An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats.

BACKGROUND: Decabromodiphenyl ether (DecaBDE; CASRN 1163-19-5) is a flame retardant used in a variety of manufactured products. A single oral dose of 20.1 mg/kg administered to mice on postnatal day 3 has been reported to alter motor activity at 2, 4, and 6 months of age. METHODS: To further evaluate these results, a developmental neurotoxicity study was conducted in the most commonly used species for studies of this type, the rat, according to international validated testing guidelines and Good Laboratory Practice Standards. DecaBDE was administered orally via gavage in corn oil to dams from gestation day 6 to weaning at doses of 0, 1, 10, 100, or 1,000 mg/kg/day. Standard measures of growth, development, and neurological endpoints were evaluated in the offspring. Motor activity was assessed at 2 months of age. Additional motor activity assessments were conducted at 4 and 6 months of age. Neuropathology and morphometry evaluations of the offspring were performed at weaning and adulthood. RESULTS: No treatment-related neurobehavioral changes were observed in detailed clinical observations, startle response, or learning and memory tests. No test substance-related changes were noted in motor activity assessments performed at 2, 4, or 6 months of age. Finally, no treatment-related neuropathological or morphometric alterations were found. CONCLUSIONS: Under the conditions of this study, the no-observed-adverse-effect level for developmental neurotoxicity of DecaBDE was 1,000 mg/kg/day, the highest dose tested.

Prenatal developmental toxicity of decabromodiphenyl ethane in the rat and rabbit.

BACKGROUND: The potential embryotoxic and teratogenic effects of decabromodiphenyl ethane (DBDPEthane; CASRN 84852-53-9) were evaluated in prenatal developmental studies using rats and rabbits and performed in accordance with international guidelines and Good Laboratory Practice standards. Preliminary dose-range-finding studies were conducted, which indicated doses up to 1,250 mg/kg-day were well tolerated by both rats and rabbits. METHODS: For the developmental studies, animals were administered DBDPEthane via gavage at dosage levels of 0, 125, 400, or 1,250 mg/kg-day from gestation day (GD) 6 through 15 for rats and GDs 6 through 18 for rabbits. All female rats and rabbits were sacrificed on GD 20 or GD 29, respectively, and subjected to cesarean section. Fetuses were individually weighed, sexed, and examined for external, visceral and skeletal abnormalities. RESULTS: No treatment-related mortality, abortions, or clinical signs of toxicity were observed during the study. Body weights, body weight gain, and food consumption were not affected by treatment. No significant internal abnormalities were observed in either species on necropsy. Cesarean section parameters were comparable between control and treated groups. No treatment-induced malformations or developmental variations occurred. CONCLUSIONS: Based on these results, no evidence of maternal toxicity, developmental toxicity, or teratogenicity was observed in rats or rabbits treated with DBDPEthane at dosage levels up to 1,250 mg/kg-day.

Toxicology and human health assessment of decabromodiphenyl ether.

We evaluated the available pharmacokinetic data and human and animal toxicity data for 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) (CASRN 1163-19-5) with the objective of deriving a reference dose (RfD) based on the best available science. The available studies for deriving an RfD were first screened using the Klimisch criteria and further evaluated using the United States Environmental Protection Agency's general assessment factors for data quality and relevance (i.e., soundness, applicability and utility, clarity and completeness, uncertainty and variability, and evaluation and review). The chronic 2-year dietary feeding study conducted by the United States National Toxicology Program ( NTP, 1986 , Technical Report Series No. 309) was selected for RfD derivation. Hepatocellular degeneration in male rats was chosen as the critical endpoint in the development of an RfD. For dose-response characterization, we applied benchmark-dose modeling to animal data and determined a point of departure (the 95% lower confidence limit for a 10% increase in hepatocellular degeneration) of 419 mg/kg-day for oral exposures. Based on the similar pharmacokinetic characteristics of BDE-209 across species, this value was converted to a human equivalence dose of 113 mg/kg-day by applying a dosimetric adjustment factor based on body weight scaling to the (3/4) power. An oral RfD of 4 mg/kg-day was calculated by using a composite uncertainty factor of 30, which consisted of 10 for intraspecies uncertainty, 3 for interspecies uncertainty (i.e., 3 for toxicodynamics x 1 for toxicokinetics), and 1 for deficiencies with the database. We consider the RfD to be adequately protective of sensitive subpopulations, including women, their fetuses, children, and people with hepatocellular diseases.

A comparison of the fish bioconcentration factors for brominated flame retardants with their nonbrominated analogues.

Flame retardants (FR) play a significant role in reducing the flammability of many consumer products. On a volume basis, approximately 25% of the FRs in use today utilize bromine as the active flame-retarding moiety. Their applications are those requiring high FR performance or in resins needing an FR that is active during the gas phase. Laboratory fish bioconcentration factors (BCFs) for 11 brominated FRs (BFRs) or their components were compared with those for their nonbrominated analogues. Bioconcentration, defined here as a BCF of greater than 1,000, was not observed in those brominated molecules examined with molecular weights of 700 or greater. These included the decabromodiphenyl oxide and octabromodiphenyl oxide commercial products, ethane 1,2-bis(pentabromophenyl), ethylene bis-tetrabromophthalimide, and decabromobiphenyl. Tetrabromobisphenol A, with a molecular weight of less than 700, also did not bioconcentrate. This likely relates to the ease with which it is metabolized and eliminated. Within the BFR class of polybrominated diphenyl oxides/ethers, the BCFs for those congeners with molecular weights of between approximately 450 and 700 varied with the number and position of the bromine atoms. The BCF of hexabromocyclododecane appeared to be related to its cyclododecane substructure, not to its bromine content. Bioconcentration was not a characteristic feature of the BFRs examined here.