NTP technical report on the toxicity studies of N,N-Dimethylformamide (CAS No. 68-12-2) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.

N,N-Dimethylformamide (DMF), a colorless liquid with a high boiling point, is a solvent used in a large number of industrial processes. Male and female F344/N rats (30/sex/group) and B6C3F1 mice (10/sex/group) were exposed to DMF vapors at concentrations of 0, 50, 100, 200, 400, or 800 ppm, 6 hours/day, 5 days/week, for 13 weeks in whole body exposure inhalation studies. In addition to histopathology, sperm morphology, and vaginal cytology, which were evaluated in both species, the studies examined clinical pathology, cardiovascular, and renal function in rats only. In genetic toxicity studies, DMF was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9 activation, nor did it induce germ cell mutations in male Drosophila melanogaster treated by feeding or injection. No induction of sister chromatid exchanges or chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated in vitro with DMF, with or without an S9 metabolic activation system. In one laboratory, a marginal increase in mutant colonies was observed after treatment of mouse lymphoma L5178Y/TK+/- cells with DMF in the absence of S9; results from studies in 2 other laboratories were negative. In the 13-week studies, all rats survived exposures to DMF. Body weight gains were reduced by 50-65% in rats exposed at 800 ppm and to a lesser extent in the 400 ppm group. Evidence of hepatocellular injury was noted as early as day 4, based on increases in activities of liver-specific enzymes in serum in rats of both sexes exposed at 200-800 ppm. Serum cholesterol levels were increased at all exposure concentrations. Relative liver weights were increased in male rats exposed at 100 ppm and higher concentrations, and in female rats at all concentrations. Minimal to moderate centrilobular hepatocellular necrosis was seen in rats of both sexes exposed at 400 and 800 ppm; the lesion was more severe in females. There were no clear, adverse effects seen in urinalyses, in electrocardiographic studies, or in male reproductive system evaluations that could be related to DMF exposure. Hematologic studies showed mild hemoconcentration in males and females. Prolonged diestrus was observed in females exposed at 800 ppm. Among mice exposed to DMF for 13 weeks, there was no chemically related mortality. Body weight gains were approximately 30% less than controls in females exposed at 800 ppm. Relative liver weights were increased in males and females at all exposure concentrations. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of male mice exposed to DMF, and in female mice exposed at 100 ppm and higher concentrations. The length of the estrous cycle in mice increased with increasing DMF exposure. In summary, DMF-related effects were seen in the liver of both rats and mice, with rats being more severely affected. For rats of both sexes, the no-observed-adverse-effect level (NOAEL) was 200 ppm, based on the absence of liver histopathology, although liver function assays and liver weights showed changes at all exposure levels (as low as 50 ppm). For mice, hepatocellular hypertrophy or increased liver weights occurred at all exposure concentrations. Synonyms: DMF, DMFA.