Chronic Toxicity/Oncogenicity of Dimethylformamide in Rats and Mice Following Inhalation Exposure

Abstract

The potential chronic toxicity and oncogenicity of dimethylformamide (DMF) was evaluated by exposing male and female rats and mice to 0, 25, 100, or 400 ppm DMF for 6 hr/day, 5 days/week for 18 months (mice) or 2 years (rats). Clinical pathology was evaluated at 3, 6, 12, 18, and 24 (rats only) months. An interim euthanasia for rats occurred at 12 months and hepatic cell proliferation in rats and mice was examined at 2 weeks, 3 months, and 12 months. No compound-related effects on clinical observations or survival were observed. Body weights of rats exposed to 100 (males only) and 400 ppm were reduced. Conversely, body weights were increased in 400 ppm mice. No hematologic changes were observed in either species. Serum sorbitol dehydrogenase activity was increased in rats exposed to 100 or 400 ppm. There were no compound-related effects on the estrous cycle of rats or mice at any concentration. Compound-related morphological changes were observed only in the liver. In rats, exposure to 100 and 400 ppm produced increased relative liver weights, centrilobular hepatocellular hypertrophy, lipofuscin/hemosiderin accumulation in Kupifer cells, and centrilobular single cell necrosis (400 ppm only). In mice, increased liver weights (100 ppm males, 400 ppm both sexes), centrilobular hepatocellular hypertrophy, accumulation of lipofuscin/hemosiderin in Kupffer cells, and centrilobular single cell necrosis were observed in all exposure groups. These observations occurred in a dose-response fashion and were minimal at 25 ppm. No increase in hepatic cell proliferation was seen in mice or female rats. Slightly higher proliferation was seen in male rats exposed to 400 ppm at 2 weeks and 3 months but not at 12 months. Dimethylformamide was not oncogenic under these experimental conditions in either the rat or mouse.