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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
Study period:
2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was not conducted under GLP conditions but was well documented.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Objective of study:
other: Serum uptake, liver distribtuion, and excresion profile of the test article.
Test guideline
Qualifier:
according to guideline
Guideline:
other: Internal protocol
Principles of method if other than guideline:
The study was conducted to evaluate the serum uptake, liver distribution, and excretion profile of the test article. The test article (unchanged) was dosed via oral gavage to non-fasted male rats (3dose) at 100, 300, or 1000 mg/kg body weight. Milli-q water was dosed to negative control rats. Interim urine and feces were collected from 0-12 hours, 12-24 hours, and 24-48 hours post-dose from all animals. At 48 hours post-dose, all animals were euthanized via CO2 asphyxiation followed by gross necropsy. Blood (processed to serum) and liver were harvested during necropsy. All specimens collected during the study (urine, feces, serum, and liver) were analyzed for concentrations of test article by GC/MS. Urine samples obtained from the 1000 mg/kg dose group were analyzed for potential test article metabolites by 19F-NMR.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report): MTDID 7145
- Physical state: Liquid
- Analytical purity: 94.2%
- Purity test date: 22 April, 2015
- Lot/batch No.: 040032
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 238-261 grams
- Fasting period before study: None
- Housing: group-housed in solid bottom cages prior to the study. All animals were single housed in wire bottomed metabolism cages during the in-life portion of the study until study termination.
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Harlan Teklad Rat/Mouse 2018 Diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum

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

IN-LIFE DATES: From: 3 August, 2015 To: 5 August, 2015

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was dosed neat (unchanged) at 100, 300, or 1000 mg/kg body weight.
Duration and frequency of treatment / exposure:
Each rat received a single oral dose via gavage at 100, 300, or 1000 mg/kg body weight.
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, or 1000 mg/kg body weight.
No. of animals per sex per dose / concentration:
3 males per dose
Control animals:
yes, sham-exposed
Positive control reference chemical:
Not applicable
Details on study design:
- Dose selection rationale: Doses were within the range of previous acute oral studies.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood (processed to serum), liver
- Time and frequency of sampling: Interim urine and feces were collected from 0-12 hours, 12-24 hours, and 24-48 hours post-dose from all animals. Blood (processed to serum) and liver were harvested during necropsy at 48 hours post-dose.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, blood (processed to serum), liver
- Time and frequency of sampling: Interim urine and feces were collected from 0-12 hours, 12-24 hours, and 24-48 hours post-dose from all animals. Blood (processed to serum) and liver were harvested during necropsy at 48 hours post-dose.
- From how many animals: All 12 animals, samples not pooled
- Method type(s) for identification: GC/MS for liver, serum, urine, and fecal samples, F-NMR for urine metabolite determination.
- Limits of detection and quantification: LOQ: Serum: 0.5 ug/mL, Liver: 2.0 ug/g, Urine: 0.5 ug/mL, Feces: 1.5 ug/g


TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):

Results and discussion

Main ADME results
Type:
absorption
Results:
The test article was not quantifiable in serum, liver or urine samples. No test article, its isomer, ring-opened isomeric forms of the test article, or other fluorochemical metabolites derived from the test article were detected in the urine F-NMR spectra

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The test article was not quantifiable in serum, liver or urine samples collected throughout the study. No test article or its isomers, no rign-opened isomeric forms of the test article, and no other fluorochemical metabolite species of any kind derived from the test article were detected in the 19F-NMR spectra for urine samples. The data suggest that the test article is not likely to be absorbed into the blood or undergo metabolic biotransformation.
Details on distribution in tissues:
The test article was not quantifiable in serum or liver tissue samples taken at necropsy.
Details on excretion:
The test article was quantifiable in most of the fecal samples collected. Test article recovery in the feces ranged from 19-27%. Due to the volatility of the test article, it is likely that evaporative loss accounts for the low recovery.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
The test article or any metabolites were not quantifiable in urine samples collected from the highest dose group animals from the study.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the results of the study, given that only fecal samples had quantifiable test article present after oral administration, these data suggest that the test article was not likely to be absorbed into the blood, does not undergo metabolic biotransformation, and has a very low potential to bioaccumulate in rats.
Executive summary:

The study was conducted to evaluate the serum uptake, liver distribution, and excretion profile of the test article. The study was not conducted under GLP conditions and the test method was based on an internal protocol. The test article (unchanged) was dosed via oral gavage to non-fasted male rats (3 doses) at 100, 300, or 1000 mg/kg body weight. Milli-Q water was dosed to negative control rats. Interim urine and feces were collected from 0-12 hours, 12-24 hours, and 24-48 hours post-dose from all animals. At 48 hours post-dose, all animals were euthanized via CO2 asphyxiation followed by gross necropsy. Blood (processed to serum) and liver were harvested during necropsy. Urine samples obtained from the 1000 mg/kg dose group were analyzed for potential test article metabolites. All animals appeared normal during the study and they all survived until the scheduled necropsy. There were no treatment-related findings or gross lesions noted in any animals. The test article was not quantifiable in either serum or liver samples at 48 hours post-dose; and the test article was not quantifiable in the urine samples collected throughout the study. No test article parent compound or its isomers, no ring-opened isomeric forms of the parent study compound, and no other fluorochemical metabolite species of any kind derived from the test article mixture are detected in the urine samples. The test article was quantifiable in most of the fecal samples collected and the overall test article recovery in the feces ranged from 19 -27%. Since the test article is highly volatile, in conjunction with the fact that the fecal samples were left at room temperature for an extended period of time during collection (12 -24 hours), the low recovery in the feces likely reflects evaporative loss. Based on the results of the study, given that only fecal samples had quantifiable test article present after oral administration, these data suggest that the test article was not likely to be absorbed into the blood, does not undergo metabolic biotransformation, and has a very low potential to bioaccumulate in rats.