Potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

The study was not conducted in strict compliance with FDA GLP. However, the study was conducted according to the protocol and applicable standard operating procedures of the research laboratory. All study procedues, data recording and reporting were performed in a manner consistent with the standard of GLPs.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Objective of study:

distribution

excretion

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The objectives of the study were to determine the concentration of the test article in serum and to estimate urinary clearance at various times following administration of a single intravenous dose to monkeys.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate

EC Number:

249-616-3

EC Name:

Potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate

Cas Number:

29420-49-3

Molecular formula:

C4HF9O3S.K

IUPAC Name:

potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: EO4/L-1
- Expiration date of the lot/batch: No data
- Purity test date: 26 February, 2001

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test article was disolved in sterile saline prior to dosing.
- Final dilution of a dissolved solid, stock liquid or gel: The test article was prepared to deliver 10 mg/kg to each animal at a dose volume of 2 mL/kg.

FORM AS APPLIED IN THE TEST: The test article was dissolved in sterile saline.

Radiolabelling:

no

Test animals

Species:

monkey

Strain:

other:

Details on species / strain selection:

Cynomolgus monkeys were utilized for this study.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River BRF, Inc. (Houston, TX).
- Age at study initiation: No data
- Weight at study initiation: Males: 4.4-5.8 kg, Females: 3.3-3.9 kg
- Housing: Individually in stainless steel cages.
- Diet (e.g. ad libitum): Certified commercial dry monkey chow #5048 (PMI Feeds, Inc., St. Louis, MO) fed to the monkeys 2-3 times each day.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: Unspecified quarantine period.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21.3
- Humidity (%): 22.2-65.7
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test article was dissolved in sterile saline.

Duration and frequency of treatment / exposure:

Each animal received a single intravenous bolus dose of 10 mg/kg of the test article.

Doses / concentrations

Dose / conc.:

10 mg/kg bw (total dose)

Remarks:

Doses were administered at a volume of 2 mL/kg body weight.

No. of animals per sex per dose / concentration:

3

Control animals:

no

Positive control reference chemical:

None

Details on study design:

Three male and three female monkeys were administered a single IV bolus dose of 10 mg/kg of perfluorobutanesulfonate, potassium salt. At various times through 31 days after dosing, serum and urine (24-hour collections) samples were obtained and analyzed by HPLC/MS/MS for levels of intact perfluorobutanesulfonate.

- Dose selection rationale: No data
- Rationale for animal assignment: No randomization was required as there was only one treatment group.

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: urine, faeces, serum
- Time and frequency of sampling: Urine and feces were collected for 24-hour intervals on the following days: prior to dose administration (Day -1; baseline), on Day 0 (0-24 hours postdose), and on Days 7 and 14. The volume of each urine sample was measured upon collection. Samples were stored frozen at -20 °C or below. Blood samples (approximately 2 mL) were collected from each primate at approximately 0 (predose) minutes; 2, 4, 8, 24, and 48 hours; and on Days 4, 7, 11, 14, and 31 postdose. Samples were collected into tubes without anticoagulant and were allowed to clot at room temperature. The blood samples were then centrifuged, and the serum separated and stored frozen (-20 °C or below) until analyzed.

CHARACTERISATION STUDIES
- Tissues and body fluids sampled urine, feces, serum
- Time and frequency of sampling: Urine and feces were collected for 24-hour intervals on the following days: prior to dose administration (Day -1; baseline), on Day 0 (0-24 hours postdose), and on Days 7 and 14. The volume of each urine sample was measured upon collection. Samples were stored frozen at -20 °C or below. Blood samples (approximately 2 mL) were collected from each primate at approximately 0 (predose) minutes; 2, 4, 8, 24, and 48 hours; and on Days 4, 7, 11, 14, and 31 postdose. Samples were collected into tubes without anticoagulant and were allowed to clot at room temperature. The blood samples were then centrifuged, and the serum separated and stored frozen (-20 °C or below) until analyzed.
- From how many animals: Samples were taked from all three males and all three females.
- Method type(s) for identification: HPLC-MS-MS
- Limits of detection and quantification: LOD: 0.5 ng/mL, LOQ: 1 ng/mL

Results and discussion

Main ADME results

Main ADME results 1

Type:

distribution

Results:

The volume of distribution at steady state was 254 or 255 mL/kg in male or female monkeys, respectively.

Main ADME results 2

Type:

excretion

Results:

The mean terminal serum half-life of the test article in male and female monkeys was 3.5-4.0 days. Urinary excretion was the major route of elimination of unchanged test article.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

The volume of distribution at steady state was 254 or 255 mL/kg in male or female monkeys, respectively.

Details on excretion:

Mean half-life values for the test article in serum were 0.04, 0.55, and 4.0 days in male monkeys and 0.06, 0.47, and 3.5 days in female monkeys.

Toxicokinetic parameters

Key result

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 3.5-4.0 days

Remarks:

Male and female monkeys.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Based on the results of the study, the mean terminal half-life values for the test article in male and female monkeys was 3.5 - 4.0 days. In monkeys, urinary excretion was a major route of elimination of unchanged test article.

Executive summary:

The pharmacokinetics and urinary excretion of the test article were investigated in male and female cynomolgus monkeys. The study was not conducted in strict compliance with FDA GLP. However, the study was conducted according to the protocol and applicable standard operating procedures of the research laboratory. All study procedues, data recording and reporting were performed in a manner consistent with the standard of GLPs. Three male and three female monkeys were administered a single IV bolus dose of 10 mg/kg of test article. Urine and feces were collected for 24-hour intervals on the following days: prior to dose administration (Day -1; baseline), on Day 0 (0-24 hours postdose), and on Days 7 and 14. The volume of each urine sample was measured upon collection. Blood samples (approximately 2 mL) were collected from each primate at approximately 0 (predose) minutes; 2, 4, 8, 24, and 48 hours; and on Days 4, 7, 11, 14, and 31 postdose. Samples were collected into tubes without anticoagulant and were allowed to clot at room temperature. The blood samples were then centrifuged, and the serum separated and stored frozen (-20 °C or below) until analyzed by HPLC/MS/MS for levels of intact test article. The lower limit of detection of the analytical method was 0.5 ng/mL. No sex-related differences in serum concentrations of test article were apparent among the six dosed monkeys. In individual animals, the concentration of test article in serum ranged from 19,628 to 61,740 ng/mL at 2 hours after dosing (earliest time point). By 48 hours after dosing, the serum concentration of test article ranged from 463 to 8,172 ng/mL in individual monkeys. The test article was not detectable in serum collected from any monkey on Day 31 post dose. The serum concentration versus time data were best fit to a three-compartment model. Mean serum half-life values for the test article were 0.04, 0.55, and 4.0 days in male monkeys, and 0.06, 0.47, and 3.5 days in female monkeys. The mean AUC value calculated from serum concentrations of the test article was 24,258 or 35,401 ng.day/mL in male or female monkeys, respectively. The total body clearance of the test article was 511 mL/day/kg in male monkeys and 368 mL/day/kg in female monkeys. The volume of distribution at steady state (Vdss) was 254 or 255 mL/kg in male or female monkeys, respectively. For 5 of 6 monkeys, from 33.8 to 86.8% of the dose was recovered in urine within 24 hours after administration of the test article. On Day 14, individual monkeys excreted less than 0.01% of the dose within a 24-hour interval. Based on the results of the study, the mean terminal half-life values for the test article in male and female monkeys was 3.5 - 4.0 days. In monkeys, urinary excretion was a major route of elimination of unchanged test article.