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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 July 1998 and 14 August 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study (OECD 401)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid
Details on test material:
Storage conditions: 40°C in the dark
Lot number: EG 605
Expiry:13 July 1999
Purity:Not advised

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan U.K. Ltd. Bicester, Oxon, England.
- Age at study initiation: 5-7 weeks old
- Weight at study initiation: 127 to 170 g
- Fasting period before study:
- Housing: in groups of up to five rats of the same sex in metal cages
- Diet (e.g. ad libitum): standard laboratory rodent diet , ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days prior to the start of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ° C
- Humidity (%): 30-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12, artificial light (0700 - 1900 hours)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Dose volume of 4.429 ml/kg bw.
The appropriate dose volume of the test substance was administered to each rat by oral gavage using a syringe and either a plastic cannula (18 g) or catheter (8 choke).
Doses:
5000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
Cages of rats were checked at least twice daily for mortalities.
Animals were observed soon after dosing and at frequent intervals for the remainder of Day l. On subsequent days animals were observed on at least two occasions during the day (once in the morning and again at the end of the experimental day, with the exception of the day of study termination - morning only). The nature and severity of clinical signs and the time these were observed were recorded at each observation.
Animals surviving treatment were observed for 7 or 14 days respectively after dosing.
The bodyweight of each rat was recorded Days 1 (prior to dosing) 8 and 15 (or at death).
All surviving animals in the main study were killed by carbon dioxide asphyxiation at study termination (Day 15).
All animals were subjected to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.


Statistics:
no

Results and discussion

Preliminary study:
In the absence of precise toxicological information, a preliminary study comprising of two rats (one male and one female) dosed at 3200 mg/kg bodyweight was conducted to help define the toxic potential of the test substance and aid in selection of a suitable dosage for the main study.
There were no deaths. Clinical signs comprised piloerection, hunched posture, increased salivation, abnormal faeces and ungroomed appearance seen in both rats with lethargy and pallid extremities seen in the female only. Bodyweight gain for both rats were considered satisfactory for a study of this nature.
There were no macroscopic abnormalities noted in either animal at the terminal necropsy on Day 8.

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 40% of mortality was observed at this dose
Mortality:
Two males and two females died (Day 2) during the study.
Clinical signs:
Piloerection was observed in all rats within two minutes of dosing. This sign persisted and was accompanied in rats later on Day 1 and/or at later intervals during the study by abnormal faeces and ungroomed appearance seen in all rats, with hunched posture, waddling/unsteady gait, lethargy, pallid extremities, increased salivation and thin appearance less commonly observed. Recovery of surviving rats, as judged by external appearance and behaviour, was complete in all animals by Day 15.
Body weight:
All surviving rats were considered to have achieved satisfactory bodyweight gains during the study.
Gross pathology:
Macroscopic examination of decedent animals revealed congestive changes (characterised by dark tissue/prominent blood vessels) in the heart, liver, spleen, stomach and along the alimentary tract. Gaseous distension and fluid contents were also noted in the stomach and along the alimentary tract. No macroscopic abnormalities were observed for surviving animals killed at study termination on Day 15.
Other findings:
no

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these experimental conditions, the acute median lethal oral dose (LD50) to rats of SR-494 was indicated to be slightly greater than 5000 mg/kg bodyweight.
Executive summary:

A group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance administered. as supplied, at a dosage of 5000 mg/kg bodyweight. Two males and two females died during the study. All remaining animais were killed as scheduled at study termination (Day 15) and subjected to a macroscopic examination.

Clinical signs of reaction to treatment characterised by piloerection, abnormal faeces and ungroomed appearance were seen in all rats, with hunched posture, waddling/unsteady gait, lethargy, pallid extremities, increased salivation and thin appearance less commonly observed. There were no other signs of reaction to treatment and recovery was complete in all surviving rats by Day 15. All surviving rats were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination of the decedents revealed congestive changes to the majority of tissues and organs with gaseous distension and fluid contents in the stomach and along the alimentary tract. No macroscopic abnormalities were observed for surviving animais killed at study termination on Day 15.

On the basis of 40% mortality at a dosage of 5000 mg/kg bodyweight, the acute median lethal oral dose (LD50) to rats of SR-494 was indicated to be slightly greater than 5000 mg/kg bodyweight.