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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Frequency of measurements (ophtalmological examination, haematology, clinical biochemistry and urinalysis) was lower than the recommended one in the guideline
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
Supplier: BASF

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Chbb : Thom (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl THOMAE, Biberach/Riss FRG
- Age at study initiation: 42 days
- Weight at study initiation: On test day -1: males 167 (157-178) g and females 139 (131-148) g
- Housing: Individual stainless steel wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

DETAILS OF FOOD AND WATER QUALITY: The drinking water is regularly assayed for chemical contaminants by the municipal authorities of Frankenthal and the Technical Services of BASF Aktiengesellschaft, as well as for the presence of microbes by a contract laboratory. The food used in the study was assayed for chemical as well as for microbiological contaminants.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The preparations of the drinking water solutions was carried out twice a week. Weighed amounts of the test substance for the specific test group were diluted with the appropriate weighed amounts of drinking water. The mixtures were subsequently stirred with at magnetic stirrer for a least 30 minutes to reach complete solubility of the test substance in the drinking water.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in drinking water over a period of 4 days was checked analytically at the beginning of the study. To check the correctness of the concentrations of the drinking water solutions samples of each concentration were sent for analysis at the beginning and at the end of the study.
Duration of treatment / exposure:
3 months
Frequency of treatment:
Continuous
Doses / concentrationsopen allclose all
Dose / conc.:
500 ppm
Remarks:
Corresponding to ca. 40 mg/kg b.w. Basis: nominal in water.
Dose / conc.:
2 000 ppm
Remarks:
Corresponding to ca. 143 mg/kg b.w. Basis: nominal in water.
Dose / conc.:
7 000 ppm
Remarks:
Corresponding to ca. 407 mg/kg b.w. Basis: nominal in water.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Data used for dose selection: 1. Subchronic studies of cyclohexanone, Final report from Frederick Cancer Research Center to NCI, January 10, 1979 partly published in 2 . W . Lijinsky and R.M. Kovatch (1986) Chronic Toxicity Study of Cyclohexanone in Rats and Mice. JNCI 77, pp. 941 - 949. 3. Preliminary results of a palatability test study (Project No. 12S0332/92069).

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily (twice on working days and once on weekends or holidays)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to the begining of the treatment in all animals and in the high dose group and control group at the end of treatment period

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the treatment period

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the treatment period

URINALYSIS: Yes
- Time schedule for collection of urine: At the end of the treatment period

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
The statistical evaluation and calculation of the data were carried out on the computer systems of the Department of Toxicology of BASF AG.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A statistically significant reduction of body weights was observed in the animals of the high dosage group, which occurred earlier during the study period in male animals than in females. At the end an about 10% reduction of body weight resulted in this test group. This reduced body weight development was also demonstrated by decreased body weight change in animals of the 7000 ppm dose group. In the female animals of the 2000 ppm dose group, a reduction of weight change values occurred without leading to a statistically significant reduction of the absolute body weight.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption was not influenced in the 500 ppm dose group and male animals in the 2000 ppm dose group. It was sporadically significantly reduced in female animals of the 2000 and 7000 ppm dose groups, but nearly over the whole administration period in males of 7000 ppm dose group.
Food efficiency:
no effects observed
Description (incidence and severity):
There was no clear influence of treatment on food efficiency.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decreases in water consumption occurred sporadically in the 500 ppm dose group, more often in the 2000 ppm dose group and over the whole study period in the 7000 ppm dose group. In the 7000 ppm dose group, the overall water consumption of males was reduced about 31% and that of females about 37%.
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
At 7000 ppm:
- Increase in total cholesterol, total protein and globulins in both sexes.
- Increase in platelets in the females.
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
The findings on food and water consumption were attributed to the strong odor and taste the test substance, preventing full acceptance of the treated water and the food by the animals.The increase in total cholesterol in the serum of both sexes is probably due to a slight impairment of lipid metabolism. The increase in serum proteins seen in the high-dose animals might be related to the reduced water consumption, however, the significance of this isolated finding is not obvious. These results are probably a result of slight changes in lipid metabolism or of reduced water consumption.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
143 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

A yellowish-orange discoloration of urine in the bedding in the mid and high dosage groups is judged to be due to excretion of some metabolites of the test substance.

Applicant's summary and conclusion

Conclusions:
The NOAEL for this drinking water study is 2000 ppm, corresponding to a dose of 143 mg/kg bw/day.
Executive summary:

This drinking water study was performed according to the OECD Guideline 408 and under GLP. Ten female and ten male Wistar rats per dose group were continuously exposed to 500, 2000 or 7000 ppm through the drinking water (corresponding to 40, 143 and 407 mg/kg bw) for 90 days. Weighing of all animals was done daily, food and water consumption weekly, and detailed observations (ophtalmological examination, haematology, clinical biochemistry and urinalysis), as well as gross necropsy and histopathology, at the end of the study. At the concentration of 7000 ppm signs of toxicity were observed. In this dosage group, an increase in total cholesterol, total protein and globulins in both sexes, and an increase in platelets in the females, were observed. The only substance related pathomorphological effect was the decreased terminal body weight. The reduction of water and food consumption at the lower concentrations is not considered to be an adverse health effect, but caused by the strong odor and taste of the test substance. Therefore, the NOAEL for this drinking water study is 2000 ppm, corresponding to a dose of 143 mg/kg body weight/day.