1-Propene, 1,3,3,3-tetrafluoro-

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:

data from handbook or collection of data

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

The biotransformation of HFO-1234ze following inhalation exposure was evaluated by determining urinary metabolites excreted for up to 48 hours following exposure.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

471-480-0

EC Name:

-

Cas Number:

1645-83-6

Molecular formula:

Hill formula: C3H2F4 CAS formula: C3H2F4

IUPAC Name:

(1E)-1,3,3,3-tetrafluoroprop-1-ene

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan-Winkelmann, Borchen Germany
- Weight at study initiation: 220 - 250 g

Administration / exposure

Route of administration:

inhalation: gas

Details on exposure:

TYPE OF INHALATION EXPOSURE: nose only

Male rats (n = 5) were exposed to targeted concentrations of 2000, 10000, and 50000 ppm HFO-1234ze in a dynamic exposure chamber consisting of a 20.6-L desiccator, a stirrer and connections to compressed air and a cylinder of HFO-1234ze fitted with flow meters. Metered amounts of HFO-1234ze were mixed with air and introduced into the exposure chamber. Chamber concentrations of HFO-1234ze were monitored at 15-min intervals by taking samples (100 µL) of the chamber atmosphere with a gastight syringe. The content of HFO-1234ze in these samples was determined by GC/MS.

Duration and frequency of treatment / exposure:

acute 6 hour exposure

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2 000 ppm

Doses / concentrations 2

Dose / conc.:

10 000 ppm

Doses / concentrations 3

Dose / conc.:

50 000 ppm

No. of animals per sex per dose / concentration:

5

Control animals:

no

Details on study design:

- Dose selection rationale: doses used were the same as those used for a study on a comparable fluorocarbon (HFO-1234yf)

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: every 6 hours for 48 hours
- From how many animals: not pooled
- Method type(s) for identification: NMR, LC/MS, GC/MS
- Limits of detection and quantification: 1.2 pmol/mL N-acetyl-S-(3,3,3-trifluoro-trans-propenyl)-L-cysteine, 2.9 pmol/mL S-(3,3,3-trifluoro-trans-propenyl)-mercaptolactic acid, 250 pmol/mL of 3,3,3-trifluoropropionic acid

- Tissues and body fluids sampled : urine
- Time and frequency of sampling: every 6 - 12 hours for 48 hours
- From how many animals: 5
- Method type(s) for identification: NMR, LC/MS, GC/MS

Statistics:

Not described

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

S-(3,3,3-trifluoro-trans-propenyl)-mercaptolactic acid, S-(3,3,3-Trifluoro-trans-propenyl)-l-cysteine, N-acetyl-S-(3,3,3-trifluoro-trans-propenyl)-l-cysteine and 3,3,3-trifluoropropionic acid

Any other information on results incl. tables

In urine samples of rats exposed to 50,000 ppm HFO-1234ze, the predominant metabolite was S-(3,3,3-trifluoro-trans-propenyl)-mercaptolactic acid and accounted for 66% of all integrated (19)F-NMR signals in urines. No (19)F-NMR signals were found in spectra of rat urine samples collected after inhalation exposure to 2000 or 10,000 ppm HFO-1234ze likely due to insufficient sensitivity.

S-(3,3,3-Trifluoro-trans-propenyl)-l-cysteine, N-acetyl-S-(3,3,3-trifluoro-trans-propenyl)-l-cysteine and 3,3,3-trifluoropropionic acid were also present as metabolites in urine samples of rats.

Quantification of three metabolites in urines of rats was performed, using LC/MS-MS and GC/MS. The quantified amounts of the metabolites excreted with urine in both mice and rats, suggest only a low extent (<1% of dose received) of biotransformation of HFO-1234ze and 95% of all metabolites were excreted within 18 h after the end of the exposures (t(1/2) app. 6 h). The obtained results suggest that HFO-1234ze is likely subjected to an addition-elimination reaction with glutathione and to a CYP 450 mediated epoxidation at low rates.

The very low extent of biotransformation following inhalation to high exposures of HFO-1234ze indicates covalent binding resulting in potential liver toxicity is likely prevented by effecient detoxification by glutathione. These results are consistent with the lack of hepatotoxic in rats following 90 day inhalation exposure to HFO-1234ze (see section 7.5 for details of this study).

Applicant's summary and conclusion

Conclusions:

In urine samples of rats exposed to 50000 ppm HFO-1234ze, the predominant metabolite was S-(3,3,3-trifluoro-trans-propenyl)-mercaptolactic acid and accounted for 66 % of all integrated (19)F-NMR signals in urines. S-(3,3,3-Trifluoro-trans-propenyl)-l-cysteine, N-acetyl-S-(3,3,3-trifluoro-trans-propenyl)-l-cysteine and 3,3,3-trifluoropropionic acid were also present as metabolites in urine samples of rats. Quantification of three metabolites in urines of rats was performed, using LC/MS-MS and GC/MS. This quantification suggest only a low extent (<1% of dose received) of biotransformation of HFO-1234ze and 95 % of all metabolites were excreted within 18 h after the end of the exposures (t(1/2) app. 6 h). The main difference between the rat and mice metabolites is the fact the concentration of S-(3,3,3-Trifluoro-trans-propenyl)-mercaptolactic acid attributes to 66 % of the metabolites in rat in comparison to only 8 % in mice. The obtained results suggest that HFO-1234ze is likely subjected to an addition-elimination reaction with glutathione and to a CYP 450 mediated epoxidation at low rates. The very low extent of biotransformation following inhalation to high exposures of HFO-1234ze indicates covalent binding resulting in potential liver toxicity is likely prevented by efficient detoxification by glutathione. These results are consistent with the lack of hepatotoxic in rats following 90 day inhalation exposure to HFO-1234ze (see section 7.5 for details of this study).