(2S-cis)-(diphenylmethyl)-N-(phenylmethyl)-1-azabicyclo[2.2.2.]octan-3-amine (1-R camphor-10-sulfonate)

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

444-810-6

EC Name:

-

Molecular formula:

C27 H30 N2 * C10 H16 O4 S

IUPAC Name:

(2S-cis)-(diphenylmethyl)-N-(phenylmethyl)-1-azabicyclo[2.2.2.]octan-3-amine (1-R camphor-10-sulfonate)

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Identity:
Chemical name:
Intended use:
TEST SUBSTANCE
CP-163,625-BV
(2-Benzhydry1-1-aza-bicyclo[2.2.2]oct-3-y1)-benzylamine
Pharmaceutical intermediate
Appearance: White powder
Storage conditions: Room temperature in the dark
Lot No: 38654-187-3
Purity: 99%

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White
strain, obtained from Harlan UK Ltd, Bicester, Oxon, England.
They were in the weight range of 2.6 to 2.9 kg and approximately 11 to 12 weeks of age, prior to treatment
(Day 1). All rabbits were acclimatised to the experimental environment for a period of 13 days prior to the
start of the study.
The rabbits were selected without conscious bias for the study. They were housed individually in stainless
steel cages with perforated floors in Building R14 Room 5.
A standard laboratory rabbit diet (Special Diet Services STANRAB (P) SQC pellet) and drinking water
were provided ad libitum. The batch of diet used for the study was analysed by the supplier for nutrients,
possible contaminants and micro-organisms likely to be present in the diet and which, if in excess of
specified amounts, might have an undesirable effect on the test system.
The water supplied to Huntingdon Life Sciences by Anglian Water was potable water for human
consumption. Anglian Water takes its guidelines on water quality from the EEC directive relating to water
for human consumption (80/778/EEC) and conforms to the United Kingdom Water Act 1989 and
subsequent amendments. Results of routine physical and chemical examination of drinking water at
Consumers' taps, as conducted by the supplier, are made available to Huntingdon Life Sciences Ltd as
quarterly summaries.
Hay was also made available to the rabbits on a regular basis, for environmental enrichment.
Animal room temperature was maintained at 17.5 to 19°C and relative humidity at 52 - 72%. These
environmental parameters were recorded daily. Lighting was controlled by means of a time switch to give
12 hours of artificial light (0700 - 1900 hours) in each 24 hours period.
Each animal was identified by a numbered aluminium tag placed through the edge of one ear. This number
was unique within the Huntingdon Life Sciences Acute Toxicology Department throughout the duration of
the study. Each cage was identified by a coloured label displaying the study schedule number, animal
number and initials of the Study Director and Home Office licensee.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5g

Duration of treatment / exposure:

4 hours

Observation period:

upto 72 hours

Number of animals:

3 females

Details on study design:

TEST SUBSTANCE PREPARATION
CP-163,625-BV was administered as supplied by the Sponsor.
The absorption of the test substance was not determined.
Stability information for the test article was not available at the time of study conduct and was not
determined during the study.

TREATMENT PROCEDURE
Approximately 24 hours prior to application of the test substance, hair was removed with electric clippers
from the dorso-lumbar region of each rabbit exposing an area of skin approximately 100 mm x 100 mm.
Approximately 0.5 g of the test substance was applied under a 25 mm x 25 mm gauze pad, which was then
moistened with 0.5 ml of distilled water, to one intact site on each animal.
Each treatment site was covered with "Elastoplast" elastic adhesive dressing for four hours. The animals
were not restrained during the exposure period and were returned to their cages immediately after
treatment.
At the end of the exposure period, the semi-occlusive dressing and gauze pad were removed and the
treatment site was washed with warm water (34°C) to remove any residual test substance. The treated area
was blotted dry with absorbent paper.

OBSERVATIONS
Clinical signs
All animals were observed daily for signs of ill health or toxicity.
Dermal responses
Examination of the treated skin was made on Day 1 (ie approximately 60 minutes after removal of the
dressings) and on Days 2, 3 and 4 (equivalent to 24, 48 and 72 hours after exposure).
Local dermal irritation was assessed using the prescribed numerical system:

Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) or eschar formation (injuries in depth)
preventing erythema reading 4

Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (edges raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending
beyond the area of exposure) 4

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 0

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 0

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No dermal response to treatment was observed in any animal throughout the study.

Other effects:

There were no signs of toxicity or ill health in any rabbit during the observation period.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

A single semi-occlusive application of CP-163,625-BV to intact rabbit skin for four hours elicited no dermal irritation.

Executive summary:

A study was performed to assess the skin irritation potential of CP-163,625-BV to the rabbit. The method followed was that described in: EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (0J No. L3 83A, 29.12.92), Part B, Method 8 .4. Acute toxicity (Skin Irritation). OECD Guideline for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion". Adopted 17 July 1992. Three rabbits were each administered a single dermal dose of 0.5 g of the test substance and observed for four days. No dermal irritation was observed following a single semi-occlusive application of CP-163,625-BV to intact rabbit skin for four hours. CP-163,625-BV will not require labelling with the risk phrase R38, "Irritating to skin", in accordance with Commission Directive 93/21/EEC.