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

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003-01-21 to 2003-03-05

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 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

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:

- Name of test material (as cited in study report): T002615
- Substance type: no data
- Physical state: white solid
- Analytical purity: > 98 %
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: 00403487
- Expiration date of the lot/batch: 2003-12-31
- Stability under test conditions: stable for at least 7 days in PEG 300 at room temperature; determined at RCC Study No. 846996 (Non GLP)
- Storage condition of test material: in the original container, at room temperature (range of 20 +/- 3 °C), away from direct sunlight
- Other: no data

Test animals

Species:

rat

Strain:

Wistar

Remarks:

HanBrl: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd. Biotechnology & Animal Breeding Division, CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: Males: 8-9 weeks; females: 11-12 weeks.
- Weight at study initiation: Male: 246.9-257.3 g; Females: 191.0-204.9 g.
- Fasting period before study: no data
- Housing: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz) during treatment and observation
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433, batch no. 67/02 rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst) available ad libitum.
- Water (e.g. ad libitum): Community tap water from Itingen, available ad libitum.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-3 °C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs flourescent light / 12 hrs dark

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on dermal exposure:

TEST SITE
- Area of exposure: back of the animals (free of fur)
- Type of wrap if used: dressing (the dressing was wrapped around abdomen and fixed with an elastic adhesive bandage)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes (with lukewarm tap water and dried with disposable paper towels)
- Time after start of exposure: 24 hours after the application the dressing was removed

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL/kg bw
- Concentration (if solution): not applicable
- Constant volume or concentration used: yes
- For solids, paste formed: no

VEHICLE
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): a weight by volume dilution was prepared. Homogenity of the test item in the vehicle was maintained during administration using a magnetic stirrer.
- Lot/batch no. (if required):435875/1 43002
- Purity: no data

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 male and 5 female rats per dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortaliy/viability: daily during acclimatization and twice daily during 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 hours after administration on test day 1. Once daily during days 2-15.
- Necropsy of survivors performed: yes. All animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 mL/kg/bw (equivalent to at least 324 mg sodium pentobarbitone/kg/bw) and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Statistics:

No statistical analysis was used.

Results and discussion

Preliminary study:

No data

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No systematic or local signs of toxicity were observed during the study period.

Gross pathology:

No macroscopic findings were observed at necroscopy.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

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