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

Endpoint summary

Description of key information

One acute oral toxicity study and two dermal toxicity studies completed.  All studies indicate substance is not classified with LD 50 > 2000 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 18, 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterize

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Principles of method if other than guideline:

A representative sample of the process intermediate CP-89,575 was evaluated in rats for potential toxicity following oral exposure . The test conditions used to assess toxicity following oral administration were designed to incorporate those described by the United States Department of Transportation (DOT) under CFR Title 49, Section 173.343. These studies were also compatible with classification of the compound by the EEC according to the guidelines presented in the Official Journal of the European Communities (No. C33/18; dated 2/13/90).

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

other: Albino Rat (Cr1:CD BR,VAF/Plus™)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 8 weeks
- Weight at study initiation: 222.7 - 230.3 g
- Fasting period before study: Overnight fast
- housed 2 or 3/cage,

Route of administration:

oral: gavage

Vehicle:

other: deionized water containing a small amount of Tween 80 (-3 drops/10 ml).

Details on oral exposure:

Following an overnight fast, all rats were given a single oral (gavage) dose of a 100 mg/ml suspension (pH = 4.80) of the compound. The vehicle was deionized water containing a small amount of Tween 80 (-3 drops/10 ml).

Doses:

dose level, 2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

The animals were observed for clinical signs of toxicity for 2 days after dosing and were weighed daily. Each animal was individually marked on the dorsal surface with an innocuous colored dye to facilitate identification. The rats were housed 2 or 3/cage, and the cages were identified with a label containing all pertinent study information. The animals were dosed on 9/16/92 (day 1) and euthanized by carbon dioxide inhalation on 9/18/92 (day 3). All rats were then necropsied
and examined for gross tissue and organ changes. Doses were calculated on a weight basis (i.e., mg compound as supplied/kg); the purity (activity) of the compound (95.6%) was not taken into consideration for dose calculations. The actual concentration and stability of the test suspension used to dose the animals were not determined.

Preliminary study:

N/A

Sex:

male

Dose descriptor:

approximate LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

0/5 deaths

Clinical signs:

other: CLINICAL OBSERVATIONS: Throughout the test period, all rats were asymptomatic, and their overall body weight gain was essentially normal. There were a few faintly orange-tinged urine stains in the cages on the morning of day 2; thereafter, the urine appea

Gross pathology:

GROSS NECROPSY: There were no gross tissue or organ changes observed in any of the rats 2 days after dosing.


at 2000
lungs - dark red
stomachal meteroism
dried blood on the muzzle
intestinal congestion
liver pale

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CONCLUSION: No deaths were produced by an oral dose of 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via dermal route

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

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.

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.

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.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Justification for selection of acute toxicity – dermal endpoint

GLP and OECD method

Justification for classification or non-classification

One acute oral toxicity study and two dermal toxicity studies completed. All studies indicate substance is not classified with LD 50 > 2000 mg/kg