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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
adopted in 1981
Deviations:
yes
Remarks:
lack of details on test substance; lack of urinary and ophthalmoscopic examination.
GLP compliance:
yes
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: Charles River Laboratories, Wilmington, MA, USA.
- Age at study initiation: 6 - 8 weeks old
- Weight at study initiation: 150 - 250 g
- Housing: group housed on hardwood chip bedding.
- Diet: rodent ration, AgWay Prolab, Waverly, NY. USA, ad libitum
- Water: municipal tap water, ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-13
- 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 dissolved in vehicle at the following concentrations: 0.025 g/mL, 0.075 g/mL and 0.250 g/mL.
- Dosing volume: 4 mL/kg bw, the doses were adjusted at weekly intervals to maintain a constant dose level by body weight.

VEHICLE
- Justification for use and choice of vehicle: water-insolubility
- Lot/batch no.: CSC-91-01-001VIV

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The three dose levels were employed based on the known toxicity of the test material.

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to study initiation and prior to the terminal sacrifice
- Anaesthetic used for blood collection: Yes, carbon dioxide
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: erythrocyte count (RBC), hemoglobin (Hgb), hematocrit (Hct), platelet count (PT), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin conc. (MCHC), mean corpuscular volume (MCV), white blood cell (WBC) differential

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to study initiation and prior to the terminal sacrifice
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: albumin, glucose, LDH, blood urea, ASAT, ALAT, AP, nitrogen (BUN), serum creatinine, total bilirubin, total serum protein, globulin, chloride, phosphorus, potassium, sodium, calcium

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: 1 and 6 hours after dosing and on Days 1, 7, 14, 21 and 28.
Parameters scored: Respiratory, Motor activities, Convulsion, Reflexes, Ocular signs, Cardiovascular signs, Salivation, Piloerection, Analgesia, Muscle tone, Gastrointestinal signs, Skin, Vocalization, Forelimb/Hindlimb grip strength.
The observations for neurotoxicity were made by a technician which was blind with respect to the animals´treatment. The animal to be observed was removed from the cage and placed in a designated area for the neurotoxicological observation. The observations was graded at 1 and 6 h after dosing, and on day 1, 7, 14, 21 and 28 using the following scale: 0 = normal, 1 = mild, 2 = moderate, 3 = severe


ORGAN WEIGHTS:
liver, kidney, adrenals and gonads

DETAILS:
- Hematology/Biochemistry:
Prior to the initiation of the study and prior to the terminal sacrifice, all animals were anesthetized with carbon dioxide and bled for clinical pathological evaluation of the following parameters:
* hematology: erythrocyte count, hemoglobin, hematocrit, platelet count, mean corpuscular volume, mean corpuscular hemoglobin conc., mean corpuscular hemoglobin, WBC differential
* biochemistry: albumin, blood urea, nitrogen, electrolyte (chloride, phosphorus, potassium, sodium, calcium), glucose, serum aspartate aminotransferase, serum alanine aminotransferase, serum creatinine, total bilirubin, total serum protein, globulin, LDH, cholesterol, alkaline phosphatase.

- Procedures during treatment:
Body weight and food consumption were measured weekly. Daily clinical observations included all clinical signs.






Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals. (Examination of the external surface, all orifices, cranial, thoracic and abdominal cavities)
HISTOPATHOLOGY: Yes, from animals of the control and highest dose group
The following organs were examined histopathologically: adrenal glands, heart, lung, liver, kidney, spleen, ovaries and testes.

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:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical manifestations were observed during the course of the study in either the control or test animals.

BODY WEIGHT AND WEIGHT GAIN
All animals showed the expected gain in body weigh during the course of the study.

FOOD CONSUMPTION AND COMPOUND INTAKE
There were no significant differences between control and test groups.

HAEMATOLOGY
No treatment-related significant differences were observed. The observed changes had no dose-response.

CLINICAL CHEMISTRY
No treatment-related differences between control and tested groups were observed.

NEUROBEHAVIOUR
No signs of neurotoxicity were observed during the course of the study.

ORGAN WEIGHTS
The relative kidney and liver weights were significantly different in male animals treated with 100 mg/kg compared with control animals.
As the other organs from groups with higher doses showed no significant differences, no dose-response relation occurred. Therefore these changes can be regarded as non-treatment related.

GROSS PATHOLOGY
There were no abnormal signs observed during the gross necropsy of any animal.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related effects were observed in the analysed organs.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on: clinical manifestation, neurotoxicity, on various blood parameters (hematology and clinical chemistry), necropsy, organ weights, body weights, food consumption and histopathological findings.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion