User Guide to Thresholds and Classification - Environmental ...

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254User Guide for Thresholds and Classificationsexposure to the substance that would not result in the substance being classified in any of subclasses 6.1and 6.3–6.8 and that are produced at low exposure concentrations and are of relevance to human health.Category 6.9B – substances that are harmful to human target organs or systemsA substance for which data indicate to an expert evidence of a significant adverse biological effect on thefunction or morphology of an organ or on the biochemistry or haematology of an organism or humanbeing as a result of exposure to the substance that would not result in the substance being classified inany of subclasses 6.1 and 6.3–6.8, and that are produced at moderate exposure concentrations and areof relevance to human health.The classification criteria above are based on the Globally Harmonised System for Classification andLabelling (GHS) (United Nations, 2007). See Appendix 17C for a comparison of the HSNO Act and GHScriteria. See Appendix 17D for a comparison with the EU risk phrases for target organ toxicity.17.2.3. Considerations for specific target organ toxicity (single or repeated exposure)classificationThe relevant route of exposure by which the classified substance produces damage should be identified.Classification is determined by expert judgement, on the basis of the weight of all evidence available,including the guidance presented below.A weight-of-evidence approach to all data, including human incidents, epidemiology, and studies conductedin experimental animals, is used to substantiate specific target organ or systemic toxic effects that meritclassification.The information required to evaluate specific target organ toxicity (single exposure) comes from singleexposure in humans (for example, exposure at home, in the workplace, or environmentally) or from studiesconducted in experimental animals. The standard animal studies in rats or mice that provide this informationare acute toxicity studies that can include clinical observations and detailed macroscopic and microscopicexamination to enable the toxic effects on target tissues or organs to be identified. Results of acute toxicitystudies conducted in other species may also provide relevant information.The information required to evaluate specific target organ toxicity (repeated exposure) comes from repeatedexposure in humans (for example, exposure at home, in the workplace, or environmentally) or from studiesconducted in experimental animals. The standard animal studies in rats or mice that provide this informationare 28-day, 90-day, or lifetime studies (up to two years) that include haematological, clinicochemical, anddetailed macroscopic and microscopic examination to enable the toxic effects on target tissues or organs tobe identified. Data from repeat-dose studies performed in other species may also be used. Other long-termexposure studies (for example, for carcinogenicity, neurotoxicity, or reproductive toxicity) may also provideevidence of specific target organ or systemic toxicity that could be used in the assessment of classification.In exceptional cases, based on expert judgement, it may be appropriate to classify certain substances withhuman evidence of specific target organ or systemic toxicity as 6.9B when the weight of human evidence isnot sufficiently convincing to warrant a 6.9A classification and/or based on the nature and severity of effects.January 2012 EPA0109
255User Guide for Thresholds and ClassificationsDose or concentration levels in humans should not be considered in the classification, and any availableevidence from animal studies should be consistent with the 6.9B classification. In other words, if animal dataare also available on the chemical that it warrants 6.9A classification, the chemical should be classified as6.9A.17.2.4. Effects considered to support classificationReliable evidence associating single or repeated exposure to the substance with a consistent and identifiabletoxic effect demonstrates support for classification.It is recognised that evidence from human experience and incidents is usually restricted to reports of adversehealth consequences, often with uncertainty about exposure conditions (for example, information on doseand exposure to other substances or confounding factors that may have influenced the outcome). Thisevidence may not provide the scientific detail that can be obtained from well-conducted studies inexperimental animals.Evidence from appropriate studies in experimental animals can furnish much more detail than can be gainedfrom human experience and incidents, in the form of clinical observations, and macroscopic and microscopicpathological examination (haematology and clinical chemistry for repeat dose studies). This can often revealhazards that may not be life-threatening, but may indicate functional impairment. Consequently, all availableevidence and relevance to human health must be taken into consideration in the classification process.Relevant toxic effects in humans and/or animals are as follows.Morbidity resulting from single exposure.Morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result fromrepeated exposure, even to relatively low doses or concentrations, due to the bioaccumulation of thesubstance or its metabolites, or the accumulation of effect as a result of the detoxification processbecoming overwhelmed by repeated exposure to the substance or its metabolites.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 (for example, sight,hearing, and smell).Any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysisparameters.Significant organ damage that may be noted at necropsy and/or subsequently seen or confirmed atmicroscopic examination.Multifocal of diffuse necrosis, fibrosis, or granuloma formation in vital organs with regenerative capacity.Morphological changes that are potentially reversible but provide clear evidence of marked organdysfunction (for example, severe fatty change in the liver).Evidence of appreciable cell death (including cell degeneration, severe acute tubular nephrosis in thekidney, ulcerative gastritis, and reduced cell numbers) in vital organs incapable of regeneration (forexample, fibrosis of the myocardium or dying back of a nerve) or in stem cell populations (for example,aplasia or hypoplasia of the bone marrow).January 2012 EPA0109
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