D-threo-Pentitol, 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[[[1-[(1S,2S)-1-ethyl-2-(phenylmethoxy)propyl]hydrazino]carbonyl]amino]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-

Eye irritation

Administrative data

Endpoint:

eye irritation, other

Remarks:

in-vivo study completed

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 December - 20 December, 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterized

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Remarks:

OECD ENV/MC/CHEM(98)17

Test material

Test material information

Constituent 1

Reference substance name:

2,5-anhydro-4-{[4-(4-{4-[({1-[(2S,3S)- 2-(benzyloxy)pentan-3-yl]hydrazino}carbonyl)amino]phenyl}piperazin1-yl)phenoxy]methyl}-1,3,4-trideoxy-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-

EC Number:

701-059-1

Cas Number:

345217-03-0

Molecular formula:

C43H50F2N8O4

IUPAC Name:

2,5-anhydro-4-{[4-(4-{4-[({1-[(2S,3S)- 2-(benzyloxy)pentan-3-yl]hydrazino}carbonyl)amino]phenyl}piperazin1-yl)phenoxy]methyl}-1,3,4-trideoxy-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-

Test material form:

other: White solid

Details on test material:

store at room temperature in the dark.

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

At the start of the study the male rabbits weighed 2.83 -3.01 kg and were 12 - 16 weeks old. Free access to mains drinking water and food (STANRAB SQC) was allowed throughout the study. The temperature and relative humidity were set to achieve limits of 17°C - 21°C and 48% - 65% respectively. The rate of air exchange was approx. 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 acclimatisation period was a minimum of 5 days and the animals were housed individually in suspended metal cages.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: other: left eye of each animal was untreated

Amount / concentration applied:

0.1ml, equivalent to approx. 39mg

Duration of treatment / exposure:

0.1ml of test material to the right eye of three rabbits 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):

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 New Zealand White female rabbits

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 from a standard ophthalmoscope. Animals showing evidence of ocular lesions were rejected and replaced.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: 24 hr

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 24 hr

Results 2

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: 48 and 72 hours

Score:

0

Results 3

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

other: 24 hr

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 24 hr

Results 4

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

other: 48 and 72 hours

Score:

0

Results 5

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

other: 24 hr

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 24 hr

Results 6

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

other: 48 and 72 hours

Score:

0

Results 7

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 8

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 9

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 10

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 11

Irritation parameter:

iris score

Basis:

animal #2

Time point:

other: 24, 48 and 72 hrs

Score:

0

Results 12

Irritation parameter:

iris score

Basis:

animal #3

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 13

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 14

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

other: 24, 48 and 72 hours

Score:

0

Results 15

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

other: 24, 48 and 72 hours

Score:

0

Irritant / corrosive response data:

No adverse corneal effects were noted during the study.
Iridial inflammation was confined to two treated eyes one hour after application. No other iridial inflammation was noted.
The test material produced a maximum Group Mean Score of 12.7 in a modified Kay and Calandra classification system.

Other effects:

A single application of the test material to the non-irrigated eye of three rabbits produced transient iridial inflammation (two treated eyes) and moderate conjunctival irritation.

Any other information on results incl. tables

The test substance produced a maximum group mean score of 12.7 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.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Mild Irritant (Class 4 on a 1 to 8 scale) Criteria used for interpretation of results: EU

Conclusions:

The test material did not produce positive criteria in any rabbit according to the EU regulations. No classification or labelling is required.

The test substance produced a maximum group mean score of 12.7 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 test substance produced a maximum group mean score of 12.7 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.

The test material did not produce positive criteria in any rabbit according to the EU labelling regulations. No symbol and risk phrase are therefore required.

No adverse corneal effects were noted during the study.

Iridial inflammation was confined to two treated eyes one hour after application. No other iridial inflammation was noted.

Moderate conjunctival irritation was noted in all treated eyes one hour after application. The conjunctival irritation regressed to minimal in all treated eyes at the 24 hr observation period and persisted in only one treated eye at the 48 hr observation. All treated eyes appeared normal 48 to 72 hours after treatment.