User Guide to Thresholds and Classification - Environmental ...

272User Guide for Thresholds and Classificationsavailable knowledge on related compounds.No further studies are required and the metabolite is not considered ecotoxicologically relevant if themetabolite is:carbon dioxide (CO 2 ) or an inorganic compound, not being or containing a heavy metal; oran organic compound of aliphatic structure, with a chain length of four or less, which consists only ofcarbon (C), hydrogen (H), nitrogen (N) or oxygen (O) atoms and has no ‗structures‘ or functional groupsthat are known to be of ecotoxicological concern.Test data on metabolites may not be required when they are formed relatively rapidly and are short-lived, astheir toxicity may be exerted in the tests on the parent substance. Such conclusions should be supported byanalytical measurements or other justifiable arguments (for example, data from laboratory or field studies).If there is more than one metabolite, it may be sufficient to conduct tests only with the most importantmetabolite (that is, the one with the highest concentration or the most comparable structure with the parent).Where the parent substance degrades to a more hazardous metabolite, consider the rate at which it isformed when assigning a classification to the parent substance.Metabolites in or on potential feed items have to be considered. However, apart from the generalconsiderations explained above, experimental toxicity testing is not necessary in the following cases.If the metabolite in question also appears in birds and mammals, it may be assumed that any toxiceffects would be expressed in the toxicity test with the parent compound, and that the risk from themetabolite is covered. Note that the toxicology section of the dossier or monograph always providesinformation on metabolism in rats, but not necessarily on metabolism in birds (poultry), and it cannot beassumed that the metabolic pathway in birds is identical to that in mammals.The toxicology data package may already contain mammalian toxicity tests with the metabolite. Theabsolute toxicity of the metabolite cannot be directly extrapolated from mammals to birds, but the relationcan be used as an indication that such information might be sufficient for an assessment. For example,consider the following information.LD 50 rat (parent) = 238 mg/kg,LD 50 rat (metabolite) = 680 mg/kg,LD 50 quail (parent) = 42 mg/kg.So, in rats the metabolite is 2.9 times less toxic than the parent. It is not appropriate to multiply the quailLD 50 (parent) by 2.9 because that would imply an undue level of accuracy. However, it would bereasonable in most cases to assume that also in birds the metabolite is not more toxic than the parentcompound.Should testing become necessary an acute oral study would be the first choice to serve as a bridgingstudy, that is, to compare the inherent toxicity of the metabolite with that of the parent compound.18.3. Classification of mixtures: generic guidanceJanuary 2012 EPA0109