(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

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

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:

no guideline followed

Principles of method if other than guideline:

- Principle of test: 7-day repeat-dose range-finding study

GLP compliance:

no

Limit test:

no

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

Details on species / strain selection:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: 20% Cremophor EL

Details on oral exposure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

7 days

Frequency of treatment:

once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

Low dose

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Mid dose

Doses / concentrations 4

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

High dose

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

not specified

Positive control:

no

Examinations

Observations and examinations performed and frequency:

no specified

Sacrifice and pathology:

Rats were sacrificed moribund on Days 6 and 7 in the 100 and 300 mg/kg bw groups.

Statistics:

no specified

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section below "details on results"

Histopathological findings: neoplastic:

not examined

Details on results:

Rats were sacrificed moribund on Days 6 and 7 in the 100 and 300 mg/kg bw groups. Rats dosed at 100 and 300 mg/kg bw/day exhibited decreased feces, salivation, stained/rough haircoat, ataxia, hunched/low posture, labored breathing, anogenital staining, decreased activity, head tilt, temperature that was cold to the touch, scabbed skin, and drooping eyelids. Body weights and food consumption were generally lower for the animals dosed at 100 and 300 mg/kg bw/day when compared to the control group throughout this study.
Increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transferase (GGT) levels, glucose, and cholesterol values were observed.
Absolute and relative liver weights of the rats dosed orally at 30 and 100 mg/kg bw/day were increased compared to the controls. For animals dosed at 100 mg/kg bw/day, absolute and relative prostate weight in males, absolute thymus weight, and absolute and relative spleen weight were lower when compared to the controls. Test-item related microscopic findings were present in the liver of the males and females dosed orally at 30, 100, and 300 mg/kg bw/day and in the epididymides and testes of males dosed orally at 100 and 300 mg/kg bw/day. Microscopic findings in the liver were dose-dependent and consisted of mild to moderate, diffuse hepatocellular hypertrophy in males and females (30, 100, and 300 mg/kg bw/day) and minimal to moderate multifocal vacuolation of midzonal and centrilobular hepatocytes in rats dosed at 100 and 300 mg/kg bw/day. At 100 mg/kg bw/day and 300 mg/kg bw/day, microscopic findings in the epididymides consisted of minimal, multifocal, bilateral, multinucleate spermatids (symplasts) in the epididymidal tubules. At 100 mg/kg bw/day and 300 mg/kg bw/day, findings in the testes consisted of mild, multifocal, bilateral, multinucleate spermatids (symplasts) in the seminiferous tubules with mild, multifocal, bilateral degeneration of the seminiferous tubules.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

2

Dose descriptor:

NOEL

Effect level:

< 30 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: at 30 mg/kg bw/day effects on the organ weight and in the histopathology were observed

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Blood analysis:

On Day 7, the 30 mg/kg bw/day Cmax was 80,100 ng/mL for males and 77,200 ng/mL for females. Corresponding AUC^2-24 values were 1,530,000 h x ng/mL for males and 1,520,000 h x ng/mL for females.

Applicant's summary and conclusion

Conclusions:

In a 7-day repeated dose range finding study, rats were orally exposed to the test item at doses of 0, 30, 100 and 300 mg/kg bw/day. Based on the organ weight and histopathology data, the no-observed-effect-level (NOEL) was considered to be less than 30 mg/kg bw/day.

Executive summary:

In a 7-day repeated dose range finding study, the test item in 20% Cremophor EL was administered to three Sprague Dawley rats/sex/dose via the oral route with dose levels of 0, 30, 100, or 300 mg/kg bw/day. Rats dosed at 100 and 300 mg/kg bw/day exhibited clinical signs. Body weights and food consumption were generally lower for the animals dosed at 100 and 300 mg/kg bw/day, when compared to the control group throughout this study. The clinical chemistry parameter values were increased. Absolute and relative liver weights of the rats dosed orally at 30 and 100 mg/kg bw/day were increased compared to the controls. For animals dosed at 100 mg/kg bw/day, absolute and relative prostate weight in males, absolute thymus weight, and absolute and relative spleen weight were lower when compared to the controls. Test item-related microscopic findings were present in the liver of the males and females dosed orally at 30, 100, and 300 mg/kg bw/day and in the epididymides and testes of males dosed orally at 100 and 300 mg/kg/day.

Microscopic findings in the liver were dose-dependent and consisted of mild to moderate, diffuse hepatocellular hypertrophy in males and females (30, 100, and 300 mg/kg bw/day) and minimal to moderate multifocal vacuolation of midzonal and centrilobular hepatocytes in rats dosed at 100 and 300 mg/kg bw/day. At 100 mg/kg bw/day and 300 mg/kg bw/day, microscopic findings in the epididymides consisted of minimal, multifocal, bilateral, multinucleate spermatids (symplasts) in the epididymidal tubules. At 100 mg/kg bw/day and 300 mg/kg bw/day, findings in the testes consisted of mild, multifocal, bilateral, multinucleate spermatids (symplasts) in the seminiferous tubules with mild, multifocal, bilateral degeneration of the seminiferous tubule. Based on the organ weight and histopathology data in the limited number of animals, the NOEL was considered to be less than 30 mg/kg bw/day, the lowest dose tested.