Toxicokinetic testing strategies to demonstrate bone marrow exposure in in vivo micronucleus study for genotoxicity assessment of agrochemicals

Abstract 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.