Registration Dossier

Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
other information
Study period:
November 19 to 27, 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well documented and reported study, conducted according to internationally accepted technical guideline in recognized industrial research organization. A quality assurance inspection report with reference to GLP, but not a GLP compliance statement, was included in the study report.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" 1959, FOOD AND DRUG ADMINISTRATION, Association of Food and Drug Officials, U.S.A., Austin, Texas, 107 pp.
Deviations:
not specified
Principles of method if other than guideline:
Eye irritation was tested in 3 male and 3 female rabbits by topical administration of 10 mg unchanged test material onto the cornea of the left eye. In 3 of these rabbits both eyes were rinsed with physiological saline, approximately one minute after dosing. Eyes were examined for ocular lesions: prior to dosing and 1 and 6 hours as well as 1, 2, 3, 6 and 8 days after dosing.
GLP compliance:
no
Remarks:
but Quality Assurance statement with reference to IKS GLP guidance document was included in the report

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): PBS 2354.0 (Iminodi-benzyl)
- Description: dark yellow flakes
- Expiration date of the lot/batch: December 1986
- Storage conditions: room temperature
Analyzed by Pharmaceuticals Production: Test Article Data Sheet of September 30, 1985

Test animals / tissue source

Species:
rabbit
Strain:
other: rabbit, Chbb:HM (SPF)
Details on test animals or tissues and environmental conditions:
- Animal supplier: Thomae, FRG
- Age: 5 - 7 months.
- Number and Sex: 3 males and 3 females
- Weight on day of treatment (before application): Minimum 1.83 kg, maximum 2.24 kg.
- Housing: Individual housing in metal cages.
- Diet (ad libitum): Commercially available pelleted standard diet (NAFAG No. 814, batch 83/85, analysed by the
manufacturer, NAFAG, Gossau, Switzerland).
- Water (ad libitum): Tap water. (Periodically analysed for compliance with Swiss drinking water specifications) - Acclimation period: Approximately 4 weeks under laboratory conditions.


ENVIRONMENTAL CONDITIONS

Air conditioned room:
- Temperature (°C): 18 ± 2°C
- Relative Humidity (%): 60 ± 10%
- Photoperiod: 14 hrs light/day

Test system

Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
Single topical administration of 10 mg of unchanged test material onto the cornea of the left eye of 3 male and 3 female rabbits.


Duration of treatment / exposure:
In 3 of the 6 treated rabbits approximately 1 minute, as in these 3 animals both eyes were rinsed with physiological saline, approximately 1 minute after dosing. Eyes of the other three treated rabbits were not rinsed. Consequently, their treatment/exposure period was equivalent to the entire observation period following administration, which was 8 days, or lasted until removal of the test material by physiological mechanisms, whichever happened sooner.

Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
6 rabbits (3 males and 3 females)
Details on study design:
Control animals were not required, as only one eye/animal was treated the other eye serving as a control. In three of the six treated animals both eyes were rinsed with physiological saline, approximately one minute after dosing.

Eyes were evaluated for ocular lesions [corneal opacity (degree of severity and area of cornea involved), iridic effects and effects on the conjunctiva (degree of redness, degree of chemosis and degree of discharge)] prior to dosing and 1 and 6 hours as well as 1, 2, 3, 6 and 8 days afterwards in all animals. Grading and numerical evaluation of ocular lesions are outlined in Tables 1 and 2.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
4
Reversibility:
other: Corneal opacity was not evident
Remarks on result:
other: eyes not rinsed after dosing
Irritation parameter:
iris score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
2
Reversibility:
other: Iridal changes were not evident
Remarks on result:
other: eyes not rinsed after dosing
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0.22
Max. score:
3
Reversibility:
fully reversible within: 2 days
Remarks on result:
other: eyes not rinsed after dosing
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 6 hours
Remarks on result:
other: eyes not rinsed after dosing
Irritation parameter:
other: discharge score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 2 days
Remarks on result:
other: eyes not rinsed after dosing
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
4
Reversibility:
other: Corneal opacity was not evident
Remarks on result:
other: eyes rinsed ca. 1 minute after dosing
Irritation parameter:
iris score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
2
Reversibility:
other: Iridal changes were not evident
Remarks on result:
other: eyes rinsed ca. 1 minute after dosing
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0.22
Max. score:
3
Reversibility:
fully reversible within: 2 days
Remarks on result:
other: eyes rinsed ca. 1 minute after dosing
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
4
Reversibility:
other: Chemosis was not evident
Remarks on result:
other: eyes rinsed ca. 1 minute after dosing
Irritation parameter:
other: discharge score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 1, 2, 3 day(s)
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 1 day
Remarks on result:
other: eyes rinsed ca. 1 minute after dosing
Irritant / corrosive response data:
Rinsed and unrinsed control eyes were unaffected in all animals. In addition, ocular lesions in any eyes prior to dosing were not reported. Corneal and iridic lesions were not evident throughout the study. Conjunctival redness up to grade 1 or 2 was seen in all treated eyes (rinsed and unrinsed) at 1 and/or 6 hours post dosing. By 1 day post dosing, this finding had completely disappeared in 2 animals (1 unrinsed and 1 rinsed) and was only grade 1 in the other four animals (2 rinsed and 2 unrinsed). Only one incidence of chemosis (which was grade 1 in one treated unrinsed eye at 1 hour post dosing) was seen in the present study. Discharge grade 1 or 2 was seen in two treated unrinsed eyes at 1 hour post dosing and was followed by grade 1 in all treated unrinsed eyes at 6 hours and 1 day post dosing. In treated rinsed eyes, only one incidence of discharge (grade 1 at 6 hours post dosing) was evident having fully reversed by 1 day post dosing in the affected animal. As from two days post dosing until termination of the study, 8 days post dosing, all animals were entirely free from ocular lesions.
Other effects:
There was no mortality. Signs of toxicity or relevant changes in body weight were not evident.

Applicant's summary and conclusion

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
PBS 2354.0 had only minimal irritation effects on the eye, when administered topically onto the cornea at a single dose of 10 mg. The irritation results attained do not necessitate any labelling regarding eye irritation according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008], provided the reduced dose of only 10 mg test material administered topically onto the cornea (instead of administering 100 mg of test material into the conjunctival sac) is acceptable.
Executive summary:

PBS 2354.0 (Iminodi-benzyl) was tested for eye irritation based on “Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics", 1959, FDA, Association of Food and Drug Officials, U.S.A., Austin, Texas, 107 pp.”

 

Reliability grade 1 was assigned to the study. It was not conducted in compliance with GLP, but a Quality Assurance statement with reference to an IKS GLP guidance document* was included in the study report.

 

Eye irritation was tested in 3 male and 3 female rabbits by topical administration of 10 mg unchanged test material onto the cornea of the left eye. In 3 of these rabbits, both eyes were rinsed with physiological saline approximately one minute after dosing. Eyes were examined for ocular lesions: prior to dosing and 1 and 6 hours as well as 1, 2, 3, 6 and 8 days after dosing.

 

There was no mortality. Signs of toxicity or relevant changes in body weight were not evident.

 

Corneal and iridic lesions were not evident throughout the study. Conjunctival redness up to grade 1 or 2 was seen in all treated eyes (rinsed and unrinsed) at 1 and/or 6 hours post dosing. By 1 day post dosing, this finding had completely disappeared in 2 animals (1 unrinsed and 1 rinsed) and was only grade 1 in the other four animals (2 rinsed and 2 unrinsed). Chemosis was seen only once (grade 1 in one treated unrinsed eye at 1 hour post dosing). In addition, discharge, usually grade 1, in one incidence grade 2, was seen in treated unrinsed eyes at 1 and 6 hours and 1 day post dosing. In a treated rinsed eye there was only one incidence of discharge (Grade 1 at 6 hours post dosing in one animal). As from two days post dosing until termination of the study, all animals were entirely free from ocular lesions.

 

Based on FDA classification the author of the study report concluded that a single dose of 10 mg PBS 2354.0 administered topically onto the rabbit cornea caused minimal irritation. The primary eye irritation indices (derived from weighted ocular lesions at 6 hours, 1 day and 3 days post dosing) in treated unrinsed and treated rinsed eyes were 2.7 and 1.5, respectively, indicating a slight improvement induced by the rinsing with physiological saline. Rinsed and unrinsed control eyes remained unaffected.

 

The minor incidence and degree of eye irritation induced by PBS 2354.0 does not necessitate any labelling regarding eye irritation according to EU classification rules (DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008), provided the reduced dose of only 10 mg test material administered topically onto the cornea (instead of administering 100 mg of test material into the conjunctival sac) is acceptable.

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* "Wegleitung der IKS betreffend gute Laboratoriumspraxis für nichtklinische Laborversuche, Unterabschnitt B.4.a.v."