3-aminopropyltriethoxysilane

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988-08-08 to 1988-08 19 (in life)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Reference 2

Reference Type:

secondary source

Title:

SIDS Initial Assessment Report For SIAM 17, Arona, Italy, 11-14 November 2003. 3-Aminopropyltriethoxysilane.

Author:

OECD SIDS

Year:

2003

Bibliographic source:

SIDS Initial Assessment Report For SIAM 17

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The objective of this 11-day repeated cutaneous dose toxicity study was to evaluate the potential skin irritancy and systemic toxicity of the test article in rabbit resulting from 9 applications.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-aminopropyltriethoxysilane

EC Number:

213-048-4

EC Name:

3-aminopropyltriethoxysilane

Cas Number:

919-30-2

Molecular formula:

C9H23NO3Si

IUPAC Name:

silane

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 18 weeks
- Weight at study initiation: 2976 to 3388 grams for males and from 2885 to 3484 grams for females.
- Fasting period before study: No
- Housing: not specified
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: not specified

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: mineral oil

Details on exposure:

The test article was administered at a constant volume of 2.0 ml/kg/day in mineral oil (1%, 5% or 7.5% solutions) and the resulting dose levels corresponded to 17, 84 and 126 mg bw/kg/day. These dose levels were chosen based upon the results of a four-day probe with the test material diluted to 1, 5, 7.5 and 10% in mineral oil. The control group was treated with mineral oil only, at the same volume. The doses were applied using the treatment regimen identified above. The animals given 126 mg/kg/day were treated with the test material at least 6 hours/day for 3 consecutive days and observed for any reversal of the cutaneous irritation for the remainder of the study. Prior to dosing and subsequently as required, the fur was clipped from the dorsal area of the trunk of each animal. The clipped area was covered with a gauze patch and the test solution was applied to the gauze patch. Each animal was then wrapped and returned to its cage for a period of 6 hours. At the end of the exposure period, the wrappings were removed and the exposure area was wiped with a dry cloth to remove any remaining test material.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 h/day, 3 days or 9 days (over 11 days)

Frequency of treatment:

See table 1, below.

Animals in the 0, 17, and 84 mg/kg bw/day groups were treated for five consecutive days in the first week, followed by two days without treatment, and subsequently four consecutive days of treatment in the second week for a total of nine applications. Those in the 126 mg/kg bw/day group were treated on 3 consecutive days.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

17 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

84 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

126 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: Not applicable. All animals were euthanized and necropsied upon completion of the treatment period; no recovery or other satellite groups were included.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked in table were included: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

DERMAL IRRITATION: Yes
- Time schedule for examinations: daily immediately before each application of the test material, on the days when no test material was applied and on the day of necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of treatment (Day 1) and on Days 8 and 12.

FOOD CONSUMPTION: yes, daily
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY: not specified
- 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 data

WATER CONSUMPTION: No data
- Time schedule for examinations: n/a

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: n/a
- Dose groups that were examined: n/a

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination (day 12)
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All animals
- Parameters checked in table were examined: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At study termination (day 12)
- Animals fasted: No data
- How many animals: All animals
- Parameters checked in table were examined: Yes

URINALYSIS: Yes
- Time schedule for collection of urine: At study termination (day 12)
- Metabolism cages used for collection of urine: No, urine was collected from the urinary bladder following anaesthesia.
- Animals fasted: No data
- Parameters checked in table were examined: Not specified

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations: n/a
- Dose groups that were examined: n/a
- Battery of functions tested: sensory activity / grip strength / motor activity / other: n/a

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)

HISTOPATHOLOGY: Yes (see table)

Statistics:

Levene's test was done to test for variance homogeneity. In the case of heterogeneity of variance at p 0.05, transformations were used to stabilize the variance. Analysis of variance (ANOVA) was done on the homogeneous or ranked data. If the ANOVA was significant, Dunnett's t-test was used for pairwise comparison between groups. When no transformation established variance homogeneity at p 0.001, the data were also examined by nonparametric techniques. These statistics include the Kruskal-Wallis H-test ANOVA and, if this test was significant, the Nemenyi-Kruskal-Wallis test for multiple comparisons or the Wilcoxon-Mann-Whitney two-sample rank test. Standard one-way ANOVA was used to analyze initial body weights, food consumptions, clinical chemistry and hematology values (except red blood cell morphology), organ weights, organ-to-body weight percentages, and organ-to-body weight ratios. Standard one-way analysis of covariance (ANCOVA) was used to analyze body weight, with initial body weight as the covariate. Although Levene's test for variance homogeneity was done, no transformations were used because covariance adjustment removed extraneous heterogeneity. If the ANCOVA was significant, Dunnett's t-test was used for pairwise comparisons between groups.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

In the control and the low dose group, mild erythema and desquamation resulted from treatment with mineral oil. The lesions occurred earlier in the animals in the 17 mg/kg bw/day group. Moderate to severe erythema, edema, desquamation, atonia, and fissuring developed progressively in both sexes treated with 84 mg/kg bw/day. Moderate to severe lesions were observed in the high dose group animals following the second treatment and dosing was terminated after the third treatment. A slight improvement in erythema, oedema, and atonia occurred following termination of the dosing, however, desquamation and fissuring showed no significant improvement by the end of the study. Observations related to the test article at necropsy were restricted to cutaneous lesions at the treatment site.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopically, the test material resulted in moderately severe local skin changes characterized by crusting, acanthosis/hyperkeratosis, and ulcerative dermatitis primarily in the mid and high dose groups

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

Application for 9 days (over 11 days)

Effect level:

84 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No observable effects

2

Dose descriptor:

NOAEL

Remarks:

Application for 3 days

Effect level:

126 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No observable effects

3

Dose descriptor:

LOAEL

Remarks:

local effects

Effect level:

17 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: skin irritation

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The site of contact NOAEL was less than 17 mg/kg bw/day.

Applicant's summary and conclusion

Conclusions:

A generally well reported 11-day dermal study, conducted in accordance with GLP but not to a current guideline, found skin irritation but no systemic toxicity in rabbits after 9 repeated doses of 84 mg/kg bw/day or 3 repeated doses of 126 mg/kg bw/day.