[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

Carcinogenicity

Description of key information

In a dermal carcinogenicity study (BRRC, 1982) conducted to GLP, 25 µl of 25% [3-(2,3-epoxypropoxy)propyl]trimethoxysilane 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 or test system 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

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.

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)propyl]trimethoxysilane (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)propyl]trimethoxysilane (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.