Polyhaloalkene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted at reputable university laboratory under GLP-like conditions, principle investigator well recognized expert on fluorocarbon metabolism, and study published in peer reviewed journal

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2008

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The biotransformation of the test substance 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:

754-12-1

Cas Number:

754-12-1

IUPAC Name:

754-12-1

Constituent 2

Reference substance name:

-

EC Number:

468-710-7

EC Name:

-

Cas Number:

754-12-1

Molecular formula:

C3H2F4

IUPAC Name:

2,3,3,3-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 test substance in a dynamic exposure chamber consisting of a 20.6-L desiccator, a stirrer and connections to compressed air and a cylinder of test substance fitted with flow meters. Metered amounts of ttest substance were mixed with air and introduced into the exposure chamber. Chamber concentrations of test substance were monitored at 15-min intervals by taking samples (100 μL) of the chamber atmosphere with a gastight syringe. The content of test substance in these samples was determined by GC/MS.

Duration and frequency of treatment / exposure:

6 hours exposure, once.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2 000 ppm

Remarks:

Group 1: Low dose.

Doses / concentrations 2

Dose / conc.:

10 000 ppm

Remarks:

Group 2: Mid dose.

Doses / concentrations 3

Dose / conc.:

50 000 ppm

Remarks:

Group 3: High dose.

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 the 13 week and other inhalation toxicity studies.

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: 5
- Method types for identification: NMR, LC/MS/MS, GC/MS
- Limits of detection and quantification: 2.5 pmol/mL N-acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-L-cysteine

Statistics:

Not described

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Inorganic fluoride, N-acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-Lcysteine

Any other information on results incl. tables

In all rat urine samples, the predominant metabolites were two diastereomers of N-Acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-L-cysteine. In 19F-NMR, the signal intensity of these metabolites represented more than 85% (50000 ppm) of total 19F related signals in the urine samples. Trifluoroacetic acid, 3,3,3-trifluorolactic acid, 3,3,3- trifluoro-1-hydroxyacetone, 3,3,3-trifluoroacetone and 3,3,3-trifluoro-1,2-dihydroxypropane were present as minor metabolites. Quantification of N-Acetyl-S-(3,3,3-trifluoro-2-hydroxypropyl)- L-cysteine by LC/MS-MS showed that most of this metabolite (90%) was excreted within 18 h after the end of exposure (t1/2 app. 6 h). In rats, the recovery of N-Acetyl-S- (3,3,3-trifluoro-2-hydroxy-propyl)-L-cysteine excreted within 48 h in urine was determined as 0.297 ± 0.028, 0.627 ± 0.155, and 2.432 ± 0.864 μmoles at 2000, 10000 and 50000 ppm, respectively suggesting only a low extent ( << 1% dose received) of biotransformation of test substance.

The very low extent of biotransformation following inhalation to high exposures of test substance 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 test substance (see section 7.5 for details of this study).

Applicant's summary and conclusion

Conclusions:

Evaluation of urinary metabolites from rats exposed to the test substance at exposure levels up to 50000 ppm (233000 mg/m3) showed very low levels of metabolism (<< 1%).