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Acute Toxicity: oral

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acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
The study was conducted according to guideline in effect at time of study conduct.
GLP compliance:
Test type:
fixed dose procedure
Limit test:

Test material

Constituent 1
Details on test material:
- Purity: 99.8%

Test animals

other: Sprague-Dawley Crl:OFA(SD)
Details on test animals or test system and environmental conditions:
- Age at study initiation: 6 or 7 weeks
- Weight at study initiation: 132-186 g
- Fasting period before study: Animals were fasted for at least 16 hours before dosing. Food was given 3 to 4 hours after dosing.
- Housing: Animals were housed individually (during up and down procedure) or in groups of 4 or 5 (during acclimatisation period or main study) of the same sex in polycarbonate cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

- Temperature (°C): 22 ± 2 °C
- Humidity (%): ≥ 40 %
- Air Changes (per hr):minimum 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
other: sterile water
100, 75, 50, 25 mg/kg
No. of animals per sex per dose:
1, 2, 1, and 5 at 100, 75 , 50, and 25 mg/kg, respectively
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Morbidity/mortality checks and clinical observations were performed approximately 30 minutes, 1, 2, 4 and 6 hours after administration of the test substance, then twice daily during the observation period. Additional observations were performed in some animals on day 0.
- Frequency of weighing: Individual body weights were recorded on day 0 before treatment, then on days 2, 7 and 14.
- Necropsy of survivors performed: Yes; Animals found dead during the study were necropsied. All surviving animals were sacrificed and necropsied after the final observation (day 14).
No statistical analyses were performed. Body weight data were compared with historical control data concurrently available at the testing facility.

Results and discussion

Preliminary study:
The study was conducted according to an up and down procedure in order to determine the Maximum Tolerated Dose (MTD) then a main study was performed with 5 females. The starting dose level was 100 mg/kg, as chosen by the Study Sponsor. The first female initially received the test item at the starting dose level of 100 mg/kg and died 90 minutes after dosing. Based on the clinical observations of the first female (severe clinical signs and death), a second female received a lower dose level of 75 mg/kg. As no death occured, a third female received the same dose level (75 mg/kg) to confirm the toxicity observed. As mortality was noted at 75 mg/kg in 1/2 females, a fourth female was treated at the dose level of 50 mg/kg. As severe clinial signs were observed in the female treated at 50 mg/kg, an additional female was treated at the dose level of 25 mg/kg. No relevant clinical signs were observed, therefore the up and down procedure was considered ended and 4 additionnal females received the same dose level.
Effect levels
Dose descriptor:
other: minimum lethal dose
Effect level:
75 mg/kg bw
One animal died at 100 mg/kg within 90 minutes and one animal died at 75 mg/kg 2 hours and 45 minutes after treatment.
Clinical signs:
other: Treatment-related clinical signs, including marked subdued behaviour and unsteady gait, were observed in the female dosed at 100 mg/kg one hour after treatment. Orange traces in the bedding, probably due to coloured urine, were observed on day 0. The firs
Gross pathology:
No macroscopic findings were seen in animals found dead during the study or at scheduled necropsy on day 14.

Applicant's summary and conclusion

This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability). The minimum lethal dose was 75 mg/kg of body weight in female rats
Executive summary:

Under the designated experimental conditions of the study, a single administration of the test substance by the oral route to female Sprague-Dawley rats induced deaths at 100 and 75 mg/kg and severe clinical signs at 50 mg/kg. No mortality and no clinical signs were noted at 25 mg/kg, whereas orange traces in the bedding were observed, probably related to orange-coloured urine. In conclusion, the minimal lethal dose of the test substance following single oral gavage to fasted rats was 75 mg/kg, the maximal non-lethal dose was 50 mg/kg and the no observed adverse effect level (NOAEL) was 25 mg/kg.