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

Endpoint summary

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

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

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

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.

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.

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 - 28 August 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/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: males 283-304 g, females 219-256 g
- Fasting period before study: not applicable
- Housing: in suspended solid-floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- 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

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 10% of the total body surface area
- % coverage: 100
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): the test material was moistened with distilled water
- Constant volume or concentration used: yes/no
- For solids, paste formed: no

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

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 fourteen days. Individual bodyweights were recorded prior to application of the test material on day 0 and on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: There were no signs of systemic toxicity. There were no signs of dermal irritation.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on an acute dermal toxicity study with male and female rats performed according to EU and/or OECD guidelines and GLP principles, the LD50 of the test substance was found to be greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed