Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Storage: The test article was stored at room temperature and humidity.
Description: Yellow crystalline solid.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Animals were received from Ace Animals, Boyertown, PA.
- Age at study initiation: Approximately four to twelve weeks.
- Weight at study initiation: 220 - 299 grams for male and 224 - 268 grams for females.
- Fasting period before study: 16-20 hours prior to dosing.
- Housing: The animals were housed 5/sex/cage in suspended wire cages.
- Diet (e.g. ad libitum): Fresh Purina Rat Chow was freely avaiable (except during fasting period).
- Water (e.g. ad libitum): Water was freely available at all times.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The animal room was temperatue controlled.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE:
Corn oil

DOSAGE PREPARATION:
The test article was ground with a mortar and pestle. 15 g was mixed with corn oil to a total volume of 30 ml and dosed from a stir plate. The dose was based on the dry weight of the test article. A single dose was administered orally by syringe and dosing needle.

Doses:
5000 mg/kg bw and 2000 mg/kg bw
No. of animals per sex per dose:
5 per sex per dose.
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed 1, 2 and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects.
The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, on days 3 and 7, at death or at termination in the survivors.
- Necropsy of survivors performed: yes, all animals were examined for gross pathology.
Statistics:
An estimate of the LD50 was made based on the results.

Results and discussion

Preliminary study:
Not applicable.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
One male rat from the high dose group (5000 mg/kg) died on day 3 and one from the 2000 mg/kg dose group died on day 2.
Clinical signs:
5000 mg/kg: One male died on day 3 with predeath physical signs of diarrhea, chromodacryorrhea, soiling of the anogenital area, piloerection,
lethargy, flaccid muscle tone, brown staining of the nose/mouth area and wetness of the anogenital area.
Physical signs noted in survivors included diarrhea, soiling of the anogenital area, lethargy, bloated abdomen, piloerection, wetness of body areas, brown staining of the nose/mouth area and localized alopecia.

2000 mg/kg: One male died on day 2 with predeath physical signs of lethargy, dyspnea and soiling of the anogenital area.
Physical signs of diarrhea, soiling of the anogenital area, lethargy, brown staining of the nose/mouth area and wetness of the anogenital area were noted in survivors.
Body weight:
Body weight changes were normal in 7/9 surviving animals in the 5000 mg/kg group. Two males lost weight by day 3 but gained normally by day 7.
Body weight changes were normal in 8/9 survivors dosed at 2000 mg/kg. One female lost weight during the second week of the observation period.
Gross pathology:
Necropsy of the animal that died at the 5000 mg/kg level revealed abnormalities of the thymus, lungs, liver, kidneys, spleen and gastrointestinal tract, as well as soiling and wetness of the anogenital area. Necropsy results of survivors were normal in 2/9 animals dosed at 5000 mg/kg.
Localized alopecia was noted in the remaining seven animals.
All animals dosed at 2000 mg/kg appeared normal at necropsy.
No necropsy was performed on the animal that died at the 2000 mg/kg level since it was cannibalized.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 is greater than 5000 mg/kg.
Executive summary:

Objective:

To determine the potential for toxicity of the test article when administered orally to rats. This study was designed to comply with the standards set forth by:

EC Official Joumal of the European Communities. L 383 A Part B, Method B.l. Acute Oral Toxicity 12/29/92.

OECD Guidelines for Testing of Chemicals, No. 401, Acute Oral Toxicity, adopted 2/24/87.

Method:

Five healthy male and five healthy female Wistar albino rats were dosed orally with the test substance at 5000 mg/kg of body weight. Since test article related mortality occurred at this level, an additional group of five male and five females were dosed at 2000 mg/kg of body weight. The rats were observed 1,2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, on days 3 and 7, at death or at tennination in the survivors. All animals were examined for gross pathology.

Results:

5000 mg/kg: Nine of ten animals survived the 5000 mg/kg oral dose. One male died on day 3 with predeath physical signs of diarrhea, chromodacryonliea, soiling of the anogenital area, piloerection, lethargy, flaccid muscle tone, brown staining of the nose/mouth area and wetness of the anogenital area. Necropsy revealed abnonnalities of the thymus, lungs, liver, kidneys, spleen and gastrointestinal tract, as well as soiling and wetness of the anogenital area. Physical signs noted in survivors included diarrhea, soiling of the anogenital area, lethargy, bloated abdomen, piloerection, wetness of body areas, brown staining of the nose/mouth area and localized alopecia. Body weight changes were nonnal in 7/9 survivors. Two males lost weight by day 3 but gained normally by day 7. Necropsy results of survivors were normal in 2/9 animals. Localized alopecia was noted in 7/9 animals.

2000 mg/kg: Nine of ten animals survived the 2000 mg/kg oral dose. One male died on day 2 with predeath physical signs of lethargy, dyspnea and soiling of the anogenital area. A necropsy was not performed since the animal was cannibalized. Physical signs of diarrhea, soiling of the anogenital area, lethargy, brown staining of the nose/mouth area and wetness of the anogenital area were noted in survivors. Body weight changes were normal in 8/9 survivors. One female lost weight during the second week of the observation period. Necropsy results of survivors were normal.

Conclusion:

The LD50 is greater than 5000 mg/kg.