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Toxicological information

Carcinogenicity

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Description of key information

In a dermal carcinogenicity study (BRRC, 1982) conducted to GLP, 25 µl of 25% 3-(2,3-epoxypropoxy)propyltrimethoxysilane in acetone was not carcinogenic in male C3H mice when administered three times per week.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
This study was designed to determine the dermal carcinogenic potential of the test material by applying it to the skin of male C3H/HeJ mice over the period of their lifetime and determining the gross and microscopic appearance of the resulting lesions.  
GLP compliance:
yes
Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Jackson Laboratories, ME
- Age at study initiation: 51 to 76 days.
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: Five per cage in stainless steel suspended cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data


IN-LIFE DATES: From: 12.03.1979 until death of animal.
Route of administration:
dermal
Vehicle:
acetone
Details on exposure:
TEST SITE
- Area of exposure: No data
- % coverage: No data
- Type of wrap if used: No data
- Time intervals for shavings or clippings: Fur clipped once per week.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data
- Time after start of exposure: No data


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 µl
- Concentration (if solution): 25%
- Constant volume or concentration used: yes


VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Amount(s) applied (volume or weight with unit): No data
- Concentration (if solution): 25%
- Lot/batch no. (if required): No data
- Purity: 100%


USE OF RESTRAINERS FOR PREVENTING INGESTION: No data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Lifetime
Frequency of treatment:
3 applications/week (Monday, Wednesday and Friday)
Post exposure period:
None
Dose / conc.:
5 mg/kg bw/day
Dose / conc.:
25 other: µl of 25% of the test material in acetone/application
No. of animals per sex per dose:
40
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: Not applicable
Positive control:
0.1% methylcholanthrene in acetone
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily for mortality


DETAILED CLINICAL OBSERVATIONS: No


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Carefully examined for skin lesions once per month.


BODY WEIGHT: No


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


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: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No
Sacrifice and pathology:
A necropsy was performed on all dead mice and on moribund mice, which were sacrificed.  A necropsy consisted of a careful examination of the skin and body cavities.  All observations were recorded.  The dorsal skin and any suspect internal tumours from all non-autolyzed mice were fixed in 10% neutral buffered formalin.  Tissues fixed in formalin were carefully trimmed, embedded, sectioned and stained with haematoxylin and eosin for examination by a pathologist.  All neoplastic and non-neoplastic lesions discovered during the histopathologic examination were recorded and tabulated.
Statistics:
Mortality rates and skin tumour incidence were compared by the product-limit method. The Mantel-Cox and Breslow statistics were used to test the equality of the survival and time-to-tumour curves.
Clinical signs:
no effects observed
Description (incidence and severity):
The mean survival time of the test material group was 482 days versus 502 days for the acetone controls. The difference was not statistically significant. The mean survival time in the methylcholanthrene (MC) group was 204 days reflecting the early mortality associated with the high incidence of skin tumours.
Mortality:
no mortality observed
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See Table 1. No epidermal or subcutaneous tumours were observed in the test material group. Eight animals had hyperkeratosis (compared to the acetone controls) suggesting a possible irritating effect on the epidermis. No epidermal tumours were observed in the group treated with acetone though two mice had subcutaneous sarcomas outside the treatment area (one subcutaneous fibrosarcoma of the left foreleg and one subcutaneous lymphosarcoma over the left hip).  One mouse had epidermal hyperplasia. The positive control (MC) group had 39 animals with skin tumours including 33 with confirmed squamous cell carcinomas, two mice with papillomas four mice had gross carcinomas that were not confirmed histologically because of cannibalism. These results confirm the sensitivity of the animals to a known skin carcinogen.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 5 other: mg/kg bw/day for 3 applications per week
Sex:
male
Basis for effect level:
other: No effects observed.
Critical effects observed:
not specified

Table 1 Summary of tumour data

   Test material  MC  Acetone
 Concentration  25%  0.1%  100%
 Volume (µ l)  25  25  25
 Mean survival time (d)  482  204  502
 Animals with papillomas  0  2  0
 Animals with carcinomas  0  37  0
 Animals with subcutaneous sarcomas  0  0  2
 Time to first skin tumour (d)  -  31  -
 Time to median skin tumour (d)  -  92  -




Conclusions:
In a dermal carcinogenicity study (reliability score 2) conducted to GLP, 25 µl of 25% of the test material in acetone was not carcinogenic in male C3H mice when administered three times per week.
Executive summary:

In a dermal carcinogenicity study (reliability score 2) conducted to GLP, 25 µl of 25% of the test material in acetone was not carcinogenic in male C3H mice when administered three times per week.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
chronic
Species:
mouse

Additional information

Two dermal carcinogenicity studies are available. These studies are of limited value in addressing the carcinogenicity endpoint, but together provide good negative evidence for dermal carcinogenicity.

A dermal carcinogenicity study which meets generally accepted scientific principles but was not conducted in compliance with GLP found 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8) not carcinogenic in male C3H mice when administered three times per week for the duration of a lifespan (BRRC, 1982). The NOAEL for carcinogenicity is reported to be >= 5 mg/kg bw/day for 3 applications per week. The test material was administered at 25% in acetone per application to 40 animals per sex per dose. A necropsy was performed on all dead mice and on moribund mice which were sacrificed. The necropsy consisted of a careful examination of the skin and body cavities, with all observations recorded as suspect internal tumours subjected to histopathological analysis. No epidermal or subcutaneous tumours were observed in the test group, with appropriate positive and negative control groups and expected results (BRRC, 1982).

A second dermal carcinogenicity study was also available for the registered substance, which found 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8) not carcinogenic in C3H mice when administered three times per week for the duration of a lifespan (Oak Ridge National Laboratory, 1987). The NOAEL for carcinogenicity is reported to be >11.1 mg/kg bw/day (male/female) for 3 applications per week. The test material was administered at 46.8, 62.4 and 78 mg/week in 50 µl cyclohexane to 40 animals per sex per dose. A necropsy was performed on all dead mice and on moribund mice which were sacrificed. The necropsy consisted of a careful examination of the skin and body cavities, with all observations recorded as suspect internal tumours subjected to histopathological analysis. None of the materials caused a significant increase in skin tumours. The only tumours (benign papillomas) were in the cyclohexane solvent control groups. There was a dose-dependent and marked increase in skin cancer with benzo(a)pyrene. The 24-month survival rates were 52.6, 32.5 and 48.7 % for females and 47.5, 51.3 and 51.3 % for males of the 46.8, 62.4 and 78 mg/week groups, respectively. The mid-dose females were significantly reduced compared with the solvent controls. In addition, there were no apparent treatment-related effect on body weight and organ weight (Oak Ridge National Laboratory, 1987).



The study was conducted according to a scientifically acceptable protocol.

Justification for classification or non-classification

Based on the available evidence, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane does not require classification for carcinogenicity according to Regulation (EC) 1272/2008.