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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 1978 - November 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is old, but appears well performed and reported.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978

Materials and methods

Objective of study:
other: to determine the rate of absorption, distribution, metabolism, and excretion of PHT-4 in rats
Principles of method if other than guideline:
A single oral gavage dose was administered to 10 female and 2 adult male rats. One male rat was sham gavaged. The remaining animals recieved the test article (14C-labelled and nonlabelled). Urine and feces collected daily in metabolism cages. Blood collected 1,2,4,8,17, 24,48and 72 post dosing from each of 4 rats (tail incision). At sacrifice, blood collected by cardiac puncture. Ten tissues excised and frozen.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrabromophthalic anhydride
EC Number:
211-185-4
EC Name:
Tetrabromophthalic anhydride
Cas Number:
632-79-1
Molecular formula:
C8Br4O3
IUPAC Name:
tetrabromophthalic anhydride
Details on test material:
14C-tetrabromophthalic anhydride. Uniformly aromatic ring labeled. Specific Activity = 11.6 mCi/mM. Synthesized by Midwest Research Institute.
Radiolabelling:
yes
Remarks:
14C-TBPA

Test animals

Species:
rat
Strain:
other: Holtzman
Sex:
male/female
Details on test animals or test system and environmental conditions:
14C-PHT-4 with specific activity of 11.6 mCi/mM, synthesized at Midwest Research Institute. PHT-4 and tetrabromophthalic acid synthesized by Velsicol.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
DMSO
Details on exposure:
Each rat's dose consisted of 0.338 ml of a DMSO/PHT-4 stock solution (40 mg PHT-4 in 10 ml DMSO) and 190 ug of 14C-PHT-4 in DMSO. Each dose contained 1.542 mg PHT-4 having a specific activity of 1.42 mCi/mM. Dose was ca. 4-6 mg/kg bw.
Duration and frequency of treatment / exposure:
One oral gavage dose
Doses / concentrations
Remarks:
Doses / Concentrations:
4 to 6 mg/kg bw. Each rat recieved a known dose of 1 - 1.4 mg of the compound depending on body weight.
No. of animals per sex per dose / concentration:
One dose level, 10 females and 1 male treated with test article. One male sham gavaged.
Control animals:
yes, concurrent vehicle
Statistics:
Software calculated: curve fit of [test article] in urine, feces and blood as function of time against 6 mathematical models for best fit. Best fit curve subjected to ANOVA for goodness of fit. Calculated Ke, t1/2, t0.95, Co, C(max), N98 (# of doses until 98% of Cmax is reached assuming 24 hr intervals between doses)

Results and discussion

Main ADME results
Type:
absorption
Results:
see below

Toxicokinetic / pharmacokinetic studies

Details on absorption:
TBPA was hydrolyzed to TBPA-acid in the gastrointestinal tract and partially absorbed. The absorbed fraction was readily eliminated in the urine. (~20%) within 24 hr and the unabsorbed portion was eliminated in the feces within 48 hr (~75%)
Details on distribution in tissues:
No significant difference was observed between males and females.total residues in tissues amounted ot <0.2% of the administered dose two days after treatment. Distribution was rapid.
Details on excretion:
Rate of elimination in urine was proportional to the concentration in blood.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
see below

Any other information on results incl. tables

Cummulative elimination of the dose (%) at 48, 72, and 96 hrs was 91.66, 96.89 and 101.09. Approximately 59% of the dose was recovered in urine, feces and gut contents 17 hr after dosing.

The pharmacokinetics followed a 1 compartment open model. A portion of the orally administered chemical was rapidly absorbed from the digestive system and the rest of the dose was voided in the feces within 48 hrs. The rate constant for elimination (Ke) from the blood was 0.081 and the time required to reduce the blood concentration by one half was 8.5 hrs.

14C-activity in the urine consisted mainly of TBPA-acid. Approximately half of the 14C-activity was lost during acidification. The loss was investigated using urine from treated rats and an aqueous solution of a TBPA authentic standard. The 'loss' was found to be due to adherence or adsorption of the radiocarbon to the walls of the separatory funnel which could be removed by rinsing with methanol. The interface formed during parttioning of the urine samples was also extracted. These steps demonstrated that only 14% of the 14C-activity in urine was 'lost' during analysis.

In feces, 25% of the 14C-activity consisted of TBPA-acid, 20% unextractable solids, with remainder lost during acidification.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
A single oral dose of 14C-TBPA was administered to male and female rats. The test article was hydrolyzed to the acid form and partly absorbed in the gastro-intestinal tract. The absorbed portion was readily eliminated in the urine (~20%) within 24 hrs, and the unabsorbed portion was eliminated in the feces within 48 hrs (~75%). The 14C-activity in the urine consisted of 27% acid released TBPA-acid, 27% water solubles and 45% of the 14C-activity was lost upon acidification to pH 1.0. The lost 14C-activity was determined to be recoverable with a methanol rinse of extraction vessels and analysis of the aqueous/organic layer interface. The 14C-activity in the feces consisted of 25% acide released TBPA-acide, 20% unextractable solids and again 55% was lost upon acidification. There was no significant difference in the pharmacokinetics between male and female rats. Total residues in all tissues amounted to <0.2% of the dose 2 days after treatment. Blood concentrations of TBPA-equivalents peaked 2 hrs after dosing at 3.462 ppm then gradually decreased to 0.013 ppm after 72 hrs. The portion absorbed appeared to follow a one compartment open model. The test article was rapidly distributed in the body and the rate of elimination in urine was proportional to the concentration in the blood. The rate constant for elimination was 0.081 and the half life in blood was 8.5 hr. The absorbed 14C-activity (>20%) should neither be persistent nor accumulative since the maximum half life in any tissue was < 7 hrs. The extrapolated maximum residues (plateau) could be reached within 2 d in a continuous feeding study of daily dosing.
Executive summary:

A single oral dose of 14C-TBPA was administered to male and female rats. The test article was hydrolyzed to the acid form and partly absorbed in the gastro-intestinal tract. The absorbed portion was readily eliminated in the urine (~20%) within 24 hrs, and the unabsorbed portion was eliminated in the feces within 48 hrs (~75%). The 14C-activity in the urine consisted of 27% acid released TBPA-acid, 27% water solubles and 45% of the 14C-activity was lost upon acidification to pH 1.0. The lost 14C-activity was determined to be recoverable with a methanol rinse of extraction vessels and analysis of the aqueous/organic layer interface. The 14C-activity in the feces consisted of 25% acide released TBPA-acide, 20% unextractable solids and again 55% was lost upon acidification. There was no significant difference in the pharmacokinetics between male and female rats. Total residues in all tissues amounted to <0.2% of the dose 2 days after treatment. Blood concentrations of TBPA-equivalents peaked 2 hrs after dosing at 3.462 ppm then gradually decreased to 0.013 ppm after 72 hrs. The portion absorbed appeared to follow a one compartment open model. The test article was rapidly distributed in the body and the rate of elimination in urine was proportional to the concentration in the blood. The rate constant for elimination was 0.081 and the half life in blood was 8.5 hr. The absorbed 14C-activity (>20%) should neither be persistent nor accumulative since the maximum half life in any tissue was < 7 hrs. The extrapolated maximum residues (plateau) could be reached within 2 d in a continuous feeding study of daily dosing.