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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
12 Jul - 9 Aug 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
no analytical purity reported

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
adopted in 1982
Deviations:
yes
Remarks:
no analytical purity reported
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
130905-60-1
EC Number:
603-445-4
Cas Number:
130905-60-1
IUPAC Name:
130905-60-1

Test animals

Species:
rat
Strain:
other: Wistar Albino rats of the Crl: Wi/Br strain
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH (Laboratory Animal Breeding), Sulzfeld, Germany
- Age at study initiation: about 6 weeks
- Weight at study initiation: 121-152 g (males); 123-143 g (females)
- Housing: individual in Makrolon type II cages, bedding was produced from pure soft wood, dried, freed from dust and sterilized at 180 °C.
- Diet: “Ssniff R” diet in pellet form (laboratory standard rat diet), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 ± 1.5
- Humidity (%): 60 ±10
- Air changes (per hr): 16 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was diluted with corn oil to give the final concentrations. For this purpose, the test material was heated to about 70°C to liquefy the test article and appropriate amounts were weighed and mixed with corn oil in volume/volume proportions.

VEHICLE
- Concentration in vehicle: 2.0, 20.0 and 50%
- Amount of vehicle (if gavage): 10 mL
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test material was determined in the vehicle prior to the initiation of the study. In fact a 20% suspension of the test article was analysed at preparation and 2, 4 and 24 hours thereafter.
Analytical results indicated that the dosing suspensions were stable for at least 24 hours.
These analyses provided information on the homogeneity of the test item in suspension as well.
The concentration and identity of the dosing solutions were determined at the start and at the end of the study. All values obtained were in reasonable accordance with the nominal values.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
once daily, 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
180 mg/kg bw/day (actual dose received)
Dose / conc.:
1 800 mg/kg bw/day (actual dose received)
Dose / conc.:
4 500 mg/kg bw/day (actual dose received)
Dose / conc.:
0.2 other: mL/kg bw/day
Dose / conc.:
2 other: mL/kg bw/day
Dose / conc.:
5 other: mL/kg bw/day
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels used in the present study were chosen on the basis of results obtained during a 7-day range finding study. A dosage of 5 mL/kg bw was used and did not cause overt signs of toxicity. On the basis of these results, 5 mL/kg bw was selected as the highest dose in the present study with the purpose to get information on target organ toxicity. The low and mid doses were chosen in order to obtain a clear no adverse effect level.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical observations were conducted daily. Mortality checks were performed twice daily.
- Cage side observations checked in table [animals´ sensory and motor behaviour, coat, body orifices, urine, feces and general health status] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Special clinical examinations were conducted prior to study initiation (week 0) and thereafter on week 2 and 4.

BODY WEIGHT: Yes
- Time schedule for examinations: Measurements of body weight were made at weekly intervals.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Time schedule for examinations: at weekly intervals
- Food conversion ratio was calculated from the change in weight and the food consumption over the same periods of time: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: cornea, episcleral vessels, anterior chamber, pupil, lens and, if possible, retina were examined with a slit lamp and an ophthalmoscope fitted with a selection of lenses prior to study initiation (week 0) and thereafter on week 2 and 4.
- Dose groups that were examined: on male and female rats of each test group.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the administration period
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: on male and female rats of each test group
- Parameters examined: erythrocytes (RBC), leukocytes (WBC), thrombocytes, haemoglobin, hematocrit, MCV, MCH and MCHC, differential blood count, reticulocytes, inclusion bodies, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the administration period
- Animals fasted: No
- How many animals: on male and female rats of each test group
- Parameters examined: Glucose, triglyceride, cholesterol, protein (total), albumin, bilirubin (total), creatinine, urea nitrogen (BUN), uric acid, calcium, chloride, inorg. Phosphorus, iron, potassium, sodium, Na/K ratio by statistical evaluation, alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), creatinine kinase (CK), glutamate dehydrogenase (GLDH), AST/ALT ratio by statistical evaluation

URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the administration period
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters examined: color, protein, pH value, glucose, bilirubin, urobilinogen, blood, nitrite, ketones, sediment, specific gravity

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to study initiation (week 0) and thereafter on week 2 and 4.
- Dose groups that were examined: on male and female rats of each test group
- Battery of functions tested: hearing activity (tested by simple noise production)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. All animals were sacrificed at the end of the experimental phase by CO2 asphyxiation. Rapid exsanguination was carried out by cutting the A.carotis. The following organs were examined: cranial, thoracic, abdominal and pelvis cavities.

HISTOPATHOLOGY: Yes. A complete histopathological examination was performed on all male and female animals of control group and high dose group on the following organs: adrenals (2x), heart, kidneys (2x), liver, spleen, prostate.
Other examinations:
The following organ weights were determined: liver, kidneys, adrenals, spleen, prostate gland, uterus, testes (left and right) with epididymides
Statistics:
Statistical analyses were performed separately on data from male and female animals. One or two-factorial analysis of variance was conducted on weight changes and food consumption. Group means were compared by the “Scheffe´” test.
Organ weights were evaluated by analysis of covariance and the mean values were compared by the “Scheffe´” test of covariance.
Values form chemical chemistry and hematology were analysed by analysis of variance with subsequent the “Scheffe´” test of variance.

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:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
significant increase in prostate weight in high dose animals. However, this increase was not attended by any histopathologcal changes.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 800 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Under the experimental conditions of this study a daily oral administration of 1800 mg/kg bw/day had no adverse effects on rats after 4 weeks

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion