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

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

GLP compliance:

yes (incl. QA statement)

Type of assay:

mammalian bone marrow chromosome aberration test

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide

Cas Number:

357336-20-0

Molecular formula:

C11H20N2O2

IUPAC Name:

(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

HsdOla:WI

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

The vehicle control material used was 1% w/v aqueous methylcellulose (400 cps)

Details on exposure:

Because of the short half-life, the animals were doced twice a day (2 equal sub-doses given 6 h apart)

Duration of treatment / exposure:

2 consecitive days

Frequency of treatment:

twice a day (2 equal sub-doses given 6 h apart) for 2 consecitive days

Post exposure period:

48 h bone marrow sampling

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

500 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

1 000 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

standard 5 males and 5 females

Control animals:

yes, concurrent vehicle

Positive control(s):

control material used was 1% w/v aqueous methylcellulose

Results and discussion

Test results

Key result

Sex:

male/female

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Applicant's summary and conclusion

Conclusions:

It was concluded that ucb 34714 did not induce micronuclei in bone marrow cells when tested, in male and female Wistar rats, to the maximum tolerated oral dose of 2000 mg.kg-l day-l given as 2 equal daily sub-doses 6 h apart for 2 consecutive days.

Executive summary:

he in vivo genotoxic potential of ucb 34714 was evaluated in a micronucleus test in bone marrow erythrocytes of young, male and female Wistar rats. The animals were dosed twice daily (2 equal sub-doses given 6 h apart) for 2 consecutive days (ie 4 consecutive doses at O, 6, 24 and 30 h). The dosing regimen was based on Sponsor information that the test material has a short half-life in rats. The rats were dosed orally by gavage.

A toxicity study was undertaken to establish a suitable dose range for the micronucleus experiment. Based on the findings of the toxicity study, the maximum tolerated dose of ucb 34714 was judged to be in the region of 2000 mg.kg-l.day-l.

In the micronucleus test, male rats were dosed with the test item at concentrations equivalent to 500, 1000 and 2000 mg.kg-l.day-l. Female rats were dosed with the test item at 2000 mg.kg-’ day-l. Bone marrow samples were taken 48 h after the initial dose. Two control groups of Wistar rats were dosed orally with either the vehicle, (1YOw/v aqueous methyl cellulose), (males and females) or the positive control agent, (50 mg cyclophosphamide. kg-i. day-l (males only). The experimental schedule for the control groups followed that of the test item treated rats. Each group consisted of 5 rats per sex where applicable. An additional 5 animals/sex were dosed with the test item at 2000 mg.kg-l day-l, and served as a contingency in case of unscheduled deaths. Blood samples for toxicokinetic analysis were taken 1.5 h after the last dose.

No micronucleus induction was detected in bone marrow erythrocytes of rats dosed with ucb 34714.

Animals treated with the vehicle alone showed normal background levels of micronuclei, while animals dosed with cyclophosphamide responded with substantial increases in the numbers of bone marrow micronuclei.

It was concluded that ucb 34714 did not induce micronuclei in bone marrow cells when tested, in male and female Wistar rats, to the maximum tolerated oral dose of 2000 mg.kg-l day-l given as 2 equal daily sub-doses 6 h apart for 2 consecutive days.

The toxicokinetic analysis indicated that the males dosed with 500, 1000 and 2000 mg.kg-l.day-l had mean plasma levels of 76.7*3.9, 98.9+30.7 and 265fl 33 pg.ml-i respectively 1.5 h after the last sub-dose. The females dosed with 2000 mg.kg-l.day-l were found to have plasma levels of 393*6 pg.ml-l 1.5 h after the last sub-dose.

This study was performed in accordance with the Principles of Good Laboratory Practice.