Toxicokinetics of the flame retardant hexabromocyclododecane gamma: effect of dose, timing, route, repeated exposure, and metabolism.
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.
Szabo
David T
DT
University of North Carolina Curriculum in Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. szabo@email.unc.edu
Diliberto
Janet J
JJ
Hakk
Heldur
H
Huwe
Janice K
JK
Birnbaum
Linda S
LS
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005411:Flame Retardants / Q000493:pharmacokinetics* / Q000633:toxicity*; D006207:Half-Life; D006842:Hydrocarbons, Brominated / Q000493:pharmacokinetics* / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013237:Stereoisomerism
D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; C089796:hexabromocyclododecane