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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well designed and performed study reported in the peer-reviewed literature. Not GLP or specific testing guidelines

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

2006

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Objective of study:

other: other: Determine systemic bioavailability after oral adminstration in rats; disposition in humans

Test guideline

Qualifier:

no guideline followed

GLP compliance:

no

Test material

Test material information

Constituent 1

Radiolabelling:

yes

Test animals

Species:

other: rat, human

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

6 male rats; 3 male and 2 female human volunteers

Administration / exposure

Route of administration:

other: oral gavage (rat); gel capsule (human)

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

Rats: single oral gavage dose of 300 mg/kg bw, dose volume of 3.2 ml
Humans: single gel capsule orally, 0.1 mg/kg bw

Doses / concentrations

Remarks:

Doses / Concentrations:
Rats: single oral gavage dose of 300 mg/kg bw, dose volume of 3.2 ml
Humans: single gel capsule orally, 0.1 mg/kg bw

No. of animals per sex per dose / concentration:

6 male rats
3 human males; 2 human females

Control animals:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

metabolism

Results:

Metabolized mainly to sulfate conjugates in the rat, and to glucuronide conjugates in humans.

Main ADME results 2

Type:

excretion

Results:

Rats: fecal excretion of unchanged TBBPA (>80% dose), trace amounts of sulfate-congugate in urine; Human: <0.1% dose in urine; feces not collected

Main ADME results 3

Type:

distribution

Results:

Rats: TBBPA-sulfate main form in plasma followed by TBBPA and trace amounts of TBBPA-glucuronide ; Humans: TBBPA not detected in plasma, TBBPA-glucuronide was circulating form; trace amounts of TBBPA-sulfate in blood

Toxicokinetic / pharmacokinetic studies

Details on excretion:

Results in rats indicate sulfate and glucuronide conjugates are cleaved in the feces to the parent molecule.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Rats: primarily TBBPA-sulfate
Humans: primarily TBBPA-glucuronide
Trace amounts of the disulfate and diglucuronide and/or tribombisphenol A conjugates

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
TBBPA is rapidly metabolized and eliminated as glucuronide and/or sulfate conjugates by humans and rats, such that its systemic bioavailability is low. The conjugate(s) is/are the circulating form of TBBPA in blood

Executive summary:

This study reports the characterization of the toxicokinetics of TBBPA in human subjects and in rats. A single oral dose of 0.1 mg/kg TBBPA was administered to five human subjects. Rats were administered a single oral dose of 300 mg TBBPA/kg body weight. Urine and blood concentrations of TBBPA and its metabolites were determined by LC/MS-MS. TBBPA-glucuronide and TBBPA-sulfate were identified as metabolites of TBBPA in blood and urine of the human subjects 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-glucuronide (16 nmol/l) were obtained within 4 h after administration. In two individuals where TBBPA-sulfate was present in blood, maximum concentrations were obtained at the 4-h sampling point; the concentrations rapidly declined to reach the limit of detection (LOD) after 8 h. Parent TBBPA was not present in detectable concentrations in any of the human plasma samples. TBBPA-glucuronide was slowly eliminated in urine to reach the LOD 124 h after administration. In rats, TBBPA-glucuronide and TBBPA-sulfate were also the major metabolites of TBBPA present in blood; in addition, 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 peaked at 103 μmol/l 3 h after administration and thereafter declined with a half-life of 13 h; maximal concentrations of TBBPA-glucuronide (25 μmol/l) were also observed 3 h after administration. Peak plasma concentrations of TBBPA-sulfate (694 μmol/l) were reached within 6 h after administration. In conclusion, TBBPA is rapidly metabolized after absorption by conjugation resulting in a low systemic bioavailability of TBBPA.