The Effects of Dose, Route, and Repeated Dosing on the Disposition and Kinetics of Tetrabromobisphenol A in Male F-344 Rats

Abstract

Studies were conducted to characterize the metabolic and dispositional fate of (14)C-tetrabromobisphenol A (TBBPA)-a commonly used brominated flame retardant, in male Fischer-344 rats. The percent of dose eliminated as total radioactivity in feces at 72 h following three different single oral doses (2, 20, or 200 mg/kg) of (14)C-TBBPA was 90% or greater for all doses. Most of the dose was eliminated in the first 24 h. At 72 h after administration of the highest dose, the amounts of (14)C found in the tissues were minimal (0.2-0.9%). With repeated daily oral doses (20 mg/kg) for 5 or 10 days, the cumulative percent dose eliminated in the feces was 85.1+/-2.8 and 97.9+/-1.1, respectively. In all studies radioactivity recovered in urine was minimal, <2%. Repeated dosing did not lead to retention in tissues. Following iv administration, feces was also the major route of elimination. Following iv administration of TBBPA, the radiolabel found in the blood decreased rapidly and could be described by a biexponential equation, consistent with a two-compartment model. The key calculated kinetic parameters are terminal elimination half-life (t(1/2)beta)=82 min; area under the blood concentration-time curve from time 0 to infinity (AUC)=1440 mug x min/ml; and apparent clearance (CL)=2.44 ml/min. Although readily absorbed from the gut, systemic bioavailability of TBBPA is low (<2%). It is extensively extracted and metabolized by the liver and the metabolites (glucuronides) exported into the bile. About 50% of an oral dose (20 mg/kg) was found in the bile within 2 h. This extensive extraction and metabolism by the liver greatly limits exposure of internal tissues to TBBPA following oral exposures.