Reaction mass of (3E)-1,1,1,2,2,3,4,5,6,6,7,7,7-tridecafluoro-5-methoxyhept-3-ene and (2E)-1,1,1,2,3,4,5,5,6,6,7,7,7-tridecafluoro-4-methoxyhept-2-ene and (3E)-1,1,1,2,2,4,5,5,6,6,7,7,7-tridecafluoro-3-methoxyhept-3-ene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment. Although data provided have a report year after 2008, the study was performed to fulfill needs required by government regulators and/or for product stewardship purposes. DuPont’s stewardship principle states that “We will adhere to the highest standards for the safe operation of facilities and the protection of our environment, our employees, our customers and the people of the communities in which we do business”. The study was carried out in accordance with our internal Product Stewardship standard which is part of the American Chemical Council’s “Responsible Care Program”. This study was not performed to fulfill an information requirement under REACH, but since the test data were already available they were provided as part of the REACH submission.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Objective of study:

absorption

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: The Guidelines for the Testing of Chemicals issued by Ministry of Environmental Protection of the People's Republic of China, 2004.5 (417, Toxicokinetics Study).

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: The Guidelines for the Hazard Evaluation of New Chemical Substances issued by Ministry of Environmental Protection of the People's Republic of China, 2004.6

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2E)-1,1,1,2,3,4,5,5,6,6,7,7,7-tridecafluoro-4-methoxyhept-2-ene; (3E)-1,1,1,2,2,3,4,5,6,6,7,7,7-tridecafluoro-5-methoxyhept-3-ene; (3E)-1,1,1,2,2,4,5,5,6,6,7,7,7-tridecafluoro-3-methoxyhept-3-ene

EC Number:

700-755-2

Molecular formula:

C8H3F13O

IUPAC Name:

(2E)-1,1,1,2,3,4,5,5,6,6,7,7,7-tridecafluoro-4-methoxyhept-2-ene; (3E)-1,1,1,2,2,3,4,5,6,6,7,7,7-tridecafluoro-5-methoxyhept-3-ene; (3E)-1,1,1,2,2,4,5,5,6,6,7,7,7-tridecafluoro-3-methoxyhept-3-ene

Details on test material:

- Purity: not reported

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control Beijing
- Age at study initiation: not reported
- Weight at study initiation: 250± 10g
- Fasting period before study: Food was withheld 12 hour prior to the administration of the test substance.
- Housing: Every five animals were housed in a stainless steel cage.
- Individual metabolism cages: no
- Diet (e.g. ad libitum): comply with the relevant provisions of GB14925
- Water (e.g. ad libitum): Reverse osmosis filtered water was used, ad libitum
- Acclimation period: least 3 days prior to the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23°C
- Humidity (%): 40%-50%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light and 12-hour dark cycle

Administration / exposure

Route of administration:

other: intravenous administration, acute oral administration and repeated dose 14-day oral administration

Vehicle:

other: suspended homogeneously with ethyl acetate (final concentration 1%) and polyoxyethylene - 35 - castor oil (final concentration 4.3%)

Details on exposure:

The test substance was suspended homogeneously with ethyl acetate (final concentration 1%) and polyoxethylene-35-castor oil (final concentration 4.3%). The preparation and the test substance were stored at room temperature. The preparation was prepared before treatment.

Duration and frequency of treatment / exposure:

One day to 14 days

Doses / concentrations

Remarks:

Doses / Concentrations:
Intravenously into the tail vein, single dose: 10 mg/kg
Single oral administration: 1500 mg/kg and 30000 mg/kg
Repeated oral dose 14-day: 1500 mg/kg

No. of animals per sex per dose / concentration:

4 males/dose (test substance groups)
2 males (control groups)

Control animals:

other: Oral: concurrent blank control; Intravenous: concurrent solvent control

Details on study design:

- Dose selection rationale: For the main studies, a minimum of two doses was preferred since information gathered from at least two dose groups may aid in dose setting in other toxicity studies, and help in the dose-response assessment of already available toxicity tests. A value for the low dose should have beenless than NOAEL. The high dose should have been high enough to allow for causing toxic symptoms or changing the metabolic parameters, while not producing apparent toxicity. Therefore, 1500 mg/kg and 30000 mg/kg were set as dosages for acute oral administration. The dosage of acute intravenous administration was about the 1/100 of that of low dose by acute oral administration, which was 10 mg/kg. The dosage of 14-day repeated dose test was equal to the low dose of acute oral administration, which was 1500 mg/kg.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling:
Oral administration: Blood was withdrawn (by direct venous puncture) from the jugular vein at 0.5, 2, 4, 6, 8, l0, 12, 14, 16, 20, 24, and 36 hours after the last oral administration
Intravenous administration: Blood was withdrawn (by direct venous puncture) from the jugular vein at 1, 5, 15, 30 minutes, and 1, 2, 4, 6, 10, and 24 hours after the intravenous administration
- Sample analysis: Gas chromatograph-mass Chromatographic column: USB667l14H, multi-tube spectrometer (GC-MS): 7890A-5975C GC-MS.
DB-l701 (60 m x 0.25 mm x l.0 µm)

Statistics:

software DAS2.0

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Single intravenous injection (10 mg/kg):
A: AUC(0-t) 66.48 ± 9.91 µg/L*h, Cmax 335.72 ± 68.73 µg/L, Vz 7.68 ± 3.54 L/kg, T1/2z 0.31 ± 0.13 h.
C: AUC(0-t) 337.32 ± 51.53 µg/L*h, Cmax 1492.25 ± 297.84 µg/L, Vz 8.62 ± 3.84 L/kg, T1/2z 0.36 ± 0.12 h.
E: AUC(0-t) 90.72 ± 16.58 µg/L*h, Cmax 471.27 ± 88.04 µg/L, Vz 7.33 ± 1.38 L/kg, T1/2z 0.25 ± 0.07 h.
 
Single oral administration (1500 mg/kg and 30000 mg/kg):
A: AUC(0-t) 210.85 ± 44.40 µg/L*h and 2129.26 ± 325.82 µg/L*h, 1:10, Cmax 23.17 ± 5.42 µg/L and 517.50 ± 59.93 µg/l, 1 :22, Tmax 4.67 ± 1.63 h and 2.00 ± 0 h, T1/2z 20.40 ± 15.59 h and 12.54 ± 4.87 h, bioavailability 2.11% and 1.07%.
C: AUC(0-t) 1121.56 ± 187.12 µg/L*h and 10226.39 ± 1163.75 µg/L*h, 1:9, Cmax 106.40 ± 22.40 µg/L and 2331.20 ± 222.82 µg/L, 1:21.9, Tmax 5.67 ± 0.82 h and 2.00 ± 0 h, T1/2z 13.09 ± 7.79 h and 11.39 ± 2.65 h, bioavailability 2.22% and 1.01%.
E: AUC(0-t) 308.50 ± 68.94 µg/L*h and 3527.55 ± 488.99 µg/L*h, 1:11.4, Cmax 31.19 ± 6.62 µg/L and 814.97 ± 69.92 µg/L, 1:26.1, Tmax 5.67 ± 0.82 h and 2.00 ± 0 h, T1/2z 17.53 ± 23.91 h and 13.81 ± 3.98 h, bioavailability 2.27% and 1.30%.

Repeated dose 14-day (1500 mg/kg)
A: AUC(0-t) 183 .02 ± 39.90 µg/L *h,
C: AUC(0-t) 1631.73 ± 302.66 µg/L *h
E: AUC(0-t) 308.21 ± 51.83 µg/L*h
P value was 0.28, 0.0056 and 0.99 for A, C and E in t-test when compared the AUC value of repeated dose 14-day study with that of acute oral administration study. The P value of C was significant but the increase was small. This result indicated that the test substance may have limited cumulative effects in rats after repeated exposure. Activities of rats slightly reduced immediately after single oral exposure to the test substance (30000 mg/kg). No abnormal symptoms of rats treated with the test substance (30000 mg/kg) were found after one hour treatment. No abnormal symptoms of rats in other groups were found during the test period.

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: The test substance may have limited cumulative effects in rats after repeated exposure.
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
The test substance may have limited cumulative effects in rats after repeated exposure.

Executive summary:

Absorption toxicokinetics study of the test substance in SD rats was performed to obtain toxicokinetic information by different doses and routes of administration. Three parts were contained in this study, including toxicokinetics study by acute intravenous administration, toxicokinetics study by acute oral administration and toxicokinetics study by repeated dose 14-day oral administration.

Dosing: Intravenously into the tail vein, single dose - 10 mg/kg; Single oral administration - 1500 mg/kg and 30000 mg/kg; Repeated oral dose 14-day - 1500 mg/kg. Blood was withdrawn (by direct venous puncture) from the jugular vein at 0.5, 2, 4, 6, 8, l0, 12, 14, 16, 20, 24, and 36 hours after the last oral administration. Blood was withdrawn (by direct venous puncture) from the jugular vein at 1, 5, 15, 30 minutes, and 1, 2, 4, 6, 10, and 24 hours after the intravenous administration. The concentration of the test substance was determined by gas chromatography-mass spectrometry (GC-MS) method.

Parameters of C_max (maximal concentration in blood after administration), AUC (Area under the plasma concentration-time curve), half-life (t_1/2, T_max (time to reach C_max) and bioavailibility were compared among different groups.

Single intravenous injection:

A: AUC(0-t) 66.48 ± 9.91 µg/L*h, Cmax 335.72 ± 68.73 µg/L, Vz 7.68 ± 3.54 L/kg, T1/2z 0.31 ± 0.13 h.

C: AUC(0-t) 337.32 ± 51.53 µg/L*h, Cmax 1492.25 ± 297.84 µg/L, Vz 8.62 ± 3.84 L/kg, T1/2z 0.36 ± 0.12 h.

E: AUC(0-t) 90.72 ± 16.58 µg/L*h, Cmax 471.27 ± 88.04 µg/L, Vz 7.33 ± 1.38 L/kg, T1/2z 0.25 ± 0.07 h.

Single oral administration (1500 mg/kg and 30000 mg/kg):

A: AUC(0-t) 210.85 ± 44.40 µg/L*h and 2129.26 ± 325.82 µg/L*h, 1:10, Cmax 23.17 ± 5.42 µg/L and 517.50 ± 59.93 µg/l, 1 :22, Tmax 4.67 ± 1.63 h and 2.00 ± 0 h, T1/2z 20.40 ± 15.59 h and 12.54 ± 4.87 h, bioavailability 2.11% and 1.07%.

C: AUC(0-t) 1121.56 ± 187.12 µg/L*h and 10226.39 ± 1163.75 µg/L*h, 1:9, Cmax 106.40 ± 22.40 µg/L and 2331.20 ± 222.82 µg/L, 1:21.9, Tmax 5.67 ± 0.82 h and 2.00 ± 0 h, T1/2z 13.09 ± 7.79 h and 11.39 ± 2.65 h, bioavailability 2.22% and 1.01%.

E: AUC(0-t) 308.50 ± 68.94 µg/L*h and 3527.55 ± 488.99 µg/L*h, 1:11.4, Cmax 31.19 ± 6.62 µg/L and 814.97 ± 69.92 µg/L, 1:26.1, Tmax 5.67 ± 0.82 h and 2.00 ± 0 h, T1/2z 17.53 ± 23.91 h and 13.81 ± 3.98 h, bioavailability 2.27% and 1.30%.

Repeated dose 14-day

A: AUC(0-t) 183 .02 ± 39.90 µg/L *h,

C: AUC(0-t) 1631.73 ± 302.66 µg/L *h

E: AUC(0-t) 308.21 ± 51.83 µg/L*h

Activities of rats slightly reduced immediately after single oral exposure to the test substance (30000 mg/kg). No abnormal symptoms of rats treated with the test substance (30000 mg/kg) were found after one hour treatment. No abnormal symptoms of rats in other groups were found during the test period. P value was 0.28, 0.0056 and 0.99 for A, C and E in t test when compared the AUC value of repeated dose 14-day study with that of acute oral administration study. The P value of C was significant but the increase was small. This result indicated that the test substance may have limited cumulative effects in rats after repeated exposure.