User Guide to Thresholds and Classification - Environmental ...

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238User Guide for Thresholds and ClassificationsEvidence from human data suggests a reproductive and/or developmental effect, but the evidence is notsufficiently convincing to classify the substance as a known human reproductive or developmentaltoxicant, and evidence from animal data establishes a causal relationship between the substance andthe development of reproductive and/or developmental effects.There is clear evidence in one animal species of impaired fertility, with supporting evidence on themechanism of action or site of action and information that would lead to the conclusion that the effectwould likely to be seen in humans.There is a chemical relationship to other known anti-fertility agents.When studies are in only one species without other relevant supporting evidence then classification incategory 6.8B may be appropriate.Since impaired fertility may occur as a non-specific accompaniment to severe generalised toxicity or wherethere is severe inanition, classification in this category should be made only when there is evidence thatthere is some degree of specificity of toxicity for the reproductive system. If it is demonstrated that impairedfertility in animals studies was due to a failure to mate, then for classification it would normally be necessaryto have evidence on the mechanism of action in order to interpret whether any adverse effect such asalteration in pattern of hormonal release would be likely to occur in humans.Classify as category 6.8B (suspected human reproductive or developmental toxicant), if:evidence from human data shows a positive association between exposure to the substance and thedevelopment of reproductive and/or developmental effects , but chance, bias, or confounding could notbe ruled out with reasonable confidence; orevidence from animal data suggests a reproductive and/or developmental effect, but the evidence is notsufficiently convincing to place the substance in category 6.8A; for example:a. the evidence of adverse effects is restricted to a single experiment; orb. there are unresolved questions regarding the adequacy of the design, conduct, or interpretation ofthe study.Classify as category 6.8C (causing effects on or via lactation), if one of the following is the case.Evidence from human data establishes a causal relationship between exposure to the substance andevidence of toxicity to babies, where that substance interferes with lactation or which may be present(including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfedchild.Evidence from absorption, metabolism, distribution, and excretion studies indicates the likelihood thesubstance would be present at potentially toxic levels in breast milk.Results of one- or two-generation studies in animals provide clear evidence of an adverse effect inoffspring due to the transfer of the substance in the milk or an adverse effect on the quality of the milk.Special studies, such as cross-fostering studies, may also demonstrate an adverse effect on or vialactation.Substances are known to accumulate in the body and subsequently may be released into milk atpotentially toxic levels during lactation.January 2012 EPA0109
239User Guide for Thresholds and ClassificationsA classification is not assigned, if it can be shown:the clearly identified mechanism or mode of action has no relevance for humans;the toxicokinetic differences are so marked it is certain that the hazardous property will not be expressedin humans; orthat the route of administration (for example intravenous or intraperitoneal injection) results in exposureof the reproductive organs to unrealistically high levels of test substance or elicits local damage to thereproductive organs (such as irritation). This effect in isolation is not considered to be above thereproductive or development effect threshold.16.2.3. Considerations for reproductive and developmental toxicity classificationClassification as a reproductive or developmental toxicant is made on the basis of an assessment of the totalweight of evidence. This means that all available information that bears on the determination of reproductiveor developmental toxicity is considered together. This includes epidemiological studies and case reports inhumans and specific reproduction studies along with subchronic, chronic, and special study results inanimals that provide relevant information about toxicity to reproductive and related endocrine organs.An evaluation of substances chemically related to the material under study may also be undertaken,particularly when information on the material is scarce. The weight given to the available evidence isinfluenced by factors such as the quality of the study, the consistency of results, the nature and severity ofeffects, the level of statistical significance for intergroup differences, the number of endpoints affected, therelevance of the route of administration to humans, and freedom from bias. Both positive and negativeresults are assembled together into a weight-of-evidence determination. However, a single, positive studyperformed according to good scientific principles and with statistically or biologically significant positiveresults may justify classification.Toxicokinetic studies in animals and humans, and results from site of action and mechanism or mode ofaction studies may provide relevant information that could reduce or increase concerns about the hazard tohuman health. If it can be conclusively demonstrated that the clearly identified mechanism or mode of actionin the animal model has no relevance for humans or the toxicokinetic differences are so marked that it iscertain that the hazardous property will not be expressed in humans, then a substance that produces anadverse effect on reproduction in experimental animals should not be classified.In some reproductive toxicity studies in experimental animals, the only effects recorded may be consideredof low or minimal toxicological significance, and classification may not necessarily be the outcome. Theseinclude, for example, small changes in semen parameters or in the incidence of spontaneous defects in thefoetus, small changes in the proportions of common foetal variants such as are observed in skeletalexaminations or in foetal weights, or small differences in postnatal developmental assessments.Data from animal studies ideally should provide clear evidence of specific reproductive or developmentaltoxicity in the absence of other, systemic, toxic effects. However, if developmental toxicity occurs togetherwith other toxic effects in the dams in a study, the potential influence of the generalised adverse effectsshould be assessed to the extent possible. The preferred approach is to consider adverse effects in theJanuary 2012 EPA0109
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