Bis(trimethoxysilylpropyl)amine

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: 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: see remark

Remarks:

There were positive skin reactions observed with the vehicle control, light paraffin oil. The mild to moderate microscopic skin lesions found for animals treated with the vehicle alone suggests that the vehicle and/or test procedure contributed to the skin irritation observed in the Silane-treated animals. Hence, no clear resulton both the local and the systemic, repeated dose toxicity hazard could be obtained from this study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Version / remarks:

(1983)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis(trimethoxysilylpropyl)amine

EC Number:

280-084-5

EC Name:

Bis(trimethoxysilylpropyl)amine

Cas Number:

82985-35-1

Molecular formula:

C12H31NO6Si2

IUPAC Name:

3,3,11,11-tetramethoxy-2,12-dioxa-7-aza-3,11-disilatridecane

Details on test material:

- Name of test material (as cited in study report): Organofunctional silane Y-9492
- Physical state: clear, colourless, nonviscous liquid
- Lot/batch No.: 0121GG010987
- Stability: at room temperature, when stored in closed container (analyses indicated test material stability in the dosing solution for at least 14 days)
- Storage condition of test material: sealed at room temperature
- Date of Receipt: 08 January 1988

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Dutchland (Denver, PA)
- Age at study initiation: 17-19 weeks
- Weight at study initiation: 3531.0±163.44 g (control group males); 3535.6±138.82 g (low dose males); 3476.7±172.42 g (mid dose males); 3532.2±172.82 g (high dose males); 3498.6±204.20 g (control females); 3430.7±110.13 g (low dose females); 3452.6±130.63 g (mid dose females); 3493.2±213.12 g (high dose females)
- Housing: The rabbits were housed individually in stainless steel cages with wire floors. A layer of Deotized Animal Cage Board@ (Shepherd Specialty Papers, Inc., Kalamazoo, MI) was kept under each cage and changed daily.
- Diet: Agway Prolab Certified Rabbit Diet (Agway, Inc., St. Mary's, OH, and Waverly, NY) was available to the rabbits on a restricted basis during the acclimation period. The amount of food was increased gradually from 4 ounces/day/rabbit at the time of arrival to 12 ounces/day/rabbit 3 days prior to dosing and were maintained on 12 ounces/day until the first day of dosing. Food was available ad libitum from day 1 until the end of the study.
- Water: Water (Municipal Authority of Westmoreland County, Greensburg, PA) was administered ad libitum by an automatic watering system with demand control valves mounted on each rack.
- Acclimation period: approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8-22.2 (64-72°F)
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: from 12 April 1988 to 23 May 1988

Administration / exposure

Type of coverage:

occlusive

Vehicle:

paraffin oil

Remarks:

mineral oil

Details on exposure:

TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: at least 10
- Type of wrap if used: Lycra/Spandex jacket that was lined with Vinyllite and held in place with velcro strips
- Time intervals for shavings or clipplings: Prior to the first dose and subsequently as needed (care was taken to avoid abrading the skin.)
- Other: Prior to the initiation of the study, the animals were sham-wrapped once in the manner used during the study to minimise the stress involved with the first application of the dose.

REMOVAL OF TEST SUBSTANCE
- Washing: Yes (The back of each animal was wiped with a dry cloth. The use of a damp cloth seemed unappropriated , since this might exacerbate the irritant properties. The test material reacts rapidly with water to form methanol.)
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied: 2 ml/kg bw
- Concentration (if solution): 0.5, 1, and 5% in vehicle
- Constant volume or concentration used: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): Probe studies indicate that the test article is severely irritating and must be diluted with and appropriate vehicle prior to application. The test material reacts rapidly with water to form methanol.
- Appearance: clear, oily viscous liquid
- Source: Fisher Scientific, Pittsburgh, PA
- CAS No.: 8012-95-1
- Lot/batch no.: 875079, 871981, and 870338
- Stability: stable at room temperature
- Storage conditions: room temperature
- Purity: > 99%

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Dosing solutions were analysed by a gas chromatographic procedure developed at the test facility. Prior to the start of the study, stability and homogeneity ofthe test item solutions in light paraffin oil were determined at nominal concentrations of 0.5, 3.0, and 5.0% test substance. The test substance concentrations in the dosing solutions used in the study were confirmed prior to administration of the solutions to the animals.
The results indicated that the distribution of the test item in the vehicle was uniform. Concentration verification analyses on formulations used for dosing showed analytical values ranging from 96.3-104.2% of the nominal concentration.

Duration of treatment / exposure:

6 h/day

Frequency of treatment:

5 days/week for 4 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

8.4 mg/kg bw/day (nominal)

Remarks:

0.5%: nominal test material concentration in mineral oil

Doses / concentrations 2

Dose / conc.:

16.8 mg/kg bw/day (nominal)

Remarks:

1%: nominal test material concentration in mineral oil

Doses / concentrations 3

Dose / conc.:

84 mg/kg bw/day (nominal)

Remarks:

5%: nominal test material concentration in mineral oil

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses for the study were selected based on the results of the acute toxicity and primary irritancy studies (BRRC Project Report 45-49) and a series of repeated dose percutaneous dose-range finding studies conducted on the test item.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily (twice daily for mortality)
- Cage side observations checked: signs of toxicity, with particular attention being paid to the treated area of skin

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION: Yes
- Time schedule for examinations: Careful examination was made prior to dosing each day for signs of irritation.
- Scoring system for skin irritation: Skin irritation signs were graded for erythema and edema according to the Draize scoring system.
The scoring system used for erythema was: 0 = no erythema; 1 = barely perceptible erythema; 2 = well defined erythema; 3 = moderate to severe erythema; 4 = severe erythema.
The scoring system used for edema was: 0 = no edema; 1 = barely perceptible edema; 2 = slight, well defined edema; 3 = moderate edema; 4 = severe edema

BODY WEIGHT: Yes
- Time schedule for examinations: immediately prior to the first dose (Day 1), prior to the 6th, 11th, and 16th doses (days 8, 15, and 22, respectively), and on day 28 prior to fasting; fasted body weights were also measured prior to sacrifice (day 29) to allow expression of organ weights relative to body weight

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes
- Time schedule: on days 1, 3, 5, 7, 8, 10, 12, 14, 15, 17, 19, 21, 22, 24, 26, and 28

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice by cardiac puncture
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: erythrocyte count, haemoglobin concentration, haematocrit, erythrocyte indices, total leukocyte count, differential leukocyte count, and platelet count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice by cardiac puncture
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: glucose, urea nitrogen, creatinine, total protein, albumin, globulin, serum haemoglobin, indirect bilirubin, total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), gamma-glutamyl transferase (GGT), lactate dehydrogenase, alkaline phosphatase, creatinine phosphokinase, calcium, phosphorus, sodium, potassium, and chloride

URINALYSIS: Yes
- Time schedule for collection of urine: at necropsy, urine was taken from the urinary bladder for urinalysis measurements
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked: specific gravity, pH, protein, glucose, ketone, bilirubin, blood, urobilinogen, microscopic elements, and volume (bladder contents)

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
A complete necropsy was performed on each animal.
- Organs checked: brain (cerebral cortex, cerebellar cortex, medulla/pons), eyes, pituitary, salivary gland, heart, aorta, thymic region, thyroid (with parathyroid), lungs (2 coronal sections including all lobes and mainstem bronchi), trachea, oesophagus, spinal cord (cervical, thoracic, lumbar), pancreas, liver (2 lobes) with gallbladder, kidneys, urinary bladder, testes, prostate, epididymis, ovaries, vagina, uterus (corpus and cervix), spleen, lymph nodes (mesenteric & non-mesenteric), skeletal muscle, stomach, duodenum, jejunum, ileum, caecum, colon, rectum, adrenals, sciatic nerve, mammary gland (females), skin (treated and untreated), and sternum (including marrow)

HISTOPATHOLOGY: Yes
- How many animals: rabbits of the vehicle control and high dose groups and for treated and untreated skin from rabbits in the low and mid dose treatment groups
- Organs checked: brain, pituitary, heart, thymic region, thyroid, lungs, liver, kidneys, testes, epididymis, ovaries, uterus, spleen, lymph nodes, adrenals, skin (treated and untreated), sternum (including marrow)

ORGAN WEIGHTS. Yes
- Organs checked: liver, kidneys, adrenals, brain, and heart

Statistics:

Food consumption, body weight, and organ weight data were intercompared for the dose and control groups by use of Levene's test for homogeneity of variances, by analysis of variance, and by pooled variance t-tests. The t-tests were used, if the analysis of variance was significant, to delineate which groups differed from the control group. If Levene's test indicated heterogeneous variances, the groups were compared by an analysis of variance for unequal variances followed, if necessary, by separate variance t-tests. Medians and quartile deviations were calculated for non-parametric data. These data were statistically analysed by the Kruskal-Wallis test and, if necessary, by the Wilcoxon rank sum test as modified by Mann-Whitney. Frequency data were compared using Fisher's exact tests where appropriate. All statistical tests, except the frequency comparisons were performed using BMDP Statistical Software (Dixon, 1985). The frequency data tests are described in Biometry (Sokal, R. R. and Rohlf, F. J., W. 8. Freeman and Company: San Francisco, 1969). The fiducial limit of 0.05 was used as the critical level of significance for all tests.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Mild to moderate skin irritation in the low dose group and mild to marked irritation in mid and high dose groups. Since some effects were observed in the solvent controls, irritations seen in test gruops may partly have been caused by the solvent.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weight gain was observed in both treated males and females as compared to the controls, but the effects were not statistically significant.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Decreased food consumption was observed in both treated males and females as compared to the controls, but the effects were not statistically significant.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A treatment related decrease in absolute and relative liver weights was observed in mid and high dose males as compared to the controls. However, the effects were not statistically significant.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related gross lesions were observed only in the treated skin of both males and females of all treatment and control groups, with higher severity and/or incidence of severity tending to the treatment groups.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related microscopic lesions were observed only in the treated skin of both males and females of all treatment and control groups, with higher severity and/or incidence of severity tending to the treatmen groups.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No animals died during the study.
Treatment-related clinical signs of toxicity were restricted to the site of application of test material or vehicle. Erythema and oedema were observed in some animals from most groups including controls. These lesions tended to occur earlier and were more severe in the high and mid dose groups. Erythema was observed for all males in the high dose group with maximum severity scores of well defined (2 males) and moderately severe (3 males). Erythema was also observed for all animals in the mid dose group with maximum severity scores of barely perceptible (4 males) and moderately severe (1 male). Erythema, scored as barely perceptible or well defined, was observed for 2 males in the control group and 1 male in the low dose group. Oedema was observed for all males in the high dose group with maximum severity scores of well defined (1 male) and moderate (4 males). Oedema, scored principally as well defined, was observed for 1 male from each of the control and mid dose groups. Oedema was not observed for males in the low dose group. Findings of erythema and/or oedema occurred principally during the 3rd or 4th week of dosing for the 2 males in the control group, from days 5-13 for the male in the low dose group, and in all weeks of dosing for males in the mid and high dose treatment groups.
Erythema was scored principally as well defined for females in the high dose group and barely perceptible for females in the control, low dose, and mid dose groups. All females in the high dose group had erythema starting in the first week of dosing. The incidence of erythema for the control (1 animal), low dose (1 animal), and mid dose (3 animals) groups observed near the end of the first week of dosing increased to 4 or 5 females per group at the end of the last week of dosing. Oedema (barely perceptible to moderate severity) was observed for all females in the high dose group after the first week of dosing. Oedema, scored principally as barely perceptible, was observed for 2 females from the mid dose group after the first week of dosing and 2 additional females each from this group and the low dose group at the end of the dosing period. Oedema (barely perceptible and/or well defined) was observed for 3 females in the control group during the 3rd or 4th weeks of the study.
Other treatment-related clinical signs of toxicity (in addition to erythema and oedema) were limited to the skin at the application site and included exfoliation, ecchymosis, excoriation, encrustation, ulceration, and fissuring for both males and females. Lesions were observed predominantly in the mid and high dose groups with more animals in the high dose groups affected than in the other groups. Exfoliation and ecchymosis were observed in approximately equal incidence for all groups of females including controls. The incidence of all lesions in males and all other lesions in females appeared to show a dose response. Pustule and abscess were observed for 1 low dose female. No other treatment-related clinical signs of toxicity were observed in this study.

BODY WEIGHT AND WEIGHT GAIN
Statistically significant alterations in absolute body weights and body weight gain were not observed in male or female rabbits administered 8.4, 16.8, or 84.0 mg/kg bw/day of the test material. However, decreased mean body weight gain compared to controls or mean body weight losses were observed for males in the mid dose and high dose groups during the study. Mean body weight loss was observed for males in the mid dose group during the first week of the study and for males in the high dose group during the first and second weeks of the study compared to a mean body weight gain of 78.5 g and 166.2 g for controls for the first and second week of treatment, respectively. Mean body weight gains during the remainder of the study for the mid and high dose groups compared to controls were decreased: 38% to 57% (mid dose males) and 86% to 89% (high dose males).
Mean body weight losses were observed throughout the study for females in the control and high dose groups. The maximum loss for both groups occurred during the first week of the study with mean losses of 89.3 g for controls and 204.4 g for the high dose treatment group. Mean body weight losses during the 4 week exposure period were 49.5 g for controls and 161.0 g for the high dose females.

FOOD CONSUMPTION
Statistically significant alterations in food consumption were not observed in male or female rabbits administered 8.4, 16.8, or 84.0 mg/kg bw/day of the test material. However, mean food consumptions were decreased compared to the control group for males in the high dose treatment group (15% to 28%) during the 4 weeks of exposure and for males in the mid dose treatment group (4% to 18%) during days 1-15. Additionally, mean food consumption was decreased for females from the high dose treatment group compared to the control group (4% to 17%) during the days 1-22.

HAEMATOLOGY
There were no statistically significant differences between the values for any of the haematoligic parameters in treated rabbits compared with those of the control rabbits, nor were there any biologically important trends.

CLINICAL CHEMISTRY
The only statistically significant change in serum chemistry parameters was observed in 8.4 and 84 mg/kg bw/ dosed male rabbits where SDH values were lower than in control rabbits. This coupled with somewhat lower values, albeit not statistically significant, for both AST and ALT in the high dose male rabbits suggests a possible effect on synthesis of liver enzymes. However, no such trend was observed either in the high dose female rabbits, or a dose relationship in the lower dose male rabbits. Therefore, this alteration is not likely to be biologically important. Liver necrosis would result in increased rather than decreased liver enzyme values.

URINALYSIS
No biologically or statistically significant changes were observed in the urine parameters for either male or female rabbits.

ORGAN WEIGHTS
Statistically significant alterations in organ weights were not observed for male or female rabbits administered 8.4, 16.8, or 84.0 mg/kg bw/day of the test item. However, a dose-related decrease in mean absolute liver weight compared to the control group was observed for males in the mid dose (-16%) and high dose (-21%) treatment groups. Dose-related decreases in mean liver weights expressed relative to body weight or brain weight were also observed for males in the mid dose (-9% and -12%, respectively) and high dose (-14% and -15%, respectively) groups. An apparent dose-related decrease in mean liver weight was also observed for males in the low dose group. However, this decrease was a result of an exceptionally small liver in one animal (approximately 50% of control mean) and was not considered to be related to treatment based on the lack of effect on body weight, supporting clinical chemistry findings or gross or microscopic findings in the liver, and the lack of similar effects on liver weight for the four remaining males in this group (mean liver weight for the remaining animals = 2% greater than control mean).

GROSS PATHOLOGY AND HISTOPATHOLOGY
Treatment-related gross and microscopic lesions were observed only in the treated skin of both males and females. Gross lesions were observed on the treated and untreated skin of animals from all groups. Treatment-related gross skin lesions were limited to the treatment area. Gross lesions observed included exfoliation, erythema, surface crust, haemorrhage, and/or fissuring. The severity and/or incidence for several of the gross lesions tended to be greater in the treated groups than in control groups. Microscopic lesions indicative of both chronic and acute inflammation were observed in all treatment groups (including controls). Acanthosis, ulceration, folliculitis, and dermatitis for males, and oedema, congestion, haemorrhage, and hyperkeratosis for both males and females occurred in approximately equal frequency for control and treated animals. A dose-related increase in the incidence of ulceration was observed for females in the mid dose (3 animals) and high dose (4 animals) groups and the incidence of folliculitis for females was greatest in the mid and high dose groups (3 animals each). The severity of epidermitis and ulceration for males and acanthosis, epidermitis, ulceration, dermatitis, and dermal fibrosis for females increased in a dose-related manner. The range of severity for these lesions was mild to moderate for the control and low dose animals and mild to marked for the mid and high dose animals. Microscopic lesions were also observed in untreated skin of rabbits from all dosage groups. These lesions were less frequent and generally less severe than those observed at the application site.

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

>= 84 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The effect level is based on systemic toxicity. No systemic toxicity was observed in any of the test doses. All effects seen in the treatment groups are based on local skin irritation and consequently indisposition of the animals.

2

Dose descriptor:

NOAEL

Remarks:

local

Remarks on result:

not determinable because of methodological limitations

Remarks:

It cannot clearly be determined to what extend the skin irritating effects are the result of the test substance treatment because skin irritation was also observed in the controls

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Mild to moderate skin irritation was seen at the lowest dosage level, 8.4 mg/kg bw/day. Mild to marked irritation was noted at dosage levels of 16.8 mg/kg/day and above. Since some effects were observed with the silane-free solvent control animals, the irritation seen in the test groups may in part have been caused by the solvent.  

Tab. 1: Summary of Skin irritation data

	control								8.4 mg/kg bw (0.5%)
Day	Erythema				Oedema				Erythema				Oedema
	males		females		males		females		males		females		males		females
	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range
1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
2	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
3	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
4	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
5	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
6	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
7	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
8	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
9	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
10	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
11	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
12	0.2±0.4	0-1	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
13	0.2±0.4	0-1	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
14	0.2±0.4	0-1	0.4±0.9	0-2	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0	0.0±0.0	0-0
15	0.2±0.4	0-1	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
16	0.2±0.4	0-1	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
17	0.2±0.4	0-1	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
18	0.2±0.5	0-1	0.6±0.9	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
19	0.4±0.5	0-1	0.6±0.9	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
20	0.2±0.4	0-1	0.6±0.9	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
21	0.2±0.4	0-1	0.4±0.5	0-1	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
22	0.2±0.4	0-1	0.4±0.5	0-1	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
23	0.2±0.4	0-1	0.4±0.5	0-1	0.0±0.0	0-0	0.2±0.4	0-1	0.0±0.0	0-0	0.4±0.5	0-1	0.0±0.0	0-0	0.0±0.0	0-0
24	0.2±0.4	0-1	0.8±0.8	0-2	0.0±0.0	0-0	0.4±0.9	0-2	0.0±0.0	0-0	0.8±0.4	0-1	0.0±0.0	0-0	0.2±0.4	0-1
25	0.2±0.4	0-1	0.8±0.8	0-2	0.2±0.4	0-1	0.4±0.9	0-2	0.0±0.0	0-0	0.8±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
26	0.4±0.9	0-2	0.6±0.5	0-1	0.4±0.9	0-2	0.4±0.9	0-2	0.0±0.0	0-0	0.8±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
27	0.4±0.9	0-2	0.6±0.5	0-1	0.4±0.9	0-2	0.4±0.9	0-2	0.0±0.0	0-0	0.8±0.4	0-1	0.0±0.0	0-0	0.0±0.0	0-0
28	0.4±0.9	0-2	0.6±0.5	0-1	0.4±0.9	0-2	0.6±0.9	0-2	0.0±0.0	0-0	0.8±0.4	0-1	0.0±0.0	0-0	0.6±0.5	0-1
29	0.4±0.9	0-2	0.6±0.5	0-1	0.4±0.9	0-2	0.6±0.9	0-2	0.0±0.0	0-0	0.8±0.4	0-1	0.0±0.0	0-0	1.2±1.1	0-3

Applicant's summary and conclusion

Conclusions:

A dermal repeated dose toxicity conducted according to the OECD TG 410 and in compliance with GLP with bis(trimethoxysilylpropyl)amine (CAS 82985-35-1) is available, although the results were disregarded as there were positive skin reactions observed with the vehicle control, light paraffin oil. The mild to moderate microscopic skin lesions found for animals treated with the vehicle alone suggests that the vehicle and/or test procedure contributed to the skin irritation observed in the Silane-treated animals. Bis(trimethoxysilylpropyl)amine (CAS 82985-35-1) was tested on both male and female New Zealand White rabbits to determine specific target organ toxicity after repeated skin contact. Solutions of differing concentrations of the test item (0.5, 1, and 5%, referring to 8.4, 16.8, and 84.0 mg/kg bw) in a light paraffin oil were applied to the clipped dorsal trunk skin under an impervious covering for 6 hours/day, 5 days/week for 4 weeks. No mortality occurred throughout the study period. Decreased body weight gain and decreased food consumption were observed in both treated males and females as compared to the controls, but the effects were not statistically significant. A treatment related decrease in absolute and relative liver weights was observed in mid and high dose males as compared to the controls. However, the effects were not statistically significant. Mild to moderate skin irritation was seen at the lowest dosage level, 8.4 mg/kg/day, whereas mild to marked irritation was noted at dosage levels of 16.8 mg/kg/day and above. Treatment-related gross and microscopic lesions were observed only in the treated skin of both males and females of all treatment and control groups, with higher severity and/or incidence of severity tending to the treatment groups. The predominant finding was hyperkeratosis. However, degenerative effects to the skin were not observed. Since some findings were also observed with the solvent control animals, the irritation seen in the test groups may in part have been caused by the solvent. Among this, light paraffin oil is known to be irritating to the skin (Nessel et al. (1999) Toxicological Sciences 49:48-55). The study provided evidence for cumulative irritation from repeated skin contact with the test item, but there was no evidence of systemic toxicity. The other effects observed in this study (decreases in food consumption, body weight gain, and liver weight for males in the mid and high dose groups) were not indicative of a consistent systemic effect of the test material and may have been partially related to debility resulting from skin irritation. Therefore, no clear result on both the local and the systemic repeated dose toxicity hazard could be obtained from this study..