Mycophenolic acid

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 08 to 11, 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented and reported study, conducted according to internationally accepted technical guidelines and in compliance with GLP in recognized contract research organization.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

of 1992

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

of 1992

Deviations:

no

GLP compliance:

yes

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

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

- Age at study initiation (day of dosing): 9 - 12 weeks.
- Number and Sex: 3 males
- Animal supplier: Charles River, Nederland
- Weight at study initiation: Minimum 1453 g, maximum 1719 g (3 males each 8 weeks old).
- Housing: Individual housing in cages with perforated floor and automatic drinking system.
- Diet (approx. 100 g/day): Commercially available pelleted rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits Altromin, Germany).
- Hay (once/week): Supplier: BMI, Helmond, The Netherlands)
- Water (ad libitum): Tap water
- Acclimation period: At least 5 days before treatment start under laboratory conditions.


ENVIRONMENTAL CONDITIONS

Animal housing and environmental conditions were appropriate for skin irritation / corrosion testing in the rabbit: Controlled environment with approximately 15 air changes per hour, 12 hours artificial fluorescent light and 12 hours darkness per day and optimal conditions considered to be 21ºC and 50% relative humidity. Fluctuations from these optimal conditions were not considered to have affected the study integrity.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

other: once or, if appropriate more often, clipped with electric clipper

Vehicle:

water

Controls:

not required

Amount / concentration applied:

0.5 g test substance moistened with water per approx. 6 cm2 (2 x 3 cm) skin per animal.

Duration of treatment / exposure:

4 hours

Observation period:

72 hours post patch removal

Number of animals:

3

Details on study design:

TEST SITE PREPARATION:

Approximately 24 hours before exposure an area of approximately 10x15 cm on the back of the animal was clipped. If considered necessary, area foreseen for treatment was re-clipped at least 3 hours before treatment start to facilitate evaluation of the skin reactions. During health inspection of the animals prior to commencement of treatment, special attention was paid to the skin to be treated, which was intact and free from abnormalities.

- Area of treated skin: Approx. 6 cm2 (= 2x3 cm).
- Type of wrap used: Metalline patch (2x3 cm) mounted on micropore tape which was wrapped around the abdomen
and secured with Coban elastic bandage.

TEST MATERIAL AND DOSE PREPARATION

- Administration Volume/animal (2x3 cm):
0.5 g Mycophenolic Acid moistened with water (= vehicle) to ensure close contact with the animal's skin.

- Vehicle: Water (Milli-U).

- Justification for choice of vehicle:
The test substance is stable for at least 96 hours in water and no adverse side effects of this vehicle on the animals
are to be expected

TREATMENT PERIOD AND REMOVAL OF TEST SUBSTANCE

Semi-occlusive treatment lasted 4 hours. Then the dressings were removed and the skin cleaned of residual test substance using water.

SCORING SYSTEM:

The treated skin patches were evaluated at 1 hour post end of exposure (not included in the mean dermal irritation score nor used for irritation/corrosion classification) and at 24, 48 and 72 h post end of exposure (included in the mean dermal irritation score and used for irritation/corrosion classification).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Remarks:

as defined in Table 1

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: erythema or eschar formation was not evident

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

edema score

Remarks:

as defined in Table 1

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: edma formation was not evident

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

In each animal, erythema, eschar or edema formation was not evident at any observation time point of the study.

Other effects:

Mortality, symptoms of systemic toxicity or staining of the treated skin were not evident.

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In view of the absence of any irritating effects during the present study and according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008] the test substance is considered "not irritant" and not having any labelling requirement regarding skin irritation.

Executive summary:

Mycophenolic Acid was tested for skin irritation/corrosion according to OECD TG 404 of 1992 and the corresponding EC Technical Guideline B.4 of 1992 in compliance with GLP. Reliability grade 1 was assigned to the study.

 

Each of three New Zealand White rabbits was treated for 4 hours by semi-occlusive administration of a single dose of 0.5 g Mycophenolic Acid moistened with water. The test substance was administered to clipped intact skin (approximately 6 cm2/animal). Skin reactions were assessed 1, 24, 48 and 72 hours post patch removal.

 

In each animal, erythema, eschar or edema formation was not evident at any observation time point of the study. In addition, mortality, symptoms of systemic toxicity or staining of the treated skin were not evident.

 

In view of the absence of any irritating effects during the present study and according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008] the test substance is considered "not irritant" and not having any labelling requirement regarding skin irritation.