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:

Feb - May 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

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

Cas Number:

571188-59-5

Molecular formula:

C14H22N4O2

IUPAC Name:

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

Test material form:

solid: bulk

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

9 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.
Age and body weight
Young adult animals (approx. 8 or 9 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

Oral gavage, using plastic feeding tubes. If practically possible, test substance (formulations) were stirred on a magnetic stirrer during dosing.

Doses:

Dose level (volume)
- 2000 mg/kg (10 mL/kg) body weight.
- 300 mg/kg (10 mL/kg) body weight.

No. of animals per sex per dose:

Initially, LEE011-A2 was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 300 mg/kg body weight.

Control animals:

no

Statistics:

No statistical analysis was performed

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 500 mg/kg bw

Based on:

test mat.

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 300 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg, all animals were found dead on Day 1.
At 300 mg/kg, two animals were found dead, on Days 1 and 3. No further mortality occurred.

Clinical signs:

other: At 2000 mg/kg, hunched posture, squeaking, lateral recumbency, tremor, rolling movements and/or laboured respiration were noted for the animals on Day 1. At 300 mg/kg, lethargy, tremor, flat posture, hunched posture, uncoordinated movements, piloerection

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 value of LEE011-A2 in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.

Based on these results:
- according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments), LEE011-A2 should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route.
- according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments), LEE011-A2 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.