Ethyl 4-oxopiperidine-1-carboxylate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-04-26 to 2006-05-26

Reliability:

1 (reliable without restriction)

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:

Ethyl 4-oxopiperidine-1-carboxylate

EC Number:

249-984-5

EC Name:

Ethyl 4-oxopiperidine-1-carboxylate

Cas Number:

29976-53-2

Molecular formula:

C8H13NO3

IUPAC Name:

ethyl 4-oxopiperidine-1-carboxylate

Test material form:

liquid

Details on test material:

- Name of test material (as cited in study reports): JNJ-126971-AAA (T000509)
- Physical state: liquid
- Appearance: clear colourless to light yellow liquid

Test animals

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 9 female Wistar rats, HanRcc: WIST (SPF); RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf, Switzerland
- Age when treated: 12-13 weeks
- Weight at treatment (day 1): 178.0 - 190.7 grams (females, 2000 mg/kg), 170.1 - 174.6 grams (females, 300 mg/kg), 173.4 - 190.3 grams (females, 300 mg/kg)
- Fasting period before study: no data
- Housing: Standard Laboratory Conditions, 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): pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 001/06 (Provimi Kliba AG, CH-4303 Kaiseraugst, Switzerland) ad libitum. Analysis of contaminants performed.
- Water (e.g. ad libitum): community tap water from Füllinsdorf ad libitum. Bacteriological, chemical and contaminant analysis performed.
- Acclimation period: one week (2006-04-26 to 2006-05-02 for females, 2000 mg/kg; 2006-04-28 to 2006-05-04 for females, 300 mg/kg; 2006-05-05 to 2006-05-11 for females, 300 mg/kg), under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

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, music during the daytime light period.

IN-LIFE DATES:
- Females, 2000 mg/kg: from: 2006-05-03 to: 2006-05-17
- Females, 300 mg/kg: from: 2006-05-05 to: 2006-05-19
- Females, 300 mg/kg: from: 2006-05-12 to: 2006-05-26

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0,03 and 0,2 g/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Justification for choice of vehicle: PEG 300 was found to be a suitable vehicle. The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This formulation trial is excluded from the GLP statement of compliance.
- Lot/batch no. (if required): 1204719
- Expiry date: 2007-02
- Decription: colourless viscous liquid
- Source: FLUKA Chemie GmbH, CH-9471 Buchs
- Stability of vehicle: stable under storage conditions
- Storage conditions: at room temperature (range of 20 +/- 5°C), light protected
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg body weight

DOSAGE PREPARATION (if unusual):
- The dose formulations were made shortly before each dosing occasion using a magnetic stirrer as homogenizer.
- The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The glass beaker was wrapped with aluminium foil to protect the test item solution against light.
- 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: no data

Doses:

300 and 2000 mg/kg body weight

No. of animals per sex per dose:

3 females per group; 3 groups

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: mortality/viability: daily during the acclimatization period, during the first 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: on test days 1 (prior to administration), 8 and 15; clinical signs: daily during the acclimatization period, during the first 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 deaths: as soon as they were killed for ethical reason. The two animals which were killed approximately 3 hours and 2 days respectively after test item administration were killed by an intraperitoneal injection of 1:1 (v/v) mixture of Eutha ® 77 (containing 400 mg pentobarbitalum natricum) and physiological saline at a dose of at least 2.0 ml/kg body weight.
- Necropsy of survivors performed: yes, all surviving animals were killed at the end of the observation period by carbon dioxide asphyxation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Statistics:

No statistical analysis was used.

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 of three animals treated with 2000 mg/kg had to be killed for ethical reasons 3 hours and 2 days after application respectively. One of the 2000 mg/kg and all the 300 mg/kg treated animals survived until the end of the study.
2000 mg/kg: 2/3
300 mg/kg: 0/3
300 mg/kg: 0/3

Clinical signs:

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:

One of the 2000 mg/kg treated animal, which had to be killed in extremis on test day 2, showed a stomach, duodenum, jejunum and ileum filled with liquid contents. In addition the kidneys were light brown and discolored and the urine bladder was distended and filled with urine. The other sacrificed animal showed a light brown discoloration of the kidney and a stomach filled with liquid contents. The 300 mg/kg treated animals and the surviving 2000 mg/kg treated animal showed no macroscopic findings at necropsy.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The median lethal dose of T000509 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. Based on GHS criteria, T000509 is a Category 4 for Acute Oral Toxicity in rats.