[No public or meaningful name is available]

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2014-04-23 to 2014-05-22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

17 December 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

Cas Number:

1398609-81-8

Molecular formula:

C17H21NO4

IUPAC Name:

tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

Specific details on test material used for the study:

Batch No.: DBKD-BK-D1301p
Purity: 99.4% w/w

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: supplied by Harlan Laboratories UK Ltd.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: eight to twelve weeks
- Weight at study initiation:146- 182 g
- Fasting period before study: overnight before dosing
- Housing: housed in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 or 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

DOSAGE PREPARATION (if unusual):
The test item was formulated within two hours of being applied to the test system.

CLASS METHOD
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.

Doses:

300, 2000 and 2000 mg/kg

No. of animals per sex per dose:

3 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen days.
Individual body weights were recorded prior to dosing and seven and fourteen days after treatment or at death.
- Necropsy of survivors performed: yes, at the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Mortality:

One animal was killed for humane reasons, 1 day after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence.
There were no deaths at a dose level of 300 mg/kg.

Clinical signs:

other: Signs of systemic toxicity noted at a dose level of 2000 mg/kg were hunched posture, pilo-erection, body tremors or occasional body tremors, lethargy, ataxia, tiptoe or splayed gait, increased respiratory rate and hypothermia. There were no signs of syste

Gross pathology:

Dark liver and dark kidneys were noted at necropsy of the animal that was humanely killed during the study. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Applicant's summary and conclusion

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg body weight (Globally Harmonized Classification System - Category 5, >2000 - 5000 mg/kg body weight).

Executive summary:

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat according to OECD 423.

A group of three fasted females was treated with the test item at a dose level of 300 mg/kg body weight. Based on the results from this dose level, further groups of fasted females were treated at a dose level of 2000 mg/kg body weight. Dosing was performed sequentially.

The test item was administered orally as a suspension in arachis oil BP. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality: One animal was killed for humane reasons, 1 day after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence. There were no deaths at a dose level of 300 mg/kg.

Clinical Observations: Signs of systemic toxicity noted at a dose level of 2000 mg/kg were hunched posture, pilo-erection, body tremors or occasional body tremors, lethargy, ataxia, tiptoe or splayed gait, increased respiratory rate and hypothermia. There were no signs of systemic toxicity at a dose level of 300 mg/kg.

Body Weight: Surviving animals showed expected gains in body weight.

Necropsy: Dark liver and dark kidneys were noted at necropsy of the animal that was humanely killed during the study. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg body weight (Globally Harmonized Classification System - Category 5, >2000 - 5000 mg/kg body weight).