(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}-3-(1H-tetrazol-1-yl)propan-2-ol

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2018

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Deviations:

yes

Remarks:

number of animals used, exposure period, use of a valid controls were not reported

GLP compliance:

yes

Type of assay:

mammalian erythrocyte micronucleus test

Test material

Test material information

Constituent 1

Reference substance name:

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol

EC Number:

841-499-2

Cas Number:

1340593-59-0

Molecular formula:

C23H16F7N5O2

IUPAC Name:

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

not specified

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

not specified

Duration of treatment / exposure:

not specified

Frequency of treatment:

not specified

Post exposure period:

not specified

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

200 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

400 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

800 mg/kg bw/day

No. of animals per sex per dose:

not specified

Control animals:

not specified

Positive control(s):

not specified

Examinations

Tissues and cell types examined:

Micronucleated polychromatic erythrocytes in the bone marrow of male rats.

Details of tissue and slide preparation:

CRITERIA FOR DOSE SELECTION:
The micronucleus test was conducted in two phases: a dose-range-finding phase in which the toxicity of the test item was evaluated and a definitive phase that evaluated the ability of the test item to increase the incidence of micronucleated polychromatic erythrocytes in the bone marrow of male rats.
Based on the findings of clinical observations and mortality at doses of ≥1000 mg/kg obtained in the dose-range-finding study, a dose of 800 mg/kg was determined to be the maximum tolerated dose and was set as high dose for the definitive micronucleus study. As no differences between the sexes in the clinical signs of toxicity were observed, the main study was conducted using male rats only.

Evaluation criteria:

The ability of the test item to increase the incidence of micronucleated polychromatic erythrocytes in the bone marrow of male rats was evaluated.

Statistics:

not specified

Results and discussion

Test results

Key result

Sex:

male

Genotoxicity:

negative

Toxicity:

not specified

Vehicle controls validity:

not specified

Negative controls validity:

not specified

Positive controls validity:

not specified

Applicant's summary and conclusion

Conclusions:

Under the experimental conditions reported (2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl]propan-2-ol was determined to be negative for mutagenicity in an in vivo rat bone marrow micronucleus assay.

Executive summary:

In a GLP rats bone marrow micronucleus assay, were treated orally with(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl]propan-2-ol.The micronucleus test was conducted in two phases: a dose-range-finding phase in which the toxicity of the test item was evaluated and a definitive phase that evaluated the ability of the test item to increase the incidence of micronucleated polychromatic erythrocytes in the bone marrow of male rats. Based on the findings of clinical observations and mortality at doses of ≥1000 mg/kg obtained in the dose-range-finding study, a dose of 800 mg/kg was determined to be the maximum tolerated dose and was set as high dose for the definitive micronucleus study. As no differences between the sexes in the clinical signs of toxicity were observed, the main study was conducted using male rats only.

 

In the definitive phase rats were treated with the test item atdoses of 200, 400, or 800 mg/kg. There was not a significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow in all tested dose.

 

Therefore, the test item was concluded to be negative in the rat micronucleus assay