)

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(f)

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction;

(g)

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

3.8.2.1.8. Effects considered not to support classification for Category 1 and 2

It is recognised that effects may be seen that does not justify classification. Such effects in humans and/or animals include, but are not limited to:

(a)

clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

(b)

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

(c)

changes in organ weights with no evidence of organ dysfunction;

(d)

adaptive responses that are not considered toxicologically relevant;

(e)

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

3.8.2.1.9. Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals for Category 1 and 2

3.8.2.1.9.1. In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged.

3.8.2.1.9.2. Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the dose/concentration at which these effects were seen, in relation to the suggested guidance values, provides useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the dose/concentration).

3.8.2.1.9.3. The guidance value (C) ranges for single-dose exposure which has produced a significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in Table 3.8.2.

Table 3.8.2

Guidance value ranges for single-dose exposures ^a

			Guidance value ranges for:
Route of exposure	Units	Category 1	Category 2	Category 3
Oral (rat)	mg/kg body weight	C ≤ 300	2 000 ≥ C > 300	Guidance values do not apply b
Dermal (rat or rabbit)	mg/kg body weight	C ≤ 1 000	2 000 ≥ C > 1 000
Inhalation (rat) gas	ppmV/4h	C ≤ 2 500	20 000 ≥ C > 2 500
Inhalation (rat) vapour	mg/l/4h	C ≤ 10	20 ≥ C > 10
Inhalation (rat) dust/mist/fume	mg/l/4h	C ≤ 1,0	5,0 ≥ C > 1,0

Note

(a)

The guidance values and ranges mentioned in Table 3.8.2 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decision about classification. They are not intended as strict demarcation values.

(b)

Guidance values are not provided for Category 3 substances since this classification is primarily based on human data. Animal data, if available, shall be included in the weight of evidence evaluation.

3.8.2.1.10. Other considerations

3.8.2.1.10.1. When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.

3.8.2.1.10.2. When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to single exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because specific target organ toxicity observed was considered not relevant or significant to humans, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.

3.8.2.1.10.3. A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.

3.8.2.1.10.4. Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection

3.8.2.2. Substances of Category 3: Transient target organ effects

3.8.2.2.1. Criteria for respiratory tract irritation

The criteria for classifying substances as Category 3 for respiratory tract irritation are:

(a)

respiratory irritant effects (characterised by localised redness, oedema, pruritis and/or pain) that impair function with symptoms such as cough, pain, choking, and breathing difficulties are included. This evaluation will be based primarily on human data;

(b)

subjective human observations could be supported by objective measurements of clear respiratory tract irritation (RTI) (such as electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);

(c)

the symptoms observed in humans shall also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction or response triggered only in individuals with hypersensitive airways. Ambiguous reports simply of ‘irritation’ shall be excluded as this term is commonly used to describe a wide range of sensations including those such as smell, unpleasant taste, a tickling sensation, and dryness, which are outside the scope of classification for respiratory irritation;

(d)

there are currently no validated animal tests that deal specifically with RTI, however, useful information may be obtained from the single and repeated inhalation toxicity tests. For example, animal studies may provide useful information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc) and histopathology (e.g. hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible and may be reflective of the characteristic clinical symptoms described above. Such animal studies can be used as part of weight of evidence evaluation;

(e)

this special classification would occur only when more severe organ effects including in the respiratory system are not observed.

3.8.2.2.2 Criteria for narcotic effects

The criteria for classifying substances as Category 3 for narcotic effects are:

(a)

central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness;

(b)

narcotic effects observed in animal studies may include lethargy, lack of coordination, loss of righting reflex, and ataxia. If these effects are not transient in nature, then they shall be considered to support classification for Category 1 or 2 specific target organ toxicity single exposure.

3.8.3. Classification criteria for mixtures

3.8.3.1. Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures shall be classified for specific target organ toxicity following single exposure.

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

3.8.3.2.1. 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 shall be classified by weight of evidence evaluation of these data (see 1.1.1.4). Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.

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

3.8.3.3.1. Where the mixture itself has not been tested to determine its specific target organ toxicity, 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 principles set out in section 1.1.3.

3.8.3.4. Classification of mixtures when data are available for all components or only for some components of the mixture

3.8.3.4.1. Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant and is present at or above the appropriate generic concentration limit as mentioned in Table 3.8.3 for Category 1 and 2 respectively.

3.8.3.4.2. These generic concentration limits and consequent classifications shall be applied appropriately to single-dose specific target organ toxicants.

3.8.3.4.3. Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.

Table 3.8.3

Generic concentration limits of ingredients of a mixture classified as a specific target organ toxicant that trigger classification of the mixture as Category 1 or 2

Ingredient classified as:	Generic concentration limits triggering classification of the mixture as:
	Category 1	Category 2
Category 1 Specific Target Organ Toxicant	Concentration ≥ 10 %	1,0 % ≤ concentration < 10 %
Category 2 Specific Target Organ Toxicant		Concentration ≥ 10 % [(Note 1)]

Note 1

If a Category 2 specific target organ toxicant is present in the mixture as an ingredient at a concentration ≥ 1,0 % a SDS shall be available for the mixture upon request.

3.8.3.4.4. Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at < 1 % concentration when other ingredients in the mixture are known to potentiate its toxic effect.

3.8.3.4.5. Care shall be exercised when extrapolating toxicity of a mixture that contains Category 3 ingredient(s). A generic concentration limit of 20 % is appropriate; however, it shall be recognised that this concentration limit may be higher or lower depending on the Category 3 ingredient(s) and that some effects such as respiratory tract irritation may not occur below a certain concentration while other effects such as narcotic effects may occur below this 20 % value. Expert judgement shall be exercised.

3.8.4. Hazard Communication

3.8.4.1 Label elements shall be used in accordance with Table 3.8.4., for substances or mixtures meeting the criteria for classification in this hazard class.

Table 3.8.4
Label elements for specific target organ toxicity after single exposure
Classification	Category 1	Category 2	Category 3
GHS Pictograms
Signal Word	Danger	Warning	Warning
Hazard Statement	H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H335: May cause respiratory irritation; or H336: May cause drowsiness or dizziness
Precautionary Statement Prevention	P260 P264 P270	P260 P264 P270	P261 P271
Precautionary Statement Response	P307 + P311 P321	P309 + P311	P304 + P340 P312
Precautionary Statement Storage	P405	P405	P403 + P233 P405
Precautionary Statement Disposal	P501	P501	P501

3.9. Specific target organ toxicity — repeated exposure

3.9.1. Definitions and general considerations

3.9.1.1. Target organ toxicity (repeated exposure) means specific, target organ toxicity arising from a repeated exposure to a substance or mixture. All significant health effects that can impair function, both reversible and irreversible, immediate and/or delayed are included. However, other specific toxic effects that are specifically addressed in sections 3.1 to 3.8 and 3.10 are not included here.

3.9.1.2. Classification for target organ toxicity (repeated exposure) identifies the substance as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.

3.9.1.3. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

3.9.1.4. Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs.

3.9.1.5. Specific target organ toxicity can occur by any route that is relevant for humans, i.e. principally oral, dermal or inhalation.

3.9.1.6. Non-lethal toxic effects observed after a single-event exposure are classified as described in Specific target organ toxicity — Single exposure (section 3.8) and are therefore excluded from section 3.9.

3.9.2. Classification criteria for substances

3.9.2.1. Substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement (see 1.1.1), on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), (see 3.9.2.9), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed (Table 3.9.1).

Table 3.9.1

Categories for specific target organ toxicity-repeated exposure

Categories	Criteria
Category 1	Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of: reliable and good quality evidence from human cases or epidemiological studies; or observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.
Category 2	Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure. Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification. In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Note

Attempts shall be made to determine the primary target organ of toxicity and classify for that purpose, such as hepatotoxicants, neurotoxicants. One shall carefully evaluate the data and, where possible, not include secondary effects (a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

3.9.2.2. The relevant route or routes of exposure by which the classified substance produces damage shall be identified.

3.9.2.3. Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.

3.9.2.4. Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification. This taps the considerable body of industrial toxicology data collected over the years. Evaluation shall be based on all existing data, including peer-reviewed published studies and additional acceptable data.

3.9.2.5. The information required to evaluate specific target organ toxicity comes either from repeated exposure in humans, such as exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are 28 day, 90 day or lifetime studies (up to 2 years) that include haematological, clinicochemical and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies performed in other species shall also be used, if available. Other long-term exposure studies, such as on carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific target organ toxicity that could be used in the assessment of classification.

3.9.2.6. In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of specific target organ toxicity in Category 2:

(a)

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification; and/or

(b)

based on the nature and severity of effects.

Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.

3.9.2.7. Effects considered to support classification for specific target organ toxicity following repeated exposure

3.9.2.7.1. Reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification.

3.9.2.7.2. Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.

3.9.2.7.3. Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, haematology, clinical chemistry, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, shall be taken into consideration in the classification process, including but not limited to the following toxic effects in humans and/or animals:

(a)

morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, and/or due to the overwhelming of the de-toxification process by repeated exposure to the substance or its metabolites;

(b)

significant functional changes in the central or peripheral nervous systems or other organ systems, including signs of central nervous system depression and effects on special senses (e.g. sight, hearing and sense of smell);

(c)

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

(d)

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(e)

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(f)

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction (e.g., severe fatty change in the liver);

(g)

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

3.9.2.8. Effects considered not to support classification for specific target organ toxicity following repeated exposure

3.9.2.8.1. It is recognised that effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:

(a)

clinical observations or small changes in bodyweight gain, food consumption or water intake that have toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

(b)

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

(c)

changes in organ weights with no evidence of organ dysfunction;

(d)

adaptive responses that are not considered toxicologically relevant;

(e)

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

3.9.2.9. Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals

3.9.2.9.1. In studies conducted in experimental animals, reliance on observation of effects alone, without reference to the duration of experimental exposure and dose/concentration, omits a fundamental concept of toxicology, i.e. all substances are potentially toxic, and what determines the toxicity is a function of the dose/concentration and the duration of exposure. In most studies conducted in experimental animals the test guidelines use an upper limit dose value.

3.9.2.9.2. In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged. Also, repeated-dose studies conducted in experimental animals are designed to produce toxicity at the highest dose used in order to optimise the test objective and so most studies will reveal some toxic effect at least at this highest dose. What is therefore to be decided is not only what effects have been produced, but also at what dose/concentration they were produced and how relevant is that for humans.

3.9.2.9.3. Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the duration of experimental exposure and the dose/concentration at which these effects were seen, in relation to the suggested guidance values, can provide useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the duration of exposure and the dose/concentration).

3.9.2.9.4. The decision to classify at all can be influenced by reference to the dose/concentration guidance values at or below which a significant toxic effect has been observed.

3.9.2.9.5. The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The assessment shall be done on a case-by-case basis; for a 28-day study the guidance values below is increased by a factor of three.

3.9.2.9.6. Thus classification in Category 1 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur at or below the guidance values (C) as indicated in Table 3.9.2:

Table 3.9.2
Guidance values to assist in Category 1 classification
Route of exposure	Units	Guidance values (dose/concentration)
Oral (rat)	mg/kg body weight/day	C ≤ 10
Dermal (rat or rabbit)	mg/kg body weight/day	C ≤ 20
Inhalation (rat)gas	ppmV/6h/day	C ≤ 50
Inhalation (rat)vapour	mg/litre/6h/day	C ≤ 0,2
Inhalation (rat) dust/mist/fume	mg/litre/6h/day	C ≤ 0,02

3.9.2.9.7. Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as indicated in Table 3.9.3:

Table 3.9.3
Guidance values to assist in Category 2 classification
Route of Exposure	Units	Guidance Value Ranges:(dose/concentration)
Oral (rat)	mg/kg body weight/day	10 < C ≤ 100
Dermal (rat or rabbit)	mg/kg body weight/day	20 < C ≤ 200
Inhalation (rat) gas	ppmV/6h/day	50 < C ≤ 250
Inhalation (rat)vapour	mg/litre/6h/day	0,2 < C ≤ 1,0
Inhalation (rat) dust/mist/fume	mg/litre/6h/day	0,02 < C ≤ 0,2

3.9.2.9.8. The guidance values and ranges mentioned in paragraphs 3.9.2.9.6 and 3.9.2.9.7 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decisions about classification. They are not intended as strict demarcation values.

3.9.2.9.9. Thus it is feasible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, such as < 100 mg/kg bw/day by the oral route, however the nature of the effect, such as nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen in animal studies occurring at above a guidance value, such as ≥ 100 mg/kg bw/day by the oral route, and in addition there is supplementary information from other sources, such as other long-term administration studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is the prudent action to take.

3.9.2.10. Other considerations

3.9.2.10.1. When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.

3.9.2.10.2. When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to repeated or prolonged exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because no specific target organ toxicity was seen at or below the dose/concentration guidance value for animal testing, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.

3.9.2.10.3. A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.

3.9.2.10.4. Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection

3.9.3. Classification criteria for mixtures

3.9.3.1. Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures shall be classified for specific target organ toxicity following repeated exposure.

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

3.9.3.2.1. 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 (see 1.1.1.4), then the mixture shall be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.

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

3.9.3.3.1. Where the mixture itself has not been tested to determine its specific target organ toxicity, 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 principles set out in section 1.1.3.

3.9.3.4. Classification of mixtures when data are available for all components or only for some components of the mixture

3.9.3.4.1. Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, repeat exposure, or both when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant and is present at or above the appropriate generic concentration limit as laid out in Table 3.9.4 for Category 1 and 2 respectively.

Table 3.9.4

Generic concentration limits of ingredients of a mixture classified as a specific target organ toxicant that trigger classification of the mixture

Ingredient classified as:	Generic concentration limits triggering classification of the mixture as:
	Category 1	Category 2
Category 1 Specific Target Organ Toxicant	Concentration ≥ 10 %	1,0 % ≤ concentration < 10 %
Category 2 Specific Target Organ Toxicant		Concentration ≥ 10 % [(Note 1)]

Note 1

If a Category 2 specific target organ toxicant is present in the mixture as an ingredient at a concentration ≥ 1,0 % a SDS shall be available for the mixture upon request.

3.9.3.4.2. These generic concentration limits and consequent classifications apply to repeated-dose target organ toxicants.

3.9.3.4.3. Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.

3.9.3.4.4. Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at < 1 % concentration when other ingredients in the mixture are known to potentiate its toxic effect.

3.9.4. Hazard Communication

3.9.4.1. Label elements shall be used in accordance with Table 3.9.5 for substances or mixtures meeting the criteria for classification in this hazard class.

Table 3.9.5
Label elements for specific target organ toxicity after repeated exposure
Classification	Category 1	Category 2
GHS Pictograms
Signal word	Danger	Warning
Hazard Statement	H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)	H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)
Precautionary Statement Prevention	P260 P264 P270	P260
Precautionary Statement Response	P314	P314
Precautionary Statement Storage
Precautionary Statement Disposal	P501	P501

3.10. Aspiration hazard

3.10.1. Definitions and general considerations

3.10.1.1. These criteria provide a means of classifying substances or mixtures that may pose an aspiration toxicity hazard to humans.

3.10.1.2 ‘Aspiration’ means the entry of a liquid or solid substance or mixture directly through the oral or nasal cavity, or indirectly from vomiting, into the trachea and lower respiratory system.

3.10.1.3. Aspiration toxicity includes severe acute effects such as chemical pneumonia, varying degrees of pulmonary injury or death following aspiration.

3.10.1.4. Aspiration is initiated at the moment of inspiration, in the time required to take one breath, as the causative material lodges at the crossroad of the upper respiratory and digestive tracts in the laryngopharyngeal region.

3.10.1.5. Aspiration of a substance or mixture can occur as it is vomited following ingestion. This has consequences for labelling, particularly where, due to acute toxicity, a recommendation may be considered to induce vomiting after ingestion. However, if the substance/mixture also presents an aspiration toxicity hazard, the recommendation to induce vomiting shall be modified.

3.10.1.6. Specific considerations

3.10.1.6.1. A review of the medical literature on chemical aspiration revealed that some hydrocarbons (petroleum distillates) and certain chlorinated hydrocarbons have been shown to pose an aspiration hazard in humans.

3.10.1.6.2. The classification criteria refer to kinematic viscosity. The following provides the conversion between dynamic and kinematic viscosity:

3.10.1.6.3. Classification of aerosol/mist products

Aerosol and mist forms of a substance or a mixture (product) are usually dispensed in containers such as self-pressurised containers, trigger and pump sprayers. The key to classifying these products is whether a pool of product is formed in the mouth, which then may be aspirated. If the mist or aerosol from a pressurised container is fine, a pool may not be formed. On the other hand, if a pressurised container dispenses product in a stream, a pool may be formed that may then be aspirated. Usually, the mist produced by trigger and pump sprayers is coarse and therefore, a pool may be formed that then may be aspirated. When the pump mechanism may be removed, and the contents are available to be swallowed then the classification of the substance or mixture shall be considered.

3.10.2. Classification criteria for substances

Table 3.10.1

Hazard category for aspiration toxicity

Category	Criteria
Category 1	Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard A substance is classified in Category 1: (a) based on reliable and good quality human evidence or (b) if it is a hydrocarbon and has a kinematic viscosity of 20,5 mm2/s or less, measured at 40 oC.

Note:

Substances in Category 1 include but are not limited to certain hydrocarbons, turpentine and pine oil.

3.10.3. Classification criteria for mixtures

3.10.3.1. Classification when data are available for the complete mixture

A mixture is classified in Category 1 based on reliable and good quality human evidence.

3.10.3.2. Classification when data are not available for the complete mixture: bridging principles

3.10.3.2.1. Where the mixture itself has not been tested to determine its aspiration toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazard of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3. However, in the case of application of the dilution bridging principle, the concentration of aspiration toxicant(s) shall be 10 % or more.

3.10.3.3. Classification when data are available for all components or only some components of the mixture

3.10.3.3.1. Category 1

3.10.3.3.1.1. A mixture which contains a total of 10 % or more of a substance or substances classified in Category 1, and has a kinematic viscosity of 20,5 mm² /s or less, measured at 40 ^oC, shall be classified in Category 1.

3.10.3.3.1.2. In the case of a mixture which separates into two or more distinct layers, one of which contains 10 % or more of a substance or substances classified in Category 1 and has a kinematic viscosity of 20,5 mm^o /s or less, measured at 40 ^oC, then the entire mixture is classified in Category 1.

3.10.4. Hazard Communication

3.10.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.10.2.

Table 3.10.2
Aspiration toxicity label elements
Classification	Category 1
GHS Pictogram
Signal Word	Danger
Hazard Statement	H304: May be fatal if swallowed and enters airways
Precautionary Statement Prevention
Precautionary Statement Response	P301 + P310 P331
Precautionary Statement Storage	P405
Precautionary Statement Disposal	P501

(1)

For ingredients with acute toxicity estimates available for other than the most appropriate exposure route, values may be extrapolated from the available exposure route(s) to the most appropriate route. Dermal and inhalation route data are not always required for ingredients. However, in case data requirements for specific ingredients include acute toxicity estimates for the dermal and inhalation route, the values to be used in the formula need to be from the required exposure route.

(2)

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

(3)

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.

(4)

It is recognised that the Mating index and the Fertility index can also be affected by the male.