5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 23, 2003 to January 24, 2004

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:

2003

Report date:

2004

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)

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Bristol-Myers Squibb Animal Test Method Number PGEHS-7-2 for Acute Toxicity in Rodents

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide

EC Number:

695-686-7

Cas Number:

302964-08-5

Molecular formula:

C16 H13 C12 N5 O S

IUPAC Name:

2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

other: HanBrl: Wist (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Fullinsdorf I Switzerland
- Age at study initiation: 12 weeks
- Fasting period before study: 17-18 hours

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-2 C
- Humidity (%): 40-70 %
- Air changes (per hr): 10 to 11
- Photoperiod (hrs dark / hrs light):12/24

IN-LIFE DATES: From: Oct 30th to Nov 25th

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

0.6 % methyl cellulose aqueous solution

Details on oral exposure:

Using all available information on the toxicity of the test material,3000 mg/kg was chosen as the starting dose.
The application volume was 10 mUkg body weight.
The presence of only one death in the 300 mg/kg treated females six days after the administration, determined the next step, i.e. a further dosing of three additional animals at 2000 mg/kg. As no death was recorded in the second step, a third step was performed in three further females at 2000 mg/kg. A total of nine females (per step three animals of a single set.

Doses:

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

No. of animals per sex per dose:

3 females @ 300 mg/kg and 6 females at 2000 mg/kg

Control animals:

no

Details on study design:

Dose Formulation:
The dose formulations were made shortly before each dosing occasion using a magnetic stirrer and/or spatula as homogenizers.
The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume).
Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

Observatuon:
Mortality I Viability Daily during acclimatization and twice daily during days 1-15.
Body weights On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during acclimatization and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.

NECROPSY
All animals which died spontaneously during the observation period were necropsied as soon as they were found dead.
All surviving animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Statistics:

None

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One animal of the first group dosed with 300 mg/kg body weight was found dead at day 5 of observation period.

Clinical signs:

other: In the 300 mg/kg treated group, two animals showed slightly ruffled fur between the 1-hour and 2-day reading and one animal between the 1-hour and 4-day reading before death oc­ curred on test day 5. Additionally this latter showed hunched posture from t

Gross pathology:

The 300 mg/kg female found dead on day 5 of observation period showed congestion in the lung. Two 2000 mg/kg treated females showed congestion in the lungs. No macroscopic findings were seen in the remaining animals.

Other findings:

The median lethal dose of BMS 540268 after single oral administration to rats of both sexes, observed over a period of 14 days is:

LD50 (rat): greater than 2000 mg/kg body weight

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 was > 2000 mg/kg bw.