NTP Toxicology and Carcinogenesis Studies of 2,3-Dibromo-1-Propanol (CAS No. 96-13-9) in F344/N Rats and B6C3F1 Mice (Dermal Studies).
2,3-Dibromo-l-propanol, a colorless liquid, has been used as a flame retardant, as an intermediate in the preparation of the flame retardant tris(2,3-dibromopropyl) phosphate, and as an intermediate in the manufacture of pesticides and pharmaceutical preparations. Toxicology and carcinogenicity studies were conducted by applying 2,3-dibromo-1-propanol (approximately 98% pure) in ethanol to the subscapular area of the skin of male and female F344/N rats and B6C3F1 mice 5 days per week for 16 days, 13 weeks, 48 to 51 weeks (male rats), 52 to 55 weeks (female rats), 36 to 39 weeks (male mice), or 39 to 42 weeks (female mice). Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, mouse Iymphoma cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS Groups of five male and five female rats received dermal applications of 0, 44, 88, 177, 375, or or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 16 days. One male and one female receiving 750 mg/kg died before the end of the study. The mean body weight gains and final mean body weights of dosed rats were similar to those of the controls. There were no clinical findings or gross lesions associated with chemical application. 16-DAY STUDY IN MICE Groups of five male and five female mice received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 16 days. Four males and one female receiving 750 mg/kg died before the end of the study. The mean body weight gains and final mean body weights of dosed mice were similar to those of the controls. There were no clinical findings or gross lesions associated with chemical application. 13-WEEK STUDY IN RATS Groups of 10 male and 10 female rats received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 13 weeks. All rats survived until the end of the for 16 days. One male and one female receiving study. For rats in the 750 mg/kg groups, the mean 750 mg/kg died before the end of the study. The body weight gain was 11% lower than that of the controls for males and 13% lower for females. The mean liver weights and liver-weight-to-body-weight ratios of males receiving 375 or 750 mg/kg and of females receiving 750 mg/kg were increased. Chemical-related lesions occurred in the kidney of male rats and in the liver of female rats. The average severity of nephropathy was slightly increased in males receiving dermal applications of 750 mg/kg, while individual cell necrosis was observed in the liver of all female rats in the 750 mg/kg group. 13-WEEK STUDY IN MICE Groups of 10 male and 10 female mice received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 13 weeks. Eight male mice receiving 750 mg/kg died during the study, while all female mice survived. The final mean body weights of dosed and control mice were similar. The mean liver weights and liver weight-to-body-weight ratios of males receiving 375 or 750 mg/kg and of females receiving 750 mg/kg were increased. Chemical-related lesions occurred in the liver and lung of mice. Centrilobular hepatocellular necrosis occurred in all males in the 750 mg/kg group that died during the study, while individual cell necrosis was observed in the liver of females receiving 177, 375, or 750 mg/kg. Pleomorphism of the epithelium in pulmonary bronchioles occurred with a dose related increased incidence in males and females. Necrosis of the bronchiolar epithelium was observed in males receiving 750 mg/kg. LONG-TERM STUDY IN RATS Originally planned to last for 2 years, the chronic study in rats was terminated early because of reduced survival in the high-dose groups related to chemical induced neoplasms and because of the detection of antibodies to Iymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female rats received dermal applications of 0,188, or 375 mg/kg 2,3-dibromo-1-propanol 5 days per week for 48 to 51 weeks (males) or 52 to 55 weeks (females). Su5 weeks (females). Survival, Body Weights, and Clinical Findings The survival of 375 mg/kg male and female rats was significantly lower than that of the controls (males: 50/50, 41/50,16/50; females: 48/50, 38/50, 24/50). In the 375 mg/kg groups, the final mean body weight was 23&percnt; lower than that of the controls for males and 14&percnt; lower for females. There were no chemical related clinical findings. Pathology Findings Application of 2,3-dibromo-1-propanol to the skin produced significant dose-related increases in the incidences of neoplasms at numerous sites in male and female rats. Almost all dosed rats had malignant neoplasms; only one control male and one control female had malignant neoplasms. In male rats, the incidences of benign or malignant neoplasms of the skin, nose, Zymbal's gland, oral mucosa, esophagus, and small and large intestines were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the forestomach and liver were significantly increased only in the high-dose group. Neoplasms of the kidney, vascular neoplasms of the spleen, and mesotheliomas in males occurred with a significant positive trend. In female rats, the incidences of benign or malignant neoplasms of the nose, Zymbal's gland, oral mucosa, esophagus, large intestine, and liver were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the skin, forestomach, small intestine, mammary gland, and clitoral gland were significantly increased in the high-dose group only. Neoplasms of the kidney in females occurred with a significant positive trend. LONG-TERM STUDY IN MICE Originally planned to last for 2 years, the chronic study in mice was terminated early because of the detection of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female mice received dermal applications of 0, 88, or 177 mg/kg 2,3-dibromo-1-propanol 5 days per week for 36 to 39 weeks (males) or 39 to 42 weeks (females). Survival, Body Weights, and Clinical Findings All mice (except two low-dose females) survived until study termination. Mean body weights of control and dosed mice were similar throughout the study, and there were no clinical findings attributed to 2,3-dibromo-l-propanol. Pathology Findings Application of 2,3-dibromo-1-propanol to the skin produced significant dose-related increases in the incidences of neoplasms at several sites in male and female mice. Benign or malignant neoplasms were observed in 40&percnt; of the low-dose males, 66&percnt; of the high-dose males, 52&percnt; of the low-dose females, and 56&percnt; of the high-dose females. In control groups, neoplasms occurred in 6&percnt; of the males and 10&percnt; of the females. In male and female mice, the incidences of benign or malignant neoplasms of the forestomach were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the skin were significantly increased only in the high-dose groups. The incidences of liver and lung neoplasms were increased in high-dose males. GENETIC TOXICOLOGY 2,3-Dibromo-l-propanol was mutagenic in a variety of short-term tests, independent of exogenous metabolic activation (S9). It induced gene mutations in three strains of Salmonella typhimurium (TA98, TA100, and TA1535) and was positive in the mouse Iymphoma assay for induction of trifluorothymidine resistance in L5178Y cells. 2,3-Dibromo-l-propanol induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. In germ cells of male Drosophila melanogaster, 2,3-dibromo-1-propanol induced sex-linked recessive lethal mutations and reciprocal translocations. Results of an in vivo bone marrow micronucleus assay in male mice treated with 2,3-dibromo-1-propanol were negative. CONCLUSIONS Under the conditions of these long-term dermal studies, there was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in male F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, tunica vaginalis, and spleen. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, clitoral gland, and mammary gland. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in male B6C3F1 mice based on increased incidences of neoplasms of the skin, forestomach, liver, and lung. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female B6C3F1 mice based on increased incidences of neoplasms of the skin and the forestomach. The increased incidences of alveolar/bronchiolar adenomas in female mice may have been related to chemical administration. In rats, 2,3-dibromo-1-propanol caused increased incidences of hyperkeratosis in the skin, forestomach, and esophagus, epithelial dysplasia in the nose, pleomorphism and basophilic and clear cell changes in the liver, and nuclear enlargement in the kidney. There were also chemical-related increases in the incidences of forestomach ulcers and acanthosis, angiectasis in the liver, and renal hyperplasia in male rats and epithelial dysplasia of the forestomach and bile duct hyperplasia in the liver in female rats. Chemical-related increases occurred in the incidences of hyperplasia in the skin, epithelial dysplasia of the forestomach, and bronchiolar epithelial pleomorphism and hyperplasia in male and female mice and in the incidence of eosinophilic cytoplasmic change in the liver in males. Synonyms: 2,3-dibromopropanol; 2,3-dibromopropyl alcohol.