Pentanedioic acid, compd. with (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1:1)

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

29 December 1997 and 7 January 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

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

Test material

Test material information

Constituent 1

Reference substance name:

Abacavir Hemisulphate

IUPAC Name:

Abacavir Hemisulphate

Constituent 2

Reference substance name:

188062-50-2

Cas Number:

188062-50-2

IUPAC Name:

188062-50-2

Details on test material:

- Name of test material (as cited in study report): 1592U89 Hemisulphate
- Molecular formula (if other than submission substance): Please see Attachment 1.
- Molecular weight (if other than submission substance): Please see Attachment 1.
- Structural formula attached as image file (if other than submission substance): Please see Attachment 1.
- Description: off white granular solid
- Date received: 24 November 1997
- Storage conditions: room temperature, in the dark, over silica gel

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: Twelve to sixteen weeks old.
- Weight at study initiation: 2.74 to 3.20 kg
- Housing: Individually housed in suspended metal cages.
- Diet: ad libitum: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK
- Water: ad libitum: Mains drinking water.
- Acclimation period: Nineteen to twenty-seven days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 20°C
- Humidity (%): 50 to 59%
- Air changes (per hr): Approximately 15 changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours continuous light (light cycle 06.00 to 18.00) and 12 hours darkness.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: Concurrent: untreated left eye.

Amount / concentration applied:

TEST MATERIAL
- Amounts applied:
Animal 1: 10 mg
Animal 2: 78 mg

Duration of treatment / exposure:

PROCEDURE
On the day before the start of the test, both eyes of the provisionally selected test rabbits were examined under ultra-violet Iight, after treatment with Sodium Fluorescein BP (FLUORETS: Smith & Nephew Pharmaceuticals Limited, Batch number 704008). The cornea, conjunctivae and iris were examined for lesions. Immediately before treatment, the rabbit eyes were again examined with the aid of a light source from an ophthalmoscope. Only animals free of ocular damage
were used.
Initially, a single rabbit was treated. 10 mg of the test material was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The eyelids were held together for approximately one second. The initial local pain reaction was assessed immediately after treatment.
After consideration of the ocular responses produced in the first treated animal, a second animal was treated. A volume of 0.1 mL weighing
approximately 78 mg (as measured by gently compacting the required volume into an adapted syringe) was placed into the eye in a similar manner to the first treated animal. The initial local pain reaction was assessed in a similar manner to the first treated animal.

After consideration of the ocular responses produced in the second treated animal, no further animals were treated.

Observation period (in vivo):

Assessment of ocular damage/irritation was made approximately 1, 3, 6 and 24 hours following treatment, according to the numerical evaluation
given in "any other information on materials and methods".

Number of animals or in vitro replicates:

Two male animals.

Details on study design:

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by use of the light source from a standard ophthalmoscope. At the 24-hour observation, confirmation of the presence or absence of corneal opacity was made under ultra-violet illumination following treatment with Sodium Fluorescein BP.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

animal: 27 Male

Time point:

other: 24 hours

Score:

4

Max. score:

4

Reversibility:

other: Animal terminated at 24 hours due to effects.

Remarks on result:

other: 78 mg dose

Results 2

Irritation parameter:

cornea opacity score

Basis:

animal: 141 Male

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Remarks on result:

other: 10 mg dose.

Results 3

Irritation parameter:

iris score

Basis:

animal: 141 Male

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

2

Reversibility:

other: No effects noted.

Remarks on result:

other: 10 mg dose.

Results 4

Irritation parameter:

iris score

Basis:

animal: 27 Male

Time point:

other: 24 hours

Score:

1

Max. score:

2

Reversibility:

other: Animal terminated at 24 hours due to effects on cornea.

Remarks on result:

other: 78 mg dose.

Results 5

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal: 141 Male

Time point:

other: Mean of 24, 28 and 72 hours

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: 10 mg dose.

Results 6

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal: 27 Male

Time point:

other: 24 hours

Score:

2

Max. score:

3

Reversibility:

other: Animal terminated at 24 hours due to effects on cornea.

Remarks on result:

other: 78 mg dose.

Results 7

Irritation parameter:

chemosis score

Basis:

animal: 141 Male

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: Effects noted at 1, 3 and 6 hours.

Remarks on result:

other: 10 mg dose.

Results 8

Irritation parameter:

chemosis score

Basis:

animal: 27 Male

Time point:

other: 24 hours

Score:

2

Max. score:

4

Reversibility:

other: Animal terminated at 24 hours due to effects on cornea.

Remarks on result:

other: 78 mg dose.

Irritant / corrosive response data:

10 mg Dose
A slight initial local pain reaction was noted on administration of the test material.
No corneal or iridial reactions were noted during the study.
A moderate conjunctival reaction was noted (maximum total score of 12 at 6 hours). Conjunctival irritation was noted at the 1, 3, 6 and 24-hour
observations. The treated eye appeared normal 48 hours after treatment.

0.1 mL (78 mg) Dose
A slight initial local pain reaction was noted on administration of the test
material.
A marked corneal reaction was noted (maximum total score of 60 at 3 hours). Diffuse corneal opacity was noted at the 1-hour observation. At the 3, 6 and 24-hour observations a very thin margin of opaque corneal opacity was noted on the lower edge of the cornea with diffuse to translucent opacity over the remainder of the affected area. Sloughing of the corneal membrane was also noted at these times.
A moderate iridial readion was noted (maximum total score of 5). Iridial inflammation (grade 1) was noted at the 1, 3, 6 and 24-hour observations.
A moderate conjunctival reaction was noted (maximum total score of 14). Conjunctival irritation (redness grade 2, chemosis grade 2 and discharge
grade 2 or 3) was noted at the 1, 3, 6 and 24-hour observations.

The animal was killed immediately following the 24-hour observation due to the persistence of grade 4 corneal opacity for a 24-hour period with no
evidence of recovery. This was in accordance with company policy and current UK Home Office guidelines.

Applicant's summary and conclusion

Interpretation of results:

highly irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material can be considered to be an irritant based on the results of the study.

Executive summary:

A study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit. The method was based on that described in the OECD Guidelines for Testing of Chemicals (1987) No. 405 "Acute Eye Irritation/Corrosion" which essentially complies with Method B5 in Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

A single application of 10 mg test material to the non-irrigated eye of one rabbit produced a moderate conjunctival reaction. The treated eye appeared normal at the 48-hour observation.

A single application of 0.1 mL (78 mg) test material to the non-irrigated eye of one rabbit produced a marked corneal, moderate iridial and moderate conjunctival reaction. Sloughing of the corneal membrane was also noted. The animal was killed immediately following the 24-hour observation due to the persistence of grade 4 corneal opacity for a 24-hour period with no evidence of recovery. This was in accordance with company policy and current UK Home Office guidelines.

The test material (10 mg Dose), produced a maximum total score of 12 in a single rabbit.

The test material (0.1 mL Dose), produced a maximum total score of 77 and was considered to present a very severe risk of eye damage (grade 5) to the rabbit eye according to the Draize classification scheme (based on one rabbit).

Conclusion

The test material was considered to be an irritant according to EC labelling regulations.