[2R-(2α,3Z,5α)]-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, compound with tert-butylamine (1:1)

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

7 October 1991 and 12 October 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

tBA Clavulanate

IUPAC Name:

tBA Clavulanate

Details on test material:

- Name of test material (as cited in study report): BRL 14151C
- Substance type: pure substance
- Physical state: cream powder
- Storage condition of test material: room temperature over silica gel
- Other:
Batch Number: 941/11
Date Recieved: 14 August 1991
Container: clear glass jar

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: supplied by David Percival ltd., Moston, Sandbach, Cheshire, U.k.
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.73-2.94 kg
- Housing: suspended metal cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 57-66%
- Air changes (per hr): 15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 light / 12 dark

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: left eye untreated for control purposes.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
A volume of 0.1 ml of the test material, which was found to weigh approximately 77 mg (as measured by gently compacting the required volume into an adapted syringe) was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball.

Duration of treatment / exposure:

single application, no washing

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing

SCORING SYSTEM: Assessment of occular damage/irritation was made approximately 1 hour and 24, 24 and 72 hours following treatment, according to the numerical evaluation from Draize J.H. 1959, Association of Food and Frug Officials of the United States, Austin, Texas, "The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics"

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by use of the light source from a standard opthalmoscope.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Remarks:

199 male

Basis:

mean

Time point:

other: average for 24,48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Results 2

Irritation parameter:

iris score

Remarks:

199 male

Basis:

mean

Time point:

other: average for 24, 48 and 72 hours

Score:

0.3

Max. score:

2

Reversibility:

fully reversible

Results 3

Irritation parameter:

chemosis score

Remarks:

199 male

Basis:

mean

Time point:

other: average for 24, 48 and 72 hours

Score:

1

Max. score:

4

Reversibility:

fully reversible

Results 4

Irritation parameter:

cornea opacity score

Remarks:

194 female

Basis:

mean

Time point:

other: average

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Results 5

Irritation parameter:

iris score

Remarks:

194 female

Basis:

mean

Time point:

other: average for 24, 48 and 72 hours

Score:

0

Max. score:

2

Reversibility:

other: no effects seen

Results 6

Irritation parameter:

chemosis score

Remarks:

194 female

Basis:

mean

Time point:

other: average for 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Results 7

Irritation parameter:

cornea opacity score

Remarks:

197 female

Basis:

mean

Time point:

other: average of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Results 8

Irritation parameter:

iris score

Remarks:

197 female

Basis:

mean

Time point:

other: average of 24, 48 and 72 hours

Score:

0.3

Max. score:

2

Reversibility:

fully reversible

Results 9

Irritation parameter:

chemosis score

Remarks:

197 female

Basis:

mean

Time point:

other: average of 24, 48 and 72 hours

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritant / corrosive response data:

Individual and group mean scores for ocular irritation are given in Tables 1 and 2. the Individual mean scores as required for the EEC labelling regulations are presented in Table 3.
Residual Test material was noted around the treated eyes of all anmals during the study.
No adverse corneal effects were noted during the study.
Iridial Inflamation was noted in one treated eye at the 24-hour observation. No other Adverse iridial effects were noted.
Minimal conunctival irritation was noted in all treated eyes one hour after treatment and in two treated eyes at the 24-hour observation. The reaction increased to moderate conjunctival irritation in one treated eye at the 24 hour observation with minimal conjunctival irritation ath the 48-hour observation.
All treated eyes appeared normal 72 hours after treatment.

Any other information on results incl. tables

Table 1: Individual Scores and Individual Total Scores for Occular Irritation

Rabbit Number and Sex (Bodyweight kg)	199 Male (2.76) (IPR = 3)				194 Female (2.94) (IPR = 3)				197 Female (2.73) (IPR= 2)
Time After Treatment	1hr	24hr	48hr	72hr	1hr	24hr	48hr	72hr	1hr	24hr	48hr	72hr
Cornea
E = Degree of Opacity	0	0	0	0	0	0	0	0	0	0	0	0
F = Area of Opacity	0	0	0	0	0	0	0	0	0	0	0	0
Score = (E x F) x 5	0	0	0	0	0	0	0	0	0	0	0	0
Iris
D	0	1	0	0	0	0	0	0	0	0	0	0
Score = (Dx5)	0	5	0	0	0	0	0	0	0	0	0	0
Conjunctivae
A = Redness	1	2	1	0	1	1	0	0	1	1	0	0
B = Chemosis	1	2	1	0	1	0	0	0	1	1	0	0
C = Discharge	0 Re	1	0	0	0 Re	0 Re	0 Re	0 Re	0 Re	0 Re	0	0
Score = (A+B+C)x2	4	10	4	0	4	2	0	0	4	4	0	0
Total Score	4	15	4	0	4	2	0	0	4	4	0	0
Key:  hr = hour(s)               IPR = initial pain reaction               Re = residual test material around the treated eye

Table 2 : Individual Total Scores and Group Mean Scores for Occular irritation

Rabbit Number and Sex	Individual Total Scores At:
	1 hour	24 hours	48 hours	72 hours
199 Male	4	15	4	0
194 Female	4	2	0	0
197 Female	4	4	0	0
Group Total	12	21	4	0
Group Mean Score	4	7	1.3	0

Table 3 : Individual & Mean Scores for Cornea, Iris & Conjunctivae Required for EEC labelling regulations

Rabbit Number & Sex (Bodyweight Kg)	Time After Treatment	Corneal Opacity	Iridial Inflamation	Conjunctival Redness	Conjunctival Chemosis
199 Male (2.76)	24 hours	0	1	2	2
	48 hours	0	0	1	1
	72 hours	0	0	0	0
Total		0	1	3	3
Mean		0	0.3	1	1
194 Female (2.94)	24 hours	0	0	1	0
	48 hours	0	0	0	0
	72 hours	0	0	0	0
Total		0	0	1	0
Mean		0	0	0.3	0
197 Female (2.73)	24 hours	0	0	1	1
	48 hours	0	0	0	0
	72 hours	0	0	0	0
Total		0	0	1	1
Mean		0	0.3	0.3	0.3

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material did not produce positive criteria in any rabbit according to the EEC labelling regulations and was classified as non-irritant to the rabbit eye.

Executive summary:

A single application of the test material to the non-irrigated eye of three rabbits produced transient minimal to moderate conjunctival irritation. All trreated eyes appeared normal eye at the 24 -hour observation. All treated eyes appeared normal 72 hours after treatment.

However the test material did not produce positive criteria in any rabbit according to the EEC labelling regulations and was classified as non-irritant to the rabbit eye according to the EEC labelling regulations. No symbol and risk phrase are required.