1H-Indole-6-carboxylic acid, 1-(2-chloroacetyl)-2,3-dihydro-2-oxo-, methyl ester

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 January - 4 February 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study (OECD 404) and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

PD 282 XX

IUPAC Name:

PD 282 XX

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): PD 282 XX
- Molecular weight (if other than submission substance): 267.67
- Physical state: rust-coloured crystals
- Analytical purity: 99.6 % (HPLC)
- Purity test date: 12 january 2006
- Lot/batch No.: V12SRE00325
- Expiration date of the lot/batch: stability confirmed until november 2006
- 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: Biological Laboratory Service of Boehringer Ingelheim Pharma GmbH & Co. KG
- Age at study initiation: approximately 6 - 8 months
- Weight at study initiation: 3.8 – 4.2 kg (day of application)
- Housing: individually in solid wire cages
- Diet (e.g. ad libitum): Dry food (Kliba No. 3413.0.25, Provimi Kliba SA, CH-4303 Kaiseraugst, Switzerland), ad libitum
- Water (e.g. ad libitum): municipal drinking water were supplied ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +-2°C
- Humidity (%): 45 - 75 %
- Air changes (per hr): approx. 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:

water

Controls:

yes, concurrent no treatment

Amount / concentration applied:

ca. 500 mg per animal

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48 and 72 hrs after exposure

Number of animals:

3 female rabbits

Details on study design:

TEST SITE
- Area of exposure: 6 cm², dorsal skin of the rabbit
- Type of wrap if used: muslin tissue, non-skin-irritating plaster

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal: #1 and #2

Time point:

other: 1, 24, 48, 72 hours

Score:

0

Max. score:

0

Results 2

Irritation parameter:

edema score

Basis:

animal: #1 and #2

Time point:

other: 1, 24, 48, 72 hours

Score:

0

Max. score:

0

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 24, 48, 72 hours

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 h post application

Results 4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 1, 24, 48, 72 hours

Score:

0

Max. score:

0

Any other information on results incl. tables

PD 282 XX had no irritating or corrosive effect on rabbit skin subsequent to dermal application. The slight erythema observed 24 h after a 4 h exposure in one animal was reversible until 48 h post application.

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test item is non-irritating to skin according to EU classification.

Executive summary:

The test item PD 282 XX is an intermediate in the chemical synthesis of BIBF 1120 ES, a

VEGFR-2 inhibitor intended for the treatment of cancer.

Based on current German law (Chemikaliengesetz [Chemicals Act], 20 June 2002, and

Gefahrstoffverordnung [Ordinance on Dangerous Substances], 23 December 2004), this

study was designed to evaluate the dermal tolerance of PD 282 XX subsequent to topical

application in rabbits. It was performed according to OECD Guideline 404 (Acute Dermal

Irritation/Corrosion, adopted 24 April 2002) and in accordance with the principles of Good

Laboratory Practice, as described by the respective OECD Guidelines and current German

law (Chemikaliengesetz).

A total of three female New Zealand White rabbits were exposed dermally to a paste of

approximately 0.5 g test item mixed with demineralized water. One female was treated at

three different sites for 3 min, 1 h, and 4 h, respectively, whereas the remaining two

females were exposed for 4 h on one site only. Skin reactions were recorded 1 h, as well as

24 h, 48 h, and 72 h following the end of exposure and graded. Further investigations

included recording of clinical signs and body weight.

Under the conditions of the present study, PD 282 XX was well tolerated subsequent to

topical application on rabbit skin. Slight erythema was observed in one out of three

females only, 24 h after a 4 h exposure of the test item PD 282 XX. This effect, however,

was reversible within 48 h post application. 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 PD 282 XX is not classified.