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

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003-03-18 to 2003-05-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study performed according to OECD Guideline 405 and EU Method B.5 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 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye 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 deg C), away from direct sunlight.
- Stability under test conditions: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: not applicable, 0.1 g (per animal) was weighed and applied undiluted as it was delivered by the sponsor

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: 1 male and 2 female New Zealdn White rabbits, SPF; Elevage Scientifique des Dombes, F-01400 Chatillon sur Chalaronne, France.
- Age at study initiation: 12 weeks (male); 11 weeks (females)
- Weight at study initiation: male 2025 g; 2221 - 2278 g (females)
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood and haysticks for gnawing.
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 02/03) and results of analysis are archived by RCC Ltd., Itingen.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, ad libitum.
- Acclimation period: 6 days (2003-03-18 to 2003-03-23), under laboratory conditions after health examination, only animals without any visual signs of illness were used for the study.

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

IN-LIFE DATES: From: 2003-03-24 To 2003-03-27

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: The right eye remained untreaded and served as the reference control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g (left eye only)

Duration of treatment / exposure:

single application

Observation period (in vivo):

75 hours

Number of animals or in vitro replicates:

3 animals (one male and two females)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

OBSERVATION TIME POINTS
- Viability/mortality and clinical signs: daily from delivery of the animals to termination of test.
- Body weights: at start of acclimatization, on the day of application and at termination of observation.
- Ocular reaction: 1, 24, 48 and 75 hours after test substance application.

SCORING SYSTEM:
The ocular reaction was assessed according to the numerical scoring system listed in the EEC Commission directive 92/69/EEC at approximately 1, 24, 48 and 72 h, as well as 7, 14 and 21 days after administration. When present, corrosion of and/or staining of sclera and cornea by the test article were recorded and reported. Eye examinations were made with Varta Cliptrix diagnostic lamp (Roth AG, CH-41-4153 Reinach/Switzerland).

Cornea: Opacity degree of density (area most dense taken for reading)
0 = No ulceration or opacity
1 = Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible
2 = Easily discernible translucent area, details of iris slightly obscured
3 = Nacreous area, no details of iris visible, size of pupil barely discernible
4 = Opaque cornea, iris not discernible through the opacity

Area of cornea involved:
0 = Zero
1 = One quarter (or less), but not zero
2 =Greater than one quarter, but less than half
3 = Greater than half, but less than three quarters
4 = Greater than three quarters, up to whole area

Iris:
0 = Normal
1 = Markedly deepened rugae, congestion, swelling moderate circumcorneal hyperemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)
2 = No reaction to light, hemorrhage, gross destruction (any or all of these)

Conjunctivae:
Redness (refers to most severe reading of palpebral and bulbar conjunctivae when compared with control eye; excluding cornea and iris)
0 = Blood vessels normal
1 = Some blood vessels definitely hyperemic (injected)
2 = Diffuse crimson color, individual vessels not easily discernible
3 = Diffuse beefy red

Chemosis: lids and/or nictitating membranes
0 = No swelling
1 = Some swelling above normal (including nictitating membranes)
2 = Obvious swelling, with partial eversion of lids
3 = Swelling, with lids about half closed
4 = Swelling, with lids more than half closed

Discharge:
0=No discharge
1=Any amount different to normal (does not include small amount observed in inner canthus of normal animal)
2=Discharge with moistening of the lids anad hairs just adjacent to the lids
3=Discharge with moistening of the lids and hairs, and a considerable area around the eye (running)

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Results 2

Irritation parameter:

iris score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Results 3

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Results 4

Irritation parameter:

chemosis score

Remarks:

chemosis

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Results 5

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Results 6

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

not fully reversible within: 48 hours

Irritant / corrosive response data:

-Irritation: no abnormal findings were observed in the cornea or iris of any animal at any of the measurement intervals; slight to moderate reddening of the conjunctivae was observed in all animals at 1-hour reading. Slight reddening of the conjunctivae was observed in 2/3 animals 24 hours after treatment. Slight swelling was noted in 2/3 animals at the 1-hour examination. Slight to moderate reddening of the sclerae was observed in 3/3 animals at 1-hour reading. Slight occular discharge was present in 1/3 animals at 1 hour after treatment.
-Corrosion: no corrosion of the cornea was observed at any of the reading times

Other effects:

-viability/mortality and clinical signs; no clinical signs of systematic toxicity were observed in the animals during the study and no mortality occured
-coloration: no staining of the treated eyes produced vy the test item was observed. Beige remnants of the test item were observed in the eye or conjunctival sac of all animals 1 hour after treatment.
- body weights: the body weights were considered to be within the normal range of variability.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the referred classification criteria (EEC Commission Directive 2001/59/EC of August 06, 2001), T002615 is considered to be "not irritating" to the rabbit eye.