Methylene dianiline-induced liver toxicity supporting cytotoxicity-regenerative repair key events of parenchymal and non-parenchymal cells

Lifetime 4,4'-methylenedianiline (MDA) administration culminates in hepatic neoplastic nodules in male F344 rats. Numerous published studies demonstrate MDA-induced periportal/bile duct region pathology that eventually spreads throughout the acinus. Severe reductions in body weight gain, and food and water intake accompany MDA-induced liver injury. This paper presents the results of a 90-day drinking water and a 14/28-day oral gavage study of MDA in rats. The 90-day study demonstrated decreased drinking water and food consumption, resulting in severe body weight gain reductions. Male and female rats developed liver pathology and hemolytic anemia. The 14/28-day administration results consisted of adverse clinical changes, increased periportal and lobular pathology findings, increased cell death, cell proliferation, and stellate cell and macrophage activation accompanied by evidence of hemolytic anemia. No increase in activation of selected nuclear receptors, DNA damage or carcinogenesis-related biological pathways occurred. These findings support a cytotoxicity-induced, regenerative repair adverse outcome pathway (AOP) mode-of-action for hepatic neoplastic development that is well aligned with an OECD-adopted protein alkylation-hepatic fibrosis AOP.