Genotoxicity of 4,4′-methylenedianiline in the context of liver damage in rodents

4,4'-Methylenedianiline (MDA) is currently regarded as a non-threshold carcinogen based on its harmonized classifications as suspected mutagen and presumed human carcinogen in Annex VI of Regulation (EC) No 1272/2008 (CLP). The available in vivo studies with MDA in rodents report genotoxicity mainly in the liver - where MDA also causes tissue damage after single and repeated exposure - and often do not provide a detailed evaluation of potentially confounding hepatotoxic effects. To gain clarity regarding the specificity of MDA's genotoxic effects in the context of general tissue toxicity, we performed new genotoxicity studies in rats and mice. Several target organs were investigated in both species with regard to gene mutations or chromosomal damage, with concomitant analyses of target organ toxicity by means of histopathology and clinical chemical markers. Of all effects and tissues examined, MDA only induced formation of micronuclei in the liver at doses causing severe body weight decrements and adverse histopathological changes. The results support that MDA, in chronic studies, acts as a liver tumor promoter via cytotoxicity and regenerative proliferation rather than as a direct genotoxic carcinogen that is presumed to have no threshold.