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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
4th to 22nd August 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
yes
Remarks:
an upper temperature range of 27.5°C for approx 24 hrs. This deviation was not considered to have affected the integrity or validity of the study.
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes

Test material

1
Chemical structure
Reference substance name:
4-[2-Ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzamido]-1-3-propyl-1H-pyrazole-5-carboxamide
EC Number:
639-263-7
Cas Number:
200575-15-1
Molecular formula:
C22H32N6O5S
IUPAC Name:
4-[2-Ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzamido]-1-3-propyl-1H-pyrazole-5-carboxamide
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
TEST MATERIAL
- Batch No.of test material: 92480/N/9/1
- Expiration date of the lot/batch: Not supplied
- Purity: 95%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:Room temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: UK-220,955 was prepared at a concentration of 20% w/v in 1% w/v aqueous methylcellulose and administered at
a volume of 10 ml/kg bodyweight in the main study.

The test substance was prepared on the day of dosing.

The absorption of the test substance was not determined.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan U.K. Ltd
- Age at study initiation: 4-7 weeks
- Weight at study initiation: 91 to 108 g
- Housing: housed in groups of up to five rats of the same sex in metal cages with wire mesh floors
- Fasting: access to food only was prevented overnight prior to and for approximately 4 hours after dosing.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 27.5°C
- Humidity (%): 42-65 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light (0700 - 1900 hours) in each 24-hour period.

IN-LIFE DATES: From: 0 To: 15 (All animals in the main study were killed on Day 15 by carbon dioxide asphyxiation.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: UK-220,955 was prepared at a concentration of 20% w/v in 1% w/v aqueous methylcellulose.


MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg of UK-220,955 in 1% w/v aqueous methylcellulose.

- Rationale for the selection of the starting dose: after review of the results from the preliminary study using doses of 500 and 2000 mg/kg.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5/sex/group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality
Cages of rats were checked at least twice daily for any mortalities.

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.

Bodyweight
The bodyweight of each rat in the main study was recorded on Days 1, 2, 3, 4, 8 and 15

- Necropsy of survivors performed: All animals in the main study were killed on Day 15. All animals were subjected to a macroscopic examination.

- Other examinations performed: mortality, clinical signs, body weight, macroscopic pathology

Results and discussion

Preliminary study:
One female rat was treated at 500 or 2000 mg/kg bodyweight to establish a dosing regime for the main study.
Effect levels
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
ca. 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths following a single oral dose of UK-220,955 to a group of ten rats (five males and five females) at a dosage of 2000 mg/kg bodyweight.
Clinical signs:
Pilocrection was observed in all rats within four minutes of dosing. This sign persisted and was accompanied in all rats on Day 1 by abnormal faeces (characterised by soft to liquid faeces). There were no other clinical signs and recovery, as judged by external appearance and behaviour, was complete in all animals by Day 2.
Body weight:
All rats were considered to have achieved satisfactory bodyweight gains during the study.
Gross pathology:
Macroscopic examination of animals killed on Day 15 revealed no abnormalities.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The discriminating dose to rats of UK-220,955 was demonstrated to be 2000 mg/kg bodyweight.
Executive summary:

A study was performed to assess the acute oral toxicity of UK-220,955 to the rat. The method followed was that described in EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (OJ No. L383A, 29. 12.92), Part B, Method B.1 bis. Acute toxicity (oral) -Fixed Dose Method.

A group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance, formulated in 1 % w/v aqueous methylcellulose and administered at a dose level of 2000 mg/kg bodywcight. The dose level was chosen on the basis of preliminary study investigations. All animals were killed and examined macroscopically on Day 15, the end of the observation period.

Clinical signs of reaction to treatment included piloerection and abnormal faeces, seen in all rats. There were no other signs of reaction to treatment and recovery was complete in all animals by Day 2.

All rats were considered to have achieved satisfactory bodyvveight gains during the study.

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

The discriminating dose to rats of UK-220,955 was demonstrated to be 2000 mg/kg bodyweight.

UK-220,955 will not require labelling in accordance with GHS