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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-06-18 until 1990-09-21
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
Application was performed on 5 days per week as opposed to 7 days per week with no analytical verification of test concentrations.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
151661-88-0
Cas Number:
151661-88-0
IUPAC Name:
151661-88-0
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Specific details on test material used for the study:
- Name of test material: Stabiol VP 1711
- Substance type: fatty acid ester
- Physical state: white powder
- Lot/batch No.: 041/8/055 (1988-02-04)
- Stability under test conditions: stable under test conditions

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: 4 weeks
- Weight at study initiation: 62 - 82 g (females); 58 - 80 g (males)
- Housing: Makrolon Cage type III
- Diet: Altromin 1324, ad libitum, supplied by Altromin GmbH
- Water: tap water (drinking water quality analytically verified), ad libitum
- Acclimation period: 13 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The testing solution was prepared daily just before administration by weighing out an appropriate amount of test substance and dispersing it in the vehicle.

VEHICLE
- The administration volume was 5 mL/kg bw.
- The concentration of test item in the vehicle was: 200, 60, 20 and 0 mg/mL
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
107 to 108 days starting with animal acclimation, with a total treatment of 68 to 69 administrations
Frequency of treatment:
5 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 animals/ sex/ dose.
Satellite groups of 5 male and 5 female animals were used for the control and 1000 mg/kg bw day dose groups.
Control animals:
yes, concurrent vehicle
Details on study design:
- On the day of arrival the animals were subjected to an acclimatization period during which they received ground diet and drinking water ad libitum.
- The total number of application was 68 to 69, corresponding to a total administered amount of 6800 to 6900, 20400 to 20700, 68000 to 69000 mg/kg bw for the respective 100, 300, 1000 mg/kg bw/day dose groups. -
- Satellite groups of 5 male and 5 female animals were used for the control and 1000 mg/kg bw day dose groups. Following concurrent treatment these satellite animals were not treated for an additional observation period of 33 days in order to investigate the reversibility of potential toxic responses.
Positive control:
Not required

Examinations

Observations and examinations performed and frequency:
MORTALITY
A check for moribund and dead animals was made twice daily on working days. If animals were in a moribund state, they were sacrificed and necropsied.

CLINICAL OBSERVATIONS
All animals were checked twice daily for any abnormal clinically signs on working days.

FOOD CONSUMPTION
Group food consumption was determined weekly for each cage.

DRINKING WATER CONSUMPTION
Drinking water consumption was determined weekly for each cage.

BODY WEIGHT
Body weight was determined before the start of the administration period. During the administration period body weight was determined on study day 0 (start of the administration period) and thereafter at weekly intervals.

HAEMATOLOGY
The following parameters were determined in blood: Leukocyte count (WBC), Erythrocyte count (RBC), Hemoglobin (HGB), Hematocrit (HCT), Mean corpuscular volume (MCV), Platelet count (PLT), Differential blood count

CLINICAL CHEMISTRY
Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (AP), γ-Glutamyltransferase (GGT), Sodium (NA), Potassium (K), Chloride (CL), Calcium (CA), Urea (UREA), Creatinine (CREA), Glucose (GLUC), Total bilirubin (TBIL), Total protein (TPROT), Cholesterol (CHOL)

OPHTHALMOSCOPY
Prior to the start of necropsy the eyes of all animals of the control and high dose animals were treated with Mydriaticum and examined for any changes using a slit lamp.


Sacrifice and pathology:
NECROPSY
The animals were sacrificed by exsanguination under an overdose of ether. The exsanguinated
animals were necropsied and assessed by gross pathology.

ORGAN WEIGHTS
The following weights were determined in all animals sacrificed on schedule: Anesthetized animals, Adrenal glands, Brain, Heart, Kidneys, Liver, Spleen, Testes, Thymus

HISTOPATHOLOGY
Fixation was followed by histotechnical processing, examination by light microscopy and assessment of findings on following organs: Adrenal glands, Aorta, Skeletal muscle, Brain, Cecum, Uterus, Coagulating glands, Colon, Duodenum, Epididymis (left), Esophagus, Heart, Ileum, Jejunum, Kidneys, Liver, Lung, Lymph nodes (mesenteric and axillary lymph nodes), Pancreas, Tounge, Pituitary gland, Prostate, Salivary gland, Seminal vesicles, Skin, Semen vesicles, Spleen, Forestomach, Testis, Thymus, Thyroid glands, Trachea, Uterus
Statistics:
- A comparison of inter-group differences (clinical chemistry, hematology and body weight) was performed using the t-test.
- DUNNETT's test was used to test the hypothesis of equal means.
- Steel-test was used to evaluate the inter-group differences relating to organ weights of each dose group.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No test substance-related findings were observed
Mortality:
no mortality observed
Description (incidence):
In the present study no animal died ahead of schedule.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance-related findings were observed in all parameters under investigation.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance-related findings were observed.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No test substance-related findings were observed.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No test substance-related findings were observed in all parameters under investigation.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
A decrease of the haematocrit (HCT) value in the male groups 2 - 4 was observed. The decrease of the HCT seems to be compound-and partially dose-related. Additionally the intermediate analysis showed slightly reduced Red Blood Cell (RBC)-value for the male group 4. The observed deviation of the HCT is considered to be incidental/ because the diagnosed values are within the ranges of the historical control. In addition to this, there are no corresponding deviations of the RBC- or MCV-values to prove the biological relevance of this findings.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No test substance-related findings were observed in all parameters under investigation.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
- Absolute organ weights: No test substance-related findings were observed in all parameters under investigation.
- Relative organ weights: No test substance-related findings were observed in all parameters under investigation.
Gross pathological findings:
no effects observed
Description (incidence and severity):
The macroscopical examination of the organs displayed some observations like discolouration of the thymus deformation of the spleen, cyst of the kidney, hydronephrosis, atrophy of the testes, hydrometra and necrosis of the fatty tissue which were considered to be spontaneous. Compound-related macroscopical effects were not observed. The male and female animals of the recovery group 4 (recovery period 33 days) showed no macroscopical compound-related alterations.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance-related findings were observed in all parameters under investigation. However, in the male and female animals of all groups (including the recovery group 1 and 4) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The observed germinal hyperplasia of the mandibulary lymph node can be interpreted as a consequence of this bacteriosis.
Histopathological findings: neoplastic:
no effects observed

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 adverse effects observed at the highest dose tested.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

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