3.8. Specific target organ toxicity — single exposure

3.8.1.1. Specific target organ toxicity – single exposure means specific, non-lethal toxic effects on target organs occurring after 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 section 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:

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

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:

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:

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.

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

3.8.3.1. 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.

3.8.3.2.1. 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.

3.8.3.3.1. 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.

3.8.3.4.1. 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.

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. ►M2  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.

3.8.4.1 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.