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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2003-02-25 to 2003-04-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study conducted according to OECD Guideline 404 and EU Method B.4 without deviations.

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 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

: from the Swiss GLP Monitoring Authorities

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: 2003-12-01 (retest date)
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the original container, at room temperature (range of 17-23 °C), away from direct sunlight.
- Stability under test conditions:
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: 0.5 g (per animal) of test item was weighed as delivered by the sponsor and then moistened with approximately 0.1 mL of purified water before application.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 2 female and 1 male NewZealand White Rabbit, SPF; Elevage Scientifique des Dombes F-014000 Chatillon sur Chalaronne/France
- Age at study initiation: 10 weeks (male), 11 weeks (females)
- Weight at study initiation: 2357-2342 g (females) 2555 g (male)
- Housing:individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd. Fullinsdorf) and haysticks 4646 (batch no. 0206, Provimi Kliba AG) were provided for gnawing.
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no.64/02) provided by Provimi Kliba AG, CH-4303 Kaiseraugust
- Water (e.g. ad libitum): community tap water from Füllinsdorf, ad libitum
- Acclimation period: 5 days (from 2003-02-25 to 2003-03-02), ubder laboratory conditions, after health examination, only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light (music was played during the daytime light period)

IN-LIFE DATES: From: 2003-03-25 To: 2003-03-06

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin areas were used as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.5 g per animal
- The test item was weighed as delivered by the sponsor and the moistened with approximately 0.1 mL of purified water before application.

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 (one male and two females)

Details on study design:

TEST SITE
- Area of exposure: one flank , clipped free of fur (exposed area of app. 100 cm² =10 cm x 10 cm)
- % coverage: no data
- Type of wrap if used: the test item was placed on a surgical gauze patch (ca.4 cm x 4 cm). This gauze patch was applied to the intact skin of the clipped area. The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the dressig was removed and the skin was flushed with lukewarm tap water to clean the application site so that any reactions (erythema) were clearly visible at that time.
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
- Viability/mortality and clinical signs: daily from delivery of the animals to the termination of the test.
- Body weights: at start of acclimatization, on the day of application and at termination of observation
- Skin reactions: 1, 24, 48 and 72 hours after the removal of the dressing, gauze patch and test item

SCORING SYSTEM:
- The skin reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992 (see scoring table below in any other information on materials and methods).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3 animals (1 Male+2 Females)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Results 2

Irritation parameter:

edema score

Basis:

mean

Remarks:

3 animals (1 Male +2 Females)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

Irritation:
- The test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0).

Corrosion:
- Neither alterations of the treated skin were observed nor were corrosive effects evident on the skin.

Other effects:

Viability/Mortality/Clinical Signs:
- No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.

Coloration:
- No staining produced by the test item of the treated skin was observed.

Body weights:
- The body weights of all rabbits were considered to be within the normal range of variability.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based upon the refered classification criteria (Commission Directive 2001/59/EC of August 06, 2001), T002615 is considered to be "not irritating" to rabbit skin.