Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 (Text with EEA relevance)

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.
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).	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).

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:	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	Guidance values do not apply b
Inhalation (rat) gas	ppmV/4h	C ≤ 2 500	20 000 ≥ C > 2 500	Guidance values do not apply b
Inhalation (rat) vapour	mg/l/4h	C ≤ 10	20 ≥ C > 10	Guidance values do not apply b
Inhalation (rat) dust/mist/fume	mg/l/4h	C ≤ 1,0	5,0 ≥ C > 1,0	Guidance values do not apply b

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 (single exposure) 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:	Generic concentration limits triggering classification of the mixture as:
Ingredient classified 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.  Respiratory tract irritation and narcotic effects are to be evaluated separately in accordance with the criteria given in section 3.8.2.2. When conducting classifications for these hazards, the contribution of each component should be considered additive, unless there is evidence that the effects are not additive.

• 3.8.3.4.6.In cases where the additivity approach is used for Category 3 ingredients, the ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists, and vapours and v/v for gases), unless there is a reason to suspect that an ingredient present at a concentration < 1 % is still relevant when classifying the mixture for respiratory tract irritation or narcotic effects.

3.8.4.   Hazard Communication

• 3.8.4.1Label 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	Image omitted; see official source	Image omitted; see official source	Image omitted; see official source
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	P308 + P311 P321	P308 + 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.Specific target organ toxicity-repeated exposure means specific toxic effects on target organs occurring after repeated exposure to a substances or mixture. All significant health effects that can impair function, 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  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.

• 3.9.1.3.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 or 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 repeated exposure when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant (repeated exposure) 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:	Generic concentration limits triggering classification of the mixture as:
Ingredient classified 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	Image omitted; see official source	Image omitted; see official source
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 hazard means severe acute effects such as chemical pneumonia, pulmonary injury or death occurring after aspiration of a substance or mixture.

• 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:

Image omitted; see official source

• 3.10.1.6.2aAlthough the definition of aspiration in section 3.10.1.2 includes the entry of solids into the respiratory system, classification according to point (b) in Table 3.10.1 for Category 1 is intended to apply to liquid substances and mixtures only.

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.The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 %.

• 3.10.3.3.1.2.A mixture is classified as Category 1 when the sum of the concentrations of Category 1 ingredients is ≥ 10 % and the mixture has a kinematic viscosity ≤ 20,5 mm²/s, measured at 40 °C.

• 3.10.3.3.1.3.In the case of a mixture which separates into two or more distinct layers, the entire mixture is classified as Category 1 if in any distinct layer the sum of the concentrations of Category 1 ingredients is ≥ 10 %, and it has a kinematic viscosity ≤ 20,5 mm²/s, measured at 40 °C.

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	Image omitted; see official source
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

3.11.   Endocrine disruption for human health

3.11.1.   Definitions and general considerations

3.11.1.1.   Definitions

For the purposes of Section 3.11, the following definitions shall apply:

• (a) ‘endocrine disruptor’ means a substance or a mixture that alters one or more functions of the endocrine system and consequently causes adverse effects in an intact organism, its progeny, populations or subpopulations;

• (b) ‘endocrine disruption’ means the alteration of one or more functions of the endocrine system caused by an endocrine disruptor;

• (c) ‘endocrine activity’ means an interaction with the endocrine system that may result in a response of that system, of target organs or target tissues, and that confers on a substance or the mixture the potential to alter one or more functions of the endocrine system;

• (d) ‘adverse effect’ means a change in morphology, physiology, growth, development, reproduction or lifespan of an organism, system, population or subpopulation that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;

• (e) ‘biologically plausible link’ means the correlation between an endocrine activity and an adverse effect, based on biological processes, where the correlation is consistent with existing scientific knowledge.

3.11.1.2.   General considerations

• 3.11.1.2.1.Substances and mixtures fulfilling the criteria of endocrine disruptors for human health based on evidence referred to in Table 3.11.1 shall be considered to be known, presumed or suspected endocrine disruptors for human health unless there is evidence conclusively demonstrating that the adverse effects are not relevant to humans.

• 3.11.1.2.2.Evidence that is to be considered for classification of substances in accordance with other Sections of this Annex may also be used for classification of substances as an endocrine disruptor for human health where the criteria provided in this Section are met.

3.11.2.   Classification criteria for substances

3.11.2.1.   Hazard categories

For the purpose of classification for endocrine disruption for human health, substances shall be allocated to one of two categories.

Table 3.11.1.

Hazard categories for endocrine disruptors for human health

Categories	Criteria
CATEGORY 1	Known or presumed endocrine disruptors for human health The classification in Category 1 shall be largely based on evidence from at least one of the following: a) human data; b) animal data; c) non-animal data providing an equivalent predictive capacity as data in points a or b. Such data shall provide evidence that the substance meets all the following criteria: (a) endocrine activity; (b) an adverse effect in an intact organism or its offspring or future generations; (c) a biologically plausible link between the endocrine activity and the adverse effect. However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.
CATEGORY 2	Suspected endocrine disruptors for human health A substance shall be classified in Category 2 where all the following criteria are fulfilled: (a) there is evidence of: i. an endocrine activity; and ii. an adverse effect in an intact organism or its offspring or future generations; (b) the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1; (c) there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

Where there is evidence conclusively demonstrating that the adverse effects are not relevant to humans, the substance shall not be considered an endocrine disruptor for human health.

3.11.2.2.   Basis of classification

• 3.11.2.2.1.Classification shall be made on the basis of the criteria outlined above, and a weight of evidence determination of each of the criteria (see Section 3.11.2.3) and an overall weight of evidence determination (see Section 1.1.1). Classification as an endocrine disruptor for human health is intended to be used for substances which cause or may cause an endocrine-related adverse effect in humans.

• 3.11.2.2.2.Adverse effects that are solely non-specific consequences of other toxic effects shall not be considered for the identification of a substance as endocrine disruptor for human health.

3.11.2.3.   Weight of evidence and expert judgment

• 3.11.2.3.1.Classification as an endocrine disruptor for human health is made on the basis of an assessment of the total weight of evidence using expert judgment (see Section 1.1.1). This means that all available information that bears on the determination of endocrine disruption for human health is considered together, such as:

• (a) in vivo studies or other studies (e.g. in vitro, in silico studies) predictive of adverse effects, endocrine activity or biologically plausible link in humans or animals;

• (b) data from analogue substances using structure-activity relationships (SAR);

• (c) evaluation of substances chemically related to the substance under study may also be included (grouping, read-across), particularly when information on the substance is scarce;

• (d) any additional relevant and acceptable scientific data.

• 3.11.2.3.2.In applying the weight of evidence determination and expert judgment, the assessment of the scientific evidence referred to in Section 3.11.2.3.1 shall, in particular, consider all of the following factors:

• (a) both positive and negative results;

• (b) the relevance of the study designs for the assessment of adverse effects and of the endocrine activity;

• (c) the quality and consistency of the data, considering the pattern and coherence of the results within and between studies of a similar design and across different species;

• (d) the route of exposure, toxicokinetic and metabolism studies;

• (e) the concept of the limit dose (concentration), and international guidelines on maximum recommended doses (concentrations) and for assessing confounding effects of excessive toxicity.

• 3.11.2.3.3.Using a weight of evidence determination, the link between the endocrine activity and the adverse effects shall be established based on biological plausibility, which shall be determined in light of available scientific knowledge. The biologically plausible link does not need to be demonstrated with substance specific data.

• 3.11.2.3.4.Using a weight of evidence determination, evidence considered for the classification of a substance as an endocrine disruptor for the environment referred to in Section 4.2 shall be considered when assessing the classification of the substance as an endocrine disruptor for human health under Section 3.11.

3.11.2.4.   Application in time

From 1 May 2025 at the latest, substances shall be classified in accordance with the criteria laid down in Sections 3.11.2.1 to 3.11.2.3.

However, substances which were placed on the market before 1 May 2025 are not required to be classified in accordance with the criteria laid down in Sections 3.11.2.1 to 3.11.2.3 until 1 November 2026.

3.11.3.   Classification criteria for mixtures

3.11.3.1.   Classification of mixtures where data are available for all components or only for some components of the mixture

• 3.11.3.1.1.A mixture shall be classified as an endocrine disruptor for human health where at least one component has been classified as a Category 1 or Category 2 endocrine disruptor for human health and is present at or above the appropriate generic concentration limit as shown in Table 3.11.2 for Category 1 and Category 2, respectively.

Table 3.11.2.

Generic concentration limits of components of a mixture classified as endocrine disruptor for human health that trigger classification of the mixture

Component classified as:	Generic concentration limits triggering classification of a mixture as:	Generic concentration limits triggering classification of a mixture as:
Component classified as:	Category 1 endocrine disruptor for human health	Category 2 endocrine disruptor for human health
Category 1 endocrine disruptor for human health	≥ 0,1 %
Category 2 endocrine disruptor for human health		≥ 1 % [Note 1]

• Note:The concentration limits in this Table shall apply to solids and liquids (w/w units) as well as gases (v/v units).

• Note 1:If a Category 2 endocrine disruptor for human health is present in the mixture as an ingredient at a concentration ≥ 0,1 % a SDS shall be available for the mixture upon request.

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

• 3.11.3.2.1.Classification of mixtures shall be based on the available test data for the individual components of the mixture using concentration limits for the components classified as endocrine disruptor for human health. On a case-by-case basis, test data on the mixture as a whole may be used for classification when demonstrating endocrine disruption for human health that has 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 (concentration) and other factors such as duration, observations, sensitivity and statistical analysis of the test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

3.11.3.3.   Classification of mixtures where data are not available for the complete mixture: bridging principles

• 3.11.3.3.1.Where the mixture itself has not been tested to determine its endocrine disruption for human health, but there are sufficient data on the individual components and similar tested mixtures (subject to paragraph 3.11.3.2.1) to adequately characterise the hazards of the mixture, those data shall be used in accordance with the applicable bridging principles set out in Section 1.1.3.

3.11.3.4.   Application in time

From 1 May 2026 at the latest, mixtures shall be classified in accordance with the criteria laid down in Sections 3.11.3.1, 3.11.3.2 and 3.11.3.3.

However, mixtures which were placed on the market before 1 May 2026 are not required to be classified in accordance with the criteria laid down in Sections 3.11.3.1, 3.11.3.2 and 3.11.3.3 until 1 May 2028.

3.11.4.   Hazard Communication

• 3.11.4.1.Label elements shall be used in accordance with Table 3.11.3 for substances and mixtures meeting the criteria for classification in this hazard class (Endocrine disruption for human health).

Table 3.11.3.

Label elements of endocrine disruption for human health

Classification	Category 1	Category 2
Symbol/pictogram
Signal Word	Danger	Warning
Hazard Statement	EUH380: May cause endocrine disruption in humans	EUH381: Suspected of causing endocrine disruption in humans
Precautionary Statement Prevention	P201 P202 P263 P280	P201 P202 P263 P280
Precautionary Statement Response	P308 + P313	P308 + P313
Precautionary Statement Storage	P405	P405
Precautionary Statement Disposal	P501	P501

3.11.4.2.   Application in time for substances

From 1 May 2025 at the latest, substances shall be labelled in accordance with Section 3.11.4.1.

However, substances which were placed on the market before 1 May 2025 are not required to be labelled in accordance with Section 3.11.4.1 until 1 November 2026.

3.11.4.3.   Application in time for mixtures

From 1 May 2026 at the latest, mixtures shall be labelled in accordance with Section 3.11.4.1.

However, mixtures which were placed on the market before 1 May 2026 are not required to be labelled in accordance with Section 3.11.4.1 until 1 May 2028.

4. PART 4: ENVIRONMENTAL HAZARDS

4.1.   Hazardous to the aquatic environment

4.1.1.   Definitions and general considerations

4.1.1.1.   Definitions

• (a) ‘acute aquatic toxicity’ means the intrinsic property of a substance to be injurious to an aquatic organism in a short-term aquatic exposure to that substance.

• (b) ‘ short-term (acute) hazard’ means for classification purposes the hazard of a substance or mixture caused by its acute toxicity to an organism during short-term aquatic exposure to that substance or mixture.

• (c) ‘availability of a substance’ means the extent to which this substance becomes a soluble or disaggregate species. For metal availability, the extent to which the metal ion portion of a metal (M°) compound can disaggregate from the rest of the compound (molecule).

• (d) ‘bioavailability’ or ‘biological availability’ means the extent to which a substance is taken up by an organism, and distributed to an area within the organism. It is dependent upon physico-chemical properties of the substance, anatomy and physiology of the organism, pharmacokinetics, and route of exposure. Availability is not a prerequisite for bioavailability.

• (e) ‘bioaccumulation’ means the net result of uptake, transformation and elimination of a substance in an organism due to all routes of exposure (i.e. air, water, sediment/soil and food).

• (f) ‘bioconcentration’ means the net result of uptake, transformation and elimination of a substance in an organism due to waterborne exposure.

• (g) ‘chronic aquatic toxicity’ means the intrinsic property of a substance to cause adverse effects to aquatic organisms during aquatic exposures which are determined in relation to the life-cycle of the organism.

• (h) ‘degradation’ means the decomposition of organic molecules to smaller molecules and eventually to carbon dioxide, water and salts.

• (i) ‘ECx’ means the effect concentration associated with x% response.

• (j) ‘ long-term (chronic) hazard’ means for classification purposes the hazard of a substance or mixture caused by its chronic toxicity following long-term exposure in the aquatic environment.

• (k) ‘no observed effect concentration (NOEC)’ means the test concentration immediately below the lowest tested concentration with statistically significant adverse effect. The NOEC has no statistically significant adverse effect compared to the control.

4.1.1.2.   Basic elements

• 4.1.1.2.0. Hazardous to the aquatic environment is differentiated into:

• — short-term (acute) aquatic hazard

• — long-term (chronic) aquatic hazard.

• 4.1.1.2.1. The basic elements used for classification for aquatic environmental hazards are:

• — acute aquatic toxicity,

• — chronic aquatic toxicity,

• — potential for or actual bioaccumulation, and

• — degradation (biotic or abiotic) for organic chemicals.

• 4.1.1.2.2. Preferably data shall be derived using the standardised test methods referred to in Article 8(3). In practice data from other standardised test methods such as national methods shall also be used where they are considered as equivalent. Where valid data are available from non-standard testing and from non-testing methods, these shall be considered in classification provided they fulfil the requirements specified in section 1 of Annex XI to Regulation (EC) No 1907/2006. In general, both freshwater and marine species toxicity data are considered suitable for use in classification provided the test methods used are equivalent. Where such data are not available classification shall be based on the best available data. See also Part 1 of Annex I to Regulation (EC) No 1272/2008.

4.1.1.3.   Other considerations

• 4.1.1.3.1. Classification of substances and mixtures for environmental hazards requires the identification of the hazards they present to the aquatic environment.  The aquatic environment is considered in terms of the aquatic organisms that live in the water, and the aquatic ecosystem of which they are part. The basis, therefore, of the identification of short-term (acute) and long-term (chronic) hazards is the aquatic toxicity of the substance or mixture, although this shall be modified by taking account of further information on the degradation and bioaccumulation behaviour, if appropriate.

• 4.1.1.3.2. While the classification system applies to all substances and mixtures, it is recognised that for special cases (e.g. metals) the European Chemicals Agency has issued guidance.

4.1.2.   Classification criteria for substances

• 4.1.2.1. The system for classification recognises that the intrinsic hazard to aquatic organisms is represented by both the acute and chronic toxicity of a substance. For the long-term (chronic) hazard, separate hazard categories are defined representing a gradation in the level of hazard identified. The lowest of the available toxicity values between and within the different trophic levels (fish, crustacean, algae/aquatic plants) shall normally be used to define the appropriate hazard category(ies). There are circumstances, however, when a weight of evidence approach is appropriate.

• 4.1.2.2. The core classification system for substances consists of one short-term (acute) hazard classification category and three long-term (chronic) hazard classification categories. The short-term (acute) and long-term (chronic) classification categories are applied independently.

• 4.1.2.3. The criteria for classification of a substance in Acute 1 are defined on the basis of acute aquatic toxicity data only (EC50 or LC 50). The criteria for classification of a substance into Chronic 1 to 3 follow a tiered approach where the first step is to see if available information on chronic toxicity merits long-term (chronic) hazard classification. In absence of adequate chronic toxicity data, the subsequent step is to combine two types of information, i.e. acute aquatic toxicity data and environmental fate data (degradability and bioaccumulation data) (see Figure 4.1.1).

Figure 4.1.1

Categories for substances long-term (chronic) hazardous to the aquatic environment

Image omitted; see official source

Text of image

Are there adequate chronic toxicity data available for all three trophic levels?

Yes

Classify according to the criteria given in Table 4.1.0(b) (i) or 4.1.0(b)(ii) depending on information on rapid degradation

No

Are there adequate chronic toxicity data available for one or two trophic levels?

Yes

Assess both:

(a) according to the criteria given in Table 4.1.0(b)(i) or 4.1.0(b)(ii) (depending on information on rapid degradation), and

(b) (if for the other trophic level(s) adequate acute toxicity data are available) according to the criteria given in Table 4.1.0(b) (iii),

and classify according to the most stringent outcome

No

Are there adequate acute toxicity data available?

Yes

Classify according to the criteria given in Table 4.1.0(b) (iii)

• 4.1.2.4. The system also introduces a ‘safety net’ classification (referred to as Chronic 4) for use when the data available do not allow classification under the formal criteria for Acute 1 or Chronic 1 to 3 but there are nevertheless some grounds for concern (see example Table 4.1.0).

• 4.1.2.5. Substances with acute toxicities below 1 mg/l or chronic toxicities below 0,1 mg/l (if non-rapidly degradable) and 0,01 mg/l (if rapidly degradable) contribute as components of a mixture to the toxicity of the mixture even at a low concentration and shall normally be given increased weight in applying the summation of classification approach (see note 1 of Table 4.1.0 and section 4.1.3.5.5).

• 4.1.2.6. The criteria for classifying and categorising substances as ‘hazardous to the aquatic environment’ are summarised in Table 4.1.0.

Table 4.1.0

Classification categories for substances hazardous to the aquatic environment