Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Objective of study:
absorption
excretion
Test guideline
Qualifier:
according to
Guideline:
other: Custom toxicokinetic screening protocol
Principles of method if other than guideline:
Male rats (6) were adminitered a single 907 mg/kg dose of the test article via oral gavage. Serum (1, 6, 24, 48, 72, and 96 hours post-dose) and urine and feces (0-6, 6-24-24-48, 48-72, and 72-96 hours post-dose) samples were collected. Liver and subcutaneous fat samples were collected from control and treated animals at termination on Study Day 5. Serum, urine, feces and liver samples were analyzed for the parent compound.
GLP compliance:
no

Test material

Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot TFEE5-276/12/09-1
- Purity test date: 10th February, 2011

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In its original contaner at room temperature, protected from light.
- Stability under test conditions: Stable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: None, the test article was dosed as received.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Sprague-Dawley [Crl;CD(SD)IGS BR]
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 201-218 grams
- Housing: Individually in polycarbonate metabolism cages with wire bottoms
- Diet (e.g. ad libitum): Harlan Teklad Rat/Mouse 2018 Diet (Harlan Teklad, Madison, WI) ad libitum
- Water (e.g. ad libitum): Tap water (St. Paul, MN municipal water supply) ad libitum
- Acclimation period: 5 days prior to study initiation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-23.9
- Humidity (%): 30-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 12 May, 2014 To: 16 May 2014

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was dosed as received.

Duration and frequency of treatment / exposure:
Animals received a single dose via oral gavage.
Doses / concentrationsopen allclose all
Dose / conc.:
907 mg/kg bw/day (actual dose received)
Remarks:
Treatment group
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control group
No. of animals per sex per dose:
3 males were utilized in the control group (0 mg/kg body weight) and 6 males were utilized in the treatment group (907 mg/kg body weight).
Control animals:
yes, concurrent no treatment
Positive control:
None
Details on study design:
- Dose selection rationale: The dose was not expected to cause toxicity based on previous acute oral toxicity testing.
- Rationale for animal assignment (if not random): Random
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, excretion)
- Tissues and body fluids sampled: urine, faeces, serum, liver, subcutaneous fat
- Time and frequency of sampling: Serum (1, 6, 24, 48, 72, and 96 hours post-dose) and urine and feces (0-6, 6-24-24-48, 48-72, and 72-96 hours post-dose) samples were collected. Liver and subcutaneous fat samples were collected from control and treated animals at termination on Study Day 5. Serum, urine, feces, and liver samples were analyzed for the parent compound. Fat samples and potential metbolites were not analyzed since virtually all of the adminstered dose was recovered from the feces of the treated animals and all serum and urine samples had test article concentrations below the lower limit of quantitation.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Test article concentrations in the serum, urine and liver samples of treated animals were below the limit of quantitation. As a result, the test article does not appear to be absorbed following oral exposure.
Type:
excretion
Results:
Virtually all of the adminstered dose was recovered in the feces of the treated animals between 6 and 48 hours after dosing.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Test article concentrations in the serum, urine and liver samples of treated animals were below the limit of quantitation. As a result, the test article does not appear to be absorbed following oral exposure.
Details on distribution in tissues:
Test article concentrations in the serum, urine and liver samples of treated animals were below the limit of quantitation.
Transfer into organs
Transfer type:
other: Distribution to liver
Observation:
no transfer detectable
Remarks:
Test article concentrations in the serum and liver samples of the treated animals were below the limit of quantitation.
Details on excretion:
Virtually all of the administered dose was recovered in the feces of the treated animals between 6 and 48 hours after dosing.
Toxicokinetic parameters
Toxicokinetic parameters:
other:

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Metabolites were not analyzed as virtually the entire administered dose was recovered in the feces of the treated animals, indicating that the test article was likely not absorbed.

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the test article was not absorbed following oral administration in rats. Based on these findings, it is considered unlikely that bioaccumulation of the test article would occur in humans following oral exposure.
Executive summary:

The absorption and excretion of the test article was investigated in male Sprague Dawley rats. The study was not conducted under GLP conditions. The test method was based on a custom protocol. Animals were administered a single dose of 907 mg/kg (treated, n=6) or 0 mg/kg (control, n=3) via oral gavage. Serum (1, 6, 24, 48, 72, and 96 hours post-dose) and urine and feces (0-6, 6-24-24-48, 48-72, and 72-96 hours post-dose) samples were collected. Liver and subcutaneous fat samples were collected from control and treated animals at termination on Study Day 5. Serum, excreta and liver samples were analyzed for the test article. No treatment-related deaths occurred and no abnormal clinical signs were observed during the study. Treated animals gained weight over the course of the study. Test article concentrations were below the lower limits of quantitation in all serum, urine and liver samples analyzed. Virtually all of the administered dose was recovered in the feces of the treated animals between 6 and 48 hours after dosing (101.42% recovered from 0-96 hours) Recoveries were based on the lower limit of quantitation and slightly overstate actual recoveries. Based on the results of the study, the test article was not absorbed following oral administration in rats. Based on these findings, it is considered unlikely that bioaccumulation of the test article would occur in humans following oral exposure.