Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1R,4S)-, compd. with rel-(.alpha.R,.beta.S)-.alpha.-(2,4-difluorophenyl)-5-fluoro-.beta.-methyl-.alpha.-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol (1:1)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonate

EC Number:

917-473-2

Cas Number:

188416-34-4

Molecular formula:

C16H14F3N5O . C10H16O4S

IUPAC Name:

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonate

Constituent 2

Reference substance name:

(2RS,3SR)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10- camphorsulphonate

IUPAC Name:

(2RS,3SR)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10- camphorsulphonate

Details on test material:

- Batch No.: 5ABK-003
- Purity: 96.5%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% w/v aqueous methylcellulose

Doses:

A group of ten fasted rats(five males and five femals) was given a single dose by oral gavage of the test substance, formulated in 1% w/v aqueous methylcellulose and administered at an initial dose level of 500 mg/kg bodyweight. A further group of five males and five females rats was dosed at 50 mg/kg bodyweight to determine the discriminating dosage of the test material.

No. of animals per sex per dose:

Preliminary sighting study: 2 (female)
Main study: 5 (male)
Main study: 5 (female)

Control animals:

no

Details on study design:

A group of ten fasted rats(five males and five femals) was given a single dose by oral gavage of the test substance, formulated in 1% w/v aqueous methylcellulose and administered at an initial dose level of 500 mg/kg bodyweight. This dose level was chosen on the basis of preliminary study results and in compliance with the study guideling. A further group of five males and five females rats was dosed at 50 mg/kg bodyweight to determine the discriminating dosage of the test material.

Results and discussion

Preliminary study:

Species/strain: Rat (Sprague-Dawley)
2000 mg/kg bw: Evident toxicity: Y; Mortality: Y
500 mg/kg bw: Evident toxicity: Y; Mortality: N
Observations:
These results were used to set the starting dose for the main study.

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

50 mg/kg bw

Based on:

act. ingr.

Effect levels 2

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 50 - < 500 mg/kg bw

Based on:

act. ingr.

Mortality:

Three males and all females at 500 mg/kg died during the study. All deaths occurred within 4 days of dosing.
Female 500 mg/kg bw (fixed dose further) No. with evident toxicity: 5; No. of deaths: 5; No. of animals used: 5
Male 500 mg/kg bw (fixed dose further) No. with evident toxicity: 5; No. of deaths: 3; No. of animals used: 5
Female 50 mg/kg bw (fixed dose further) No. with evident toxicity: 5; No. of deaths: 0; No. of animals used: 5
Male 50 mg/kg bw (fixed dose further) No. with evident toxicity: 5; No. of deaths: 0; No. of animals used: 5

Clinical signs:

other: Signs of toxicity: Clinical signs of reaction to treatment included piloerection and hunched posture, seen in all rats at both dosages. In addition, waddling gait, lethargy, decreased respiration, partially closed eyelids, pallor of the extremities, calo

Gross pathology:

Effects on organs:
Macroscopic examination of surviving rats killed on Day 15 revealed no abnormalities.

Other findings:

Three males and all females at 500 mg/kg died during the study. All deaths occurred within four days of dosing.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 is between 50 and 500 mg/kg bw/day.