Tricyclo[3.3.1.13,7]decane-1-acetic acid, .alpha.-[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxy-, (.alpha.S)-

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 2004 and 03 December 2004.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted in 2004/2005 according to EU method B.5 and OECD Method # 405 and in accordance with GLP. The study material is well characterized.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

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

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid

EC Number:

700-361-0

Cas Number:

361442-00-4

Molecular formula:

C17H27NO5

IUPAC Name:

(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid

Constituent 2

Reference substance name:

1-Hydroxyadamantanyl-3-(S)-Boc-glycine

IUPAC Name:

1-Hydroxyadamantanyl-3-(S)-Boc-glycine

Details on test material:

Off-white powder; stored at room temperature; received at testing laboratory on 21-10-2004.

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

After an acclimatisation period of at least five days each animal At the start of the study the rabbits were in the weight range of 2.0 to 3.5 kgs and were twelve to twenty weeks old. Free access to mains drinking water and food was allowed throughout the study. The temperature and relative humidity were set to achieve limits of 17 to 23 C and 30 to 70% respectively. The rate of air exchange was at least 15 changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours of darkness.The animals were individually housed in suspended metal cages.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

volume of 0.1 ml of the test material, which was found to weigh approximately 51 mg

Duration of treatment / exposure:

Initially a single animal was treated. A single application of 0.1 ml of test material to the non-irrigated eye of one rabbit was performed by placing test material in the conjunctival sac of the right eye and gently pulling the lower eye lid away from the eyeball. The upper and lower eyelid were held closed for about one second after treatment to prevent loose of material and then released. The left eye was left untreated to serve as the control.

Observation period (in vivo):

Immediately after administration of the test material, an assessment of the initial pain reaction. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment.

Number of animals or in vitro replicates:

3 male rabbits.
Initially, a single rabbit was treated and after consideration of the ocular responses produced in the first treated animal, two additional animals were treated.

Details on study design:

Before treatment both eyes were checked for sign of ocular irritation or defect with the aid of a direct light source. Only animals free of ocular damage were used in the study. Initially a single animal was treated. A single application of 0.1 ml of test material to the non-irrigated eye of one rabbit was performed by placing test material in the conjunctival sac of the right eye and gently pulling the lower eye lid away from the eyeball. The upper and lower eyelid were held closed for about one second after treatment to prevent loose of material and then released. The left eye was left untreated to serve as the control.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 1,24,48, 72 hrs

Score:

10

Max. score:

12

Reversibility:

fully reversible within: 72 hrs

Results 2

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

other: 1 hr

Score:

10

Max. score:

12

Reversibility:

fully reversible within: 72 hrs

Results 3

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

other: 24 hrs

Score:

4.7

Max. score:

6

Reversibility:

fully reversible within: 72 hrs

Results 4

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

other: 48 hrs

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 72 hrs

Results 5

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

other: 72hrs

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 6

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 1, 24, 48, 72 hrs

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 7

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 1, 24, 48, 72 hours

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 8

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

149 male

Time point:

other: 1 hr

Score:

12

Max. score:

12

Reversibility:

fully reversible within: 72 hrs

Results 9

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

149 male

Time point:

other: 24 hrs

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 72 hrs

Results 10

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

149 male

Time point:

other: 48 hr

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 72 hr

Results 11

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

149 male

Time point:

other: 72 hr

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 12

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

111 male

Time point:

other: 1 hr

Score:

12

Max. score:

12

Reversibility:

fully reversible within: 72 hr

Results 13

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

111 male

Time point:

other: 24 hr

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 72 hr

Results 14

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

111 male

Time point:

other: 48 hr

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 72 hr

Results 15

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

111 male

Time point:

other: 72 hr

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 16

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

113 male

Time point:

other: 1 hr

Score:

6

Max. score:

6

Reversibility:

fully reversible within: 72 hr

Results 17

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

113 male

Time point:

other: 24 hr

Score:

6

Max. score:

6

Reversibility:

fully reversible within: 72 hr

Results 18

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

113 male

Time point:

other: 48 hr

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 72 hr

Results 19

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

113 male

Time point:

other: 72 hr

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritant / corrosive response data:

No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in two treated eyes with minimal conjunctival irritation in one treated eye one hour after treatment. Minimal conjunctival irritation was noted in all treated eyes at the 24 and 48-hour observations.
All treated eyes appeared normal at the 72-hour observation.

Other effects:

None noted

Any other information on results incl. tables

Individual and group mean scores for ocular irritation are given in Table 1and Table 2

 

Table 1	Individual Scores and Individual Total Scores for Ocular Irritation
Rabbit #andSex		149Male				111Male							113 Male
		IPR=2				IPR=2							IPR = 2
Time After Treatment		1Hour	24Hours	48Hours	72Hours	1 Hour		24Hours	48Hours		72 Hours		1Hour	24Hours	48Hours	72Hours
CORNEA
E=Degree of Opacity		0	0	0	0	0	0			0	0	0		0	0	0
F=Area of Cornea Involved		0	0	0	0	0	0			0	0	0		0	0	0
Score (ExF) x5		0	0	0	0	0	0			0	0	0		0	0	0
IRIS
D		0	0	0	0	0	0			0	0	0		0	0	0
Score(Dx 5)		0	0	0	0	0	0			0	0	0		0	0	0
CONJUNCTIVAE
A=Redness		2	1	1	0	2	1			1	0	1		1	1	0
B=Chemosis		2	0	0	0	2	0			0	0	1		1	0	0
C=Discharge		2	1	0	0	2	1			0	0	1		1	0	0
Score(A+B+C)x2		12	4	2	0	12	4			2	0	6		6	2	0
Total Score		12	4	2	0	12	4			2	0	6		6	2	0

Rabbit Number and Sex	Individual Total Scores At:
	1 Hour	24 Hours	48 Hours	72 Hours
149 Male	12	4	2	0
111 Male	12	4	2	0
113 Male	6	6	2	0
Group Total	30	14	6	0
Group Mean Score	10.0	4.7	2.0	0

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material produced a maximum group mean score of 10.0 and was classified as a mild irritant (Class 4 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.

Executive summary:

The study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit. A single application of the test material to the non-irrigated eye of three rabbits produced minimal to moderate conjunctival irritation. All treated eyes appeared normal atthe 72-hour observation.

The test material produced a maximum group mean score of 10.0 and was classified as a mild irritant (Class 4 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.