Toxicokinetics of the Flame Retardant Hexabromocyclododecane Gamma: Effect of Dose, Timing, Route, Repeated Exposure, and Metabolism

Hexabromocyclododecane-gamma (g-HBCD) is the predominate diastereoisomer in the commercial HBCD mixture used as a flame retardant in a wide variety of consumer products. Three main diastereoisomers, alpha (a), beta (b), and gamma (g), comprise the mixture. Despite the g-diastereoisomer being the major diastereoisomer in the mixture and environmental samples, the a-diastereoisomer predominates human tissue and wildlife. This study was conducted to characterize absorption, distribution, metabolism, and excretion parameters of g-HBCD with respect to dose and time following a single acute exposure and repeated exposure in adult female C57BL/6 mice. Results suggest that 85% of the administered dose (3 mg/kg) was absorbed after po exposure. Disposition was dose independent and did not significantly change after 10 days of exposure. Liver was the major depot (< 0.3% of dose) 4 days after treatment followed by blood, fat, and then brain. g-HBCD was rapidly metabolized and eliminated in the urine and feces. For the first time, in vivo stereoisomerization was observed of the g-diastereoisomer to the b-diastereoisomer in liver and brain tissues and to the a- and b-diastereoisomer in fat and feces. Polar metabolites in the blood and urine were a major factor in determining the initial wholebody half-life (1 day) after a single po exposure. Elimination, both whole-body and from individual tissues, was biphasic. Initial halflives were approximately 1 day, whereas terminal half-lives were up to 4 days, suggesting limited potential for g-diastereoisomer bioaccumulation. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk.