(4aR*,8aR*)-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-09-11 to 2001-09-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented study performed according to OECD and EC guidelines, in compliance with GLP. No deviations noted.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

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

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

439-750-2

EC Name:

-

Cas Number:

183487-56-1

Molecular formula:

Hill formula: C17H19BrClNO3 CAS formula: C17H19BrClNO3

IUPAC Name:

(14S)-4-bromo-2-methoxy-7-methyl-17-oxa-7-azatetracyclo[12.2.1.0^{5,16}.0^{10,15}]heptadeca-1,3,5(16),10-tetraen-12-one hydrochloride

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): T002113
- Substance type: powder
- Physical state: solid
- Analytical purity: 92.9 %
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components:no data
- Isomers composition:no data
- Purity test date:no data
- Lot/batch No.: RT002113G3A231
- Expiration date of the lot/batch: 2001-12-01 (retest date)
- Stability under test conditions:no data
- Storage condition of test material: in the original container, at room temperature (range of 17-23°C), away from direct sunlight.
- Other:
- Stability of test item: stable under storage conditions

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: New Zealand White rabbits, SPF; from Elevage Scientifique des Dombes (F-01400 Chatillon sur Chalaronne/France)
- Age at start of treatment: 9-10 weeks (male), 9-11 weeks (females)
- Weight at day of treatment: 1974 g (male), 1877 - 1896 g (females)
- Housing: Standard Laboratory Conditions; individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood (RCC Ltd, Füllinsdorf) and haysticks for gnawing.
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum
- Water (e.g. ad libitum): community tap water from Füllinsdorf, ad libitum
- Acclimation period: 6 days (from 2001-09-11 to 2001-09-16), under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23°C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12, automatically controlled light cycle. Music was played during the light period.

IN-LIFE DATES: From: 2001-09-17 To: 2001-09-20

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Remarks:

bi-distilled

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 grams/animal, as delivered by the sponsor
- The test material was moistened with approximately 0.1 ml of bi-distilled water before application.
- Prior to the application the pH of the test item was determined at a concentration of 1% in water with PH-Test-Strip (E. Merck, D64271 Darmstadt, Germany) and was found to be 3-4.

VEHICLE
- Amount(s) applied (volume or weight with unit): approximately 0.1 ml
- Lot/batch no. (if required): no data
- Purity: no data

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

1 male and 2 females

Details on study design:

TEST SITE
- Area of exposure: 6 cm² of the clipped flank
- % coverage: no data
- Type of wrap if used: the gauze patch was covered with a semi-occlusive dressing, wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was flushed with lukewarm tap water to clean the application site
- Time after start of exposure: 4 hours

SCORING SYSTEM:
- The skin reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992 approximately 1, 24, 48 and 72 hours after the removal of the dressing, gauze ppatch and test item.
- If evident, corrosive or staining properties of the test item were described and recorded.
- The mean score was calculated across 3 scoring times (24, 48 and 72 hours after patch removal) for each animal for erythema/eschar grades and for oedema grades, separately. An animal is positive when the mean score is 2 or greater. The test is positive for irritation when at least 2 animals are positive for the same endpoint (erythema/eschar or oedema).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Remarks:

male 90

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 2

Irritation parameter:

edema score

Basis:

mean

Remarks:

male 90

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 3

Irritation parameter:

other: scaling

Basis:

mean

Remarks:

male 90

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 4

Irritation parameter:

erythema score

Basis:

mean

Remarks:

female 91

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 5

Irritation parameter:

edema score

Basis:

mean

Remarks:

female 91

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 6

Irritation parameter:

other: scaling

Basis:

mean

Remarks:

female 91

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 7

Irritation parameter:

erythema score

Basis:

mean

Remarks:

female 92

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 8

Irritation parameter:

edema score

Basis:

mean

Remarks:

female 92

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 9

Irritation parameter:

other: scaling

Basis:

mean

Remarks:

female 92

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

- Irritation: the test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0). The individual mean score for erythema/eschar and oedema for each of the three animals was therefore 0.
- Corrosion: no irreversible alterations of the treated skin were observed nor were corrosive effects evident on the skin.

Other effects:

- no clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred
- no staining by the test item of treated skin was observed.
- animal number 91 showed a slight body weight loss (9.6%) during the observation period. The reason for this weight loss could not be established due to the short duration of the study. The body weights of all other rabbits were considered to be within the normal range of variability.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based upon the referred classification criteria (EEC Commission Directive 93/21/EEC of April 27, 1993), T002113 is considered to be "not irritating" to rabbit skin. According to the CLP regulation, the test item should not be classified.