Mycophenolic acid

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May 17 to 24, 1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Acceptably documented and reported study, conducted similar to internationally accepted technical guidelines in recognized contract research organization. However, deviating from the technical guidelines the study was conducted using only one, instead of three animals. Therefore, this study is only a screening test providing only an indication for classification and labelling. The study was not compliant with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

of 2002

Deviations:

yes

Remarks:

Only one, instead of three animals, was used, as this study was meant to be only a screening test.

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

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

Version / remarks:

of 2008

Deviations:

yes

Remarks:

Only one, instead of three animals, was used, as this study was meant to be only a screening test.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Mycophenolic acid

EC Number:

246-119-3

EC Name:

Mycophenolic acid

Cas Number:

24280-93-1

Molecular formula:

C17H20O6

IUPAC Name:

6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid

Constituent 2

Reference substance name:

6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methylhex-4-enoic acid

EC Number:

207-595-8

EC Name:

6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methylhex-4-enoic acid

Cas Number:

483-60-3

Molecular formula:

C17H20O6

IUPAC Name:

6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid

Details on test material:

- Name of test material (as cited in study report): MYCOPHENOLIC ACID
- Appearance: White powder
- Expiration date of the lot/batch: 01 November 2000
- Storage conditions: In refrigerator in the dark
- Stability under storage conditions: Stable

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMAL: albino rabbit (New Zealand White, SPF-quality)

Test system

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

Single dose of 67.1 mg test substance (a volume of approximately 0.1 ml) instilled into the conjunctival sac of one eye. The other eye remained untreated and served as a control.

Duration of treatment / exposure:

There was no mentioning in the report that eyes were rinsed after treatment. Consequently the treatment/exposure period was equivalent to the entire observation period following administration, which was 7 days, or lasted until removal of the test material by physiological mechanisms, whichever happened sooner.

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

1

Details on study design:

The test material treated eye was evaluated at: 1, 24, 48 and 72 hours and 7 days after application.

In addition, fluorescein treatment to support the quantitative determination of corneal opacity (percentage of total corneal area affected).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

over 3 time points

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: Corneal ulceration or opacity was not evident

Results 2

Irritation parameter:

iris score

Basis:

mean

Remarks:

over 3 time points

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

fully reversible within: 24 h

Results 3

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Remarks:

over 3 time points

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 7 days

Results 4

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

over 3 time points

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 h

Results 5

Irritation parameter:

other: discharge score

Basis:

mean

Remarks:

over 3 time points

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritant / corrosive response data:

Corneal lesions were not evident throughout the study. Iridic lesions, grade 1, were seen at 1 hour post instillation having fully reversed by 24 hours. Conjunctival redness up to grade 2 was seen at 1, 24, 48 and 72 hours having fully reversed by 7 days post instillation. Chemosis up to grade 3 and discharge grade 1 were seen at 1 and 24 hours, both findings having fully reversed by 48 hours post instillation.

Other effects:

There was no mortality.

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information This is only an indication, as it is based on 1 animal Criteria used for interpretation of results: EU

Conclusions:

The ocular effects of Mycophenolic Acid seen in the present study do not necessitate any labelling regarding eye irritation according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008]. However, this classification is based on only one animal and therefore only an indication for classification.

Executive summary:

Mycophenolic Acid was tested for eye irritation similar to EU Method B.5 (Acute Toxicity: Eye Irritation/Corrosion) of 2008 [Commission Reg. (EC) No. 440/2008] and OECD TG 405 of 2002. In deviation from these technical guidelines only one, instead of three animals, was used, as this study was meant to be a screening test. Therefore, reliability grade 3 was assigned. The study was not compliant with GLP.

 

One albino rabbit [New Zealand White, SPF-quality] was treated by administration of a single dose of 67.1 mg Mycophenolic Acid (approximately 0.1 ml) to the conjunctival sac of one eye. The other eye served as a control. The treated eye was evaluated for ocular lesions at 1, 24, 48 and 72 hours and 7 days after administration.

 

There was no mortality. Ocular lesions seen in the treated eye comprised an iridic lesion (grade 1), conjunctival redness (grade 1 and 2), chemosis (grade 1 and 3) and discharge (grade 1). The iridic lesion was restricted to the 1 h observation time point, conjunctival redness was seen at 1, 24, 48 and 72 hours after administration having fully reversed by 7 days, and chemosis and discharge were seen at 1 and 24 hours after administration having fully reversed by 48 hours. Corneal lesions were not evident throughout the study. In addition, there was no evidence of ocular corrosion.

 

In conclusion, the ocular effects of Mycophenolic Acid seen in the present study do not necessitate any labelling regarding eye irritation according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008]. However, this classification is based on only one animal and therefore only an indication for classification.