6-chloro-5-(2-chloroethyl)-1,3-dihydroindol-2-one

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 June and 9 July 1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: done under GLP and OECD method

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Test material

Test material information

Constituent 1

Reference substance name:

6-chloro-5-(2-chloroethyl)-1,3-dihydroindol-2-one

EC Number:

421-320-0

EC Name:

6-chloro-5-(2-chloroethyl)-1,3-dihydroindol-2-one

Cas Number:

118289-55-7

Molecular formula:

Hill formula: C10 H9 Cl2 N O CAS formula: C10 H9 Cl2 N O

IUPAC Name:

6-chloro-5-(2-chloroethyl)-2,3-dihydro-1H-indol-2-one

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

off-white powder

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals chosen for this study were selected from a stock supply of healthy male and female CD rats of Sprague-Dawley origin (Hsd:Sprague-Dawley (CD)) obtained from Harlan U.K. Ltd., Bicester, Oxon, England.

They were in the weight range of 237 to 250 g and approximately seven to ten weeks of age prior to dosing (Day 1). All the rats were acclimatised to the experimental environment for a minimum period of six days prior to the start of the study.

Rats were allocated without conscious bias to cages within the treatment group. They were housed individually in metal cages with wire mesh floors in Building Rl4 Room 6.

A standard laboratory rodent diet (Special Diet Services RMl(E) SQC expanded pellet) and drinking water were provided ad libitum.

Each batch of diet used for the study was analysed for certain nutrients, possible contaminants and
. .
m1cro-orgamsms.

Results of routine physical and chemical examination of drinking water, as conducted by the supplier are made available to Huntingdon Life Sciences Ltd. as quarterly summaries.

Animal room temperature was in the range 20 to 24.5°C and relative humidity was in the range 46 - 64% RH. Permanent daily recordings of these parameters were made and these are archived with other Department raw data. Air exchange was maintained at I 0 to 15 air changes per hour and lighting controlled by means of a time switch to provide 12 hours of artificial light (0700 - 1900 hours) in each 24-hour period.

Each animal was identified by cage number and ear punching. Each cage was identified by a coloured label displaying the dose level, study schedule number, animal mark and the initials of the Study Director and Home Office licensee.

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

other: 1% aqueous methyl cellulose

Details on dermal exposure:

A group often rats (five males and five females) was treated at 2000 mg/kg bodyweight.

One day prior to treatment, hair was removed from the dorso-lumbar region of each rat with electric clippers taking care to avoid damaging the skin, exposing an area equivalent to approximately I 0% of the total body surface area.

The test substance was applied by spreading it evenly over the prepared skin. The treatment area (approximately 50 mm x 50 mm) was covered with porous gauze held in place with a non irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

At the end of the 24 hours exposure period the dressings was carefully removed and the treated area of skin was washed with warm water (30° to 40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.

Control animals: No control animals were included in this study.

TEST MATERIAL

The test substance was prepared on the day of dosing. The absorption of the test substance was not determined.
The concentration, homogeneity and stability of the test substance in the vehicle was not evaluated.

VEHICLE
- Amount(s) applied (volume or weight with unit): CP-89,575 was formulated at a maximum practical concentration of 66.67% w/v in 1% w/v aqueous methylcellulose and administered at a volume of 3.0 ml/kg bodyweight.

Duration of exposure:

24 hour

Doses:

2000 mg/kg bodyweight.

No. of animals per sex per dose:

five males and five females

Control animals:

no

Details on study design:

Clinical signs
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation.

All animals were observed for 14 days after dosing. Dermal responses
Local dermal irritation at the treatment site was assessed daily using the following numerical scoring system:

The bodyweight of each rat was recorded on Days I (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.

All animals were killed on Day 15 by cervical dislocation.

All animals were subjected to a macroscopic examination which consisted of opening the abdominal and thoracic cavities. The macroscopic appearance of all tissues was recorded and macroscopic abnormalities were preserved.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths following a single dermal application of CP-89,575 to a group of ten rats (five males and five females) at a dosage of 2000 mg/kg bodyweight.

Clinical signs:

other: No systemic response was observed in any animal throughout the study.

Gross pathology:

MACROSCOPIC EXAMINATION
Macroscopic examination of animals killed on Day 15 revealed no abnormalities.

Other findings:

DERMAL RESPONSES

Very slight dermal irritation (Grade I erythema only) was seen in three females on removal of the dressings, resolving in all animals by Day 5. Localised spots/scabbing was observed in one further rat. No dermal reactions were noted in the remaining six animals.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute lethal dermal dose to rats was demonstrated to be > 2000 mg/kg bodyweight with very slight dermal irritation (Grade I erythema only) was seen in three females on removal of the dressings, resolving in all animals by Day 5. Localised spots/scabbing was observed in one further rat. No dermal reactions were noted in the remaining six animals.