Share This:
https://ntp.niehs.nih.gov/go/41452

Abstract for TR-587 - Tetrabromobisphenol A

Abstract

Toxicology Studies of Tetrabromobisphenol A (CASRN 79-94-7) in F344/NTac Rats and B6C3F1/N Mice and Toxicology and Carcinogenesis Studies of Tetrabromobisphenol A in Wistar Han [Crl:WI(Han)] Rats and B6C3F1/N Mice (Gavage Studies)

Link to the full study report in PDF. If you have difficulty accessing the document, please send email to the NTP Webmaster [ Send Email ] and identify documents/pages for which access is required.

Abstract

Tetrabromobisphenol A is a flame retardant used in epoxy resin circuit boards, in electronic enclosures (of polycarbonate-acrylonitrile-butadiene-styrene plastics), in paper, and in textiles. It may also be used as a chemical intermediate for the synthesis of other flame retardants. Tetrabromobisphenol A was nominated by the NIEHS for toxicity and carcinogenicity studies based on its high production volume, the potential for widespread human exposures, and the absence of standard toxicity and carcinogenicity studies reported in the scientific literature. Male and female F344/NTac rats and B6C3F1/N mice were administered tetrabromobisphenol A (purity of greater than 99%) in corn oil by gavage for 3 months, and male and female Wistar Han [Crl:WI(Han)] rats (referred to as Wistar Han rats) and B6C3F1/N mice were administered tetrabromobisphenol A (purity of approximately 99%) in corn oil by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.

3-MONTH STUDY IN F344/NTAC RATS

Groups of 10 male and 10 female core study rats were administered 0, 10, 50, 100, 500, or 1,000 mg tetrabromobisphenol A/kg body weight in corn oil by gavage, 5 days per week for up to 14 weeks. Additional special study groups of 10 male and 10 female rats were administered the same doses for 23 days. All core study rats survived to the end of the study. Mean body weights of dosed groups of male and female rats were similar to those of the vehicle controls.

Dose-related decreases in total thyroxine concentrations occurred on day 4 and at week 14 in 500 and 1,000 mg/kg males and females; this effect was observed with less consistency in the 100 mg/kg groups. Hematology findings on day 23 suggested small decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in 500 and 1,000 mg/kg males and females. By week 14, there was some amelioration in the severity of the erythron decreases in males and females. By week 14, there was some amelioration in the severity of the erythron decreases in these groups. At week 14, serum activities of alanine aminotransferase and sorbitol dehydrogenase generally demonstrated decreases in males and females administered 100 mg/kg or greater.

Significant increases occurred in liver weights of 500 and 1,000 mg/kg rats and significant decreases occurred in spleen weights of 500 and 1,000 mg/kg males. No treatment-related histopathologic lesions were observed in rats in the 3-month study.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female mice were administered 0, 10, 50, 100, 500, or 1,000 mg tetrabromobisphenol A/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of dosed groups of male and female mice were similar to those of the vehicle controls.

Liver weights of 500 mg/kg males and 1,000 mg/kg males and females were significantly greater than those of the vehicle controls. Kidney weights were significantly decreased and spleen weights were significantly increased in 1,000 mg/kg males.

In the kidney, incidences of renal tubule cytoplasmic alteration were significantly increased in 500 and 1,000 mg/kg male mice, and the severity of the lesion in the 1,000 mg/kg group was greater than that in the 500 mg/kg group.

2-YEAR STUDY IN WISTAR HAN RATS

Groups of 60 male and 60 female rats were administered 0 or 1,000 mg tetrabromobisphenol A/kg body weight and 50 male and 50 female rats were administered 250 or 500 mg/kg in corn oil by gavage, 5 days per week for up to 104 (males) or 105 (females) weeks. Survival of dosed groups was similar to that of the vehicle control groups. Mean body weights of 500 and 1,000 mg/kg males were at least 10% less than those of the vehicle control group after week 25. Ten vehicle control and ten 1,000 mg/kg rats of each sex were evaluated at 3 months to allow comparison to 3-month endpoints in the F344/NTac rats. At the 3-month interim evaluation, there were no treatment-related lesions in males or females, but thymus weights of 1,000 mg/kg rats were significantly less than those of the vehicle control groups, and there were increased liver weights in the 1,000 mg/kg groups similar to those seen in the 3-month F344/NTac rats.

In the original transverse review of the uterus, there were significant positive trends in the incidences of adenoma and adenocarcinoma, and the incidences of adenocarcinoma in the 500 and 1,000 mg/kg groups were greater than that in the vehicle control group. Malignant mixed Müllerian tumors were also found in treated rats. When combined, the incidences of adenoma, adenocarcinoma, or malignant mixed Müllerian tumor were significantly increased in the 500 and 1,000 mg/kg groups. Additional longitudinal reviews of residual uterine tissue were conducted and more neoplasms were identified. When the two reviews were combined, there were significant positive trends in the incidences of adenocarcinoma and of adenoma, adenocarcinoma, or malignant mixed Müllerian tumor (combined), and the incidences were significantly increased in the 500 and 1,000 mg/kg groups. In the residual longitudinal review, a new and potentially preneoplastic lesion of endometrial atypical hyperplasia was identified as statistically significant in all dosed groups.

Mutation analyses were performed comparing the mutation spectra of uterine adenocarcinomas from tetrabromobisphenol A-dosed Wistar Han rats and spontaneous uterine adenocarcinomas from control Wistar Han rats from a variety of NTP studies. Results of these analyses indicated that the rate of Tp53 mutations was significantly increased in uterine adenocarcinomas from rats dosed with tetrabromobisphenol A compared to spontaneous uterine adenocarcinomas.

In the testis, incidences of interstitial cell adenoma were slightly increased in 500 and 1,000 mg/kg males.

In the ovary, the incidences of rete ovarii cyst in 500 and 1,000 mg/kg females were significantly greater than that in the vehicle controls.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were administered 0, 250, 500, or 1,000 mg tetrabromobisphenol A/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. Survival of 1,000 mg/kg males and females was significantly less than that of the vehicle control groups. Mean body weights of 1,000 mg/kg females were at least 10% less than those of the vehicle controls after week 25.

In the liver, the incidence of multiple hepatocellular adenoma was significantly increased in 500 mg/kg males. In addition, the incidences of hepatoblastoma and of hepatocellular carcinoma or hepatoblastoma (combined) in 250 mg/kg males were significantly greater than those in the vehicle controls. The incidences of clear cell focus in 500 mg/kg males and eosinophilic focus in 250 and 500 mg/kg males were significantly increased.

The incidences of adenoma or carcinoma (combined) of the cecum or colon and the incidences of hemangiosarcoma (all organs) occurred with significant positive trends in males.

In the kidney, incidences of renal tubule cytoplasmic alteration were significantly increased in 250 and 500 mg/kg males.

In the forestomach, the incidences of ulcer, mononuclear cell cellular infiltration, inflammation, and epithelium hyperplasia were significantly increased in 500 mg/kg males and 250 and 500 mg/kg females.

GENETIC TOXICOLOGY

Tetrabromobisphenol A was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537, or E. coli strain WP2 uvrA/pKM101, with or without exogenous metabolic activation. In vivo, no increases in micronucleated normochromatic erythrocytes were observed in male or female B6C3F1/N mice following 3 months of administration of tetrabromobisphenol A by gavage; no significant changes in the percentage of circulating polychromatic erythrocytes were observed in dosed mice, suggesting that tetrabromobisphenol A did not induce bone marrow toxicity over the dose range tested.

CONCLUSIONS

Under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenic activity of tetrabromobisphenol A in male Wistar Han rats based on the occurrence of testicular adenoma. There was clear evidence of carcinogenic activity of tetrabromobisphenol A in female Wistar Han rats based on increased incidences of uterine epithelial tumors (predominantly uterine adenocarcinoma). There was some evidence of carcinogenic activity of tetrabromobisphenol A in male B6C3F1/N mice based on increased incidences of hepatoblastoma. The increased incidences of large intestine neoplasms and hemangiosarcoma (all organs) may have been related to chemical administration. There was no evidence of carcinogenic activity of tetrabromobisphenol A in female B6C3F1/N mice administered 250 or 500 mg/kg.

Administration of tetrabromobisphenol A resulted in increased incidences of nonneoplastic lesions of the uterus and ovary in female rats, the liver and kidney in male mice, and the forestomach in male and female mice.

Synonyms: 2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane; 2,2-bis(4-hydroxy-3,5-dibromophenyl)propane; 4,4′-isopropylidenebis(2,6-dibromophenol); 4,4′-(1-methylethylidene)bis(2,6-dibromophenol); 2,2′,6,6′-tetrabromobisphenol A; 3,3′,5,5′-tetrabromobisphenol A; 2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol; tetrabromodian; tetrabromodiphenylpropane
Trade names: Bromdian, Fire Guard 2000, Firemaster BP 4A, Saytex RB 100PC


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Tetrabromobisphenol A
  Male
Wistar Han Rats
Female
Wistar Han Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Doses in corn oil by gavage 0, 250, 500, or 1,000 mg/kg 0, 250, 500, or 1,000 mg/kg 0, 250, 500, or 1,000 mg/kg 0, 250, 500, or 1,000 mg/kg
Body weights 500 and 1,000 mg/kg groups at least 10% less than the vehicle control group after week 25 Dosed groups within 10% of the vehicle control group Dosed groups within 10% of the vehicle control group 1,000 mg/kg group at least 10% less than the vehicle control group after week 25
Survival rates 33/50, 28/50, 38/50, 39/50 35/50, 34/50, 29/50, 33/50 33/50, 26/50, 39/50, 12/50 40/50, 31/50, 36/50, 4/50
Nonneoplastic effects None Uterus: endometrium, hyperplasia, atypical (residual longitudinal review-2/50, 13/50, 11/50, 13/50)
Ovary: rete ovarii cyst (1/50, 0/49, 6/50, 6/49)
Liver: clear cell focus (11/50, 10/50, 25/50); eosinophilic focus (20/50, 33/50, 40/50)
Kidney: renal tubule, cytoplasmic alteration (0/50, 20/50, 47/50)
Forestomach: ulcer (9/50, 9/49, 19/50); infiltration cellular, mononuclear cell (5/50, 8/49, 21/50); inflammation (9/50, 10/49, 20/50); epithelium, hyperplasia (10/50, 13/49, 27/50
Forestomach: ulcer (2/50, 15/50, 40/50); infiltration cellular, mononuclear cell (2/50, 13/50, 33/50); inflammation (2/50, 14/50, 41/50); epithelium, hyperplasia (4/50, 16/50, 39/50)
Neoplastic effects None Uterus: adenoma (original transverse review-0/50, 0/50, 3/50, 4/50); adenocarcinoma (original transverse review-3/50, 3/50, 8/50, 9/50; original transverse and residual longitudinal reviews, combined-4/50, 10/50, 15/50, 16/50); malignant mixed Müllerian tumor (original transverse review-0/50, 4/50, 0/50, 2/50); adenoma, adenocarcinoma, or malignant mixed Müllerian tumor (original transverse review-3/50, 7/50, 11/50, 13/50; original transverse and residual longitudinal reviews, combined-6/50, 11/50, 16/50, 19/50) Liver: hepatoblastoma (2/50, 11/50, 8/50) None
Equivocal findings Testis: interstitial cell, adenoma (0/50, 0/50, 1/50, 3/50) None Large intestine (cecum or colon: adenoma or carcinoma (0/50, 0/50, 3/50)
Hemangiosarcoma (all organs): (1/50, 5/50, 8/50)
None
Level of evidence of carcinogenic activity Equivocal evidence Clear evidence Some evidence No evidence
Genetic Toxicology
Assay Results
Bacterial gene mutations:
 
Negative in S. typhimurium strains TA98, TA100, TA1535, and TA1537, with or without hamster or rat liver S9. Negative in S. typhimurium strains TA98 and TA100 and in E. coli strain WP2 uvrA/pKM101 with and without rat liver S9.
Micronucleated erythrocytes
Mouse peripheral blood in vivo:
Negative in males and females

Date: September 2014

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies