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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: methodology outdated (treatment with the test substance only twice a week, only one dose level tested), however the study meets generally accepted scientific standards and is well documented

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1985
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1985

Materials and methods

Principles of method if other than guideline:
The purpose of this investigation was to determine the carcinogenic potential of the test substance. In addition, the study provided information about the chronic dermal toxicity of the test substance. 50 male mice were treated with the test substance (25 mg, 10% solution in mineral oil) dermally twice a week for 80 weeks. The skin was examined histologically for non-neoplastic and neoplastic lesions. Histological examination of other organs was performed in 40% of the animals.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): C-178
- Physical state: liquid
- Analytical purity: no data

Test animals

Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Jackson Laboratory
- Age at study initiation: 6-8 weeks upon receipt, 9-11 weeks after quarantine
- Housing: five/cage in stainless steel suspended cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 °C +- 1 (74 °F +- 2)
- Humidity (%): 45 % +- 10 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
dermal
Vehicle:
other: mineral oil
Details on exposure:
TEST SITE
- Area of exposure: backs of the mice
- coverage: open
- Time intervals for shavings or clipplings: hair was removed before starting the repeated appliacation; during the study, hair was clipped every two weeks; when tumors were evident, care was taken to avoid damaging lesions during clipping procedures.


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 mg
- Concentration (if solution): 10% solution in mineral oil (25 mg 2x/week)
- Constant volume or concentration used: yes


VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance is immiscible in water


USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
80 weeks
Frequency of treatment:
twice weekly
Post exposure period:
none
Doses / concentrations
Remarks:
Doses / Concentrations:
25 mg
Basis:
nominal conc.
No. of animals per sex per dose:
50 male animals
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the dose was selected based on a pilot study that indicated considerable acute dermal toxicity for the test substance. Therefore a reduced dosage, 25 mg of a 10% solution in mineral oil was used in the long-term study.
Positive control:
50 mg of a 0.05% solution of benzo(a)pyrene in mineral oil

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: signs of toxicity, clinical observations of the skin


DETAILED CLINICAL OBSERVATIONS: No data


DERMAL IRRITATION (if dermal study): No data

BODY WEIGHT: Yes
- Time schedule for examinations: prior to the initial treatment, weekly during the first month and every two weeks thereafter


FOOD CONSUMPTION:
No data


FOOD EFFICIENCY:
No data


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: No data


CLINICAL CHEMISTRY: No data


URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, a complete post mortem examination was performed: the abdominal, chest, and cranial cavities were examined; all organs were removed and any abnormalities were recorded; any unusual gross observation at autopsy received special attention in the histopathological examination
HISTOPATHOLOGY: Yes, the interscapular area, that included all neoplasms and suspicious lesions; subcutaneous lymph nodes from the neck, axillary and groin areas, tissue from each organ was preserved for possible microscopic examination; the skin tissues from all animals were examined microscopically, complete microscopic examinations of internal organs were performed in the controls and in ca. 40% of the treated animals.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
The mean survival time of the test group was equal to the control group treated with mineral oil alone. Depressed survival was evident in the positive control (16 weeks less then control). The appendix with clinical observations was not included in the copy of the study. The summary page states, that no tumors were observed in the animals treated with the test substance in mineral oil and no difference of skin conditions were observed in the test group compared to controls. Skin tumors were observed in 46/50 positive control animals.

BODY WEIGHT AND WEIGHT GAIN
The weight curve of the test group was similar to those of the negative control groups.


GROSS PATHOLOGY
Neither controls nor the treated animals showed a preponderance of any pathological alterations. The incidence of hepatocarcinomas in the treated group was at least as high as that in the negative control groups after 80 weeks.

HISTOPATHOLOGY: NON-NEOPLASTIC
The mice in the two negative control groups, No Treatment and Mineral Oil, showed similar responses of the skin at the site of application. Hyperplasia of the dermis (fibrosis), acanthosis, and hyperkeratosis are common findings in areas of mouse skin that are kept hairless. Small ulcers, folliculitis,
small abscesses, and scar tissue were seen in some animals. The direct or indirect cause of these conditions is probably the repeated clipping of the
hair. 13/50 mice in the No Treatment group and 8/50 receiving Mineral Oil had no abnormalities in the skin. The test material caused pigmentation of the skin in 36% of the animals. The incidence of fibrosis of skin in the control groups was 74% to 88% and for the animals treated with the test material 94%.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
One mouse in the No Treatment group had a grade 3 squamous cell carcinoma ot the skin. This lesion was noted as a scab at autopsy. It had metastasized into a regional subcutaneous lymph node. The historical control data indicate that the incidence of spontaneous tumors of the epidermis in untreated mice of this strain is no more than 3%. No skin neoplasms were observed in animals treated with mineral oil or in the animals treated with the test substance in mineral oil. A total of 180 skin neoplasms were observed in 45 of the 49 mice examined histologically in the positiove control group. Malignent skin tumors were found in 43 mice. 40 of these animals had both benign and malignant tumors.

Applicant's summary and conclusion

Conclusions:
Under the conditions selected for this study no skin tumors were observed in animals treated with the test substance.