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Acute Toxicity: oral

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acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 03 Mar to 06 Apr 2021
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
(S)-tert-butyl 5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate
EC Number:
Cas Number:
Molecular formula:
(S)-tert-butyl 5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate
Specific details on test material used for the study:
Batch/Lot number: 465884
Description: White to off-white to slightly yellow solid
Purity: 100%

Test animals

other: Crl: WI(Han)
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Ca. 9-12 weeks
- Weight at study initiation: 175-199 g
- Fasting period before study: overnight (for a maximum of 20 hours) prior to dosing
- Housing: On arrival and following assignment to the study, animals were group housed (up to
3 animals of the same sex and same dosing group together) in polycarbonate cages containing sterilized wooden fibers as bedding material equipped with water bottles.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): > 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
propylene glycol
Details on oral exposure:
A single dose of test item was administered to the appropriate animals by oral gavage on Day 1, using a syringe with a plastic gavage cannula attached.
The dose volume for each animal was based on the body weight measurement prior to dosing.
A dose volume of 10 mL/kg body weight was used for each dose.
The dosing formulations were stirred continuously during dose administration.
Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item. Water was available.
5, 50, 300 and 2000 mg/kg
No. of animals per sex per dose:
one for 55 &175 mg/kg; 2 for 550 mg/kg, 4 for 2000 mg/kg
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day.
Animals were weighed individually on Days 1 (pre-dose), 8 and 15.
- Necropsy of survivors performed: yes, All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation period. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.

Results and discussion

Effect levels
Dose descriptor:
Effect level:
783 mg/kg bw
Based on:
test mat.
95% CL:
> 550 - < 2 000
No mortality occurred.
Clinical signs:
other: hunched posture, erected fur and uncoordinated movements
Body weight:
lower than 10% body weight loss
The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. The incidence of reduced body weight gain between Days 8-15 in Animals No. 1 was considered not indicative of toxicity, based on the absence of any corroborative findings in this animal.
Gross pathology:
No test item-related abnormalities were found at macroscopic postmortem examination of the
At macroscopic postmortem examination, an abnormality of the clitoral gland (dark-tanned
foci on the right (1x1 mm)) was found in one animal at 300 mg/kg. Incidental discoloration of
the clitoral gland is more often seen in rats of this age and strain in this type of studies and
therefore no toxicological relevance was attached to these findings.
Macroscopic postmortem examination of the other animals did not reveal any abnormalities.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
The oral LD50 value of test item in Wistar Han rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Executive summary:

This study was to assess the toxicity of the test item when administered in a
single dose to female rats at one or more defined dosages, according to OECD Guideline 423.

The oral LD50 value of test item in Wistar Han rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.