Re‐evaluation of the big blue® mouse assay of propiconazole suggests lack of mutagenicity

Abstract

Propiconazole (PPZ) is a conazole fungicide that is not mutagenic, clastogenic, or DNA damaging in standard in vitro and in vivo genetic toxicity tests for gene mutations, chromosome aberrations, DNA damage, and cell transformation. However, it was demonstrated to be a male mouse liver carcinogen when administered in food for 24 months only at a concentration of 2,500 ppm that exceeded the maximum tolerated dose based on increased mortality, decreased body weight gain, and the presence of liver necrosis. PPZ was subsequently tested for mutagenicity in the Big Blue® transgenic mouse assay at the 2,500 ppm dose, and the result was reported as positive by Ross et al. ([2009]: Mutagenesis 24:149-152). Subsets of the mutants from the control and PPZ-exposed groups were sequenced to determine the mutation spectra and a multivariate clustering analysis method purportedly substantiated the increase in mutant frequency with PPZ (Ross and Leavitt. [2010]: Mutagenesis 25:231-234). However, as reported here, the results of the analysis of the mutation spectra using a conventional method indicated no treatment-related differences in the spectra. In this article, we re-examine the Big Blue® mouse findings with PPZ and conclude that the compound does not act as a mutagen in vivo.

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“…The observed mutagenicity could not be explained by the target chemicals detected in gammarids. Although weak mutagenic activities have been reported for the insecticide imidacloprid and the industrial chemical 1H-benzotriazole 94,95 in different in vitro assays and propiconazole, a nonmutagenic fungicide, has been demonstrated to exert carcinogenic effects after long-term exposure, 96 these chemicals are probably contributing only a minor extent to the observed effect.…”