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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted prior to GLPs; study was generally conducted according to acceptable scientific standards.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1966
Report Date:
1966

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A single oral dose of TXIB-3-[14]C was given to each of three adult male rats. Urine, feces and expired air were captured via metabolism cages for the duration of the study, up to 22 days post-dose. Following sacrifice, the levels of radioactivity in excreta, select tissues and organs, and carcass were determined.

In a follow-up study Cantor, EE and Astill, BD. 1966 The Metabolic Fate and Physiological Disposition of the Diisobutyrate Ester of 2,2,4-Trimethyl-1,3-Pentanediol-3-[14]C (TXIB-3-[14]C) the metabolites of TXIB were identified along with the major routes of elimination. The current study served as a precursor to the above referenced study.
GLP compliance:
no
Remarks:
Study was conducted prior to GLPs

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
Preparation of the diisobutyrate ester of 2,2,4-Trimethyl-1,3-Pentanediol-3-[14]C (TXIB-3-[14]C):
Labeled 2,2,4-trimethyl-1,3-pentanediol-3-[14]C (TMPD-3-[14]C) was prepared in the laboratories of Eastman Kodak Company. Following preparation and purification, TMPD-3-[14]C had a stoichiometric specific activity of 0.058 μc/mg. No purity information was reported. TXIB-3-[14]C was prepared from TMPD-3-[14]C, unlabeled TMPD, isobutyric anhydride and sodium acetate. The reaction product was purified by preparative gas chromatographic analysis to yield TXIB-3-[14]C of 98.3% purity, stoichiometric specific activity 0.017 µc/mg.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS:
-Source: A and E Farms, Altamont, NY
-Test Diet: Normal Protein Test Diet (NPD, Nutritional Biochemicals Corporation, Cleveland, OH) was provided for one month prior to the experiment; for the experiment, NPD was mixed with beaten egg, formed into sticks and baked for 2 hr. The modified diet was provided during the study.
-Acclimatization: for 2 days prior to study start, rats were kept in glass metabolism cages.
-Housing during study: rats were housed in individual metabolism chambers equipped for the separation of urine and feces and collection of expired air; cages had an air flow of 1 L/min.
-Weight at study initiation: rats weighed 535, 541, and 519 g, respectively.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
Rats received a single dose of the test article and were observed for up to 22 days.
Doses / concentrations
Remarks:
Doses / Concentrations:
Rats were given actual doses of 250, 236 and 283 mg/kg (mean 256 mg/kg) of undiluted TXIB-3-[14]C by oral gavage.
No. of animals per sex per dose:
3 males/group
Control animals:
no
Details on dosing and sampling:
Collections:
Urine was collected daily, centrifuged and the supernatant brought to a known volume with water and frozen until assayed. Experimental feces were collected daily and frozen until analyzed. Food particles and hair were cleaned from the cages each day and frozen. The cages were washed on a daily basis with acetone, diluted HCl and water and the washings were frozen. Expired air was passed through two consecutive gas washing bottles containing 10% and 5% aqueous NaOH. Rats were sacrificed on days 8, 15 or 22. At necropsy, liver, kidneys, spleen, gastrointestinal tract, fat, lungs, and brain were removed, weighed and immediately covered with acetone. Carcasses were also processed for radioactivity.

Radioactive Assays:
Urine, benzene and acetone extracts of the feces, tissue extracts, extracts of food particles and hair, and wash solutions were assayed on planchets prepared by conventional methods or by liquid scintillation counting. Dried extracted tissues were combusted by a modified Schőninger procedure for radioactive assay. [14]CO2 was estimated in wash solutions by conventional BaCO3 plating techniques.

Purity analysis of TXIB:
Gas-liquid chromatography of TXIB was performed on a F and M 770 Preparative Gas Chromatograph with TC detector, He carrier gas.
Statistics:
No statistical analysis was performed on this study.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
When adult male Sprague-Dawley rats were administered a single oral dose of approximately 250 mg/kg TXIB-3-[14]C, the test material was rapidly absorbed from the gut and at least 95% of the administered dose was recovered in the urine (47.3-72.5%), feces (14.45-31.20%) and cage washings (11.9-16.5%) within a few days of dosing.
Details on distribution in tissues:
Radioactivity accounting for a total of 2.9% of the dose was found in the organs and carcass of the rat sacrificed at 8 days. This amount had decreased by 15 days (0.99%) and at 22 days there was only 0.7% of the dose evident in the organs and carcass. Radioactivity in extracted tissues and organs residues showed a generally similar pattern to the extractable radioactivity, in that quantities close to or below the limits of detection were usually present. The total non-extractable radioactivity in tissues and carcass residues was <0.6%.
Details on excretion:
The data demonstrated rapid absorption and elimination of orally administered TXIB, with renal excretion accounting for 47.3-72.5% of the dose and radioactivity in the feces accounting for 14.45-31.2% of the administered dose. Most urinary radioactivity was eliminated in the first 72 hours while fecal elimination was virtually complete by seven days after dosing. Radioactivity levels in expired CO2 were not detectable. Together with acetone and water soluble radioactivity collected as cage washings, excretions accounted for 97-99% of the dose.

Metabolite characterisation studies

Metabolites identified:
no

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The results indicate that orally administered 2,2,4-trimethyl-1,3-pentanediol diisobutyrate is rapidly absorbed, metabolized and eliminated by the male rat. Almost all of the orally administered TXIB-3-[14]C was eliminated in feces (14.45-31.2%) and urine (47.3-72.5%) within 3-4 days of dosing. Less than 3% of the administered radioactivity was retained in the tissues and carcass.
Executive summary:

In a metabolic fate and disposition study, 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB) was administered to 3 male Sprague-Dawley rats by gavage at a dose level of approximately 250 mg/kg. TXIB was rapidly absorbed and excreted, with renal excretion accounting for elimination of 47-72% of the dose. Radioactivity in the feces accounted for 14-31% of the dose and radioactivity in expired CO2 was not detected. Together with acetone and water soluble radioactivity collected as cage washings, excretions accounted for 97-99% of the dose. Less than 3% of the administered radioactivity was retained in the tissues and carcass of the rat sacrificed 8 days after TXIB administration and this value decreased to 0.7% in the rat sacrificed 22 days after TXIB administration.