Following adoption of the new OECD test guideline (TG) 474 for the in vivo mammalian erythrocyte micronucleus (MN) test (29 July 2016), demonstration of exposure of target tissue (bone marrow) is required, if the test result is negative i.e. no cytogenetic damage. It implies that for many active ingredients, relevant metabolites or significant impurities with existing in vivo MN tests resulting in negative genotoxicity findings, evidence of target tissue exposure may be lacking and is considered a data gap in regulatory reviews. We present here toxicokinetic (TK) testing strategies for the design and conduct of studies that would demonstrate evidence of delivery of the test substance to the bone marrow. To illustrate this, three examples are presented with methods utilized under each scenario. We also propose a decision tree that may help design suitable TK studies to establish evidence of bone marrow exposure.

中文翻译：

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毒性动力学测试策略，可在体内微核研究中证明骨髓暴露，以评估农用化学品的遗传毒性。

在针对体内哺乳动物红细胞微核（MN）测试采用新的OECD测试准则（TG）474之后（2016年7月29日），如果测试结果为阴性（即否），则需要证明目标组织（骨髓）的暴露情况细胞遗传学损伤。这意味着对于许多活性成分，相关代谢物或现有的体内MN测试导致显着的遗传毒性结果的重大杂质，可能缺乏目标组织暴露的证据，被认为是监管审查中的数据空白。我们在此介绍用于设计和进行研究的毒物动力学（TK）测试策略，这些策略将证明将测试物质输送到骨髓的证据。为了说明这一点，给出了三个示例以及在每种情况下使用的方法。