tert-butyl {(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-[3-hydroxyadamantan-1-yl]-2-oxoethyl}carbamate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

December 2002

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Principles of method if other than guideline:

Two groups of three male rats were given the test article as a single dose on DAy 1 by oral gavage at dose levels of 200 mg/kg. The study director requested that the first group to be dosed should be females, but males were dosed , in error. This mistake was not noticed until a second group of males had been dosed). Subsequently a group of three male and three female fasted rats were given the test article as single dose by oral gavage at a dose level of 2000 mg/kg.

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

solid - liquid: suspension

Remarks:

migrated information: dispersion

Details on test material:

Batch number ZD48725 LOT 002 (Dispensary number 0683/02-1340

Test animals

Species:

rat

Strain:

other: Crl: WI(GIx/BRL/Han)BR

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Methylcellulose

Details on oral exposure:

The test article was dispersed in 1% w/v methylcellulose. The formulated concentrations were calculated from the selected dose level and the dose volume 20 mL/Kg

Doses:

200 mg/kg
2000 mg/kg

No. of animals per sex per dose:

2 groups of three fasted male rats were treated at 200 mg/kg
1 group of three female and three male fasted rats were treated at 2000 mg/kg

Control animals:

no

Details on study design:

Two groups of three male rats were given the test article as a single dose on DAy 1 by oral gavage at dose levels of 200 mg/kg. The study director requested that the first group to be dosed should be females, but males were dosed , in error. This mistake was not noticed until a second group of males had been dosed). Subsequently a group of three male and three female fasted rats were given the test article as single dose by oral gavage at a dose level of 2000 mg/kg. The test article was dispersed in 1% w/v methylcellulose and administered at a dose volume of 20 ml/kg. All animals were killed on DAy 15 and subsequently underwent a full necropsy.

Results and discussion

Mortality:

There were no deaths folloiwng a sinle oral dose of BMS 528235-01 among male rats dosed at 200 mg/kg or among rats of both sexes dosed at 2000 mg/kg

Clinical signs:

Signs of reaction to treatment were limited to a single incidence of tachypnoea observed in one male dosed at 2000 mg/kg at 1 hour observation. This had resolved by teh 2 hour observation and is not considered to be of toxicological significance.

Body weight:

All rats achieved body weight gains during the first and second weeks of the study. The overall body weight gains of males dosed at 2000 mg/kg tended to be slightly lower than those seen in males dosed at 200 mg/kg. The body weight gains in animals dosed at 200 mg/kg ranged beteeen 35 adn 45'; the three animals dosed at 2000 mg/kg gained 31, 21, adn 42g, respectively. Body weight gains in the females also tended to be low (12, 14 adn 15g respectively). These variations in body weight gain are considered to be of equivocal toxicological significance.

Gross pathology:

No macrosocopic changes were observed for animals killed on Day 15

Any other information on results incl. tables

Dose Level (mg/kg)	Mortality Ratio - Male	Mortality Ratio - Female
200	0/6	-
2000	0/3	0/3

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Following a single oral administration of BMS 528235-01 to rats, the acute median lethal oral dose was found to exceed 2000 mg/kg