title: NTP Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol (FR-1138(R)) (CAS No. 3296-90-0) in F344 Rats and B6C3F1 Mice (Feed Studies).
abstract: 2,2-Bis(bromomethyl)-1,3-propanediol is used as a fire retardant in unsaturated polyester resins, in molded products, and in rigid polyurethane foam. 2,2-Bis(bromomethyl)-1,3-propanediol was chosen for study because it is a widely used flame retardant and little toxicity and carcinogenicity data were available. Groups of male and female F344/N rats and B6C3F1 mice were exposed to technical grade 2,2-bis(bromomethyl)-1,3-propanediol (78.6% pure) in feed for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 400, 800, or 1,700 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 100, 200, 400, 800, or 1,600 mg/kg (females). No rats died during the studies. The final mean body weights and weight gains of 5,000, 10,000, and 20,000 ppm males and females were significantly lower than those of the controls. Feed consumption by exposed animals was lower than that by controls at week 1, but was generally similar to or slightly higher than that by controls at week 13. No chemical-related clinical findings were observed. Chemical-related differences in clinical pathology parameters included increased urine volumes accompanied by decreased urine specific gravity and minimally increased protein excretion in 10,000 and 20,000 ppm males. In females, urine parameters were less affected than males. Water deprivation tests demonstrated that male and female rats were able to adequately concentrate their urine in response to decreased water intake. Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and higher were slightly lower than those of the controls. Renal papillary degeneration was present in 5,000 and 10,000 ppm males, and in 20,000 ppm males and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 500, 1,300, or 3,000 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 140, 300, 600, 1,200, or 2,900 mg/kg (females). One control female, two males and one female receiving 625 ppm, one female receiving 1,250 ppm, one female receiving 2,500 ppm, one female receiving 5,000 ppm, and three males receiving 10,000 ppm died during the study. The final mean body weights and body weight gains of males and females receiving 1,250, 2,500, 5,000, or 10,000 ppm and of females receiving 625 ppm were significantly lower than those of the controls. Feed consumption by exposed mice was generally higher than that by controls throughout the study. Clinical findings included abnormal posture and hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen concentrations of 5,000 ppm females and 10,000 ppm males and females were greater than those of controls. Also, urine specific gravity was lower in 10,000 ppm females. Differences in organ weights generally followed those in body weights. Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the kidneys of 2,500 and 5,000 ppm males and 10,000 ppm males and females. Urinary bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 weeks. Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. A stop-exposure group of 70 male rats received 20,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 3 months, after which animals received undosed feed for the remainder of the 2-year styear study. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200, or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. Stop-exposure males received an average daily dose of 800 mg/kg. Ten animals from the 0 ppm male group and the 20,000 ppm stop-exposure group were evaluated at 3 months; nine or 10 control animals and five to nine animals from each of the continuous-exposure groups were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 5,000 and 10,000 ppm continuous-exposure study males and females and 20,000 ppm stop-exposure males was significantly lower than that of the controls. Mean body weights of exposed male and female rats receiving 10,000 ppm and stop-exposure males receiving 20,000 ppm were lower than those of the controls throughout most of the study. In the continuous-exposure study, feed consumption by exposed rats was generally similar to that by controls throughout the study. In 20,000 ppm stop-exposure males, the feed consumption was lower than that by controls. Clinical findings included skin and/or subcutaneous masses on the face, tail, and the ventral and dorsal surfaces of exposed rats. Pathology Findings: In the 2-year continuous and stop-exposure studies in male rats, exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the skin, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, hematopoietic system, and seminal vesicle. Nonneoplastic effects in the kidney, lung, thyroid gland, seminal vesicle, pancreas, urinary bladder, and forestomach were also observed. In females, 2-year exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the oral cavity, esophagus, mammary gland, and thyroid gland. Nonneoplastic effects in the kidney were also observed. These findings are outlined in the two summary tables. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males) and 40, 80, or 170 mg/kg (females). Eight to 10 animals from each group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 1,250 ppm males and females was significantly lower than that of the controls. Mean body weights of exposed male and female mice were similar to controls throughout the study. Final mean body weights were also generally similar to those of controls. Feed consumption by exposed male and female mice was similar to that by controls. Clinical findings included tissue masses involving the eye in exposed mice. Pathology Findings: Exposure of male mice to 2,2-bis(bromomethyl)-1,3-propanediol for 2 years was associated with neoplastic effects in the harderian gland, lung, and kidney. Exposure of female mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with increased incidences of neoplasms of the harderian gland, lung, and skin. Nonneoplastic effects in the lung were also observed in exposed females. These findings are outlined in the two summary tables. GENETIC TOXICOLOGY: 2,2-Bis(bromomethyl)-1,3-propanediol was mutagenic in Salmonella typhimurium strain TA100 when tested in the presence of induced 30&percnt; hamster liver S9; all other strain/activation combinations gave negative results. In cultured Chinese hamster ovary cells, 2,2-bis(bromomethyl)-1,3-propanediol induced chromosomal aberrations only in the presence of S9; no induction of sister chromatid exchanges was observed in cultured Chinese hamster ovary cells after treatment with 2,2-bis(bromomethyl)-1,3-propanediol, with or without S9. In vivo, 2,2-bis(bromomethyl)-1,3-propanediol induced significant increases in the frequencies of micronucleated erythrocytes in male and female mice. Significant increases in micronuclei were observed in peripheral blood samples from male and female mice exposed to 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks via dosed feed. Results of a bone marrow micronucleus test in male mice, where 2,2-bis(bromomethyl)-1,3-propanediol was administered by gavage, were considered to be equivocal due to inconsistent results obtained in two trials. An additional bone marrow micronucleus test was performed with male and female mice and 2,2-bis(bromomethyl)-1,3-propanediol was administered as a single intraperitoneal injection; results of this test were positive in females and negative in males. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on increased incidences of neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal vesicle, and the increased incidence of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female F344/N rats based on increased incidences of neoplasms of the oral cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and subcutaneous tissue. Slight increases in the incidences of neoplasms of the pancreas and kidney in male rats; forestomach in male mice; and forestomach, mammary gland, and circulatory system in female mice may have also been related to treatment. Exposure of male and female rats to 2,2-bis(bromomethyl)-1,3-propanediol was associated with alveolar/bronchiolar hyperplasia in the lung (males only); focal atrophy, papillary degeneration, transitional epithelial hyperplasia (pelvis), and papillary epithelial hyperplasia in the kidney; follicular cell hyperplasia in the thyroid gland (males only); hyperplasia in the seminal vesicle and pancreas (males only); mucosal hyperplasia in the forestomach (males only); and urinary bladder hyperplasia (males only). Exposure of mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with hyperplasia of the alveolar epithelium in females. Synonyms: 2,2-Bis(2-bromomethyl)-1,3-propanediol; 1,3-dibromo-2,2-dihydroxymethylpropane; 1,3-dibromo-2,2-dimethylolpropane; 2,2-dibromomethyl-1,3-propanediol; dibromopentaerythritol; dibromoneopentyl glycol; pentaerythritol dibromide; pentaerythritol dibromohydrin