1-Piperazinecarboxylic acid, 4-(6-amino-3-pyridinyl)-, 1,1-dimethylethyl ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 02 to 28 May 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate

EC Number:

695-268-4

Cas Number:

571188-59-5

Molecular formula:

C14H22N4O2

IUPAC Name:

tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate

Test material form:

solid - liquid: suspension

Remarks:

migrated information: dispersion

Details on test material:

Batch No.: E010013662
Purity: 98.6%

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: eight to twelve weeks of age
- Weight at study initiation: The body weight variation did not exceed ±20% of the body weight of the initially dosed animal.
- Fasting period before study: an overnight
- Housing: in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflake
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): 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
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness

IN-LIFE DATES: From 02 to 28 May 2013

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Amount of vehicle (if gavage):
- Justification for choice of vehicle: Dimethyl sulphoxide was used because the test item did not dissolve in distilled water or arachis oil BP.
- Lot/batch no. (if required):
- Purity:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual):

CLASS METHOD (if applicable)
- 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 and 2000 mg/kg

No. of animals per sex per dose:

Preliminary study: 1 female for 300 mg/kg, 1 female for 2000 mg/kg
Additional group: 4 females for 300 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 1/2, 1, 2, and 4 hours after dosing and then daily for up to fourteen days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14 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 necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
- Other examinations performed:

Statistics:

None stated

Results and discussion

Preliminary study:

A single animal was treated at a dose level of 300 mg/kg, which resulted in no toxicity. Then an additional animal was treated at the dose level of 2000 mg/kg,which resullt in mortality. Therefore an additional group of animals were treated at a dose level of 300 mg/kg.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

The animal treated at a dose level of 2000 mg/kg was found dead 30 minutes after dosing. There were no deaths at a dose level of 300 mg/kg.

Clinical signs:

other: Clonic convulsions were noted in the animal treated at a dose level of 2000 mg/kg. There were no signs of systemic toxicity noted at a dose level of 300 mg/kg.

Gross pathology:

Brown colored liquid present in the stomach and reddened gastric mucosa were noted at necropsy of the animal treated at a dose level of 2000 mg/kg. No abnormalities were noted at necropsy of the animal treated at a dose level of 300 mg/kg.

Other findings:

No information provided

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (Globally Harmonized Classification System — Category 4).