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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from September 13, 2012 to December 03, 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

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

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

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Animals:
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 albino 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.
Number of animals: 3
Age of animals at treatment: ~11 weeks old
Sex: Male
Body weight range at the beginning of the in-life phase: 2732 – 2885 g
end of the in-life phase: 2879 – 3087 g
Acclimation time: at least 5 days
Animal identification: The animals were identified by engraved ear tags. The cages were marked with individual identity cards with information about study code, sex, cage number, dose group and individual animal number.
Husbandry
Number of animal room: 618
Lighting periods: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature range during the study: 20 ±3 °C
Relative humidity during the study: 41 – 75%
Housing/Enrichment: Rabbits were individually housed in AAALAC approved metal wire rabbit cages (64 x 68 cm with height of 45 cm). 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

Test system

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin of each animal served as a control.

Amount / concentration applied:

Dosage: The test item was used as supplied, as a single dose of 0.5 g, applied to the test area. The untreated skin of each animal served as a control.
Application of the Test Item: Patch testing was used to detect primary irritating effects of the test item. Three male animals in acceptable health condition were selected for this test.

Duration of treatment / exposure:

4 hours

Observation period:

Clinical Observations: at 1, 24, 48 and 72 hours after patch removal.
Scoring and Assessment of Local Reactions: The animals were observed for 72 hours.
Measurement of Body Weight: at the beginning and at the end of experiment.

Number of animals:

3 males

Details on study design:

Approximately 24 hours prior to the test, the hair was clipped from the back and flanks of the animals. Removal of hair was performed in two steps. The majority of hair was clipped with an electronic hair clipper and the remaining hair was moistened with water and shaved with a razor.
The test item was applied to an approximately 6 cm² area of intact skin as follows:
• A single layer of a fine medical gauze (open-weave with large holes) of approximately 5x5 cm was placed over the application area,
• The appropriate amount of test item was carefully spread over the application area (the gauze helped maintain the test item in place),
• Three more layers of gauze were placed over the test item,
• These gauze patches were kept in contact with the skin by a patch of clear plastic with a surrounding adhesive hypoallergenic plaster to ensure continued good contact between the moistened test item and the shaved skin. The entire trunks of the animals were wrapped with plastic wrap for 4 hours.
• Medical elastic tubing was placed over the plastic to keep it in place.
An initial test was performed using one animal. Three minutes and one hour after application of the test item, the application site was examined. No severe irritation or corrosive effect was found in the initial test, therefore the bandage was replaced and the exposure continued for a further 3 hours (a total 4 hours exposure). Two additional animals were then included in the study.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

8

Results 2

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 3

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

At observation one hour after patch removal, there were no observed clinical signs noted on the skin of the treated animals.
At observation 24, 48 and 72 hours after patch removal, there were no observed clinical signs noted on the skin of the treated animals.
As no clinical signs were observed at 72 hours after patch removal, the study was terminated after the 72 hours observation.
The animals’ individual mean scores (considering readings at 24, 48 and 72 hours after patch removal) for erythema were 0.00, 0.00 and 0.00 respectively.
The animals’ individual mean scores (considering readings at 24, 48 and 72 hours after patch removal) for oedema were 0.00, 0.00 and 0.00 respectively.
The Primary Irritation Index (considering readings at 24, 48 and 72 hours after patch removal) was calculated as 0.00.

Other effects:

There was no mortality observed during the study.
There was no test item related effect on body weight.
There were no test item related systemic clinical signs noted.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the results of this study, test item was not a skin irritant to rabbits.

Executive summary:

This acute skin irritation study was conducted according to OECD guideline 404 in New Zealand White rabbits. An amount of 0.5 g test item was applied to the skin of the experimental animals as a single dose. An adhesive clear plastic patch was applied. The trunk was wrapped in clear plastic with medical tubing used to hold the patch in place. After 4 hours, the remaining test item was removed with water at body temperature. To assess skin irritation, animals were examined at 1, 24, 48, and 72 hours after the patch removal. Additional general examinations were performed daily. There was no mortality during the observation period, and no test item related effect on body weight as well. At observation 1, 24, 48, 72 hours after patch removal, there were no observed clinical signs noted on the skin of the treated animals.The animals' individual mean scores for erythema and oedema were 0.00, 0.00 and 0.00 respectively. The primary irritation index was calculated as 0.00. Therefore, the test article was not considered to be a skin irritant under the experimental condition.