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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:
From Nov. 17, 1980 to Dec. 21, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study design appears to follow OECD Guideline 409 (1998). Contains sufficient detail to suggest GLP-like characteristics, but no statement of certification (reasonably thorough description of authors, dates, design, results and interpretation). Dated and signed Quality Assurance Inspection statements included.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
Deviations:
yes
Remarks:
Only one male and one female for all dose groups in recovery phase; recovery groups are optional in OECD 409
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): TK 10047 (Tinuvin P)
- Lot/batch No.: EN 42238

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 31 - 34 weeks
- Weight at study initiation: males = 8.1 kg - 12.4 kg and females = 6.4 kg - 10.7 kg
- Housing: dogs were housed in kennels equipped with underfloor heating.
- Diet (e.g. ad libitum): Pelleted standard diet; 350 g/day/animal.
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 3°C
- Photoperiod (hrs dark / hrs light): 14 hours/10 hours

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: TK 10047 was weighed and dissolved with PAG 400 before being added to feed.
Details on oral exposure:
DIET PREPARATION: TK 10047 was weighed and dissolved with PAG 400 into an Erlenmeyer flask on a Mettler balance (Type PC 4400). The pulverized dog food was then homogeneously mixed with the appropriate concentrations of the compound and about 10% of water was added before pelleting to ensure the necessary pellet quality. The pellets were subsequently air-dried.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the initiation of the study, pretest feed samples were analysed for concentration and stability of the test material. The same procedure was undertaken with the food batches applied during the test.
Duration of treatment / exposure:
3 month treatment with a 28-day recovery period for 1 dog/sex/group.
Frequency of treatment:
Once/day. 7 days/week.
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 ppm
Dose / conc.:
3 000 ppm
Dose / conc.:
10 000 ppm
No. of animals per sex per dose:
6 dogs/sex/dose.
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: not reported.
Positive control:
Not used.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Daily.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest and Weeks 13 and 17.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Pretest, and Weeks 5, 9, and 13. Also Week 17 for recovery animals.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Pretest and Weeks 5, 9, and 13. Also Week 17 for recovery animals.

URINALYSIS: Yes
- Time schedule for collection of urine: Pretest and Weeks 5, 9, and 13. Also Week 17 for recovery animals.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
At the end of the 3 month test period or after an additional recovery period of 1 month all treated and control dogs were bled under T 61 (Hoechst) anaesthesia. The total weight of each animal was then determined, complete autopsy was performed and following organs were weighed: heart, liver, kidneys, adrenal glands, thyroid, pituitary, gonads and brain.

HISTOPATHOLOGY: Yes
Tissue portions of brain (cerebrum, cerebellum, brainstem), spinal cord, eye, pituitary, salivary gland, heart, thymus, thyroid, lungs (with mainstem bronchi), trachea, spleen, bone with marrow, lymph nodes (axillary and mesenteric), aorta, urinary bladder, oesophagus, stomach, small intestine (duodenum, ileum, jejunum), large intestine (colon, caecum), adrenal glands, pancreas, liver, kidneys, ovaries or testes, uterus or prostate, skeletal muscle, sciatic nerve, gall bladder, skin (mammary area) were fixed in buffered 10 % neutral formalin. The fixed tissue samples were embedded in paraplast and cut at 3-5 ym. The routine stain was haematoxylin and eosin.
Other examinations:
Hearing test was performed monthly.
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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN: The body-weight gain of group 4 (10,000 ppm) was depressed for both male and female dogs (no statistical significance)

FOOD CONSUMPTION AND COMPOUND INTAKE : The food consumption of group 4 (10,000 ppm) was reduced for both male and female dogs.

CLINICAL CHEMISTRY: The alanine-aminotransferase (GPT) increased in group 3 (3,000 ppm) and 4 (10,000 ppm) (p < 0.01). The gamma-glutamyl-transpeptidase (GGT) increased in group 4 (10,000 ppm) (p < 0.01).

PATHOLOGY: One female dog from the 10,000 ppm group was emaciated. No other gross or microscopical changes in the organs and tissues related to the treatment with TK 10047 were noted.

Haematology: Beginning at the fifth week of treatment, animals of the highest dose groups showed values for mean cell volume and mean cell haemoglobin that were slightly lower than the limit of the normal range.

ORGAN WEIGHTS:
For females and males, the relative liver weight was increased by 21% (p < 0.05 compared to control) and 28% at 10000 ppm (p < 0.01 for dose-dependent trend) at the end of the treatment period. This was not observed in animals of the recovery groups.
No experimental significance is attributed to the decreased mean thyroid to body weight ratio at the highest dose group in male dogs (p < 0.05).

OTHER FINDINGS: HEARING TEST: No impairment of the auditory perception was found.

Effect levels

Dose descriptor:
NOEL
Effect level:
1 000 ppm
Sex:
male/female
Basis for effect level:
other: The substances caused a reversible increase in relative liver weight with increased ALT and GGT levels, but without histopathology findings. A reduction in body weight gain occured at the highest dose.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The observations made during the study demonstrate that TK 10047 fed to dogs by daily dietary administration for a 3 months period has a "no observable effect level" of 1000 ppm.