Tricyclo[3.3.1.13,7]decane-1-acetic acid, .alpha.-[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxy-, (.alpha.S)-

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3 July 2002 to 27 November 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in 2002 according to OECD Method 404 and EU Annex V test B4and in accordance with GLP. Study material is well characterized.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid

EC Number:

700-361-0

Cas Number:

361442-00-4

Molecular formula:

C17H27NO5

IUPAC Name:

(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid

Constituent 2

Reference substance name:

1-Hydroxyadamantanyl-3-(S)-Boc-glycine

IUPAC Name:

1-Hydroxyadamantanyl-3-(S)-Boc-glycine

Details on test material:

Test material is a white powder which was received at testing laboratory on 7 May 2002 and stored at room temperature in the dark.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

At the start of the study the rabbits weighed 2.57 to 3.37 kg and were ten weeks old. Free access to mains drinking water and food was allowed through out the study. The temperature and relative humidity were set to achieve limits of 16 to 22 C and 40 to 80% respectively. The rate of air exchange was at least 15 changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours of darkness. Housing: animals were individually housed in cages that were perforated polypropylene trays on steel rack with mesh walls and no bedding.Acclimation period: 14-17 days.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

500 mg of the test material, moistened with 0.1 ml of distilled water was introduced under 30 X 20 mm cotton gauze patch

Duration of treatment / exposure:

4 hours after treatment.

Observation period:

Approximately one hour after removing the patch and 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation and scored.

Number of animals:

3

Details on study design:

The day before the test the three rabbits were clipped free of fur from the dorsal/flank area and inspected for gross abnormalities of the epidermis. Only animals with an intact healthy epidermis are selected for the study. Initially only one animal was treated with three sites on the back of the rabbit selected. At each test site 500 mg of test material moistened with 0.1 ml of distilled water was introduced under a 30x20 mm cotton gauze patch which was then covered with a larger gauze patch and an open weave compression bandage which was wrapped firmly around the torso to secure the applied dose and the patch in the correct position. The condition of the treated skin was assessed for a period of three days to ensure the test article did not cause severe dermal changes. Subsequently, 2 additional rabbits were treated and then 4 hours later the patches were removed. The test sites were then evaluated after 1 hour, 24, 48, and 72 hours according to the Draize classification scheme for determination of primary irritation index.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 2

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 4

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 5

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 6

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 7

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 8

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1, 24, 48 and 72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritant / corrosive response data:

The individual scores for erythema/eschar and oedema were all zero for all three animals for the complete 72 hour observation period. No evidence of skin irritation was noted during the study.The Draize classification scheme for determination of primary irritation index was used.

Other effects:

No evidence of skin irritation was noted during the study.

Any other information on results incl. tables

Group mean values for dermal reactions

Time of observation	Erythema	Oedema
1 hr	0	0
24 hr	0	0
48 hr	0	0
72 hr	0	0
Mean of 24, 48 and 72 hour scores	0	0

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material produced a primary irritation index of 0.0 and was classified as a non-irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test material did not meet the classification as irritant or corrosive according to the EU labelling regulations.

Executive summary:

Study was assigned a reliability of 1 and followed acceptable OECD, EU or recognized standards and was in accordance with GLP. This study was conducted to determine the irritation or corrosion caused to intact rabbit skin following a single (4 hour), semi-occluded, topical application of BMS 528233-01. The test article (500 mg) was applied to a 30 x 20 mm area on the clipped and moistened dorsum of each of three New Zealand White rabbits on Day 1. The treated area of skin was covered by a semi-occlusive bandage for four hours. Dermal reactions to treatment were assessed for three days after removal of the dressings. No reactions were observed following a single semi-occluded, topical application of BMS 528233-01 to intact rabbit skin for four hours.  In conclusion, a single semi-occluded application of BMS 528233-01 to intact rabbit skin for four hours was found to be non-irritating.