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National Toxicology Program. NTP Technical Report on the Toxicity Studies of Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (CASRN 21850-44-2) Administered by Gavage to F344/NTac Rats and B6C3F1/N Mice: Toxicity Report 85 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2017 Aug.
NTP Technical Report on the Toxicity Studies of Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (CASRN 21850-44-2) Administered by Gavage to F344/NTac Rats and B6C3F1/N Mice: Toxicity Report 85 [Internet].
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Figure 1
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (CASRN 21850-44-2; Chemical Formula: C21H20Br8O2; Molecular Weight: 943.6)
Chemical and Physical Properties
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) is a white to off-white crystalline solid with a slight odor. Decomposition takes place at temperatures greater than 270°C. The relative molecular mass is 943.9; the melting point is 90° to 100°C (95°C); and the specific gravity is 0.7 to 0.9 g/cm3. The bromine content is 68% and the solubility is 1 g per liter water at 25°C.1
Production, Use, and Human Exposure
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) is used as a flame retardant in electronics, building and construction materials, and automotive materials.2 It is an additive flame retardant for polyolefins, polymers, and high- and low-density polyethylene. Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) may be used as a flame retardant in plastic products such as pipes, water barriers, kitchen hoods, and electronics.3
The U.S. Environmental Protection Agency (USEPA)4 reports the production volume in the United States is estimated to be 1 to 10 million pounds. The USEPA notes that 100 to 1,000 workers are likely to be exposed to the chemical during its manufacturing and processing.
Quantitative measurement of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) exposure in the United States is limited, and it is not part of the Centers for Disease Control and Prevention NHANES survey of chemical exposure in the United States population. However, human exposure may occur during its manufacture and use as a flame retardant. Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) has been detected in dust samples from a primary school in the United Kingdom at concentrations of 200 µg/kg3.
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) is hydrophobic and thus may bind various particles in the environment.3 Studies reported in the literature indicate that tetrabromobisphenol A-bis(2,3-dibromopropyl ether) can persist in the environment.5,6 The USEPA7 has also predicted that tetrabromobisphenol A-bis(2,3-dibromopropyl ether) would have high persistence in the environment based on an analysis of unpublished degradation tests submitted for review. Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) has been found in sewage sludge in China at up to 8,950 µg/kg dry weight.3
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) was identified in environmental samples (i.e., soil, sediments, rice hulls, and earthworms) taken near a brominated flame retardant manufacturing plant in China.6 The concentration of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) ranged from 0.7 to 293 ng/g dry weight in these samples. Mollusks collected from the Chinese Bhohai Sea were found to contain tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in 32% of the samples.6
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) is listed as an alternative flame retardant for decabromodiphenyl ether by the USEPA.7 It was considered by the EPA for an alternative to the flame retardant hexabromocyclododecane (CASRNs 25637-99-4 and 3194-55-6) in expanded and extruded polystyrene foam insulation but was excluded from consideration.7 Another alternative tetrabromobisphenol A-bis(2,3-dibromopropyl ether) derivative was considered as a possible alternative flame retardant for hexabromocyclododecane.2
Exposure to flame retardants, including tetrabromobisphenol A-bis(2,3-dibromopropyl ether), could occur by inhalation, ingestion, or dermal exposure. Of particular concern is exposure to children in the home by the oral route.8,9
Regulatory Status
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) is listed on the Toxic Substances Control Act Inventory, but no test rules have been issued for this chemical.7 This chemical is listed by the USEPA as requiring contaminant testing (EPA-1)10 and export notification (EPA-2).11
Absorption, Distribution, Metabolism, and Excretion
Experimental Animals
There are limited data on the metabolism and disposition of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in rodents. In studies conducted by the National Toxicology Program, following gavage administration of 20 mg/kg [14C]-tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in fasted F344 rats, 89% of the administered dose was excreted in feces within the first 24 hours; the total dose excreted in feces at 96 hours following dosing was approximately 95%.12,13 Excretion via urine was minimal (≤0.1%). When a similar dose was administered in bile duct-cannulated rats, approximately 1% of the dose was recovered in bile within 24 hours suggesting that the majority of fecal radioactivity was due to unabsorbed dose. The total dose in non-gastrointestinal (GI) tract tissues at 96 hours was approximately 1%, with liver, adipose, and muscle showing the highest concentrations. The percent of dose in the liver at 6, 24, 72, and 96 hours following gavage administration was 4.8, 0.9, 0.6, and 0.2, respectively, whereas the level in adipose did not change with time. Following a 20 mg/kg intravenous dose in fasted rats, fecal excretion was slower than following gavage administration, with approximately 30% of the administered dose excreted in 24 hours; the total dose recovered in feces at 96 hours was 71%. Urinary excretion accounted for approximately 0.2% of the dose. Tissues (non-GI tract) contained approximately 14% of the administered dose with liver, adipose, and muscle having the highest concentrations. Disposition was also investigated in nonfasted male rats following one, five, or 10 doses, with sacrifice 24 hours after the last dose. The pattern of disposition was similar to that in fasted rats except that the total dose in tissues at 24 hours, mainly in the liver, was higher in nonfasted rats (6.7%) than in fasted rats (0.9%), demonstrating a higher absorption in non-fasted rats. There was no difference in the pattern of disposition between single or repeated (5 or 10) doses. Blood toxicokinetic parameters were estimated following a single gavage dose of [14C]-tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in fasted male F344 rats. The time to reach the maximum blood concentration (Cmax) of 0.6 µg/mL was 7.4 hours following dosing. Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) was eliminated slowly from blood with an elimination half-life of 13.9 hours. The estimated absolute bioavailability was 2.2%. These data suggest that tetrabromobisphenol A-bis(2,3-dibromopropyl ether) is poorly absorbed and slowly eliminated following gavage administration in rodents.
Analysis of bile by radiochromatography showed two peaks that did not co-elute with the parent compound either before or after deconjugation experiments, suggesting formation of metabolites other than direct conjugates of the parent. Analysis of fecal extracts also showed some evidence of metabolism of tetrabromobisphenol A-bis(2,3-dibromopropyl ether). Approximately 5% of the radioactivity in feces was associated with a metabolite peak; however, metabolite identification was not attempted. Approximately 90% of the fecal radioactivity eluted at the retention time of the parent. In vitro studies using F344 rat hepatocytes or liver microsomes indicated very little metabolism of tetrabromobisphenol A-bis(2,3-dibromopropyl ether).12,13
Humans
There are no absorption, distribution, metabolism, or excretion studies of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in humans reported in the peer reviewed literature, and no information on tissue levels of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in humans were found in the literature.
Toxicity
Experimental Animals
The acute LD50 for tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in mice was greater than 20 g/kg when given in feed and observed for 14 days; the acute dermal LD50 for mice was greater than 20 g/kg when applied to skin for 24 hours and observed for 14 days.1 An inhalation LC50 in mice is estimated at 87 mg/L.7 There are no 14-day or 90-day toxicity studies of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) reported in the scientific literature.1,7
The World Health Organization1 reviewed unpublished studies of tetrabromobisphenol A dibromopropyl ether [another name for tetrabromobisphenol A-bis(2,3-dibromopropyl ether)] and reported that, when it was administered to mice at 200 or 2,000 mg/kg in the diet for 90 days, there were no treatment-related deaths or gross pathologic changes.1
Humans
No in vivo studies on the toxic potential of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in humans were found in the peer reviewed literature.
In vitro studies found that tetrabromobisphenol A-bis(2,3-dibromopropyl ether) did not inhibit CYP17 catalytic activity in human H295R adrenocortical carcinoma cells.14 Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) did not exhibit agonistic or antagonistic activity with aryl hydrocarbon, androgen, progesterone, or estrogen receptors in a series of chemically activated luciferase gene expression assays.14 However, tetrabromobisphenol A-bis(2,3-dibromopropyl ether) did displace the thyroid hormone precursor thyroxine from the plasma transport protein in transthyretin binding assays, and it inhibited estradiol binding in estradiol sulfotransferase assays.14 These assays were run at concentrations of 0.01 µM to 10 µM.
Reproductive and Developmental Toxicity
No information on the reproductive or developmental toxicity of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in experimental animals or humans was found in a review of the literature.
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) was found to inhibit estradiol-sulfotransferase and thereby may have an effect on sulfation of estradiol and its subsequent elimination by conjugation.14 A USEPA7 review of this chemical noted a potential for alkylation and a potential for reproductive effects from tetrabromobisphenol A-bis(2,3-dibromopropyl ether) exposure.
Carcinogenicity
Experimental Animals
No information of the carcinogenic potential of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in experimental animals was found in a review of the literature.
Humans
No epidemiology studies of the carcinogenic potential of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) in humans were found in the peer-reviewed literature.
Genetic Toxicity
No genetic toxicology studies of tetrabromobisphenol A-bis(2,3-dibromopropyl ether) were found in the peer-reviewed literature.
Study Rationale
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (TBBPA-DBPE) was nominated by the National Institute of Environmental Health Sciences for toxicology and in vivo genotoxicity study because this is a widely used flame retardant with little or no toxicity data reported in the literature, and because there is potential for human exposure.
- Introduction - NTP Technical Report on the Toxicity Studies of Tetrabromobisphen...Introduction - NTP Technical Report on the Toxicity Studies of Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (CASRN 21850-44-2) Administered by Gavage to F344/NTac Rats and B6C3F1/N Mice
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