N,N'-(methylenedi-p-phenylene)bis[hexahydro-2-oxo-1H-azepine-1-carboxamide]

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from September 20, 2012 to December 3, 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Grilbond IL-6

IUPAC Name:

Grilbond IL-6

Constituent 2

Reference substance name:

N,N'-(methylenedi-p-phenylene)bis[hexahydro-2-oxo-1H-azepine-1-carboxamide]

EC Number:

258-981-8

EC Name:

N,N'-(methylenedi-p-phenylene)bis[hexahydro-2-oxo-1H-azepine-1-carboxamide]

Cas Number:

54112-23-1

Molecular formula:

C27H32N4O4

IUPAC Name:

2-oxo-N-[4-({4-[(2-oxoazepane-1-carbonyl)amino]phenyl}methyl)phenyl]azepane-1-carboxamide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

EC no.: 258-981-8
Purity: 99%
Batch/Lot Number: 9114761/024
Production Date: 12 July 2012
Expiry Date: 11 July 2013
Molecular formula: C27H32N4O4
Chemical name: N,N’-(methylenedi-p-phenylene)bis[hexahydro-2-oxo-1H-azepine-1-carboxamide]
Storage conditions: Room temperature
Safety Precautions: Routine safety precautions (gloves, goggles, face mask, lab coat) for unknown materials were applied to assure personnel health and safety.

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Species and strain: New Zealand White rabbits
Source: S&K-LAP Kft. 2173 Kartal, Császár út 135, Hungary
Justification of strain: The New Zealand White rabbit is one of the standard strains used for acute irritation toxicity studies.
Animal health: Only animals in acceptable health condition were used for the test. Both eyes of each animal provisionally selected for testing were examined prior to starting the study. Animals showing eye irritation, ocular defects or pre-existing corneal injury were not used.
Number of animals: 3 animals
Age of animals at treatment: ~11 weeks old (adult)
Sex: Male
Body weight range at the beginning of the life phase: 2704 – 2763 g
end of the life phase: 2788 – 2852 g
Date of receipt: 19 September 2012
Acclimatization time: at least 5 days
Animal identification: The individual identification was by engraved ear tag. The cages were marked with individual identity cards with information about study code, sex, dose group, cage number and individual animal number.
HUSBANDRY
Animal health: Only healthy animals were used for the test. The veterinarian certified health status.
Number of animal room: 609
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature during the study: 20 ±3 °C
Relative humidity during the study: 44 – 80%
Housing/Enrichment: Rabbits were individually housed in AAALAC approved metal wire rabbit cages. Cages were of an open wire
structure and cages were placed together to allow some social interaction with rabbit(s) in adjoining cages
Ventilation: 15 - 20 air exchanges/hour
The environmental parameters were recorded twice daily during the study. Variations from the target relative humidity (max. 80%) were observed during the study.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: contralateral eye served as control

Amount / concentration applied:

Dosage: A single amount of 0.1 g of the solid test item Grilbond IL-6 100% was administered to each animal.
Application of the Test Item: Three male animals in acceptable health condition were selected for the test. Care was taken to select only those animals that had a normal eye condition and any with ocular lesions were rejected.
An initial test was performed using one animal. The test item was instilled into the conjunctival sac of the left eye. The eyelids were held closed for a few seconds to prevent the loss of the test item. The contra lateral eye served as the control. Immediately after the administration of the test item, an assessment of the initial pain reaction was made according to the six point scale.
After consideration of the ocular responses produced in the first animal, one hour after the treatment of the first animal, two additional animals were treated.

Duration of treatment / exposure:

1 hour

Observation period (in vivo):

Clinical Observations: The eyes were examined at 1, 24, 48 and 72 hours after treatment.
Scoring and Assessment of Local Reaction: The eye irritation scores were evaluated according to the scoring system by Draize (1977) and OECD 405 (24 April 2002).

Number of animals or in vitro replicates:

3 males

Details on study design:

The treated eye was rinsed with physiological saline solution at the 1-hour observation.
Scoring and Assessment of Local Reaction
The eye irritation scores were evaluated according to the scoring system by Draize (1977) and OECD 405 (24 April 2002).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 24-72hours

Score:

0

Max. score:

20

Reversibility:

fully reversible within: 72hours

Results 2

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Results 3

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Results 4

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Results 5

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Irritant / corrosive response data:

Initial Pain Reaction (IPR) (score 1) was observed in all animals.
One hour after the application, conjunctival redness (score 1) was seen in all animals, discharge (score 1 or 2) was observed in two rabbits and chemosis (score 1) was seen in one rabbit.
At 24, 48 and 72 hours after treatment, no signs of eye irritation or other clinical signs were observed.
As all signs of eye irritation had fully reversed the study was terminated after a period of 72 hours observation.

Other effects:

MORTALITY
There was no mortality observed during the study.
BODY WEIGHTS
The body weight and body weight change were considered to be normal with no indication of a treatment related effect.
CLINICAL OBSERVATION
General daily examination:
No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred that could be related to treatment.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results of this study, test article can not be considered to be a eye irritant.

Executive summary:

This acute eye irritation study was performed to investigate the primary eye irritation potential of test article in New Zealand White rabbits. The test item was placed into the conjunctival sac of the left eye of each animal. The untreated right eye served as control. A single amount of 0.1 g of the test item was administered as a single dose. Initial Pain Reaction (IPR) (score 1) was observed in all animals. One hour after the application, conjunctival redness (score 1) was seen in all animals, discharge (score 1 or 2) was observed in two rabbits and chemosis (score 1) was seen in one rabbit. At 24, 48 and 72 hours after treatment, no signs of eye irritation or other clinical signs were observed. As all signs of eye irritation had fully reversed the study was terminated after a period of 72 hours observation. No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred. The body weights of all rabbits were considered to be within the normal range of variability.

Therefore, test article is not considered as an irritant to rabbits' eyes under the experimental conditions.