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Diss Factsheets

Administrative data

Description of key information

28 -day repeated dose toxicity: oral, rat

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
1981
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL (as stated in study report): TK 12184

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Sponsor / Batch No. Mixt. 4/5/6
Species:
rat
Strain:
other: Tif: RAIf (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Production, CIBA-GEIGY LTD., 4332 Stein/Switzerland
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: males - 171 - 174; females - 164 - 170
- Housing: individually in Macrolon cages type 3 with standardised granulated soft wood bedding
- Diet (e.g. ad libitum): Pelleted, certified Standard diet Nafag No. 890 Tox, ad libitum except during urine collection.
- Water (e.g. ad libitum): ad libitum except during urine collection
- Acclimation period: one week

DETAILS OF FOOD AND WATER QUALITY: All batches of diet were assayed for composition and contaminant level by the manufacturer. Water
was drinking quality according to the specifications of the "Schweizerisches
Lebensmittelbuch".

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 deg C
- Humidity (%): 55 + 10 %
- Air changes (per hr): 15 - 17
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5%
Details on oral exposure:
Dosing solutions were freshly prepared every day iramediately prior to the dosing of the animals and administered within 2 hours.

Dosage volume: 10 mL/kg
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 d
Frequency of treatment:
Once daily, seven days per week
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were assigned to the different groups by means of random numbers generated by computer.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, mortality
- Time schedule: daily (a.m. and p.m. on working days)

DETAILED CLINICAL OBSERVATIONS: Yes, symptoms
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes, weekly

FOOD EFFICIENCY: Yes, weekly

WATER CONSUMPTION: Yes
- Time schedule for examinations: days 15 - 18 and days 22 - 24

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: beginning and end of treatment period
- Dose groups that were examined: control and high dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at end of treatment period
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: Yes, about 20 hours
- How many animals: 5 per sex per group
- Parameters examined: RBC count, hemoglobin, platelet count, leucocyte count, total count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at end of treatment period
- Animals fasted: Yes, about 20 hours
- How many animals: 5 per sex per group
- Parameters examined: glucose, urea, total protein, GOT, GPT, AP.

URINALYSIS: Yes
- Time schedule for collection of urine: at end of treatment period
- Metabolism cages used for collection of urine: Yes, overnight
- Animals fasted: Yes, food and water withheld
- Parameters examined: pH, protein, glucose, urobilinogen, sediment.

OTHER EXAMINATIONS: Hearing tests were conducted on control and high dose groups at the end of the treatment period.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals were subjected to detailed autopsy.

ORGAN WEIGHTS: liver, adrenals, brain, spleen, thymus, heart, kidneys and gonads.

HISTOPATHOLOGY: A standard set of 36 organs and tissues as well as any grossly abnormal tissues were preserved in 10 % neutral formalin for possible examination.
Statistics:
For each time point and parameter a uni-variate statistical analysis was conducted. Due to the routine manner of the analysis system parameter free methods were applied. Each treated group was compared to the control group in respect of dispersion and displacement. In addition a trend test was applied considering all groups.
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:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
The mean water consumption in male and female groups 4 (300 mg/kg bw.) tended to increase towards the end of the treatment period.
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
A slight decrease of the number of leucocytes in the females of the 100 and 300 mg/kg/day groups.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistical analysis of organ weights and organ weight ratios showed a statistically significant decrease in liver weights of male group 4 (300 mg/kg bw.) and a similar trend in females.

A few inconsistent but statistically significant intergroup variations in organ weights, organ to body weight and organ to brain weight ratios were found. Although statistically significant these differences were not dose related and are attributed to spontaneous variation rather than to the treatment.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Dose descriptor:
LOEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
Under these test conditions, the oral administration of TK 12 184 to rats by gavage, at dose levels of 30, 100 and 300 mg/kg bw/day did not result in mortality. No adverse effects were seen on clinical symptoms, body weight gain, food consumption, ophthamology, hearing, or on hematology, blood chemistry or urinalysis parameters. Mean water consumption tended to increase in male and female animals receiving 300 mg/kg/day toward the end of the treatment period. Statistically significantly lower liver weights were seen in males and females of the 300 mg/kg/day dose group. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 100 mg/kg bw/day.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral administration of TK 12 184 to rats by gavage, at dose levels of 30, 100 and 300 mg/kg bw/day for 28 -days did not result in mortality.  No adverse effects were seen on clinical symptoms, body weight gain, food consumption, ophthamology, hearing, or on hematology, blood chemistry or urinalysis parameters.  Mean water consumption tended to increase in male and female animals receiving 300 mg/kg/day toward the end of the treatment period.  Statistically significantly lower liver weights were seen in males and females of the 300 mg/kg/day dose group.  The ‘No Observed Effect Level’ (NOEL) for systemic  toxicity was therefore considered to be 100 mg/kg bw/day.

Justification for classification or non-classification

Based on the available data, TGEPO is not classified according to Regulation (EC) No 1272/2008.