2-(2-oxopyrrolidin-1-yl)butyramide

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

There were three study plan amendments and four study plan deviations.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

yes

Remarks:

There were three study plan amendments and four study plan deviations.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Source: RCC Ltd Laboratory Animal Science CH-4414 Fullinsdorf / Switzerland
-Total number of animals per group: Groups 1-4: 5 males; 5 females
-Total number of animals: 20 males and 20 females
-Age at delivery: 6 weeks
-Body weight range at acclimatization Males: 139.8 -156.5 grams (mean 147.1 grams) Females: 113.3 -127.4 grams (mean 120,8 grams)
-Identification Cage card and individual ear tattoo
-Randomization Computer-generated random algorithm
-Acclimatization Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

- Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a target range for temperature of 22+/- 3°C and for relative humidity between 30-70%. 12 hours fluorescent light/ 12 hours dark, music during the light period.
- Accommodation: In groups of five in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding (’Lignocel’ Schill AG, CH-4132 Muttenz/SwitzerIand).
- Diet: Pelleted standard Provimi Kliba 3433 (batch no. 40/03) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) was available ad libitum. The feed batch was analyzed for contaminants.
- Water: Community tap-water from Itingen was available ad libitum in water bottles. results of bacteriological assay, chemical and contaminant analyses of representative samples are available.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Frequency of administration: Daily
Dose volume: 10 ml/kg body weight
Duration of acclimatization period: 7 days
Duration of treatment: 28 days

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

No. of animals per sex per dose:

Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Details on results:

Evidence of test item-induced findings consisted of an increased severity of hyaline droplets in the kidneys of male animals at 1000 mg/kg.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the results of this study, 200 mg/kg body weight/day of ucb 6474 was established as the no-observed-effect-level (NOEL), whereas the no-observedadverse-effect-level (NOAEL) was considered to be 1000 mg/kg/day.

Executive summary:

Oral administration of ucb 6474 to Wstar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no unscheduled mortality, no clinical signs during daily or weekly observations, functional observational battery (week 4), no differences in mean fore- and hindlimb grip strength or mean locomotor activity, no differences in mean daily food consumption or body weights, no toxicologically relevant differences in the hematological or clinical biochemistry parameters, and no test item-related differences in the absolute or relative organ weights. All microscopical findings were considered to be typical background changes of no toxicological relevance. Microscopically, an increased severity of hyaline droplets were noted in the kidneys of male animals treated with 1000mg/kg/day. This finding was considered to be adaptive in nature and is frequently observed in the kidney of male rats treated with a xenobiotic.