3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Principles of method if other than guideline:

The test substance was administered orally by gavage once daily for 10 consecutive days to 2 groups of 5 male Crl:CD(SD)IGS BR rats at a 300 mg/kg/day dose. One group was sacrificed on Day 10, and the other group was maintained without dosing for an additional 84 days. Blood was collected on test days 1, 5, 10, 13, 24, 52, and 94. Livers and fat were collected at sacrifice. Body weights and clinical signs were recorded throughout the dosing and recovery periods. Additionally, a negative control of deionised water, and 2 positive controls, were tested as described for the test substance. Blood, liver, and fat samples were analysed for total fluorine content to determine test substance absorption and retention in these tissues.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol

EC Number:

211-477-1

EC Name:

3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol

Cas Number:

647-42-7

Molecular formula:

C8H5F13O

IUPAC Name:

3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol

Details on test material:

- Purity: 96.2%

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7 weeks
- Weight at study initiation: 184.1-192.9 gm on study day 1
- Fasting period before study: no
- Housing: Singly in stainless steel wire mesh cages suspended above cage boards
- Individual metabolism cages: no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 1°C
- Humidity (%): 50 ± 10%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle (fluorescent light)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: deionised water for test substance; acetone/corn oil for positive controls

Details on exposure:

PREPARATION OF TEST SUBSTANCE FORMULATION:
- Solvent used: deionised water
- Preparation frequency: no data
- Preparation details: the mixture of test substance in water was stirred on a magnetic stir plate throughout dosing to maintain homogeneity.
- Adjusted for purity: no

PREPARATION OF POSITIVE CONTROLS
- It was necessary to dissolve the positive controls in acetone before suspending them in corn oil. The ratio of acetone to corn oil was 20:80.

Duration and frequency of treatment / exposure:

Once per day for 10 consecutive days

Doses / concentrations

Remarks:

Doses / Concentrations:
300 mg/kg
dosing volume was 1 mL per 100 gm of body weight

No. of animals per sex per dose / concentration:

2 groups of 5

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

2 positive controls were used, one given at 10 mg/kg/day and the other at 20 mg/kg/day

Details on study design:

- Dose selection rationale: Based on existing toxicity information and the results of a rangefinder.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood, liver, and fat
- Time and frequency of sampling: Blood was collected on test days 1, 5, 10, 13, 24, 52, and 94. Livers and fat were collected at sacrifice. One group was sacrificed on Day 10 and the other on Day 94.

Statistics:

Descriptive statistics (mean, standard deviation) were used.

Results and discussion

Preliminary studies:

Groups of five rats were dosed at 0 (control) or 300 mg/kg for 6 consecutive days. The rats dosed with the test substance had an overall body weight gain of 24 grams compared to 28 grams for the control rats. The dosage of 300 mg/kg was chosen for the study and was expected to produce less than a 10% difference in mean body weight over 10 days when compared to the negative control

Toxicokinetic / pharmacokinetic studies

Details on absorption:

As a measure of total dose in the blood, an area under the curve (estimated to infinity) was calculated for each test material. The AUCINF/D for the fluorine component of the test substance was 1.07e3, compared to AUCINF/D values of 5.22e5 and 8.15e4 for the 2 positive controls. This parameter indicated a total dose in blood that was much less for the test substance than for the positive controls.

Details on distribution in tissues:

The concentration of fluorine in the livers from rats dosed with the test substance was 27.52 μM equivalents on day 10 and 2.26 μM equivalents on day 94. On the last day of dosing, the mean μM equivalent concentrations of fluorine in the livers of rats dosed with the 2 positive control materials were approximately 174-fold and 31-fold greater than values in rats treated with the test substance. By day 94, the fluorine concentrations were approximately 572x and 8x the fluorine concentration in rats treated with the test substance. Therefore, rats treated with the positive controls absorbed and retained considerably more fluorine in the liver than rats treated with the test substance.
The fluorine concentration in the fat from rats dosed with the test substance was 49.10 μM equivalents on day 10 and 10.87 μM equivalents on day 94. The fluorine concentration of one of the positive control materials was approximately 4x higher than the test substance on day 10. The fluorine concentration of the other positive control material was similar on day 10 to the fluorine concentration of the test substance. By day 94, the fluorine concentration of this positive control material was similar to the fluorine concentration in rats treated with the test substance. There was no detectable fluorine by day 94 in the fat from rats dosed with this positive control.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Under the conditions of this study, fluorine was evident in the blood during the period of dosing with the test substance, but was quickly eliminated. The amounts of fluorine in the livers and fat from rats dosed with the test substance were higher than levels in the blood, and the results indicate that there was evidence of some retention of fluorine in the liver and fat. Fluorine levels in the fat were generally slightly higher or similar to the positive control materials. Fluorine levels in the blood and liver were considerably lower than levels in rats dosed with the positive controls.

Executive summary:

The study was conducted to evaluate the potential for the test substance to be absorbed and to accumulate in a mammalian system. Two groups of 5 male rats each were dose by gavage with 300 mg/kg/day of the test substance for 10 consecutive days. One group was sacrificed on Day 10, and the other group was maintained without dosing for an additional 84 days. Blood was collected on test days 1, 5, 10, 13, 24, 52, and 94. Livers and fat were collected at sacrifice.  Body weights and clinical signs were recorded throughout the dosing and recovery periods. A negative control of deionised water, and 2 positive controls dosed at 10 mg/dg/day and 20 mg/kg/day, were tested as described for the test substance. Blood, liver, and fat samples were analysed for total fluorine content to determine test substance absorption and retention in these tissues.

No deaths occurred, and no clinical signs attributed to the test substance were observed. The mean body weight gains of rats dosed with the test substance were similar to the negative control rats during the dosing and recovery periods. Data for the AUCINF/D for the test substance and positive controls indicated that the total dose in blood was much less for the test substance than for the positive controls. Liver weights of rats dosed with the test substance were higher than the negative controls at both the end of the dosing period and at the end of the recovery period. Measurement of fluorine concentrations in the livers indicated that rats treated with the positive controls absorbed and retained considerably more fluorine in the liver than rats treated with the test substance. The fluorine concentration in the fat from rats dosed with the test substance was higher than the liver concentration. One of the positive controls had a 4x higher concentration in the fat at day 10 compared to the test substance, but the concentration was similar to the test substance group by the end of the recovery period. The other positive control had a fluorine concentration in the fat that was similar to the test substance group at day 10 and not detectable by the end of the recovery period.