4-[(6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003-01-21 to 2003-03-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

4-({6-chloro-2-[(4-cyanophenyl)amino]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

EC Number:

928-806-6

Cas Number:

1070377-34-2

Molecular formula:

C20H14ClN5O

IUPAC Name:

4-({6-chloro-2-[(4-cyanophenyl)amino]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): T002615
- Physical state: solid
- Appearance white solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 00403487
- Expiration date of the lot/batch: 2003-12-31
- Purity > 98%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the container, at room temperature (range of 20 +/- 3 °C), away from direct light.
- Stability under test conditions: Stable for at least 2 hrs in PEG 300 at room temperature; determined at RCC Study No. 847009 (non-GLP study).
- Solubility and stability of the test substance in the solvent/vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initation date.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
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.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Biotechnology and Animal Breeding Division CH-4414 Fullinsdorf/Switzerland
- Age at study initiation: Males: 8 weeks, Females: 12 weeks
- Weight at study initiation: Males: 242.2-259.3 g, Females: 186.7-192.5 g
- Fasting period before study: yes: for app. 18 h (access to water was permitted)
- Housing: In groups of three per sex in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 67/02 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water: community tap water from Fullinsdorf ad libitum
- Acclimation period: under laboratory conditions, after health examination (only animals without any visible signs of illness were used foor the study)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30-70 % (values above 70% during the cleaning process possible)
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs fluorescent light/ 12 hrs dark (music during the light period)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Justification for choice of vehicle: The vehicle was chosen after non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 435875/1 43002
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED
-10 mL/kg bw

DOSAGE PREPARATION (if unusual)
- The dose formulations were made shortly before each dosing occasion using a magnetic stirrer and a spatula.
- The test substance was weighed into a tared glass beaker on a suitable balance and the vehicle added (Weight: volume).
- Homogeneity of the test substance in the vehicle was maintained during administration using a magnetic stirrer.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females and 3 males per dose (2 groups at dose level of 2000 mg/kg bw)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/ 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 app. 1, 2, 3 and 5 h after administration on test day 1 and once daily during days 2-15.
- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occured during the study.

Clinical signs:

other: Slightly ruffled fur and hunched posture was noted in all 2000 mg/kg treated female animals one hour after the treatment. No clinical signs were observed in the male animals during the course of the study.

Gross pathology:

No macroscopic findings were recorded at necroscopy.

Other findings:

no data

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of T002615 after single oral administration to rats of both sexes observed over a period 14 days is: LD50 (rat) greater than 2000 mg/kg bw.