2-cyano-2-[2,3-dihydro-3-(tetrahydro-2,4,6-trioxo-5(2H)-pyrimidinylidene)-1H-isoindol-1-ylidene]-N-methylacetamide

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

Draize test with an observation period of 8 days

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: FED. REG. 38, NO. 187, § 1500.42, S. 27019 (27.09.1973)

Version / remarks:

equivalent to OECD test guideline 405

Principles of method if other than guideline:

Draize Test

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-cyano-2-[2,3-dihydro-3-(tetrahydro-2,4,6-trioxo-5(2H)-pyrimidinylidene)-1H-isoindol-1-ylidene]-N-methylacetamide

EC Number:

278-388-8

EC Name:

2-cyano-2-[2,3-dihydro-3-(tetrahydro-2,4,6-trioxo-5(2H)-pyrimidinylidene)-1H-isoindol-1-ylidene]-N-methylacetamide

Cas Number:

76199-85-4

Molecular formula:

C16H11N5O4

IUPAC Name:

2-cyano-N-methyl-2-[3-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)-2,3-dihydro-1H-isoindol-1-ylidene]acetamide

Details on test material:

- Physical state: solid, yellow
- Analytical purity: 88 %
- Stability: At least 2 years under normal conditions
- Expiration date of the lot/batch: October 1983

Test animals / tissue source

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Gaukler, Offenbach/Main, Germany
- Mean Weight at study initiation: males: 2.90 kg; females: 2.87 kg
- Housing: one animal per cage, stainless steel with wire mesh walk floors, floor area: 40 cm x 51 cm,
- Diet (e.g. ad libitum): Ovator Solikanin 4 mm; Muskator-Werke, Duesseldorf, Germany (about 130 g per animal per day)
- Water (e.g. ad libitum): About 250 ml per animal per day: demineralized water (Monday - Friday), tap water (Saturday/Sunday)
- Acclimation period: About 8 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): Conventional (about 30 - 70)
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: Untreated eye

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml bulk volume (about 75 mg of the triturated test substance)/undiluted

Duration of treatment / exposure:

unspecified; the substance was not washed out

Observation period (in vivo):

1 h, 24 h, 48 h, 72 h and 8 d after application

Number of animals or in vitro replicates:

6 (3 males, 3 females)

Details on study design:

APPLICATION SITE
- Single application to the conjunctival sac of the eyelid

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the substance is not washed out

SCORING SYSTEM: According to J. H. Draize: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. In Dermal Toxicity pp. 46 - 59, 1959. Austin, Tex.: Association of Food and Drug Officials of the United States, Texas, State Department of Health

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: No effects in any animal

Results 2

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: No effects in any animal

Results 3

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 8 d

Results 4

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Results 5

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Results 6

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 8 days

Results 7

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

3

Reversibility:

fully reversible within: 8 days

Results 8

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 72h

Results 9

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 72h

Results 10

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 72h

Results 11

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72h

Results 12

Irritation parameter:

chemosis score

Basis:

other: animals # 1,2,4,5,6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Other effects:

Discharge was observed in one animal at readings 24-48h (score 2) and 72h (score 1). This was reversible within 8 days.

Any other information on results incl. tables

Table 1: Irritation results

Animal	Reading	Cornea		Iritis	Conjunctiva
		Opacity	Area		Redness	Chemosis	Symptoms
1	24 h	0	0	0	0	0
2	24 h	0	0	0	0	0
3	24 h	0	0	0	2	2	RE
4	24 h	0	0	0	1	0
5	24 h	0	0	0	1	0
6	24 h	0	0	0	1	0
1	48 h	0	0	0	0	0
2	48 h	0	0	0	1	0
3	48 h	0	0	0	2	1	RE
4	48 h	0	0	0	0	0
5	48 h	0	0	0	0	0
6	48 h	0	0	0	0	0
1	72 h	0	0	0	0	0
2	72 h	0	0	0	1	0
3	72 h	0	0	0	1	0	RE
4	72 h	0	0	0	0	0
5	72 h	0	0	0	0	0
6	72 h	0	0	0	0	0
1	8 d	0	0	0	0	0
2	8 d	0	0	0	0	0
3	8 d	0	0	0	0	0	RE
4	8 d	0	0	0	0	0
5	8 d	0	0	0	0	0
6	8 d	0	0	0	0	0
Mean animal 1	24 - 72 h	0	0	0	0	0
Mean animal 2	24 - 72 h	0	0	0	0.67	0
Mean animal 3	24 - 72 h	0	0	0	1.67	1
Mean animal 4	24 - 72 h	0	0	0	0.3	0
Mean animal 5	24 - 72 h	0	0	0	0.3	0
Mean animal 6	24 - 72 h	0	0	0	0.3	0
Mean animal 1 - 6	24 - 72 h	0	0	0	0.7	0.2

RE =small retractions in the eyelids

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Considering the described ocular reactions as well as the average score for irritation, the test item is not irritating to the rabbit eye.

Executive summary:

In a primary eye irritation test the acute eye irritation or corrosion potential of the test substance was assessed by a single ocular application of 0.1 mL bulk volume (about 75 mg) of the unchanged test substance to each one eye of three Vienna White rabbits according to Fed. Reg. 38, No. 187, which is equivalent to OECD test guideline 405. The test item was not washed out. The ocular reactions were assessed approximately 1, 24, 48 and 72 hours as well as 8 days after application.

Slight or moderate conjunctival redness was observed in some animals during the course of the study, while slight to moderate conjunctival chemosis and slight to moderate discharge only were observed in one animal.

The ocular reactions were reversible in all animals within 8 days after application at the latest. The average score (24 to 72 hours) for irritation was calculated to be 0.0 for corneal opacity and for iris, 0.55 for conjunctival redness and 0.16 for chemosis. Discharge was observed in one animal at readings 24 - 48h (score 2) and 72h (score 1). This was reversible within 8 days

Considering the described ocular reactions as well as the average score for irritation, the test item is not irritating to the rabbit eye.