1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-, methyl ester, (3Z)-

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 - 19 August 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in GLP compliance and according to an OECD guideline (see below).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate

EC Number:

922-049-5

Cas Number:

656247-17-5

Molecular formula:

C31H33N5O4

IUPAC Name:

methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): BIBF 1120 BS
- Physical state:solid
- Analytical purity: 100%
- Purity test date: 18 July 2006
- Lot/batch No.: V12EUN00033
- Expiration date of the lot/batch: guaranteed until February 2007
- Storage condition of test material: at room temperature, protected from light

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, D-97633 Sulzfeld
- Age at study initiation: approximately 4 months
- Weight at study initiation: 3.6 kg – 3.9 kg
- Housing: Rabbits were housed individually in solid wire cages. The bottoms of the cages were changed at least once a week and cleaned.
- Diet (e.g. ad libitum): Dry food (Kliba No. 3413.0.25, Provimi Kliba SA, CH-4303 Kaiseraugst, Switzerland) and
municipal drinking water were supplied ad libitum
- Acclimation period: 5 - 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 2°C
- Humidity (%): 45 % – 75 %
- Air changes (per hr): approximately 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12 h, with lights on from 6:00 h to 18:00 h

Test system

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: demineralized water

Controls:

no

Amount / concentration applied:

TEST MATERIAL / VEHICLE
On each day of application, the necessary amount of the test item was mixed with the
smallest amount of demineralized water as vehicle to achieve a paste. Approximately 0.5 g of
this test item mixture was applied per skin site.

Duration of treatment / exposure:

3 min (area 1)
1 h (area 2)
4 h (area 3)

Observation period:

Treated skin sites were examined immediately after the end of exposure, as well as 1 h, 24 h,
48 h, and 72 h thereafter

Number of animals:

3 (female)

Details on study design:

On the day before application of the test item, the dorsal skin of the rabbit was shaved with an electric razor and the respective skin area was carefully washed with hand-warm water. The area to be treated (about 6 cm2) was marked with water-proof color. On the animal with multiple application sites, individual skin areas were clearly identified.

The shaved and marked skin areas were treated with the test item and occluded by muslin tissue and fixed by a non-skin-irritating plaster.

At the end of the indicated exposure times, the respective skin area was washed with demineralized water to remove the test item.

According to the test strategy described in OECD Guideline 404, only one animal was treated initially (Group 1, initial test). Sequentially, the test item was applied to three skin sites for 3 min (area 1), 1 h (area 2), and 4 h (area 3), respectively. Application to the next skin area was only performed in the absence of serious skin alterations in the previous one. When no serious skin alterations occurred subsequent to 4 h of exposure on the first rabbit, the test item was applied to two more animals (Group 2, confirmatory test) on the following day for 4 h at a single site only.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 2

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 5

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 6

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Any other information on results incl. tables

BIBF 1120 BS had no irritating or corrosive effect on rabbit skin subsequent to dermal application.

No alterations of the rabbits' general appearance were observed subsequent to local application of the test item. In addition, no skin reaction beyond the area of exposure was observed and application of BIBF 1120 BS did not result in any effect on body weight development.

Applicant's summary and conclusion

Interpretation of results:

other: not classified acc. CLP

Conclusions:

Under the conditions of the present study, BIBF 1120 BS was well tolerated subsequent to topical application on rabbit skin. There were no macroscopic signs of irritation or corrosion. In addition, there were no signs of systemic side effects or of skin alterations beyond the area of exposure.
Thus, according to the Globally Harmonized Hazard Classification and Labeling Scheme (GHS), the test item BIBF 1120 BS is not classified.