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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
according to
Guideline:
EPA OTS 795.2280 (Oral/Dermal Pharmacokinetics)
Principles of method if other than guideline:
The distribution, metabolism, and excretion of TBP was studied in Sprague-Dawley rats using 14C-labeled TBP. The test substance was given to the animals via the following routes and schedules: 1. intravenous 2. dermal 3. single oral dose 4. multiple oral dose. Urine, feces, and expired air were collected from all dose groups at 6, 12, 24, 48, and 72 h after dosing. Urine and feces were then collected at 96, 120, 144, and 168 h after dosing. After the least collection, all of the rats in a dose group were sacrificed for tissue distribution analysis. The excreta of 2 males and 2 females from each dose group were also analyzed for metabolites.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity of the labeled TBP was 99%, specific activity was 112.6 µCi/mg
Radiolabelling:
yes
Remarks:
14C-TBP

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
other: intravenous, dermal, single or multiple oral
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
168 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
intravenous: 5 mg/kg
dermal: 10 or 350 mg/kg
single oral: 10 or 350 mg/kg
multiple oral: 10 or 350 mg/kg
No. of animals per sex per dose:
4males + 4 females/group/dose
Control animals:
not specified

Results and discussion

Preliminary studies:
no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Urine, feces, expired air, and various organs and tissues were collected and analyzed for radioactivity. Recovery was about 90% or above in all treated groups except for the dermal dose groups. Dermal dose recovery was lower and ranged from 66% to 80%.
Details on distribution in tissues:
The radioactive dose residing in the tissues in all groups is very small and did not exceed 1% of dose for any tissue.
Details on excretion:
The major excretory route for the radio label was the urine. Urinary excretion always exceeded the secondary route of excretion, the faces, from 4-fold (iv dose-males) to 14-fold (multiple-oral high dose-females).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The results indicated that phase I metabolism (oxidation and hydrolysis) represented the major biotransformation pathway. Significant and representative metabolites identified in urine sample included dibutyl hydrogen phosphate (DBP), butyl hydroxybutyl hydrogen phosphate, and butyl butanoic acid hydrogen phosphate. Fifteen other metabolites were also observed which contained oxidized (acid, keto, hydroxyl) tri, di, and monobutyl substituted phosphoric acids. The parent chemical was typically less than 1% of the excreted dose. Phase II metabolism was not considered a significant route of biotransformation of TBP.

Any other information on results incl. tables

Analysis of samples by GC and HPLC indicated individual animal variability in the production of specific metabolites. Because of this variability, neither the concentration nor the specific structure of the metabolites was concluded to be dependent on dose, route, dosing regimen, or sex of the animal.

Applicant's summary and conclusion

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

The distribution, metabolism, and excretion of TBP was studied in sprague-Dawley rats using 14C-labeled TBP. The test substance was given to the animals via the following routes and schedules: 1. intravenous 2. dermal 3. single oral dose 4. multiple oral dose. Urine, feces, and expired air were collected from all dose groups at 6, 12, 24, 48, and 72 h after dosing. Urine and feces were then collected at 96, 120, 144, and 168 h after dosing. After the least collection, all of the rats in a dose group were sacrificed for tissue distribution analysis. The excreta of 2 males and 2 females from each dose group were also analyzed for metabolites.

The results indicated that phase I metabolism (oxidation and hydrolysis) represented the major biotransformation pathway. Significant and representative metabolites identified in urine sample included dibutyl hydrogen phosphate (DBP), butyl hydroxybutyl hydrogen phosphate, and butyl butanoic acid hydrogen phosphate. Fifteen other metabolites were also observed which contained oxidized (acid, keto, hydroxyl) tri, di, and monobutyl substituted phosphoric acids. The parent chemical was typically less than 1% of the excreted dose. Phase II metabolism was not considered a significant route of biotransformation of TBP.