User Guide to Thresholds and Classification - Environmental ...

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