Peter J. Becci

Teratogenicity study of N-methylpyrrolidone after dermal application to Sprague-Dawley rats.

Teratogenicity studies were performed in rats given N-methylpyrrolidone, a solvent used in chemical processing. Dosages of 75,237 and 750 mg of N-methylpyrrolidone/kg body weight/day were administered dermally to groups of 25 pregnant Sprague-Dawley rats on days 6 through 15 of gestation. Additionally, the study used a positive dermal control. Hexafluoroacetone, was chosen based on its dermal teratogenic activity. An oral positive control, aspirin, was included in order to add significance to the data generated in the experimental positive dermal control group. All animals were killed and subjected to uterine examination on day 20 of gestation. Maternal toxicity was indicated at 750 mg of N-methylpyrrolidone/kg by reduced body weight gain during gestation. Treatment with N-methylpyrrolidone resulted in dose-dependent brightly colored yellow urine and dry skin. Treatment at the high dosage level resulted in fewer live fetuses per dam, an increase in the percentage of resorption sites and skeletal abnormalities. These effects could be the result of maternal toxicity. There was no evidence of teratogenic effects nor effects on the dams at 75 and 237 mg/kg of body weight.

Subchronic Feeding Study of N,N-Dimethylformamide in Rats and Mice

Wistar rats (25/ sex • group) and CD-1 mice (30/sex • group) were fed either a control diet or diet supplemented with N,N-dimethylformamide at the levels of 215, 750, and 2500 ppm for rats and 160,540, and 1850 ppm for mice. The duration of feeding was 104 days for rats and 119 days for mice. Body weight gain, food consumption, hematological and clinical chemical data, ophthalmic, gross, and microscopic examinations were used to study possible toxic or pathologic effects. A significant reduction in body weight gain was noted for male and female rats at the high dosage level. Food consumption in male rats at the high-dosage level and female rats at both the middle- and high-dosage levels was decreased. A significant dose-related increase in relative liver weights was noted in male and female rats. Absolute liver weights of male rats were comparable among groups, however, a dose-related increase was noted in female rats. No significant differences among groups were noted in body weight and food consumption data for mice. A significant dose-related increase in relative and absolute liver weights was noted in male and female mice. Histopathological evaluation revealed no evidence of a toxic effect related to feeding of N.N-dimethylformamide to Wistar rats and CD-1 mice. The increase in liver weight is considered to be a normal phenomenon (physiological adaptation) required for the biotransformation of N,N-dimethylformamide. The lack of hepatotoxicity in the present study may be the result of feeding N,N-dimethylf ormamide over waking hours versus bolus dosing (in other studies) in which hepatotoxicity was noted.

Teratogenesis study of N-cyclohexyl-2-pyrrolidone in rats and rabbits

Teratogenesis studies were performed in rats and rabbits given N-cyclohexyl-2-pyrrolidone, an aprotic solvent used in chemical processing. Dosages of 0, 15, 50, 150, or 500 mg N-cyclohexyl-2-pyrrolidone/kg body wt/day were administered by gavage to groups of 25 pregnant Sprague-Dawley rats on Days 6 through 15 of gestation. Dosages of 0, 10, 30, 100, or 300 mg/kg/day were administered by gavage to groups of at least 15 pregnant Dutch-Belted rabbits on Days 6 through 18 of gestation. Animals were killed and subjected to uterine examination on Day 20 of gestation for rats and on Day 29 for rabbits. There were no significant differences between the vehicle control and N-cyclohexyl-2-pyrrolidone-treated groups for implantation numbers or live or dead fetuses, resorptions, and fetal body weight in rats and rabbits. Dam body weight gain during gestation was comparable among groups. External gross visual examination of the fetus as well as examination of skeletal and soft tissues revealed no effects related to treatment with N-cyclohexyl-2-pyrrolidone.

Teratogenesis study of o-toluenediamine in rats and rabbits.

o-Toluenediamine in corn oil was administered po to Sprague-Dawley rats at dosages of 10, 30, 100, or 300 mg/kg body wt/day during Days 6 through 15 of gestation. All animals were killed on Day 20 of gestation. A similar study was conducted with Dutch-Belted rabbits dosed po daily at 3, 10, 30, or 100 mg of o-toluenediamine/kg body wt/day from Days 6 through 18 of gestation. Rabbits were killed on Day 29 of gestation. Maternal toxicity was indicated at 300 mg/kg in rats and 100 mg/kg in rabbits by reduced body weight gain during gestation. Fetal body weight was reduced at the highest dosage in both rats and rabbits. In addition, at the high dosage, an increase in the number of resorption sites in rabbits were noted. Skeletal examination of rats showed increased incidence of missing sternebrae at 300 mg/kg and incompletely ossified vertebrae at 100 and 300 mg/kg in comparison to control fetuses. The effects on the fetus could be the result of maternal toxicity. There was no evidence of teratogenic effects or effects on the dams at dosages through 30 mg/kg body wt.