NTP Toxicology and Carcinogenesis Studies of Dimethyl Morpholinophosphoramidate (CAS No. 597-25-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Dimethyl morpholinophosphoramidate (DMMPA, greater than 99% pure) was developed for use as a simulant for the physical (but not biologic) properties of anticholinesterase agents in chemical defense training. Because of the potential for human exposure, the toxicity and carcinogenicity of DMMPA were investigated. Fourteen-day and 13-week studies were conducted to determine short-term toxicity, to identify target organs, and to establish doses for the 2-year toxicology and carcinogenesis studies. In the 14-day studies, groups of five male and five female F344/N rats were administered DMMPA in corn oil by gavage daily at 0, 313, 1,250, 2,500, or 5,000 mg/kg body weight for 14 consecutive days. All the rats receiving DMMPA at 2,500 or 5,000 mg/kg, except one male receiving 5,000 mg/kg, died before the end of the studies. Rats receiving DMMPA at doses of 1,250 mg/kg or less survived. The final mean body weights of the surviving dosed rats were within +/- 8% of those of the vehicle controls. Compound-related gross lesions were not found at necropsy. Groups of five B6C3F1 mice of each sex were given DMMPA by the same route on the same schedule at 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. All the mice given DMMPA at 2,000 or 4,000 mg/kg died before the end of the studies. Mice administered DMMPA at doses of 1,000 mg/kg or less survived. The final mean body weight of the male mice given DMMPA at 1,000 mg/kg was 14% greater than that of the vehicle controls, whereas that of the other dosed survivors was within 10% of that of the vehicle controls. Compound-related gross lesions were not found at necropsy. In the 13-week studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given DMMPA by gavage in corn oil at 0, 200, 400, 1,200, or 1,600 mg/kg body weight, 5 days per week for 13 weeks. All rats given DMMPA at 400 mg/kg or less survived, and no more than 3/10 died in any of the higher dose groups. The final mean body weights of the dosed male rats were 6% to 11% greater than that of the vehicle controls; weights of the dosed female rats were similar to that of the vehicle controls (-6% to 1%). There was a dose-related increase in liver weight/body weight ratio. All the mice given DMMPA at 1,600 mg/kg, except one female, died before the end of the 13-week studies; mice receiving DMMPA at 1,200 mg/kg or less survived. The final mean body weights of the dosed male mice were 3.4% to 6.9% greater than that of the vehicle controls. The final mean body weights of dosed female mice and vehicle controls were similar. Compound-related gross or histopathologic changes were not observed in rats or mice. In the 2-year toxicology and carcinogenesis studies, groups of 50 male and 50 female F344/N rats were given DMMPA in corn oil by gavage at doses of 0, 150, 300, or 600 mg/kg body weight, 5 days per week for 103 weeks. Groups of 50 male B6C3F1 mice were given DMMPA at 0, 150, 300 mg/kg body weight, and groups of 50 female B6C3F1 mice were given DMMPA at 0, 300, 600 mg/kg body weight on the same schedule. Doses of 300 or 600 mg/kg were originally selected for male mice for the 2-year study; because 19/50 high dose male mice died by week 19, all male mice were killed and doses of 0, 150, and 300 mg/kg were selected for the restart of the 2-year study in male mice. The survival of high dose male (22/50) and female (24/50) rats was reduced (P<0.025) relative to that of the male (37/50) and female (36/50) vehicle controls. Mean body weights were less than 10% lower in the mid dose and high dose male rats and in the high dose female rats than in the vehicle controls. DMMPA administration did not significantly affect body weight gain or survival of male and female mice. At the 600 mg/kg dose, increased (P<0.05) incidences of mononuclear cell leukemia occurred in both male rats (vehicle control, 14/50; 150 mg/kg, 21/50; 300 mg/kg, 19/50; 600 mg/kg, 25/50) and female rats (9/50; 13/50; 12/49; 18/50). DMMPA-related neoplastic or nonneoplastic lesions were not observed in the dosed mice. DMMPA was not mutagenic in strains TA100, TA1535ns were not observed in the dosed mice. DMMPA was not mutagenic in strains TA100, TA1535, TA1537, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. DMMPA was mutagenic in the L5178Y/TK&plusmn; mouse lymphoma assay in the absence of S9; it was not tested in the presence of S9. DMMPA induced chromosomal aberrations and sister-chromatid exchanges in Chinese hamster ovary cells in the absence of S9, but cytogenetic effects were not observed in the presence of Aroclor 1254-induced rat liver S9. An audit of the experimental data for these 2-year carcinogenesis studies on DMMPA was conducted. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenicity for male and female F344/N rats given dimethyl morpholinophosphoramidate, as indicated by increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for male and female B6C3F1 mice given dimethyl morpholinophosphoramidate at doses of 150 (male), 300, or 600 (female) mg/kg for 2 years. Synonyms: dimethyl morpholinophosphonate; phosphonic acid, morpholino, dimethyl ester; DMMPA; phosphonic acid, 4-morpholinyl-, dimethyl ester