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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 April - 03 May 1994
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
92/69/EEC
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
A mixture of: bis(1S,2S,4S)-(1-benzyl-4-tert-butoxycarboxamido-2-hydroxy-5-phenyl)pentylammonium succinate; isopropyl alcohol
EC Number:
414-810-0
EC Name:
A mixture of: bis(1S,2S,4S)-(1-benzyl-4-tert-butoxycarboxamido-2-hydroxy-5-phenyl)pentylammonium succinate; isopropyl alcohol
Cas Number:
144163-85-9
Molecular formula:
Empirical formula: C25H35N2O5
IUPAC Name:
butanedioic acid; propan-2-ol; bis(tert-butyl N-[(4R)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl]carbamate)

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Seven male rabbits from Charles River, Montreal, Canada weighing 2- 3 kg (approx. 10 to 15 weeks old) on arrival were allowed to acclimatise for 13 days before treatment. Six animals were assigned to the study.
The animals were housed in individual stainless steel ventilated hanging cages. 100 -130g Certified High Fibre Rabbit Chow was provided each day and water ad libitum. The temperature was maintained at 64 - 68°F. The animal room was on a 12 hour daily light cycle.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: other: right eye of each animal was untreated
Amount / concentration applied:
40mg (which, when gently compacted, occupied a volume of approx.0.1ml)
Duration of treatment / exposure:
40mg test material was instilled into the lower everted lid of the left eye. The material was placed in the conjuctival sac of the left eye after gently pulling the lower eye lid away from the eyeball. The upper and lower eyelid were held closed for about one or two second after treatment to prevent loose of material and then released. The right eye was left untreated to serve as the control.
Observation period (in vivo):
After the 24hr observation period the eyes of all rabbits were washed with lukewarm water.
All animals were observed daily for signs of ill health or toxicity.
Evaluations made at 1, 24, 48, 72 hrs and days 4, 7, 14 and 21 after treatments.
Number of animals or in vitro replicates:
6 male rabbits
Details on study design:
Prior to treatment the eyes were checked by a veterinarian.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
21 d
Reversibility:
not fully reversible within: 14 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
21 d
Reversibility:
other: minimal reversibility
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
21 d
Reversibility:
not fully reversible within: 14 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
21 d
Reversibility:
other: minimal reversibility
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
21 d
Reversibility:
not fully reversible within: 14 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
21 d
Reversibility:
other: minimal reversibility
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
21 d
Reversibility:
not fully reversible within: 14 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
21 d
Reversibility:
other: minimal reversibility
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
21 d
Reversibility:
not specified
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
21 d
Reversibility:
not specified
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
21 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
Severe corneal opacity , involving at least ¾ of the cornea was observed in all the rabbits in this study.
Opaque corneas were noted in four of the rabbits on day 14.
Severe chemosis and discharge were observed in all six rabbits during the observation period after treatment.
Severe conjunctival redness was noted in two rabbits with lesser degrees of redness noted in the remaining four rabbits.
Severity of chemosis, discharge and conjunctival redness decreased during the later observation periods and was minimal or not noted for each of the three irritation parameters at the final observation period.
Iritis scores were not determined during most observation periods due to the severity of the corneal opacity and the area of corneal involvement. However, in cases when it was possible to score for iritis, the iris appeared normal for this parameter.

Any other information on results incl. tables

Body weights were measured on the day of treatment.

Applicant's summary and conclusion

Interpretation of results:
other: Severe ocular damage
Conclusions:
Abbott-88820 succinate caused severe occular damage including severe ocular opacity, chemosis and discharge to the eye of rabbits in this study.
Executive summary:

Abbott-88820 succinate caused severe occular damage including severe ocular opacity, chemosis and discharge to the eye of rabbits in this study.

Although the severity for chemosis, discharge and conjunctival redness decreased with time after treatment, opaque corneas were observed in four rabbits as late as day 14 of the observation period.