Application for the Reassessment of a Hazardous Substance under ...

12 MUTAGENICITY 6.6HSNO Classification: Mutagenicity – 6.6BKEY STUDY: NoneAs the classification for mutagenicity is based on the total weight of evidence available,there is no single key study.The minimum degrees of hazard criteria for mutagenicity lists a hierachy of evidence(study types): mutagenic effects as a result of mammalian in vivo exposure; genotoxiceffects as a result of mammalian in vivo exposure, with mutagenic effects as a result ofin vitro exposure; and, mutagenic effects as a result of in vitro exposure of mammaliancells, and the substance has a structure-activity relationship to known germ cellmutagens.Justification for Classification:Weight of evidence: There is an extensive genotoxicity database for dichlorvos.Negative results were reported in in vivo host-mediated, dominant lethal, sisterchromatid exchange and micronucleus assays (except on skin after local application atcytotoxic doses). Dichlorvos was reported not to induce in vivo chromosomalaberrations in bone-marrow cells, spermatocytes or spermatogonia, DNA strand breaksor unscheduled DNA synthesis. The negative in vivo genotoxicity results wereexplained by the rapid metabolism and inactivation of dichlorvos, which appears toprevent systemic exposure to intact dichlorvos at concentrations likely to lead to directmolecular interactions.However, dichlorvos has genotoxic potential at localised high concentrations and in theabsence of metabolism, demonstrated by micronucleus formation in mouse epidermalkeratinocytes after direct application of dichlorvos to the skin; an increase in themutation frequency in the liver of transgenic mice following repeated intraperitonealinjection; and, an increased incidence of hair follicle nuclear aberrations (NA) in CD1mice after a single application at 1/8 th the dermal LD 50 .Dichlorvos was mutagenic and DNA-reactive in bacteria and other microorganisms invitro, in both the presence and absence of exogenous metabolic activation (althougheffects were commonly reduced in the presence of exogenous metabolic activation).Dichlorvos was also mutagenic and clastogenic in a range of mammalian cells exposedin vitro, including induction of UDS but not chromosomal aberrations or SCE incultured human cells.Dichlorvos is an electrophile and stated to possess a structural alert formethylating activity. While dichlorvos possesses methylating activity, thephosphorous atom of the molecule is reported to be a stronger electrophile thanthe methyl carbon atoms (phosphorylating reactivity). In tissues and blood,dichlorvos is much more likely to react with “A”-type esterases, serumcholinesterase, or acetylcholinesterase than with DNA (ATSDR, 1997; APVMA,2008a).Dichlorvos reassessment – application Page 187 of 436