Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Objective of study:
absorption
excretion
metabolism
Principles of method if other than guideline:
- Principle of test: The pharmacokinetic properties of the test article were evaluated in Sprague Dawley rats.
- Short description of test conditions: Non-fasted rats (5/sex) received a single oral 300 mg/kg body weight dose of the test article via gavage. Control rats (5/sex) received a single oral 5 mL/kg body weight dose of olive oil in place of the test article in the same manner. T
- Parameters analysed / observed: he animals were observed for mortality and morbidity immediately following dosing and throughout the duration of the study. Body weights were collected prior to treatment and on Days 1-4, 6, 8, 10, 13, and 14. Urine and feces were collected from all animals on days 1-4, 9, 11, and 14. Urine volumes were approximated and recorded and feces samples were weighed and recorded. Urine samples were analyzed with NMR. At termination, blood was collected from each animal for serum analysis. At termination gross necropsy was performed on all animals, and the livers were excised and weighed. All samples were stored at -70 C for future analysis.
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: 3M Company, NB#159571-76, Purity: 99.9%
- Expiration date of the lot/batch: Not specified
- Purity test date: 17 February, 2012

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test article was unchanged.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 124-186 g
- Housing: All animals were group housed in solid bottom cages prior to the study and on days when urine and feces collections were not scheduled. During the scheduled periods of urine and feces collections, all animals were individually housed in wire bottom metabolism caging.
- Diet (e.g. ad libitum): Harlan Teklad Rat/Mouse 2018 Diet (Harlan Teklad, Madison, WI), ad libitum.
- Water (e.g. ad libitum): Tap water, ad libitum.
- Acclimation period: At least 5 days.

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 March, 2012 To: 26 March, 2012

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was mixed with olive oil and administered as a suspension.
Duration and frequency of treatment / exposure:
Animals received a single oral dose via gavage.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw (total dose)
Dose / conc.:
300 mg/kg bw (total dose)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control:
None
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment: Random.
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, feces, serum, liver
- Time and frequency of sampling: Urine and feces were collected from all animals on days 1-4, 9, 11, and 14. Serum was collected prior to necropsy and livers collected at necropsy.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: Urine was collected from all animals on days 1-4, 9, 11 and 14.
- From how many animals: All animals
- Method type(s) for identification: 19F-NMR
- Limits of detection and quantification: Not specified.

Results and discussion

Main ADME resultsopen allclose all
Type:
excretion
Results:
Based on urine NMR analysis, less than 1% of the test article dose was recovered as perfluorosuccinate dianion and inorganic fluoride.
Type:
metabolism
Results:
Based on urine NMR analysis, less than 1% of the test article dose was recovered as perfluorosuccinate dianion and inorganic fluoride.
Type:
absorption
Results:
Based on urine NMR analysis, less than 1% of the test article dose was recovered as perfluorosuccinate dianion and inorganic fluoride.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on urine NMR analysis, less than 1% of the test article dose was recovered as perfluorosuccinate dianion and inorganic fluoride. Based on the data obtained from this study, the primary route of elimination for the test article could not be determined. The test article appeared to be eliminated more readily in males vs. females with an average urinary half life of 2.5 days and 3.32 days, respectively.
Details on excretion:
Based on urine NMR analysis, less than 1% of the test article dose was recovered as perfluorosuccinate dianion and inorganic fluoride. Based on the data obtained from this study, the primary route of elimination for the test article could not be determined. The test article appeared to be eliminated more readily in males vs. females with an average urinary half life of 2.5 days and 3.32 days, respectively.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Based on urine NMR analysis, less than 1% of the test article dose was recovered as perfluorosuccinate dianion and inorganic fluoride.

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the average urinary half-life of the test article was 2.5 days in males and 3.32 days in females. The primary route of elimination for the test article could not be determined from the data.
Executive summary:

The pharmacokinetic properties the test article were evaluated in Sprague Dawley rats. Non-fasted rats (5/sex) received a single oral 300 mg/kg body weight dose of the test article suspended in olive oil via gavage. Control rats (5/sex) received a single oral 5 mL/kg body weight dose of olive oil in place of the test article in the same manner. The animals were observed for mortality and morbidity immediately following dosing and throughout the duration of the study. Body weights were collected prior to treatment and on Days 1-4, 6, 8, 10, 13, and 14. Urine and feces were collected from all animals on days 1-4, 9, 11, and 14. Urine volumes were approximated and recorded and feces samples were weighed and recorded. Urine samples were analyzed with NMR. At termination, blood was collected from each animal for serum analysis. At termination gross necropsy was performed on all animals, and the livers were excised and weighed. All samples were stored at -70 C for future analysis. All animals survived until termination. Overall, compared to sex-matched controls, there were no statistically significant differences in terminal body weight, body weight gain, or liver weight to body ratios. Some soft stool was noted in one test female on Day 3. Dark colored urine was noted in 3 male control animals at Day 4, however, the discoloration appeared to be due to food crumbs in the collection cup. There were no gross lesions in any test animal at necropsy. F-NMR urine analysis revealed the presence of trace levels (1%) of perfluorosuccinate dianion and inorganic fluoride anion in all urine samples from all test animals from Day 1 to Day 14. The urinary half-life in males and females was 2.5 days and 3.32 days respectively. Based on the results of the study, the average urinary half-life of the test article was 2.5 days in males and 3.32 days in females. The primary route of elimination for the test article could not be determined from the data.