Reaction mass of 5-[(Disubstituted-dihydrocarbopolycyclyl)diazenyl]-6-hydroxy-4-methyl-2-substituted-1-propyl-1,2-dihydropyridine-3-carbonitrile and 1-Butyl-5-[(disubstituted-dihydrocarbopolycyclyl)diazenyl]-6-hydroxy-4-methyl-2-substituted-1,2-dihydropyridine-3-carbonitrile

Eye irritation

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Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

OECD Guidelines for Testing of Chemicals, Section 4, number 405 "Acute Eye Irritation /
Corrosion", adopted April 24, 2002.

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

Commission Directive 2004/73/EC, B.5. "Acute Toxicity: Eye Irritation/Corrosion", April 29,
2004.

Deviations:

no

Principles of method if other than guideline:

Guidelines followed

GLP compliance:

yes (incl. QA statement)

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

solid

Details on test material:

Batch: P2/05 UL
Appearance: light orange crystalline powder
Expiration date: 31.05.2011
Storage: at room temperature

Specific details on test material used for the study:

- Identity: FAT41039/A
- Description: Light orange crystalline powder
- Batch number: P2/05 UL
- Purity / Formulation: content of organic pigments > 99 %; main components: 97 %
- Stability of test item: Stable under storage conditions.
- Expiry date: 31-MAY-2011
- Stability of test item dilution: Stable in PEG 300 for at least 7 days at room temperature.
- Storage conditions: At room temperature (range of 20 ± 5 °C), light protected.
- Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Remarks:

SPF

Details on test animals or tissues and environmental conditions:

TEST SYSTEM
- Test system: Young Adult New Zealand White Rabbit, SPF
- Rationale: Recognized by the international guidelines as the recommended test system
- Source: Charles River Deutschland GmbH, Stolzenseeweg 32-36, D-88353 Kisslegg / Germany
- Number of animals per test: 3 (Animals of both sexes were used)
- Age at treatment: 13-14 weeks (male), 12 -13 weeks (females)
- Identification: By unique cage number and corresponding ear number.
- Acclimatization: Under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.

HUSBANDRY
Conditions:
Standard Laboratory Conditions
Air-conditioned with ranges for room temperature 17-23 °C, relative humidity 30-70 % and approximately 10-15 air changes per hour. Room temperature and humidity were monitored continuously and values outside of these ranges may have occasionally occurred, usually following room cleaning. These transient variations are considered not to have any influence on the study and, therefore, these data are not reported but are retained at RCC. The animals were provided with an automatically controlled light cycle of 12 hours light and 12 hours dark. Music was played during the daytime light period.

Accommodation:
Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd, Füllinsdorf) and haysticks 4642 (batch no. 35/05, Provimi Kliba AG) were provided for gnawing.

Diet:
Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 34/05) provided by Provimi Kliba AG, CH-4303 Kaiseraugst. Results of analysis for contaminants are archived at RCC Ltd.

Water:
Community tap water from Füllinsdorf, ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

100 MG

Duration of treatment / exposure:

The treated eyes were not rinsed after instillation.

Observation period (in vivo):

72 h

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE: Not performed.

SCORING SYSTEM:
The ocular reaction (i.e. corneal opacity, iridic effects, conjunctivae and Chemosis) was assessed according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004, at approximately 1, 24, 48 and 72 hours after instillation.
Additionally, ocular discharge, reddening of the sclerae and staining of conjunctivae, sclerae and cornea by the test item was assessed. When present, corrosion was recorded and reported.

TOOL USED TO ASSESS SCORE: Eye examinations were made with a Varta Cliptrix diagnostic-lamp (Roth AG, CH-4153 Reinach/Switzerland).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #1

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 72 h

Results 2

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #2

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 72 h

Results 3

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #3

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 72 h

Results 4

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 h

Results 5

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Results 6

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 h

Results 7

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Results 8

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Results 9

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Results 10

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Results 11

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Results 12

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

(mean score)

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The individual mean scores for corneal opacity and iris were 0.00 for all three animals. The individual mean scores for the conjunctivae were 0.67, 0.67 and 0.67 for reddening and 0.00 for Chemosis for all three animals, respectively.
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 noted in all animals at the 1-hour reading and persisted as slight reddening in all animals up to the 48-hour reading.
Obvious swelling (Chemosis) of the conjunctivae with partial eversion of lids was observed in two animals at the 1-hour reading.
Slight to moderate reddening of the sclerae was present in all animals at the 1-hour reading and persisted a"s slight reddening in two animals until the 24- and 48-hour examination, respectively.
Slight ocular discharge was seen in all animals at the 1-hour reading.
No abnormal findings were observed in the treated eye of any animal 72 hours after treatment, the end of the observation period for all animals.

Other effects:

No staining of the treated eyes produced by the test item was observed.
Slight red remnants of the test item were observed in the eye or conjunctival sac of two animals at the 1 -hour reading.

Any other information on results incl. tables

CORROSION

No corrosion of the cornea was observed at any of the reading times.

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:

FAT 41039/A is considered to be "not irritating" to the rabbit eye.

Executive summary:

The primary eye irritation potential of FAT 41039/A was investigated according to OECD Guideline 405. The test item was applied by instillation of 0.1 g into the left eye of each of three young adult New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours after test item instillation. The mean score was calculated across 3 scoring times (24, 48 and 72 hours after instillation) for each animal for corneal opacity, iris, redness and Chemosis of the conjunctivae, separately. The individual mean scores for corneal opacity and iris were 0.00 for all three animals. The individual mean scores for the conjunctivae were 0.67, 0.67 and

0.67 for reddening and 0.00 for Chemosis for all three animals, respectively. The instillation of FAT 41039/A into the eye resulted in moderate, early-onset and transient ocular changes, such as reddening of the conjunctivae and sclerae, discharge and Chemosis. These effects were reversible and were no longer evident 72 hours after treatment, the end of the observation period for all animals. No abnormal findings were observed in the cornea or iris of any animal at any of the examinations. No corrosion was observed at any of the measuring intervals. Slight red remnants of the test item were observed in the eye or conjunctival sac of two animals at the 1-hour reading. No staining of the treated eyes by the test item was observed and no clinical signs were observed. Thus, the test item did not induce significant or irreversible damage to the rabbit eye. Based upon the referred classification criteria (Commission Directive 2001/59/EC of August 06, 2001), FAT 41039/A is considered to be "not irritating" to the rabbit eye.