Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was performed by an experienced laboratory using 14C-radiolabel. Adequate detail on the study is provided in the report. Chemical and radiochemical purity of the test material were not provided. Total 14C-activity was determined in tissues and excreta.

Data source

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

Materials and methods

Objective of study:
other: To study excretion and tissue distribution in rats
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Corn oil suspensions were administered to rats by gavage once daily for 14 d. Urine, feces, expired air and organs collected at intervals and assessed for 14C-activity.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
14C-ring labelled; specific activity = 10.0 mCi/mM or 2.30 x 10+4 dpm/microgram or 23,000 dpm/microg.
Radio-chemical purity not provided in report.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
once daily for 14 days
Doses / concentrations
Remarks:
Doses / Concentrations:
Suspensions = approximately 1 mg/mL corn oil; confirmed by 14C-activity (Liquid Scintillation Counting) before dose initiation and daily during dosing.
Dosing volume = 0.2 ml
Based on an initial body weight of 220 g, the 14C-administered to the five rats was equivalent to 0.67 mg/kg (3.52 x 10+6 dpm or 149 micrograms).
No. of animals per sex per dose:
See below
Control animals:
yes, concurrent no treatment

Results and discussion

Main ADME resultsopen allclose all
Type:
excretion
Results:
Excreted mainly in the feces, with some 14C-activity detected in urine.
Type:
distribution
Results:
14C-activity detected in tissues taken for assay after 14 consecutive daily doses; highest concentrations found in liver and kidney. Dissipation of radioactivity occured in all tissues examined during the withdrawal period.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
At the end of dosing, the tissues with the highest 14C-activity were liver (~0.39 ppm) and kidney (~0.32 ppm). Levels in both dropped rapidly (by ~50%) during the first 7 days of withdrawal, and continued to drop over the withdrawal period. Levels in muscle (~0.08 ppm), fat (~0.075 pm) and brain (~0.032 ppm) were substantially below that of the liver and kidney after 14 days of dosing. By day 14 of the withdrawal period, no 14C-activity was detected in fat. 14C-activity in the liver, kidney, muscle and brain continued to fall between 14 and 30 days of withdrawal, and were below 0.05 ppm by 30 days post-treatment. The highest level at 30 day post-treatment was found in the skeletal muscle (0.05 ppm).
Details on excretion:
The 14C-label was excreted primarily in the feces; ~65% of the total 14-day dose was recovered in the feces during the dosing period. Approximately 15% of the total 14-day dose was detected in the urine during the dosing period. Negligible 14C-activity was detected in expired air. Thus, 80% of the total dose was recovered in the feces and urine during the 14 days of dosing.

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

No abnormal behaivor detected during the study. All animals had normal weight gain. Organs normal on gross necropsy.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

14C-labelled EBTBP (~0.67 mg/kg) was administered to 5 female Sprague Dawley rats by gavage in corn oil for 14 consecutive days. Two additional female rats served as controls. Two animals were sacrificed 24 hr after the last dose, and the remainder sacrificed after 7, 14 and 30 days of withdrawal. Feces, urine and expired air were collected during the dosing period: One test animal sacrificed on day 14 was housed in a Roth metabolism cage to allow collection of expired C02, volatile organics, feces, and urine. The other animal sacrificed on day 14 was housed in a plastic metabolism cage to allow collection of feces and urine. Skeletal muscle, brain, kidney, liver and fat were collected at each sacrifice from all animals.

The14C-label was excreted primarily in the feces; ~65% of the total 14-day dose was recovered in the feces during the dosing period. Approximately 15% of the total 14-day dose was detected in the urine during the dosing period. Negligible14C-activity was detected in expired air. Thus, 80% of the total dose was recovered in the feces and urine during the 14 days of dosing. 

At the end of dosing, the tissues with the highest14C-activity were liver (~0.39 ppm) and kidney (~0.32 ppm). Levels in both dropped rapidly (by ~50%) during the first 7 days of withdrawal, and continued to drop over the withdrawal period. Levels in muscle (~0.08 ppm), fat (~0.075 pm) and brain (~0.032 ppm) were substantially below that of the liver and kidney after 14 days of dosing. By day 14 of the withdrawal period, no14C-activity was detected in fat. 14C-activity in the liver, kidney, muscle and brain continued to fall between 14 and 30 days of withdrawal, and were below 0.05 ppm by 30 days post-treatment. The highest level at 30 day post-treatment was found in the skeletal muscle (0.05 ppm).