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.

FURTHER STUDIES ON THE ENDOCRINE CONDITIONING OF THE HEPARIN-INDUCED LIPEMIA CLEARING ACTIVITY (LCA) IN THE RAT

The effects of various endocrines and of stress on the "lipemia clearing activity" (LCA) which is elicited in rat plasma by intravenous heparin injection were studied.High dosage cortisone accelerated LCA, but low dosage cortisone did not affect it. Severe catabolic stress accelerated LCA. Application of a single mild stress was ineffective, but the combination of two mild stressors accelerated LCA. ACTH had no influence on LCA, but adrenalectomy accelerated it. Stilbestrol inhibited LCA at both a low and a high dosage level, but there was no difference in LCA production between males and females or between estrous and diestrous females. Estrous females, however, displayed less LCA than ovariectomized females. Anterior pituitary extract inhibited LCA in females and hypophysectomy accelerated it in both sexes. A synthetic oil emulsion yielded the same qualitative information as lipemic plasma wherever it was used as a substrate for the clearing activity of postheparin plasma.Thus, with the exception of the effects of sex difference and low dosage cortisone, most of the previously reported endocrine effects on the LCA that follows subcutaneous heparin were also obtained when heparin was injected intravenously. The physiological significance of these findings is discussed.

FURTHER STUDIES ON THE ENDOCRINE CONDITIONING OF THE HEPARIN-INDUCED LIPEMIA CLEARING ACTIVITY (LCA) IN THE RAT

The effects of various endocrines and of stress on the "lipemia clearing activity" (LCA) which is elicited in rat plasma by intravenous heparin injection were studied.High dosage cortisone accelerated LCA, but low dosage cortisone did not affect it. Severe catabolic stress accelerated LCA. Application of a single mild stress was ineffective, but the combination of two mild stressors accelerated LCA. ACTH had no influence on LCA, but adrenalectomy accelerated it. Stilbestrol inhibited LCA at both a low and a high dosage level, but there was no difference in LCA production between males and females or between estrous and diestrous females. Estrous females, however, displayed less LCA than ovariectomized females. Anterior pituitary extract inhibited LCA in females and hypophysectomy accelerated it in both sexes. A synthetic oil emulsion yielded the same qualitative information as lipemic plasma wherever it was used as a substrate for the clearing activity of postheparin plasma.Thus, with the exception of the effects of sex difference and low dosage cortisone, most of the previously reported endocrine effects on the LCA that follows subcutaneous heparin were also obtained when heparin was injected intravenously. The physiological significance of these findings is discussed.