Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
4 July - 18 July 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
17 Dec 2001
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test item was stored in a cold dark place (prefabricated refrigerator, 8.6 to 11.4°C), protected from light, in a well-closed container.
- Stability of test article: stable for one year, at room temperature
- Solubility and stability of the test substance in the solvent/vehicle: The test substance was dissolved in water at 200 mg/mL just before dosing.

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Slc:Wistar [SPF]
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan SLC Inc., Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: 133 - 137 g
- Fasting period before study: animals were fasted overnight prior to administration
- Housing: individual in wire-mesh cages with an automatic water flushing breeding rack (Toyoriko). The cages were exchanged every two weeks and the feeders once a week.
- Diet: pellet diet CRF-1 (Oriental Yeast, lot No. 131108), ad libitum
- Water: tap water, ad libitum (analysis was performed)
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.7 - 23.2
- Humidity (%): 49.4 to 57.7
- Air changes (per hr): ≥ 12
- Photoperiod (hrs dark / hrs light): 12/ 12

IN-LIFE DATES: From: 4 July To: 18 July 2014

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 1.0 mL/ 100 g bw
- Lot/batch no.: K3K81(Otsuka Pharmaceutical Factory, Inc.; Japan)

MAXIMUM DOSE VOLUME APPLIED: 1.0 mL per 100 g bw

- Rationale for the selection of the starting dose:
The acute oral toxicity of the test substance was predicted to be very low and the LD50 was estimated to be > 2000 mg/kg bw (information from sponsor). Therefore, 2000 mg/kg bw, the upper limit level described in the test guideline, was set for the dose level of the sighting study.
As a result of the sighting study, no animal died. Therefore, the dose of 2000 mg/kg bw was selected as a dose of the main study.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 females (including one female in the sighting study)
Control animals:
no
Remarks:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: On Day 0, all animals were observed once within 30 minutes and once each at 1, 2, 3 and 4 hours after dosing. From the next day of dosing (from Day 1 to Day 14), the animals were observed once daily. All animals were weighed on Days 0 (before dosing), 7 and 14.
- Necropsy of survivors performed: yes
- The following organs and tissues were examined macroscopically: external surfaces, orifices, the organs and tissues in the abdominal, thoracic, pelvic and cranial cavities
Statistics:
Statistical analysis was not used.

Results and discussion

Preliminary study:
No mortality or clinical signs indicative for systemic toxicity were observed during the sighting study.
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
On Day 1, diarrhea was observed in 4 of 5 animals. From Day 2 to Day 14, no clinical signs were observed in any of the animals.
Body weight:
All animals showed normal body weight gains during the observation period.
Gross pathology:
All animals showed no abnormal gross findings in the examined organs and tissues.

Applicant's summary and conclusion

Interpretation of results:
other: not classified
Conclusions:
CLP: not classified