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TOXICOKINETICS OF THE FLAME RETARDANT HEXABROMOCYCLODODECANE GAMMA: EFFECT OF DOSE, TIMING, ROUTE, REPEATED EXPOSURE AND METABOLISM
Citation:
SZABO, D., J. J. DILIBERTO, H. Hakk, J. Huwe, AND L. S. BIRNBAUM. TOXICOKINETICS OF THE FLAME RETARDANT HEXABROMOCYCLODODECANE GAMMA: EFFECT OF DOSE, TIMING, ROUTE, REPEATED EXPOSURE AND METABOLISM. TOXICOLOGY SCIENCE 117(2):282-293, (2010).
Impact/Purpose:
The objective of this study is to describe y-HBCD specific absorption, distribution, metabolism, and excretion (ADME) following an acute exposure at several doses, after repeated treatment, and up to 14 days in adult female mice.
Description:
1,2,5,6,9,10-Hexabromocyc1ododecane-gamma (y-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 (y) comprise the commercial mixture. Despite the y-diastereoisomer being the major diastereoisomer in the mixture and environmental samples, the adiastereoisomer predominates in human tissue and wildlife. This study was conducted to characterize absorption, distribution, and elimination parameters of y-HBCD with respect to dose and time following a single acute exposure and repeated exposure in adult female C57BL/6 mice. Results indicate that 85% of the administered dose (3mg/kg) was absorbed after oral exposure. Disposition was dose-independent and didn't significantly change after 10 days of exposure. Liver was the major depot (<0.3% of dose) four-days after treatment followed by blood, fat and then brain. y-HBCD was rapidly metabolized and eliminated in the urine and feces. For the first time, in vivo stereoisomerizationwas observed of the 'y- diastereoisomer to the B-diastereoisomer in liver and brain tissues, and to the a- and B-diastereoisomer in 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 oral 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 y-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.
