2,2',6,6'-tetrabromo-4,4'-isopropylidenediphenol

Endpoint summary

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

100

Additional information

In vivo studies of TBBPA's absorption, distribution, metabolism and elimination have been conducted in humans and rats. An in vitro study of TBBPA's potential for dermal absorption (using human skin) has also been performed. The in vivo studies indicate rapid absorption from the gastrointestinal tract with rapid metabolism to conjugates. As a result, systemic bioavailability is low (<2% of an oral dose). The primary route of elimination is in the feces. The in vitro dermal absorption study indicated <1% of a dermal dose would be absorbed.

After a single oral dose, sulfate and glucuronide conjugates were identified as metabolites in blood and urine of human volunteers and rats. In blood, TBBPA-glucuronide was detected in all human subjects, whereas TBBPA-sulfate was only present in blood from two individuals. Maximum plasma concentrations of TBBPA-conjugates were obtained within 4 h of dosing and rapidly declined to reach the limit of detection (LOD) after 8 h. The unconjugated, parent TBBPA moleculte was not present in detectable concentrations in any of the human plasma samples. In rats, TBBPA-glucuronide and TBBPA-sulfate were also the major metabolites in blood, but a diglucuronide of TBBPA, a mixed glucuronide-sulfate conjugate of TBBPA, tribromobisphenol A, and the glucuronide of tribromobisphenol A were also present in low concentrations. TBBPA plasma concentrations in rats peaked at 3 h after administration and thereafter declined with a half-life of 13 h; maximal concentrations of TBBPA-glucuronide were also observed 3 h after administration. Peak plasma concentrations of TBBPA-sulfate were reached within 6 h after administration. The results indicate rapid absorption of TBBPA from the gastrointestinal tract and rapid metabolism of the absorbed TBBPA by conjugation resulting in a low systemic bioavailability of TBBPA.

The effect of multiple doses and route of administration was investigated in rats using 14C-TBBPA. Rats eliminated > 90% of total radioactivity in feces by 72 hr following single oral doses of 2 to 200 mg/kg. Most of the dose was eliminated in the first 24 hr. At 72 hr after administration of the highest dose, the amounts of 14C found in the tissues were minimal (0.2 - 0.9%). With repeated daily oral doses (20 mg/kg) for 5 or 10 days, the cummulative percent dose eliminated in the feces was 85.1 +/- 2.8and 97.9 +/- 1.1, resepectively. 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, and the radioactivity in the blood decreased rapidly and was described by a biexponentail equation, consistent with a two-compartment model. The key calculated kinetic parameters are terminal elimination half-life (t1/2 Beta) = 82 min; area under the blood concentration-time curve from time 0 to infinity (AUC) = 1440 ug x min/ml; and apparent clearance (CL) = 2.44 ml/min. Althougth readily absorbed from the gut, systemic bioavailability of TBBPA was low (<2% of the dose). TBBPA underwent substantial first pass effect in the liver; TBBPA was rapidly metabolitzed and eliminated in the bile. Approximately 50% of an oral dose of 20 mg/kg was detected in the bile within 2 h. The extensive extraction and metabolism by the liver limits systemic exposure

An in vitro derrmal absorption study showed that <1% of a dermal dose would be absorbed, indicating very poor absorption through the skin. Using human skin and 14C-TBBPA, the skin's stratum corneum was an efficient barrier to absorption of TBBPA.