Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April to May 1984
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
This study used rat (male/female), and the dosage was 3, 10, 50, 200, 400 and 600 mg/kg bw.
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: CRL:CD (SD) BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Charles River Breeding Laboratories, Inc., Wilmington, MA 01887
- Age at study initiation:6 to 7 weeks
- Weight at study initiation:110 to 209 grams
- Fasting period before study:Rats were deprived of food overnight prior to, and 1 hour following administration.
- Housing:Metal and wire mesh suspended cages
- Diet (e.g. ad libitum):Purina Rodent Laboratory Chow No. 5001 (Checkers). Food is freely offered at all other times.
- Water (e.g. ad libitum):Tap water in individual bottles. Water is offered ad libitum throughout the study.
- Acclimation period:7 to 8 days

Administration / exposure

Route of administration:
other: oral gastric intubation
Vehicle:
other: sterile water
Doses:
Dose range testing:
Male: 100, 200, 400, 600, 800, 1000, 1740, 2950 mg/kg
Female: 100, 200, 280, 400, 600 mg/kg
No effect testing: 3, 10 and 50 mg/kg
Dose volume: 5 ml/kg
No. of animals per sex per dose:
3 females and 3 males per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing:during the first day amd at least daily thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs,gross visceral abnormalities

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 200 - < 400 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD0
Effect level:
>= 200 - < 280 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
approximate LD50
Effect level:
672.7 mg/kg bw
Based on:
test mat.
95% CL:
>= 327.8 - <= 1 058.8
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
336.4 mg/kg bw
Based on:
test mat.
95% CL:
>= 179.6 - <= 789.2
Mortality:
All deaths occurred from 8 minutes to approximately 4 hours after dosing. Immediate antemortem observations included tonic convulsions, a loss of righting reflex and dyspnea with subsequent respiratory arrest.
Clinical signs:
Mydriasis, salivation and evidence of a combination of central nervous system depression, motor incoordination (decreased motor activity, bradypnea, ataxia, tremors), and CNS excitation (tonic convulsions, straub tail). Effects began within 1 minute after dosing and abated in those animals that
survived within approximately 48 hours.
Gross pathology:
From gross visceral examinations, rats that died after doses of 280, 400, 600, 800, 1000, 1740 and 2950 mg/kg: heart activity was present and there were no remarkable abnormalities found.
Rats that were sacrificed 7 days after doses of 3, 10, 50, 100, 200, 280, 400, 600, 800 and 1000 mg/kg: There were no remarkable abnormalities
found.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information
Conclusions:
No-Effect dose: 50 mg/kg (male and female)
Lowest dose administered at which death occurred: Male-400 mg/kg; Female-280 mg/kg.
Highest dose administered which was non-lethal: 200 mg/kg (male and female)
Approximate Median Lenthal Doses (95% confidence limits):
Male: 672.7 (327.8-1058.8) mg/kg; Female: 336.4 (179.6-789.2) mg/kg
These results suggest a possible sex-related difference in the lethality of WY-45,030 HCl, with females having greater sensitivity than males.
Executive summary:

An acute oral toxicity study of WY-45,030 HCl showed approx.LD50 to be 672.7 and 336.4 mg/kg for males and females, respectively. And females had greater sensitivity than males.