Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-2005
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
and B 43
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 216-246 g
females: 160-190 g
- Fasting period before study: none
- Housing: individually in suspended wire-mesh cages (43 x 21.5 x 18 cm)
with metal trays, containing autoclaved sawdust (SICSA) as bedding, under the cages
- Diet (e.g. ad libitum): ad libitum, SSNIFF R/M-H pelleted maintenance diet by SSNIFF Spezialdiäten GmbH, Germany
- Water (e.g. ad libitum): ad libitum, drinking water, filtered
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 C
- Humidity (%): 50 % ± 20%
- Air changes (per hr): 12 / hour (filtered, non-recycled air)
- Photoperiod (hrs dark / hrs light): 12/12 h (7:00-19:00)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: MC (methyl cellulose) 0,5 %
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
suspension of test item in the vehicle (methylcellulose 0.5 % in purified water)
dose levels: 50, 150, 300 mg / kg / day
dosage volume: 5 ml / kg / day (constant)

VEHICLE
- Justification for use and choice of vehicle (if other than water): for solubility in water
- Concentration in vehicle: 10, 30, 60 mg / ml
- Amount of vehicle (if gavage): 5 ml / kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- homogenicity and stability checked at 1 and 60 mg/ml for 9 days at +4 ºC.
-concentrations of dosage preparation checked in week 1 and 4.
- all concentrations within the theoretical range ± 10 %.
-preparations at 1 and 60 mg/ml stable and homogenous for nine days at +4 ºC
Duration of treatment / exposure:
29 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
dose levels: 50, 150, 300 mg / kg / day dosage volume: 5 ml / kg / day (constant)
Basis:
other: gavage
No. of animals per sex per dose:
dose No. of animals / sex
0 (control) 5 (+2 satellites)
50 5 (+6 satellites)
150 5 (+6 satellites)
300 5 (+6 satellites)
Control animals:
yes, concurrent vehicle
Positive control:
No.

Examinations

Observations and examinations performed and frequency:
Mortality check (daily)
Clinical observation (daily)
FOB (end of period)
Body weight and food intake (weekly)
Hematology-clinical chemistry (end of period)
Sacrifice and pathology:
Organ weights-macroscope and microscope examinations.
Other examinations:
-Monitoring of estrous cycle (end of period)
-Toxicokinetics (satellite animals): day 1 and week 4.
-Sperm count, motility, morphology.
Statistics:
Yes (decision tree according to data set).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
Clinical signs and mortality: No mortality. Clinical sings at 300 mg/kg including piloerection, hunched posture, thin appearance, soiled regions, cold to the touch and/or ptyalism. No salient finding at neurologic observation (FOB).
Body weight and gain: affected at 300 mg/kg.
Food consumption and compound intake: affected at 300 mg/kg.
Haematology: No salient changes.
Clinical chemistry: Slightly high colesterol (x1,3) and bilirubin (x1,7) serum concentration at 300 mg/kg.
Neurobehaviour: No abnormalities (FOB).
Organ wights: increased liver weight at 150 mg/kg (x1,2) and 300 mg/kg (x1,5).
Gross pathology: no salient findings.
Histopathology: non-neoplastic centrilobular hepatocellular hypertrophy at 150 and 300 mg/kg. No changes in vaginal cyclic
nor in sperm count and morphology.

Effect levels

Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: -centrilobular hepatocellular hypertrophy from 150 mg/kg/day -clinical signs and effects on BW, FC at 300 mg/kg/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion