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

Abstract

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.

Levels, isomer profiles and chiral signatures of particle-bound hexabromocyclododecanes in ambient air around Shanghai, China

“…During the last decade, HBCDs have been detected in ambient air samples from the remote regions, urban areas and point sources in Sweden (Remberger et al, 2004), the United States (Hoh and Hites, 2005), Japan (Takigami et al, 2007), China (Hu et al, 2011;Yu et al, 2008a), and even the Arctic (1.8 pg/m 3 , ; 1e2 pg/m 3 , Xiao et al, 2010). Summarizing the published data (Table 2), the atmospheric HBCD concentrations were <0.07e280 pg/m 3 for remote, semi-remote and background areas, and 1e1800 pg/m 3 for urban and industrial areas.…”

“…Theoretically, HBCD has 16 stereoisomers in commercial products, including six pair of enantiomers and four meso forms (Heeb et al, 2005), and structures of these diastereomers have been characterized via 1 H NMR spectroscopy and X-ray crystallography (Riddell et al, 2011). a-, b-and g-HBCDs are the commonly analyzed diastereomers in environmental samples and undergo isomer inter-conversion and stereoselective processes, both in abiotic and biotic environments (Arnot et al, 2009;Covaci et al, 2006;Harrad et al, 2009a;Law et al, 2006aLaw et al, , 2006bLaw et al, , 2008aSzabo et al, 2010). Thermal rearrangement and photo-isomerization also occur between these three diastereomers, especially between g-and a-HBCDs (Harrad et al, 2009a;Heeb et al, 2008aHeeb et al, , 2008bKöppen et al, 2008).…”

“…Roosens et al (2009) found that concentrations of HBCDs in serum of adult humans correlated with exposure via air-borne dust, but not via dietary ingestion. So far, although data are still very limited, HBCDs have been detected in air samples from some places in Europe (Bergander et al, 1995;Remberger et al, 2004), America (Hoh and Hites, 2005), Asia (Hu et al, 2011;Takigami et al, 2007;Yu et al, 2008a) and even the Arctic de Wit et al, 2010;Xiao et al, 2010). Shanghai is one of the most important commercial and industrial regions of China.…”

Stoffmonographie für 1,2,5,6,9,10-Hexabromcyclododecan (HBCDD) - HBM-Werte für HBCDD im Fettanteil der Muttermilch oder des Blutplasmas

“…Die Unterschiede im Metabolismus der drei Stereoisomere wurden an weiblichen C57BL/6 Mäusen untersucht [92][93][94] …”

“…Die Metaboliten der Untersuchungen mit alpha-und gamma-HBCDD [92,93] wurden identifiziert [96]. Für alpha-HBCDD wurden einfach hydroxylierte Metaboliten von HBCDD (OH-HBCDD) und nach Ringspaltung tetra-und tri-bromierte Substanzen gefunden sowie Konjugate mit Glutathion.…”