2-fluoro-6-trifluoromethylpyridine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data provided are an assessment of the predicted toxicokinetic behavior of the test substance based on its physical-chemical properties and available toxicity data.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This report is a toxicokinetic assessment based on information from the following toxicity studies:
- Acute oral toxicity in rats
- 4-hour Acute inhalation toxicity in rats
- 28-day Subacute inhalation in rats
- Skin sensitization in guinea pigs
- Skin irritation in rabbits
- Eye irritation in rabbits
- Bacterial mutation assay in S. typhimurium and E. coli
- Cytogenic assay in human lymphocytes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

428-100-3

EC Name:

-

Cas Number:

94239-04-0

Molecular formula:

C6H3NF4

IUPAC Name:

2-fluoro-6-(trifluoromethyl)pyridine

Details on test material:

Purity: See cross-reference to other study

Specific details on test material used for the study:

Substance ID: F6TF
Purity: 99.6%

Radiolabelling:

no

Test animals

Species:

other: rat, guinea pig, rabbit, bacteria, human cells

Sex:

male/female

Administration / exposure

Route of administration:

other: See cross-reference to other study

Vehicle:

other: See cross-reference to other study

Duration and frequency of treatment / exposure:

See cross-reference to other study

Doses / concentrations

Remarks:

Doses / Concentrations:
See cross-reference to other study

No. of animals per sex per dose / concentration:

See cross-reference to other study

Control animals:

other: See cross-reference to other study

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The toxicity of high dose levels of the test substance following both oral administration and inhalation exposure show that this substance is absorbed both across the gastrointestinal and pulmonary mucosa. There was no evidence of any dermal penetration of the test substance in the rabbit study, despite occlusion of the application sites, which would have promoted any absorption. Similarly, the negative dermal sensitization result in the guinea pig study provides no evidence of any absorption through skin in this species.

Details on distribution in tissues:

A clear dose response effect on liver weight was apparent during the repeated inhalation exposure study. This was accompanied by histopathological changes in the liver and perturbations in various clinical chemistry parameters.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Based upon its structure, molecular weight and log P value, absorption of orally administered test substance across the gastrointestinal mucosa would be expected. Similarly, absorption through the lungs would be expected during inhalation exposure to the vapour. Its molecular weight is below the biliary exclusion limit in the rat, consequently, it would not be excreted directly in bile. The aqueous solubility of absorbed test substance would allow some direct urinary excretion. The absorbed molecule is therefore likely to be subject to biotransformation to promote excretion. The fluorine and trifluoromethyl moieties are unlikely to be subject to any metabolism. Ring hydroxylation is likely to be a predominate reaction and by analogy to trifluoromethylpyridine, would be expected to form metabolites of reduced toxicity. N-oxidation of the test substance is feasible, although sulphate conjugation of this product would be expected to protect against the potential toxicity of this metabolite.

Metabolism: In the bacterial mutation assays in S. typhimurium and E. coli, the test substance did not induce revertant colonies. Accordingly, it was concluded that the test substance was not mutagenic to S. typhimurium and E. coli treated in vitro in both the presence and absence of S-9 mix. Hence, no conclusions can be drawn about the metabolism of the test substance from this study. Using cultures of human lymphocytes, with an established low incidence of chromosomal aberrations in their peripheral blood lymphocytes, concentration-related reductions in mitotic activity were observed in cultures from these donors, thus demonstrating that the test substance is biologically active in this test system. In the presence of S-9 mix, the test substance caused a small but statistically significant increase (5.5%) in the percentage of aberrant cells, compared to the solvent control values in cultures from one of two experiments. In the absence on S-9 mix, statistically significant increases (up to 8%) were observed only in cultures treated for 20 hours. Accordingly, it was concluded that under the conditions of the assay, the test substance was weakly clastogenic to cultured human lymphocytes treated in vitro in both the presence and absence of S-9 mix. Hence, no conclusions can be drawn on the metabolism of the test substance from this study.

Applicant's summary and conclusion

Conclusions:

Toxicity studies show clear evidence for absorption of the test substance following oral and inhalation exposure. The aqueous solubility would allow some direct urinary excretion of the absorbed dose, but biotransformation would be expected.
Toxicity studies have shown clear evidence for the absorption of the test substance following both oral administration and inhalation exposure. There was no evidence of any dermal penetration of the test substance in the rabbit, despite occluded application; similarly, there was no evidence of any dermal absorption in the guinea pig sensitization study.
An assessment of the potential absorption of the test substance is also based upon its physico-chemical properties, which suggest that the intact molecule would be subject to absorption across the gastrointestinal mucosa following oral administration and also via the lungs during inhalation exposure. The aqueous solubility of the test substance would allow some direct urinary excretion of the absorbed dose, but biotransformation would be expected. The fluorine and trifluoromethyl moieties are unlikely to be subject to metabolism. Ring hydroxylation would be expected to be a predominate reaction and, by analogy to trifluoromethylpyridine, would form metabolites of less toxicity. N-oxidation is feasible, although sulphate conjugation of this product would be expected to protect against its potential toxicity.

Executive summary:

This report is a toxicokinetic assessment based on information from the following toxicity studies:

- Acute oral toxicity in rats

- 4-hour Acute inhalation toxicity in rats

- 28-day Subacute inhalation in rats

- Skin sensitization in guinea pigs

- Skin irritation in rabbits

- Eye irritation in rabbits

- Bacterial mutation assay in S. typhimurium and E. coli

- Cytogenic assay in human lymphocytes

 

Toxicity studies have shown clear evidence for the absorption of the test substance following both oral administration and inhalation exposure. There was no evidence of any dermal penetration of the test substance in the rabbit, despite occluded application. Similarly, there was no evidence of any dermal absorption in the guinea pig sensitization study. An assessment of the potential absorption of the test substance is also based upon its physico-chemical properties, which suggest that the intact molecule would be subject to absorption across the gastrointestinal mucosa following oral administration and also via the lungs during inhalation exposure. The aqueous solubility of the test substance would allow some direct urinary excretion of the absorbed dose, but biotransformation would be expected. The fluorine and trifluoromethyl moieties are unlikely to be subject to metabolism. Ring hydroxylation would be expected to be a predominate reaction and, by analogy to trifluoromethylpyridine, would form metabolites of less toxicity. N-oxidation is feasible, although sulphate conjugation of this product would be expected to protect against its potential toxicity.