6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole hydrochloride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-04-04 (date of report to study director and test facility management)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

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:

6-FLUORO-3-(PIPERIDIN-4-YL)-1,2-BENZOXAZOLE HYDROCHLORIDE

EC Number:

700-303-4

Cas Number:

84163-13-3

Molecular formula:

C12H13FN2O.HCl

IUPAC Name:

6-FLUORO-3-(PIPERIDIN-4-YL)-1,2-BENZOXAZOLE HYDROCHLORIDE

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: IRA091
- Expiration date of the lot/batch: Unknown
- Purity: 100%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature (20 ± 5 °C), light protected
- Stability under test conditions: Unknown in PEG 300

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: female rats (nulliparous and non-pregnant), HanRCC:WIST (SPF-Quality); RCC Ltd., Laboratory Animal Services
- Age at study initiation: 12 weeks
- Weight at study initiation: 0.177 - 0.197 kg (range of three treatment groups)
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70% (values above 70 % during cleaning process possible)
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: exact dates not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test item was diluted in vehicle (PEG 300) at a concentration of 0.03 g/mL and 0.2 g/mL
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. PEG 300 was found to be a suitable vehicle.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
- Dose levels are in terms of the test item as supplied by the sponsor.
- The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers.
The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not indicated

TREATMENT
The animals received a single dose of the test item by oral gavage administration at 300 mg/kg body weight or 2000 mg/kg body weight after being fasted for approximately 17 to 18 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing.

Doses:

2000 mg/kg, 300 mg/kg (single dosage each)

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 (until day 15)
- Frequency of observations and weighing:
mortality/viability: Daily during the acclimatization period, approximately 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
body weights: days 1 (pre-administration), 8 and 15.
clinical signs: Daily during the acclimatization period, approximately 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: The two 2000 mg/kg treated animals and one 300 mg/kg treated animal which died spontaneously approximately 30 minutes or 3 hours after test item administration and the third animal of the 2000 mg/kg treated group which was killed in extremis approximately one hour after treatment were necropsied as soon as they were found dead or killed. The animal sacrificed for ethical reasons was killed by an intraperitoneal injection of Vetanarcol.
All surviving animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Statistics:

No statistical analysis was performed.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Two 2000 mg/kg treated animals were found dead approximately 30 minutes after treatment and the remaining animal treated at the same dose was killed in extremis for ethical reasons approximately 1 hour after treatment. Two out of six 300 mg/kg treated animals were found dead approximately 3 and 6 hour after treatment, respectively.

Clinical signs:

convulsions

observations of tremors

other:

Body weight:

other body weight observations

Remarks:

The body weight of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

Liquid contents in the stomach, duodenum, jejunum, and ileum was noted in the two animals treated at 2000 mg/kg at the unscheduled necropsy. Lungs not collapsed were also noted in one of them. Liquid contents in the stomach and ileum and an empty jejunum was also noted in one 300 mg/kg treated animals at the unscheduled necropsy. Due to a technical error of the animal technician, no macroscopic findings were recorded for one 300 mg/kg treated animal.

Any other information on results incl. tables

Number of dead animals in each test group with 3 animals each:

Females 2000 mg/kg: two out of three

Females 300 mg/kg: two out of six (1 out of three in first group, 1 out of three in second group)

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The median lethal dose of T001492 after single oral administration to female rats, observed over a period of 14 days is: 300 mg/kg body weight < LD50 (female rat) < 2000 mg/kg body weight.

T001492 is to be classified as Category 4, harmful if swallowed (H302) following this study conclusion.