Registration Dossier

Some information in this page has been claimed confidential.

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:
2006
Report date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
Limit test:
no

Test material

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths occurred throughout the study. No abnormalities were observed in the clinical signs and detailed clinical observations during the dosing period and during the recovery period.

BODY WEIGHT
No abnormalities were noted in body weights.

FOOD CONSUMPTION
No abnormalities were noted during the dosing period. During the recovery period food intakes were increased in females in the 100 mg/kg bw group on day 4.

HAEMATOLOGY
In the 100 mg/kg group, at termination of the dosing period, decreased red blood cell count, hemoglobin concentrations and hematocrit values were observed in males and females. In the same group, increased reticulocyte count in females and prolonged prothrombin time in males were observed.
At termination of the recovery period, in the 100 mg/kg bw group, increased hemoglobin concentrations and hematocrit values were observed in males. In females in the 100 mg/kg bw recovery group no abnormalities were observed.

CLINICAL CHEMISTRY
In males of the 100 mg/kg bw group, at termination of the dosing period, increased alanine aminotransferase and A/G ratio, and decreased total cholesterol were observed. In females of the same group, total bilirubin was decreased.
In males of the 5 mg/kg bw group, at termination of the dosing period, total protein was decreased.
At termination of the recovery periodn, in males in the 100 mg/kg bw group, alanine aminotransferase was increased.

URINALYSIS
No abnormalities were noted in urinalysis.

NEUROBEHAVIOUR
No abnormalities were noted in sensorimotor function.

ORGAN WEIGHTS
At termination of the dosing period, absolute and relative kidney weights were increased in males of the 25 mg/kg bw group and higher. Absolute and relative liver weights were increased in males of the 100 mg/kg bw group. In females, no abnormalities were observed.
At termination of the recovery period, relative adrenal weight was increased in males in the 100 mg/kg bw group. In females in the same group, increased absolute kidney weight and decrease relative heart weight were observed.

GROSS PATHOLOGY
Elevation of limiting ridge in the forestomach in males and females and enlargement of the liver in males were observed in the 100 mg/kg bw group, at the end of the dosing period. No abnormalities were observed at the end of the recovery period.

HISTOPATHOLOGY: NON-NEOPLASTIC
After dosing period
In males round cell infiltration in the prostate and capsulitis of the spleen were observed in the vehicle control group. Hyperplasia of squamous epithelium in limiting ridge of the forestomach, diffuse hypertrophy of hepatocytes with granular degeneration in the liver, solitary cyst in medulla of the kidney, round cell infiltration in the prostate and capsulitis of the spleen were observed in the 100 mg/kg bw group.
In females mineralisation in corticomedullary junction and solitary cyst in medulla of the kidney were observed in the vehicle control group. Basophilic tubules and mineralisation in corticomedullary junction of the kidney were observed in the 5 mg/kg bw group. Basophilic tubules and mineralisation in corticomedullary junction of the kidney were observed in the 25 mg/kg bw group. Hyperplasia of squamous epithelium in limiting ridge of the forestomach, focal necrosis of hepatocytes in the liver, basophilic tubules and mineralization in corticomedullary junction of the kidney and hyperplasia of collecting tubular epithelium and transitional epithelium with interstitical cell infiltration in the unilateral kidney were observed in the 100 mg/kg bw group.

After recovery period
In males no abnormalities were observed.
In females basophilic tubules and mineralisation in corticomedullary junction of the kidney were observed in the vehicle control group. Mineralisation in corticomedullary junction of the kidney were observed in the 100 mg/kg bw group.

Effect levels

Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: increased absolute and relative kidney weights in males of the 25 mg/kg bw/day group and higher

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion