1-Pyrrolidinecarboxylic acid, 2-[5-[4'-[2-[(2S)-1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][1,1'-biphenyl]-4-yl]-1H-pyrazol-3-yl]-, 1,1-dimethylethyl ester, (2S)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 2 to September 6, 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterized.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl (2S)-2-[5-(4'-{2-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

EC Number:

941-432-8

Cas Number:

1085706-46-2

Molecular formula:

C36 H44 N6 O4

IUPAC Name:

tert-butyl (2S)-2-[5-(4'-{2-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

Test material form:

solid: crystalline

Details on test material:

Off white crystalline solid stored at room temperature in the dark over silica gel.

Test animals

Species:

rat

Strain:

other: Sprague-Dawley CD

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: Bodyweights fell within an interval of +/- 20% of the mean initial bodyweight of the first treated group.
- Fasting period before study: overnight fast
- Housing: Groups of 3 in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Certified Rat and Mouse Diet
- Water (e.g. ad libitum): Drinking water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): 30-70 %
- Air changes (per hr): At least 15
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: Aug. 2nd, 2007 To: Sept. 6th, 2007

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.
dose level: 300, 2000, 2000 mg/kg
concentration: 10 mg/ml

Doses:

dose level: 300, 2000, 2000 mg/kg ( females)

No. of animals per sex per dose:

3 females per dose

Control animals:

no

Details on study design:

All animals were dosed only once by gavage, using a metal cannula attached to a graduated syringe. The volume administered was calculated
according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to
confirm the survival of the previously dosed animals. The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after the
final dose and subsequently once daily for fourteen days. Individual bodyweights were recorded prior to dosing and seven and fourteen days after
treatment. At the end of the observation period the animals were killed by using ascending concentrations of carbon dioxide followed by cervical
dislocation. All animals were subjected to gross pathological examination. This consisted of external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities were recorded. No tissues were retained.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: Signs of system toxicity noted in animals treated at a dose lebel of 200 mg/kg were hunched posture, ataxia, pilo-erection, tiptoe gait and dehydration. Animals appeared normal nine to fourteen days after dosing, except for two animals whichi showed hunc

Gross pathology:

Pale liver was noted at necropsy of two animals treated at a dose level of 2000 mg/kg. No abnormalities were noted at necropsy of all other animals.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was approximately 2000 mg/kg bodyweight.The test material does not meet the criteria for classification according to EU labelling regulations Commission Directive 2001/59/EC for classifiationand labelling of dangerous substances.