Registration Dossier

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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
30 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
130 mg/kg bw
Basis:
actual ingested
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:
clinical signs
body weight and weight gain
food consumption and compound intake
clinical biochemistry
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology

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.