ToxSci Advance Access originally published online on March 7, 2003
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Toxicological Sciences 72, 347-358 (2003)
Copyright © 2003 by the Society of Toxicology
SAFETY EVALUATION |
Thirteen-Week Inhalation Toxicity of N,N-Dimethylformamide in F344/N Rats and B6C3F1 Mice
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* Biomonitoring and Health Assessment Branch, Division of Applied Research and Technology, National Institute for Occupational Safety and Health, 4676 Columbia Parkway, Cincinnati, Ohio 45226-1998; and
Battelle Columbus Laboratories, 505 King Ave., Columbus, Ohio 43201-2693
Male and female F-344 rats and B6C3F1 mice (10/sex/group) were exposed to N,N-dimethylformamide (DMF) by whole body inhalation exposure at 0, 50, 100, 200, 400, or 800 ppm, 6 h/day, 5 days/week, for 13 weeks. A concentration-dependent depression in body weight occurred in rats of both sexes at 400 (6–11%) and 800 ppm (20–22%). In contrast, all weight changes in both sexes of mice were within 10% of controls. No rats died, while 5 mice died from nonexposure-related causes. Relative liver weights were significantly increased at all DMF concentrations in both sexes and both species. Activities of serum sorbitol dehydrogenase (SDH) were statistically increased in male and female rats (200 to 800 ppm) on study days 4, 24, and 91 (13 weeks). Activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICD) were statistically increased in both sexes of rats exposed to 800 ppm DMF at all time points. Cholesterol (CHOL) levels were statistically increased in male and female rats (50–800 ppm) at all sampling time points. Levels of total bile acids (TBA) were statistically increased in both sexes of rats (400–800 ppm) on days 24 and 91. Centrilobular hepatocellular necrosis (minimal to moderate) was seen in rats of both sexes exposed at 400 and 800 ppm, with the lesions more severe in females. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of DMF-exposed male mice, and in female mice exposed at 100–800 ppm. For male and female rats the no-observed-adverse-effect concentration (NOAEC) for microscopic liver injury was 200 ppm. The NOAEC was 50 ppm for female mice, but an NOAEC based upon the absence of microscopic liver injury was not determined in male mice.
Key Words: dimethylformamide; DMF; 13-week inhalation study; hepatotoxicity; centrilobular hepatocellular necrosis; centrilobular hepatocellular hypertrophy.