Registration Dossier

Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13-DEC-2007 to 27-DEC-2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not specified
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
White to yellow tan colour
Specific details on test material used for the study:
Identification:
CP-902684
Description: Solid; tan
Batch Number: E010005632 or 166-TNN-73
Purity: 98%
Stability of Test Item: Stable under storage conditions.
Expiry Date: 21-MAR-2009
Storage Conditions: At room temperature (range of 20 ± 5 °C, provided by RCC), light protected.

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Animals: Young Adult New Zealand White Rabbit, SPF
Rationale: Recognized by international guidelines as a recommended test system.
Breeder: Harlan Netherlands BV, Kreuzelweg 53, NL-5961 NM, Horst! The Netherlands, Postbus 6174, NL-5960 AD Horst / The Netherlands
Number of Animals per Test: 3 (Animals of both sexes were used)
Age when Treated: 13 weeks (male), 13 weeks (females)
Identification: By unique cage number and corresponding ear number.
Acclimatization: Under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.
Allocation: Male No. 70 Female Nos. 71, 72
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room
temperature 17-23 °C and for
relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Accomodation: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd, Ftillinsdorf) and haysticks 4642 (batch no. 36/07, Provimi Kliba AG) were provided for gnawing.
Diet: Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 61/07) provided by Provimi Kliba AG, CH-4303 Kaiseraugst.
Water: Community tap water from Fiillinsdorf ad libitum.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 g (per animal) of CP-902684 was weighed and applied undiluted as it was delivered by the Sponsor.
Duration of treatment / exposure:
On the day of treatment, 0.1g of CP-902684 was placed in the conjunctival sac of the left eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of test item. The right eye remained untreated and served as the reference control. The treated eyes were not rinsed after instillation.
Observation period (in vivo):
Up to 7 days- The eyes of each animal were examined approximately 1, 24, 48, 72 hours, as well as 7 days after administration.
Number of animals or in vitro replicates:
3 (2f/1m)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing was done

SCORING SYSTEM: The eye reactions were assessed according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004

TOOL USED TO ASSESS SCORE: Eye examinations were made with a Varta Cliptrix diagnostic-lamp

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
Mean value over 24/48/72h
Time point:
24/48/72 h
Score:
0.33
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
Mean value over 24/48/72h
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
Mean value over 24/48/72h
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
Mean value over 24/48/72h
Time point:
24/48/72 h
Score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
Mean value over 24/48/72h
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
Mean value over 24/48/72h
Time point:
24/48/72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal: Animal 1, Animal 2, Animal 3
Remarks:
Mean value over 23, 48 and 72 hrs
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
other: Redness
Basis:
animal #1
Remarks:
Mean value over 24, 48 and 72 hours
Time point:
24/48/72 h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
other: Redness
Basis:
animal #2
Remarks:
Mean value over 24, 48 and 72 hours
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
other: Redness
Basis:
animal #3
Remarks:
Mean value over 24, 48 and 72 hours
Time point:
24/48/72 h
Score:
0.33
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
IrritationP: The mean score was calculated across 3 scoring times (24, 48 and 72 hours after instillation) for each animal for corneal opacity, iris, redness and chemosis of the conjunctivae, separately. The individual mean scores for corneal opacity were 0.33, 0.00 and 0.00, respectively and for the iris 0.00 in each animal. The individual mean scores for the conjunctivae were 1.33, 0.00 and 0.33 for reddening and 1.00, 0.00 and 0.00 for chemosis, respectively. A very slight opacity affecting the whole area was noted in the male 24 hours after instillation. No abnormal findings were observed in the cornea or iris of both females at any of the measurement intervals. A slight to moderate reddening of the conjunctivae was noted in all animals 1 hour after instillation and persisted decreasing to slight up to the 24-hour observation in one female or the 72- hour reading in the male. A slight to obvious swelling (chemosis) of the conjunctivae with partial eversion of the lids was observed in the three animals at the 1-hour observation time point and persisted as slight swelling up to the 48- hour observation in the male. Additionally, a slight to moderate reddening of the sclerae was recorded in all animals at the 1-hour evaluation and persisted as slight up to the 72 hours. Futhermore, slight ocular discharge was noted 1 hour after instillation in all animals and persisted up to the 24-hour reading in the male. No abnormal findings were observed in
the treated eye of any animal 7 days after treatment, the end of the observation period for all animals.

Corrosion: No corrosion of the cornea was observed at any of the reading times.
Other effects:
Viability/Mortality/Clinical Signs: No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.

Necropsy: No necropsy was performed on the animals sacrificed at termination of observation.

Any other information on results incl. tables

Please see "Results Tables- Appendix A" attached for detailed results tables.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based upon the referred classification (Commission Directive 2001/591EC of August 06, 2001), CP-902684 is considered to be "not irritating" to the rabbit eye.
Executive summary:

The primary eye irritation potential of CP-902684 was investigated according to OECD test guideline no. 405. The test item was applied by instillation of 0.1 g

into the left eye of each of three young adult New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours, as well as 7 days after test item instillation. The mean score was calculated across 3 scoring times (24, 48 and 72 hours after instillation) for each animal for corneal opacity, iris, redness and chemosis of the conjunctivae, separately. The individual mean scores for corneal opacity were 0.33, 0.00 and 0.00, respectively and for the iris 0.00 in each animal. The individual mean scores for the conjunctivae were 1.33, 0.00 and 0.33 for reddening and 1.00, 0.00 and 0.00 for chemosis, respectively. The instillation of CP-902684 into the eye resulted in mild to moderate, early-onset and transient ocular changes, such as corneal opacity, reddening of the conjunctivae and sclerae, discharge and chemosis. These effects were reversible and were no longer evident 24 hours, 48 hours or seven days after treatment. No corrosion was observed at any of the measuring intervals. No staining of the treated eyes by the test item was observed and no clinical signs were observed. Thus, the test item did not induce significant or irreversible damage to the rabbit eye. Based upon the referred classification criteria (Commission Directive 2001/59/EC of August 06, 2001), CP-902684 is considered to be "not irritating" to the rabbiteye.