Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 29 to May 19, 1999
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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
2000

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Version / remarks:
July 1992
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
GLP compliance:
yes
Remarks:
OECD Principles of Good Laboratory Practice, Statutory Instrument No. 654, 1997, ISBN 0-11-064105-1
Test type:
fixed dose procedure

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
White powder, stored in dark at ambient temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK., Margate, Kent, England
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 175 - 232g
- Fasting period before study: overnight
- Housing: The dose range-finding animal was housed singly in a cage with dimensions 42 x 27 x 20 cm, and the main study animals were housed 5 per cage per sex with dimensions 59 x 38.5 x 20 cm
- Diet: Rat and Mouse No. 1 Maintenance Diet, supplied by Special Diets Services Limited, 1 Stepfield, Witham, Essex, CMS 3AD was available ad libitum throughout the study except for a period of food deprivation overnight prior to dosing until as soon as practicable after dosing.
- Water: Domestic mains quality water was available ad libitum throughout the study
- Acclimation period: 5 days before commencement of study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): During the study, mean environmental maximum and minimum temperatures were 22°c and 19°C
- Mean Humidity (%): 50 %
- Air changes (per hr): 15 minimum
- Photoperiod (hrs dark / hrs light):12/24

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
maize oil
Details on oral exposure:
The available toxicity data suggested that an initial dose level of 2000 mg/kg would be suitable. The main study dose level was selected based on the results from the dose range-finding study.

The test material was administered orally in a single dose by means of a gavage at a constant dose volume of 10 ml/kg.
The dose was calculated based on the weight of the animal on the day of dosing.
Doses:
dose level: 2000 mg/kg
No. of animals per sex per dose:
A preliminary dose range-finding, using one female, at 2000 mg/kg indicated that this dose level would be suitable for the main study. 5 females and 5 males were used for this main study.
Control animals:
no
Details on study design:
The dose was calculated based on the weight of the animal on the day of dosing.

Formulations were administered within approximately 1 hour of preparation and were magnetically stirred during dosing.
All the animals were checked for viability early in the morning and again as late as possible on each day until sacrifice on Day 8 (dose range-finding) or Day 15 (main study).
Statistics:
No formal statistical analysis was conducted

Results and discussion

Preliminary study:
The available toxicity data suggested that an initial dose level of 2000 mg/kg would be suitable. The main study dose level was selected based on the results from the dose range-finding study.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no premature decedents during the study
Clinical signs:
Clinical signs were noted from approximately 5 to 6 hours after dosing and on Day 2. These signs were limited to wet, stained perigenital area and soft jelly­ like faeces

Body weight:
Body weight performance was considered to have been satisfactory.

Body Weight (g) Gain

Day 1 Day 2 Day 3 Day 4 Day 8 Day 15 (Days 1-15)
Dose Level Animal
(mg/kg)/Sex
2000/male 6 222 240 249 251 269 297 75
7 232 248 256 260 281 310 78
8 229 250 253 258 278 307 78
9 230 248 256 264 283 304 74
10 222 244 245 251 264 289 67
Mean 227 246 252 257 275 301 74
±SD 5 4 5 6 8 8 5


2000/female 11 175 186 179 190 200 208 33
12 194 198 192 203 203 235 41
13 178 185 178 193 203 209 31
14 190 199 190 196 214 223 33
15 207 221 212 222 236 239 32
Mean 189 198 190 201 211 223 34
±SD 13 15 14 13 15 14 4
Gross pathology:
There were no abnormalities detected at necropsy.

Dose Level
(mg/kg) Animal/Sex Necropsy Finding Day of Death
2000 6-10male No abnormalities detected 15
11-15 female No abnormalities detected 15

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study following a single oral administration of L-744,341 to Sprague-Dawley rats, no mortality and no toxicity occurred at 2000 mg/kg
Executive summary:

There were no premature decedents or major clinical signs noted during the obsevation period.

Body weight performance was considered to be satisfactory, and there were no abnormalities detected at necropsy.

Under the conditions of the study following a single oral administration of L-744,341 to Sprague-Dawley rats, no mortality and no toxicity occurred at 2000 mg/kg