title: Toxicology and carcinogenesis studies of formamide (Cas No. 75-12-7) in F344/N rats and B6C3F1 mice (gavage studies).
abstract: Formamide is used as a softener for paper, gums, and animal glues; as an ionizing solvent; and in the manufacture of formic esters and hydrocyanic acid. Formamide was nominated for reproductive and genetic toxicity evaluation by the Environmental Defense Fund and for carcinogenicity evaluation by the National Cancer Institute because of the potential for human exposure associated with its widespread industrial use, the absence of data adequately characterizing its potential for reproductive and genetic toxicity, and the fact that acetamide, a compound structurally related to form-amide, is hepatocarcinogenic in rats when administered in feed. Male and female F344/N rats and B6C3F1 mice were administered formamide (approximately 100% pure) in deionized water by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, Drosophila melanogaster, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 10, 20, 40, 80, or 160 mg formamide/kg body weight in deionized water by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) and five male and five female rats (plasma concentration study) were administered the same doses, 5 days per week for up to 14 weeks. All core study rats survived to the end of the study. Mean body weights of females in the 40 mg/kg group and males and females in the 80 and 160 mg/kg groups were significantly less than those of the vehicle controls. On day 23 and at week 14, there was a dose-related increase in the erythron, evidenced by increases in hematocrit values, hemoglobin concentrations, and erythrocyte counts. The incidences of degeneration of the germinal epithelium of the testes and epididymis were significantly increased in 160 mg/kg males. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 10, 20, 40, 80, or 160 mg formamide/kg body weight in deionized water by gavage, 5 days per week for 14 weeks. Additional groups of five male and five female mice (plasma concentration study) were administered the same doses, 5 days per week for 14 weeks. All mice survived to the end of the study. Final mean body weights of the 80 and 160 mg/kg males and mean body weight gains of 40, 80, and 160 mg/kg males were significantly less than those of the vehicle controls. Dosed females differed significantly from vehicle controls in the relative amount of time spent in the estrous stages. All 160 mg/kg males had abnormal residual bodies in the testes. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 20, 40, or 80 mg formamide/kg body weight, 5 days per week for 104 to 105 weeks in deionized water by gavage. Survival of all dosed groups of rats was similar to that of the vehicle controls. Mean body weights of 80 mg/kg males were less than those of the vehicle controls throughout most of the study. Mean body weights of 40 and 80 mg/kg females were somewhat less than those of the vehicle controls during the second year of the study. A significant increase in the incidence of bone marrow hyperplasia occurred in 80 mg/kg males. No neoplasms were attributed to exposure to formamide. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 20, 40, or 80 mg formamide/kg body weight, 5 days per week for 104 to 105 weeks in deionized water by gavage. Survival of all dosed groups of mice was similar to that of the vehicle controls. Mean body weights of 80 mg/kg males and females were generally less than those of the vehicle controls throughout the study; mean body weights of 40 mg/kg females were generally less after week 13 of the study. The incidences of hemangiosarcoma of the liver occurred with a positive trend in males, and the incidences were significantly increased in the 40 and 80 mg/kg groups. The incidence of hepatocellular adenoma or carcinoma (combined) in 80 mg/kg females was significantly increased. The incidences of mineralization of the testicular arteries and testicular tunic were significantly increased in 80 mg/kg males. The incidence of hematopoietic cell proliferation of the spleen was significantly increased in 80 mg/kg males.
  
  
  RESULTS
  Formamide gave no evidence for mutagenicity in a series of short-term assays. In three independent Ames assays, formamide was not mutagenic in any of several strains of S. typhimurium tested with and without rat or hamster liver S9 activation enzymes or in E. coli strain WP uvrA pKM101 tested with and without 10% rat liver S9. Negative results were obtained in a test for induction of sex-linked recessive lethal mutations in germ cells of male D. melanogaster treated with formamide either by feeding or injection. Formamide did not induce increases in micronucleated erythrocytes in male or female mice treated by gavage for 3 months.
  
  
  CONCLUSIONS
  Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of form-amide in male or female F344/N rats administered 20, 40, or 80 mg/kg. There was clear evidence of carcinogenic activity of formamide in male B6C3F1 mice based on increased incidences of hemangiosarcoma of the liver. There was equivocal evidence of carcinogenic activity of formamide in female B6C3F1 mice based on increased incidences of hepatocellular adenoma or carcinoma (combined). An increased incidence of bone marrow hyperplasia occurred in male rats. Mineralization of the testicular arteries and tunic and hematopoietic cell proliferation of the spleen in male mice were also associated with administration of formamide.
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002114:Calcinosis / Q000139:chemically induced / Q000473:pathology; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005559:Formamides / Q000633:toxicity*; D006965:Hyperplasia; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests
chemical_list: D004785:Environmental Pollutants; D005559:Formamides; C031066:formamide