User Guide to Thresholds and Classification - Environmental ...

237User Guide for Thresholds and ClassificationsA substance for which data from one- or two-generation studies indicate evidence of any adverseeffect in the offspring of animals due to any adverse effect on the quality of milk as a result ofexposure.The classification criteria are based on the Globally Harmonised System of Classification and Labelling(GHS) (United Nations, 2007) criteria. See Appendix 16B for a comparison for the HSNO Act criteria with theGHS and Appendix 16C for comparisons with EU risk phrases for reproductive and developmental toxicity.The placing of a substance in category 6.8A for effects on fertility and/or developmental toxicity is done onthe basis of epidemiological data. Placement into category 6.8A or 6.8B is done primarily on the basis ofanimal data. Data from in vitro studies or studies on avian eggs are regarded as ‗supportive evidence‘ andwould only exceptionally lead to classification in the absence of in vivo data.For classification into category 6.8A, for developmental toxicity, there should be clear evidence of adverseeffects in well-conducted studies in one or more species. Since adverse effects in pregnancy or postnatallymay result as a secondary consequence of events such as:maternal toxicity;reduced food or water intake;maternal stress;lack of maternal care;specific dietary deficiencies;poor animal husbandry; andintercurrent infections.It is important that the effects observed should occur in well-conducted studies and at dose levels that arenot associated with marked maternal toxicity.The route of exposure is also important. In particular, the injection of irritant material intraperitoneally mayresult in local damage to the uterus and its contents. The results of such studies should be interpreted withcaution, and on their own would not normally lead to classification.Classify as category 6.8A, (known human reproductive or developmental toxicant) if evidence from humandata shows a causal relationship between exposure to the substance and the development of reproductiveand/or developmental effects and in which chance, bias, and confounding could be ruled out with reasonableconfidence.Classify as category 6.8A (presumed human reproductive or developmental toxicant), if one of the followingis the case.Evidence from animal data establishes a causal relationship between the substance and thedevelopment of reproductive and/or developmental effects. Data should provide clear evidence ofspecific reproductive toxicity in the absence of toxic effects or, if occurring together with other toxiceffects, the adverse effect is considered not to be a secondary non-specific consequence of other toxiceffects. Mechanistic information should also support the relevance of the effect in humans.January 2012 EPA0109