STI571 F8

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Test material form:

solid: particulate/powder

Details on test material:

Batch number: 022401

Specific details on test material used for the study:

Appearance: white powder
Storage: Ambient temperature, in the dark.
pH pH = 5.80 (1% solution in deionised water, w/v, determined with a pH-Meter WTW pH 340).
The sequence of dosing of the test substance was:

• Step 1: 300 mg per kg body weight.

• Step 2: 300 mg per kg body weight.

• Step 3: 2000 mg per kg body weight.

The test substance was suspended in deionised water.
The suspensions were prepared freshly before administrati :m and were administered within 20 minutes after the preparation.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Hygiene: Optimal hygienic conditions
Room temperature: Average of 22.1 °C (contim ous control and recording).
Relative humidity: Average of 47.3 % (continu)US control and recording).
Air exchange: 12 per hour.
Light: Artificial light from 6 a.m. to 6 p.m.
Cages: Single caging in Makrolon c ages type Ill (39 cm x 23 cm bottom area, 18 cm height). Wire mesh lids. Sanitation of cages once a week.
Bedding material: Aspen wood chips (Fa. ABE:DD Dominik Mayr KEG, A-8580 Koflach}, autoclaved. The bedding material was changed weekly.
Environmental enrichment: Nibbling wood bricks (10 en, x 2 cm x 2 cm) and nesting material (Finn Tapvei Oy, SF-73620 Kortteinen), were offered to the animals once a week.
Feed: Altromin 1324 forte, gamma irradiated with 25 kGy 60Co, ad libitum (Producer: Altromin GmbH, 0-32791 Lage).
Exception: The feed was withdrawn the evening before the administration of the test substance and was offered again about three hours afterwards. Random samples of the fee d are analysed for contaminants by Altromin.
Age: Approximately 8 weeks at the time of the administration.

Water: Tap water from an automat c watering system, ad libitum.
Identification: Labelling with felt-tipped pen on the tail and on the cage.
Acckumatisation: at least 5 days.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Deionised water (suspension).

Details on oral exposure:

A peroral administration was performed once in the morning by stomach intubation using a metal gavage.
The dose volume was 10 ml per kg body weight. The individual dose volumes were calculated using the body weights determined on the day af the administration.As no prior information on the toxicity of the test substance was available, a starting dose of 300 mg of the test substance per kg body weight was chosen.

Doses:

The sequence of dosing of the test substance was:

• Step 1: 300 mg per kg body weight.

• Step 2: 300 mg per kg body weight.

• Step 3: 2000 mg per kg body weight.

No. of animals per sex per dose:

No. Step Animal Dose (mg/kg b.w.)
3 1 141, 142, 143 300
3 2 146, 147, 148 300
3 3 151, 152, 153 2000

Control animals:

no

Details on study design:

Observations were performed within the periods 0 - 0.5, 0.5 - 1, 1 - 2, 2 - 4 and 4 - 6 hours after administration (p.a.) of the test substance and then at least once a day for a total of 2 weeks. Observations included but were not limited to changes in skin, fur, eyes, the occurrence of secretions and excretions, autonomic activity, changes in gait, posture and the presence of convulsions.

Body weights were determined
• before administration.
• 7 days p.a.
• 14 days p.a.

Body weight gain was calculated for each week of the study, i.e. between
• 0 and 7 days p.a.
• 7 and 14 days p.a

Deceased animals were dissected and examined macroscopically in an attempt to identify the target organs.
Surviving animals were killed by inhalation of 80 % CO2+ 2O % air 14 days p.a. and subjected to a necropsy including a gross pathological examination.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 300 - < 500 mg/kg bw

Based on:

test mat.

Mortality:

Female: 300 mg/kg bw; Number of animals: 6; Number of deaths: 1
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 3

Clinical signs:

other: Signs of toxicity related to dose levels: Mortality: between 5 min and 30 min p.a. Body weight: There were indications of a reduced body weight gain of the surviving rats in the second week. Clinical observations: 300 mg/kg bw: clonic convulsion

Gross pathology:

Effects on organs:
Maximally filled urinary bladder in one animal at 300 mg/kg.


Systolic heart arrest (2000 mg/kg).

Any other information on results incl. tables

Dose (mg/kg)	Step No.	Animal Nos.	Number of animals
			exposed	affected	deceased
300	1	141, 142, 143	3	3	1
300	2	146, 147, 148	3	1	0
2000	3	151, 152, 153	3	3	3

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In a single dose toxicity study in rats, animals were orally administered 300 and 2000 mg/kg of STI571 F8 suspended in deionised water. The test substance caused mainly nervous effects, which were also the cause of death. LD50 for STI571 F8 is estimated to be between 300 and 500 mg/kg body weight in rats.