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Toxicological information

Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Aug 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The rum of this ex-periment was to obtain information on the local tolerance of rabbits (pigmented Himalayan) to CGP 48933 (ex tempore), batch no. 800291, during short-term administration into the conjunctival sac of the right eye. The rabbits were also examined for their systemic reactions. As control animals, further rabbits were used which were treated \\oith 0.9% sodium chloride solution, batch no. 914425, abbreviated to 'Control'.
The present paper reports on the results of an experiment m which either a 0.5% solution or a 2.0% solution of CGP 43933 was instilled into the conjunctival sac of the right eye of rabbits for a period of 5 days. The solutions were prepared according to the sponsor's instructions and administered at a volume of 50 pi/animal .either 4 times/day at intervals of 90 minutes or 8 times/day at intervals of 45 minutes.
The study was performed in compliance \\oith the principles of 'Good Laboratory Practice' regulations (cf Management Statement, QAU Statement and the 'enclosure' for details).
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine
EC Number:
604-045-2
Cas Number:
137862-53-4
Molecular formula:
C24 H29 N5 O3
IUPAC Name:
N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine

Test animals / tissue source

Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
12 male and 12 female pure-bred pigmented Himalayan rabbits aged approximately 4 months were used for this experiment (breeder: CHR.F. LEUSCHNER & Co., D-2355 Löhndorf).
Initial body weight at the start of treatment was 2.1 to 2.4 kg (males) and 2.2 to 2.6 kg (females). Animals were identified by ear tattoo and cage number.
Each rabbit received a continuous number from the breeding station Löhndorf.

Food, water and accommodation
ALTROMIN 2023 served as food. Periodic analyses of the food for contaminants are carried out at least tv.ice a year by the Landv:irtschaftliche Untersuchungs- und Forschungsanstalt · Kiel, Gutenbergstral3e 75 - 77, D-2300 Kiel 1. This food was offered ad lib. Food residue was removed and weighed.
All analyses are performed based on EPA/USA, Proposed Health Effects Test Standards for Toxic Substances Control Act Test Rules, Federal Register, 44, 27334 - 27375, May 1979_ The results were \\ithin the admissible limits.
Tap water was also given unrestrictedly (in drinking bottles). Samples of the water are analysed regularly (twice a year) by Medizinisches Zentral-Laboratorium, Lauenburger Str. 65, D-2054 Geesthacht.

Test system

Vehicle:
other: (100 mM Na2HPO4 + 50 mM 0.9% NaCl solution + 10 N NaOH
Controls:
yes, concurrent negative control
Amount / concentration applied:
Group 2:
50 ul CGP 48933 (ex tempore) (0.5% solution) referred to in this report as 0.5% CGP 48933
4 instillations/animal/day at intervals of 90 minutes
Group 3:
50 ul CGP 48933 (ex tempore) (2.0% solution), referred to in this report as 2% CGP 48933
4 instillations/animal/day at intervals of 90 minutes
Group 4:
50 ul CGP 48933 (ex tempore) (2.0% solution), referred to in this report as 2% CGP 48933
8 instillations/animal/day at intervals of 45 minutes

Group 1: Control
50 ul 0.9% NaCl solution (control solution)
8 instillations/animal/day at intervals of 45 minutes
Duration of treatment / exposure:
5 days
Observation period (in vivo):
5days
Number of animals or in vitro replicates:
24 (12 male and 12 female) rabbits
four groups each containing 3 male and 3 female rabbits
Details on study design:
Route of administration: into the conjunctival sac of the right eye; the left eye remained untreated
Treatment vwith 50 ul 0.5% CGP 48933/animal 4 times per day, or with 50 ul 2% CGP 48933/animal 4 or 8 times per day,
or with 50 ul 0.9% NaCl solution/animal 8 times per day into the conjunctival sac of the right eye did not cause any substancerelated intolerance reactions in the eye and the optic region during or after 5 test days.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
The study was 5-day ocular tolerance study, not only 72 as indicated in the table (due to validation).

Any other information on results incl. tables

During the 5 - day treatment, the conjunctivae of each animal were examined on a daily basis before the first and after the last instillation.

Redness (grade 1 or 2 based on BALDWIN) was detected as follows TD5 and/or 6:

Group 1: 50 ul 0.9% NaCl solution/animal, 8 instillations/day (control)

no. 2 m left untreated eye                                   grade 1       

no. 5 f left untreated eye, right treated eye        grade 1           

Group 2: 50 ul 0.5% CGP 48933/animal, 4 instillations/day

no. 2m right treated eye                                   grade 2

no. 3m left untreated eye                                   grade 1

no. 4 f left untreated eye                                   grade 1

Group 3: 50 ul 2% CGP 48933/animal, 4 instillations/day

no. 5 f left untreated eye                                   grade 1

no. 6f left untreated eye                                    grade 1

Opacity of the cornea (grade 1 based on BALDWIN) was observed animals in the treated right eye only, TD5 and/or 6:

Group 1: 50 ul 0.9% NaCl solution/animal, 8 instillations/day (control)

no. 1 m right treated eye                                   grade 1

Group 3: 50 ul 2% CGP 48933/animal, 4 instillations/day

no. 5 f right treated eye                                  grade 1

Group 4: 50 ul2% CGP 48933/animal, 8 instillations/day

no. 5 f right treated eye                                   grade 1

no. 6 f left untreated eye, right treated eye       grade 1

The fluorescein test resulted in slight staining (grade 1) in 50% of the cornea in one control animal (50 ,ul 0.9% NaCl solution/animal, 8 instillations/day) during both of the examinations on test day 5 and moderate staining (grade 2) in 50% of the cornea during the examination carried out on test day 6.

The fluorescein tests were negative in all other animals.

The iris was inconspicuous during the examinations. The anterior chamber and lens were inconspicuous in all 24 rabbits from all 4 groups at the various examination dates. The same was also true for the fundus of the eyes.

Miosis, mydriasis and/or ptosis were not observed.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the present test conditions, treatment for 5 days with 50 ul 05% CGP 48933/animal, by instillation into the conjunctival sac of the right eye of rabbits - 4
times/day, or wiith 50 ul 2% CGP 48933/animal, administered 4 or 8 times/day, resulted in no local or systemic substance-related macroscopic intolerance reactions. Ophthalmological and ophthalmopathological examination of the eyes revealed no changes which are considered to be related to the instillation of the test substance CGP 48933.
Furthermore, other organs revealed no substance-related changes.