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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP and did not follow specific international test guidelines. However, it was an acceptable, well-documented study report which meets basic scientific principles.

Data source

Reference
Reference Type:
other: Unpublished report
Title:
Unnamed
Year:
1961

Materials and methods

Test guideline
Deviations:
not specified
Principles of method if other than guideline:
Method: other: see below
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
dog
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
No data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily/ad libitum
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:0.10% (1000 ppm) Basis:nominal in diet
Remarks:
Doses / Concentrations:0.33% (3300 ppm)Basis:nominal in diet
Remarks:
Doses / Concentrations:1.0% (10,000 ppm)Basis:nominal in diet
No. of animals per sex per dose:
24 Beagle dogs were separated into four groups of 3 males and 3 females each.
Control animals:
yes, concurrent no treatment
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, Appearance, behavior, and survival were noted daily. BODY WEIGHT: Yes - Time schedule for examinations: weekly for the first 12 weeks, and at 4-week intervals thereafter. CLINICAL CHEMISTRY: Yes, Clinical tests included erythrocyte and leukocyte counts; blood hemoglobin, hematocrit, sugar and nonprotein nitrogen determinations; and urine protein, sugar, and sediment. Blood cholesterol levels, and prothrombin time were made at several intervals.NEUROBEHAVIOURAL EXAMINATION: Yes - Time schedule for examinations: Series of neurological reactions were tested in the control and in the highest dose level group at 12 weeks and at frequent periods thereafter (evaluation of behaviour, of patellar, tonic neck and tonic eye reflexes, and of placing, supporting and righting reactions, were made).
Sacrifice and pathology:
HISTOPATHOLOGY: Yes: Histopathological examination was performed on the liver, kidney, spleen, adrenals, thyroids, pituitary, heart, stomach, small and large intestine, pancreas, bladder, gall bladder, gonads, salivary glands, lymph nodes, lungs, bone marrow, muscle, brain and spinal cord. All tumors were examined microscopically.
Other examinations:
Organ weights included the liver, kidneys, adrenals, thyroid, and pituitary.
Statistics:
No data

Results and discussion

Results of examinations

Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITYNo changes in general appearanceBODY WEIGHT AND WEIGHT GAINNo changes inbody weightsFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)No changes in food consumption WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)HAEMATOLOGYAll hematological parameters were within normal ranges throughout the study with the exception of a slight decrease in the hemoglobin and hematocrit levels of the 1% group at 100 weeks. CLINICAL CHEMISTRYClinical chemistry parameters were normal with the exception of elevated cholesterol levels in the females of the high treatment group.NEUROBEHAVIOURNeurological parameters measured (patellar, tonic neck and tonic eye reflexes, and placing, supporting and righting reflexes) were normal at all timesORGAN WEIGHTSThe findings at necropsy revealed no changes in organ weights or significant gross abnormalitiesGROSS PATHOLOGYThe findings at necropsy revealed no changes in organ weights or significant gross abnormalities. HISTOPATHOLOGY: NON-NEOPLASTICHistopathological examination of the thyroid showed slight hyperplastic changes in one control and one high treatment group dog and a moderate degree of hyperplasia of one dog in the high treatment group. These were the only finding of possible significance in the gross histopathological examinations.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
3 300 ppm
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Questionable as to whether this should be the LOAEL or NOAEL. Hyperplasia was observed in one dog at the 10,000 ppm level, though the study authors concluded there was insufficent evidence to conclude that is was treatment related.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

All dogs survived the duration of the study with the exception of one female at the low and one female at the middle treatment group after five months. After confirmation of the diagnosis (encephalitic meningitis) at autopsy, these deaths were considered irrelevant to the study and the animals were replaced.

Applicant's summary and conclusion

Conclusions:
There were no effects reported at concentrations below 10,000 ppm in diet and the only effect reported at 10,000 ppm was in one dog and of questionable relationship to the test substance (based on the study authors conclusion). The NOAEL for both rats and dogs was set at 3300 ppm by the authors, though it appears that the actual NOAEL in dogs is 10,000 ppm based on the study report.
Executive summary:

There were no effects reported at concentrations below 10,000 ppm in diet and the only effect reported at 10,000 ppm was in one dog and of questionable relationship to the test substance (based on the study authors conclusion). The NOAEL for both rats and dogs was set at 3300 ppm by the authors, though it appears that the actual NOAEL in dogs is 10,000 ppm based on the study report.