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

Eye irritation

Administrative data

Endpoint:

eye 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 405 (Acute Eye 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)-beraylamine
Pharmaceutical intermediate
Appearance: White powder
Storage conditions: Room temperature in the dark
Lot No: 38654-187-3
Purity: 99%

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

The animal for this study was selected from a stock supply of healthy adult rabbits of the New Zealand
White strain, obtained from Charles River UK Ltd, Margate, Kent.
The animal weighed 3.1 kg, was approximately 13 weeks of age, prior to treatment (Day 1) and was
acclimatised to the experimental environment for period of 21 days prior to the start of the study.
The rabbit was selected without conscious bias for the study. It was housed individually in a metal cage
with a perforated floor 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 rabbit on a regular basis, for environmental enrichment.
Animal room temperature was maintained at 17.5 to 21°C and relative humidity at 46 - 75%. 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.
The animal was identified by a numbered aluminium tag placed through the edge of one ear. This number
was unique within the Department throughout the duration of the study. The cage, was identified by a
coloured label displaying the study number, animal number and initials of the Study Director and Home
Office licensee.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 ml (43mg)

Duration of treatment / exposure:

single exposure, exposed eye not irrigated

Observation period (in vivo):

upto 72 hours

Number of animals or in vitro replicates:

One

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
The eyes of the animal were examined prior to instillation of the test substance to ensure that there was no
pre-existing corneal damage, iridial or conjunctival inflammation.
One animal was treated in advance of the others, to ensure that if a severe response was produced, no
further animals would be exposed.

A volume of 0.1 ml of the test substance (approximately 43 mg) was placed in the lower everted lid of one
eye of the animal.
The eyelid was then gently held together for one second before releasing. The contralateral eye remained
untreated.
As a result of the severe ocular reactions observed, and in the interests of animal welfare, only one animal
was dosed.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

ca. 4

Reversibility:

other: animal sacrified in extremis

Results 2

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

ca. 1

Reversibility:

other: animal sacrified in extremis

Results 3

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

ca. 3

Reversibility:

other: animal sacrified in extremis

Results 4

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

ca. 3.33

Max. score:

4

Reversibility:

other: animal sacrified in extremis

Irritant / corrosive response data:

Corneal opacification (Grade 4) and india! inflammation (Grade 1) developed during the observation
period.
A diffuse, beefy red colouration of the conjunctivae and considerable swelling with the eyelids more than
half closed was seen. Blanching on the nictating membrane and conjunctivae was also observed.
These reactions remained unresolved with corneal opacification (Grade 4), iridial inflammation (Grade 1)
and a diffuse, beefy red colouration of the conjunctivae accompanied by blood and blisters on the lower
conjunctivae, a white discharge and swelling with the eyelids half closed evident three days after
instillation.
Due to the severity of the reactions seen in the screen animal, and in the interests of animal welfare, the
animal was sacrificed three days after instillation and no further animals were used.

Applicant's summary and conclusion

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Instillation of CP-163,625-BV into the rabbit eye elicited corneal opacification, iridial inflammation and
severe conjunctival irritation.

Executive summary:

A study was performed to assess the eye irritation potential of CP-163,625-BV to the rabbit. The method followed was that described in the following guidelines: EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (OJ No. L383A, 29.12.92), Part B, Method B.5. Acute toxicity (eye irritation). OECD Guideline for the Testing of Chemicals No. 405. "Acute Eye Irritation/Corrosion", Adopted 24 February 1987. One rabbit was administered a single ocular dose of a volume of 0.1 ml (approximately 43 g) of the test substance, and observed for 3 days after instillation. Due to the severity of the reactions seen, one animal only was used. A single instillation of CP-163,625-BV into the eye of the rabbit elicited corneal opacification with iridial inflammation and severe conjunctival irritation. Due to the severity of the reactions CP-163,625-BV will require labelling with the risk phrase R41, "Risk of serious damage to eyes", in accordance with Commission Directive 93/21/EEC.