Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic 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:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

EC Number:

227-285-6

EC Name:

Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

Cas Number:

5763-44-0

Molecular formula:

C7H9NO2

IUPAC Name:

4,5,6,6a-tetrahydro-3aH-cyclopenta[c]pyrrole-1,3-dione

Test material form:

solid: flakes

Details on test material:

- Name of test material (as cited in study report): 852 IMIDE ( = tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione)
- Substance type: solid
- Physical state: flakes
- Storage condition of test material: stable under normal storage conditions

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- test system recognized by international guidelines as the recommended system
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: 160 grams for males and 125 grams for females

- Housing:cages with sterilized sawdust as bedding material and paper as cage enrichment.
- Diet (e.g. ad libitum):free access to pelleted rodent diet
- Water (e.g. ad libitum): free access to tap-water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3°C
- Humidity (%): 40-70
- Air changes (per hr):15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

GAVAGE PREPARATION
- method : using a plastic feeding tube.
- frequency : once daily, 7 days/week approx. the same time each day (max 6 hours difference betwwen the earliest and latest dose)
- Storage temperature of food: at ambient temperature

VEHICLE
propylene glycol
- Amount of vehicle (if gavage): 5 ml/kg bw.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

at least 28 days.

Frequency of treatment:

once daily, 7 days/week.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
30 mg/kg bw
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
130 mg/kg bw
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
600 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Dose selection rationale: issued of a dose range finding study performed by NOTOX before the start of these experimentation. (see attached document n°2)
- Rationale for animal assignment (if not random):randomized

Positive control:

no.

Examinations

Observations and examinations performed and frequency:

mortality/viability : at least twice daily
clinical signs
CAGE SIDE OBSERVATIONS: No data
- Time schedule:


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations:weekly


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / weekly


OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: under anaesthesia, immedialtely prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: No data
- How many animals:40
- Parameters checked in table [1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:under anaesthesia, immedialtely prior to scheduled post mortem examination
- Animals fasted: No data
- How many animals:40
- Parameters checked in table [1] were examined.

URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:during week 4 of treatment
- Dose groups that were examined: all the groups
- Battery of functions tested: sensory activity; grip strength ; motor activity ;

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

for both, see the attached document n°3

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

hunched posture and piloerection at a dose of 600 mg/kg

Mortality:

mortality observed, treatment-related

Description (incidence):

hunched posture and piloerection at a dose of 600 mg/kg

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

at a dose of 600 mg/kg

Food efficiency:

no effects observed

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

ALAT + cholesterol, at a dose of 600 mg/kg

Urinalysis findings:

not specified

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

inrease of motor activity, at a dose of 600 mg/kg

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

higher liver weight, at a dose of 600 mg/kg.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

reduced size of prostate, at a dose of 600 mg/kg

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 130 mg/kg bw/day (nominal)

Based on:

test mat. (total fraction)

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The combined occurence of observed changes was considered warranted to set the NO OBSERVED ADVERSE EFFECT LEVEL (NOAEL) for 852 IMIDE ( = tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione) at 130 mg/kg.