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

• Published in: Toxicological sciences Vol. 117; no. 2; pp. 282 - 293
• Main Authors: Szabo, David T, Diliberto, Janet J, Hakk, Heldur, Huwe, Janice K, Birnbaum, Linda S
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2010
• Subjects: absorption; acute exposure; ADME; administered dose; Administration, Oral; Animals; bioaccumulation; blood; body fat; brain; brominated flame retardant; diastereomer; diastereomers; Dose-Response Relationship, Drug; Drug Administration Schedule; excretion; feces; Female; Flame Retardants - pharmacokinetics; Flame Retardants - toxicity; Half-Life; HBCD; Hydrocarbons, Brominated - pharmacokinetics; Hydrocarbons, Brominated - toxicity; intestinal absorption; lipids; liver; Liver - drug effects; Liver - metabolism; metabolism; metabolites; Mice; Mice, Inbred C57BL; mouse; oral administration; organobromine compounds; persistent organic pollutant; pharmacokinetics; risk assessment; Stereoisomerism; stereoisomerization; urine
• ISSN: 1096-0929; 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfq183

Hexabromocyclododecane-gamma (γ-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 (α), beta (β), and gamma (γ), comprise the mixture. Despite the γ-diastereoisomer being the major diastereoisomer in the mixture and environmental samples, the α-diastereoisomer predominates human tissue and wildlife. This study was conducted to characterize absorption, distribution, metabolism, and excretion parameters of γ-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. γ-HBCD was rapidly metabolized and eliminated in the urine and feces. For the first time, in vivo stereoisomerization was observed of the γ-diastereoisomer to the β-diastereoisomer in liver and brain tissues and to the α- and β-diastereoisomer in fat and feces. Polar metabolites in the blood and urine were a major factor in determining the initial whole-body half-life (1 day) after a single po exposure. Elimination, both whole-body and from individual tissues, was biphasic. Initial half-lives were approximately 1 day, whereas terminal half-lives were up to 4 days, suggesting limited potential for γ-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.