Reaction mass of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide and (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 November 2006 - 14 December 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

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:

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide; (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

EC Number:

700-041-0

Molecular formula:

C11 H20 N2 O2

IUPAC Name:

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide; (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

Test material form:

solid: particulate/powder

Remarks:

white powder

Details on test material:

- Name of test material (as cited in study report): ucb108628-1
- Stability under test conditions: not indicated
- Storage condition of test material: room temperature, in the dark

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Strain: CD (Crl: CD (SD) IGS BR)
- Age at study initiation: eight to twelve weeks of age
- Weight at study initiation: 199-247 g; the bodyweights fell within an interval of ± 20% of the mean initial bodyweight of the first treated group.
- Fasting period before study: overnight
- Housing: in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum, 3-4 hours after dosing
- Water (e.g. ad libitum): ad libitum, 3-4 hours after dosing
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

To aid dissolution, the test material formulation was heated in a warming bath at 40°C.

VEHICLE
- Concentration in vehicle: 200 mg/ml and 30 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Using available information on the toxicity of the test material, 2000 mg/kg was chosen as
the starting dose.

Doses:

2000 and 300 mg/kg bw

No. of animals per sex per dose:

2000 mg/kg bw: 3 females
300 mg/kg bw: 2 groups of 3 females

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 ½, 1, 2 and 4 hours after
dosing and subsequently once daily for up to fourteen days. Individual bodyweights were recorded prior to dosing and seven and fourteen days after
treatment or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: 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:

LD0

Remarks:

No deaths at 300 mg/kg

Effect level:

300 mg/kg bw

Based on:

test mat.

Mortality:

All animals treated at a dose level of 2000 mg/kg bw were found dead at the first mortality check one day after dosing.
There were no deaths noted in animals treated at a dose level of 300 mg/kg bw.

Clinical signs:

other: Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg, during the day of dosing, were hunched posture, lethargy, ataxia, ptosis, pilo-erection, decreased respiratory rate and laboured respiration. There were no signs of systemi

Gross pathology:

Abnormalities noted at necropsy of animals, dosed at 2000 mg/kg bw which were found dead on day 1 of dosing were haemorrhagic lungs, dark liver, dark kidneys and epithelial sloughing of the gastric mucosa. At necropsy of the animals receiving a dose of 300 mg/kg bw there were no abnormalities noted at the end of the 14-day observation period.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In an acute oral toxicity study with female rats conducted according to OECD/EC guidelines and GLP principles, the LD50 was found to exceed 300 mg/kg bw.