Registration Dossier

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Administrative data

Description of key information

Five in vivo skin sensitisation studies in guinea pigs conducted according to the Buehler and Guinea Pig Maximisation Test protocols form a weight of evidence for the skin sensitising potential of trimethoxy(vinyl)silane. Three Guinea Pig Maximisation Tests and one Buehler test gave clear negative results (WIL Laboratories, 1999; Huls, 1994; WIL Laboratories, 1996 and WIL Laboratories, 2000). A second Buehler test gave a positive result (Huls, 1993).


Three manufacturers of trimethoxy(vinyl)silane have provided statements which confirm that there have been no cases of skin sensitisation amongst workers during more than 40 years of manufacture (see Section 7.10.4) (Wacker, 2017; Momentive, 2017; Evonik Degussa, 2017).


Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The non-LLNA study was already available and a new test was not conducted.
Species:
guinea pig
Route:
intradermal
Vehicle:
corn oil
Concentration / amount:
10% test article in MEH 56 corn oil
Route:
epicutaneous, occlusive
Vehicle:
corn oil
Concentration / amount:
50% test article in MEH 56 corn oil
Day(s)/duration:
48 hours
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
corn oil
Concentration / amount:
25% test article in MEH 56 corn oil
Day(s)/duration:
24 hours
No. of animals per dose:
10 animals/test material
5 animals/negative control (MEH 56 corn oiil)
Details on study design:
The study consisted of three phases: the Primary Irritation Phase, an Induction Phase, and a Challenge Phase.   

Primary Irritation Phase: The Primary Irritation Phase consisted of an intradermal and a topical range-finding study. The intradermal range-finding study was used to evaluate the irritation potential of the test article in vehicle (MEH 56 corn oil) (w/w) at 0.25, 0.50, 1.0, 2.5, 5.0 and 10.0% in one animal.  Slight erythema and edema were observed at all concentrations. The topical range-finding study was used to evaluate the irritation threshold concentration of the test article following single topical applications of multiple concentrations (2.5%, 25%, or 50% in MEH 56 corn oil, or undiluted in one animal.  Erythema was observed at 50% and with undiluted test article. Based on the results, the test item concentration of 10% test article in MEH 56 corn oil was selected for intradermal induction in the main study, 50% test article in MEH 56 corn oil was selected for epidermal induction, and 25% test article in MEH 56 corn oil was selected for challenge in the main study. 

Definitive Test: The definitive sensitisation maximization test consisted of an Induction Phase (intradermal injections and topical applications of the test article to stimulate the immune system) and a Challenge Phase (a single topical application of the test article to determine if delayed contact hypersensitivity had occurred). 
The intradermal induction of sensitisation in the test group was performed in the nuchal region with 10% test article in MEH 56 corn oil.  
The epidermal induction of sensitization was conducted for 48 hours under occlusion with the test article (50% in MEH 56 corn oil) one week after the interdermal induction.  Pretreatment of the test areas with 10% sodium-lauryl-sulfate (SLS) 24 hours prior to application of the test article was not necessary.  The reaction sites were assessed 24 and 48 hours after removal of the bandage for erythema and edema according to a scale of 0 (No reaction) to 4 (Intense erythema and swelling). 

Fourteen days after epidermal induction, all animals were challenged with epidermal application of the test article (25% in MEH 56 corn oil).  All challenge doses were applied on previously unexposed areas of skin.  The patches were occluded for 24 hours. Application sites were evaluated at approximately 24 (49 hour time point) and 48 (72 hour time point) hours after patch removal for erythema and edema according to the 0-to-4 scale noted previously.    

Viability/mortality and clinical signs of toxicity were recorded daily from delivery of the animals to termination of the test. Body weights were recorded at the beginning of the study and on days 7, 14, 21 and 24.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25% in MEH 56 corn oil
No. with + reactions:
0
Total no. in group:
9
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25% in MEH 56 corn oil
No. with + reactions:
0
Total no. in group:
9
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25% in MEH 56 corn oil
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25% in MEH 56 corn oil
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
Not specified
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
other: No information about positive control.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
Not specified
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
other: No information about positive control.

One test article-treated animal died by day 14.  The death was not attributed to treatment with the test article.  No
clinical signs of toxicity or remarkable changes in body weight were noted during the study.  

Discrete/patchy to moderate/confluent erythema were observed in nine test article-treated animals (at the 49-hour reading

which was taken 24 hours after induction) and in seven test article-treated animals (at the 72-hour reading which was 48 hours

after induction) out of 9 animals after treatment with 25% test article in 56 MEH corn oil.  Control animals had comparable 

reactions at these time points.  

Challenge: No skin effects were observed 24 or 48 hours in the test article-treated or control group animals following the 

challenge application.

Interpretation of results:
GHS criteria not met
Conclusions:
In the skin sensitisation study, conducted according to OECD Test Guideline 406 and in compliance with GLP, trimethoxy(vinyl)silane was concluded to be not sensitising in albino guinea pigs.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The non-LLNA study was already available and a new test was not conducted.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Route:
intradermal
Vehicle:
other: mineral oil
Concentration / amount:
1:1 mixture of FCA and sterile saline, a 5% w/v mixture of test material in mineral oil, and a 3% w/v mixture of test material in 1:1 FCA:saline
Adequacy of induction:
other: the highest non-irritating concentration
Route:
epicutaneous, occlusive
Vehicle:
other: mineral oil
Concentration / amount:
5% test materail
Day(s)/duration:
48 hours
Adequacy of induction:
other: the highest non-irritating concentration
Route:
epicutaneous, occlusive
Vehicle:
other: mineral oil
Concentration / amount:
5% test material
Day(s)/duration:
24 hours
Adequacy of challenge:
other: the highest non-irritating concentration
No. of animals per dose:
Definitive study:
10/sex/dose with test material
5/sex/dose with Positive Control
5/sex/dsoe with Negative Control
Details on study design:
The study consisted of three phases.
The Primary Irritation Phase consisted of an intradermal and a topical range-finding study. The intradermal range-finding study evaluated the irritation potential of the test material in mineral oil and in a 1:1 Freund's Complete Adjuvant (FCA) and sterile saline mixture. The topical range-finding study was used to evaluate the irritation threshold concentration of A-171 following a single topical application.

The Primary Irritation Phase utilized 28 guinea pigs. In the intradermal range finding study, two male and two female Hartley albino guinea pigs each received six 0.1 mL intradermal injections on the dorsal surface along the spine. The animals received injections of the test material at 1%, 3%, or 5% in mineral oil or 1:1 FCA:sterile saline. In the topical range-finding study, 12 male and 12 female Hartley albino guinea pigs were each exposed at 0.3 ml/site to five concentrations of test material in acetone (2.5%, to 50%), to nine concentrations of test material in mineral oil (0.5% tor 75%), or to undiluted test material or 100% mineral oil. There were three sites per guinea pig and four sites per concentration. The treatment was applied beneath a Hill Top Chamber® and held in place for six hours. The chambers were occluded with plastic wrap and overwrapped with Elastoplast tape. The treated sites were examined approximately 24 and 48 hours after the end of exposure. Based on the results, the concentrations chosen for intradintradermal induction dosing were 3% in 1:1 FCA:saline and 5% in mineral oil, and the concentration chosen for topical induction dosing was 5% in mineral oil. The highest non-irritating concentration, 5% in mineral oil, was chosen for challenge dosing.

The definitive study consisted of the Induction Phase and the Challenge Phase.

Induction phase:
On study day 0, a group of 10 male and 10 female Hartley albino guinea pigs was dosed intradermally (0.1 mL/site) with duplicate injections of a 1:1 mixture of FCA and sterile saline, a 5% w/v mixture of test material in mineral oil, and a 3% w/v mixture of test material in 1:1 FCA:saline. On study day 6, the application site of all animals was pretreated with 0.5 mL of 10% sodium lauryl sulfate (SLS). On study day 7, the test group was topically induced with 5% test material in mineral oil (approximately 0.4 to 0.5 mL) using the procedure described above. The duration of exposure was forty-eight hours.

Challenge phase:
Two weeks after the topical induction exposure, the animals were challenge dosed for detection of sensitisation by topical application of 5% test material at 0.3 mL/site to previously unexposed areas of skin. The guinea pigs were observed twice daily for mortality for the duration of all phases of the study. All sites were depilated and graded at 24-hours and 48-hours using the 0-to-3 grading scale. The initial and final body weights of the animals were recorded. Grades of 1 or greater in the test group would indicate sensitization, provided grades of less than 1 are seen in the vehicle control animals. Body weights and clinical observations were recorded on the day before initiation of dosing and at termination.

Challenge controls:
A positive control group of 5 male and 5 female guinea pigs was induced and challenged with -Hexylcinnamaldehyde (HCA; a known sensitizer). A naïve control group of 5 male and 5 female guinea pigs was dosed only at challenge with 5% A-171 in mineral oil at 0.3 mL/site and served as an irritation control.
Positive control substance(s):
yes
Remarks:
Hexylcinnamaldehyde
Positive control results:
9/10 and 4/10 animals showed positive reactions at the 24 and 48-hour observations, respectively.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
5% TM in mineral oil
No. with + reactions:
5
Total no. in group:
20
Clinical observations:
5 slight (grade 1) reactions
Remarks on result:
no indication of skin sensitisation
Remarks:
0% sensitisation incidence index
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
5% TM in mineral oil
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Remarks:
0% sensitisation incidence index
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100% mineral oil
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100% mineral oil
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
5% TM in mineral oil
No. with + reactions:
4
Total no. in group:
10
Clinical observations:
4 slight (grade 1) reactions
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
5% TM in mineral oil
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100% mineral oil
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100% minetal oil
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
1% HCA in acetone
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
One moderate (grade 2) and 8 (grade 1) slight reactions
Remarks on result:
positive indication of skin sensitisation
Remarks:
90% sensitisation incidence index
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
1% HCA in acetone
No. with + reactions:
4
Total no. in group:
10
Clinical observations:
4 slight (grade 1) responses
Remarks on result:
positive indication of skin sensitisation
Remarks:
90% sensitisation incidence index
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
100% acetone
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
100% acetone
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation

One Negative Control Group-I male died on study day 9.  This death was considered a spontaneous occurrence and was replaced with a Negative Control Group-II male.  There were no clinical findings or remarkable body weight changes noted during the study.   The Sensitization Incidence Index for the test group was calculated to be 0% (0/20) following challenge.  The Irritation Severity Index was 0.3 and 0.0 at the 24- and 48-hour evaluation, respectively, for the Test Group.  The Irritation Severity Index for the Negative Control Group was 0.4 and 0.0 at the 24- and 48-hour evaluations, respectively.  The Sensitization Incidence Index was calculated to be 90% (9/10) for the Positive Control Group following challenge dosing with 1.0% HCA in acetone.  The Irritation Severity Indices were 1.0 and 0.4 at 24 and 48 hours, respectively, for the Positive Control Group.

Interpretation of results:
GHS criteria not met
Conclusions:
In the skin sensitisation study, conducted according to OECD Test Guideline 406 and in compliance with GLP, the test material was found to be a not a skin sensitiser.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
10.02.1995 to 23.09.1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EPA OPP 81-6 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
other: the Toxic Substance Control Act (TSCA) Health Effects Test Guidelines 40 CFR 798.4350
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
other: the Japanese Agricultural Chemicals Laws and Regulations Testing Guidelines for Toxicology Studies published by the Society of Agricultural Chemical Industry, under the auspices of the Ministry of Agriculture, Forestry and Fisheries (MAFF)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The non-LLNA study was already available and a new test was not conducted.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc.
- Age at study initiation: 'Young adult'
- Weight at study initiation: 320 to 393 g
- Housing: Individual in suspended wire-mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Seven days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 22
- Humidity (%): 36 - 66
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 02.03.1995 To: 02.04.1995
Route:
intradermal
Vehicle:
other: acetone
Concentration / amount:
5% TM in acetone, 5% TM in a 1:1 mixture of Freund's Complete Adjuvant (FCA):sterile saline and a 1:1 mixture of FCA:sterile saline
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
50% TM in acetone
Day(s)/duration:
48 hours
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
10% w/v mixture in acetone
Day(s)/duration:
24 hours
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
Definitive study:
10/sex/dose with test material
5/sex/dose with Positive Control
5/sex/dose with Negative Control
Details on study design:
The guinea pigs in the definitive sensitization maximization test undergo an intradermal induction stage, followed by a topical induction stage, and a subsequent challenge and rechallenge period.
Primary lrritation Phase: The test material was prepared for dosing as weight-to-volume suspensions at concentrations of 0.5%, 1.0%, 2.5%, 5%, 10%, 25 and 50%. The appropriate amount of test material for each concentration was weighed out and acetone added in sufficient quantity to obtain the desired concentrations. Sufficient undiluted test material and acetone were also dispensed for dosing.

Intradermal Induction Phase:
The test material, a 5% w/v mixture in acetone, was prepared for injection by diluting 0.5 g of the test material to a total volume of 10 ml with acetone.
The test material, a 5% w/v mixture in 1:1 Freund's Complete Adjuvant (FCA) and sterile saline solution, was prepared for injection by mixing 0.5 g of the test material in 5 ml of FCA and 5 ml of sterile saline.
A sufficient amount of the 1:1 mixture of FCA and sterile saline was dispensed for dosing the Test Group, Negative ControI-I and II Group and Positive Control Group.
The positive control material, 0.25% w/v mixture in 80% ethanol, was prepared for injection by diluting 0.025 g of ground dinitrochlorobenzene (DNCB) to a total volume of 10 ml with 80% ethanol.
The positive control material, 0.25% w/v mixture in 1:1 FCA and sterile saline, was prepared for injection by mixing 0.025 g of ground DNCB with 5 ml of FCA
and 5 ml of sterile saline.
The vehicle material, 5% w/v mixture in 1:1 FCA and sterile saline, was prepared for injection by mixing 0.5 g of acetone with 5 ml of FCA and 5 ml of
sterile saline.
Sufficient acetone was dispensed for dosing the vehicle control sites an the negative control animals.

Topical Induction Phase:
The test material was prepared for dosing the Test Group as a 50% w/v solution in acetone by diluting 5.0 g of test material to a total volume of 10 ml.
The positive control material, DNCB, was prepared for dosing the Positive Control Group as a 0.25% w/v solution in 80% ethanol by diluting 0.025 g of preground DNCB to a total volume of 10 ml.
Sufficient acetone was dispensed for dosing the negative control animals.

During the intradermal induction stage, the test article, vehicle, and positive control, respectively, with or without Freund's complete adjuvant (FCA), were injected intradermally. Intradermal induction consisted of injections of 5% TM in acetone, 5% TM in a 1:1 mixture of Freund's Complete Adjuvant (FCA):sterile saline and a 1:1 mixture of FCA:sterile saline. Seven days after the intradermal injections, a patch, saturated with 50% TM in acetone, vehicle control or positive control was applied to the injection area, and covered with an occlusive dressing for 48 hours.

Challenge Phase:
The test material was prepared for challenge dosing as a 10% w/v mixture in acetone by diluting 1.0 g of test material to a total volume of 10 ml.
Sufficient acetone was dispensed for dosing valide control sites.
The positive control material, DNCB, was prepared for challenge dosing as a 0.1 w/v solution in 80% ethanol by diluting 0.01 g of ground DNCB to a total volume of 10 ml.
Sufficient 80% ethanol was dispensed for dosing vehicle control sites.

14 days after topical induction, the animals were challenged with 10% TM in acetone, vehicle control or positive control. All challenge doses were applied under Hill Top Chambers® with adhesive backs removed, to previously unexposed areas of skin. The chambers were occluded with plastic wrap and over wrapped with tape for 24 hours. Twenty-four hours after dosing, the occlusive cover was removed. Application sites were evaluated at approximately 24 and 48 hours after patch removal.

Rechallenge Phase:
The test material was prepared for rechallenge dosing as a 10% w/v mixture in acetone by diluting 1.0 g of test material to a total volume of 10 ml.
Sufficient acetone was dispensed for dosing vehicle control sites.

One week following challenge dosing, 10% TM in acetone was administered to previously unexposed sites on the animals using the procedures described above. Twenty-four hours following unwrapping, the rechallenge exposure sites were scored for irritation. The sites were re-examined 24 hours following the first scoring.

Body weights were recorded prior to initiation of dosing and at termination.
Challenge controls:
A positive control group of five male and five female guinea pigs was included to verify the reliability of the test system. The positive control group was induced and challenged on a similar regimen as the test group using dinitrochlorobenzene (DNCB) in 80% ethanol as the positive control material. Separate sites were dosed with 80% ethanol to detect any reactions related to the vehicle.

Negative control groups I and II of five male and five female guinea pigs each were dosed with the vehicle during induction and in the same manner as the test group at challenge and served as irritation controls.
Positive control substance(s):
yes
Remarks:
dinitrochlorobenzene (DNCB)
Positive control results:
Based on the sensitization incidence index of 100%, the positive control material, DNCB, was found to be an extremely sensitizing agent in the albino guinea pig under the conditions of this study, thereby verifying the reliability of the test system.  The positive control vehicle, 80% ethanol, was demonstrated to be nonsensitizing under the conditions of this study.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10% TM in acetone
No. with + reactions:
1
Total no. in group:
20
Clinical observations:
Irritation severity index 1.1
Remarks on result:
no indication of skin sensitisation
Remarks:
sensitization incidence index 5%
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10% TM in acetone
No. with + reactions:
1
Total no. in group:
20
Clinical observations:
Irritation severity index 0.3
Remarks on result:
no indication of skin sensitisation
Remarks:
sensitization incidence index 5%
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100 % acetone
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Irritation severity index 0.6
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100% acetone
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Irritation severity index 0.1
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10% TM in acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0.6
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10% TM in acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0.6
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100% acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0.2
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100% acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
0.1% DNCB in 80% ethanol
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
Irritation severity index 1.6
Remarks on result:
positive indication of skin sensitisation
Remarks:
Based on the sensitization incidence index of 100%, the positive control material, DNCB, was found to be an extremely sensitizing agent in the albino guinea pig under the conditions of this study, thereby verifying the reliability of the test system.  The positive control vehicle, 80% ethanol, was demonstrated to be nonsensitizing under the conditions of this study.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
0.1% DNCB in 80% ethanol
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
Irritation severity index 2
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
80% ethanol
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
80% ethanol
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
10% TM in acetone
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Irritation severity index 1
Remarks on result:
no indication of skin sensitisation
Remarks:
sensitization incidence index 0%
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
10% TM in acetone
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Irritation severity index 0.4
Remarks on result:
no indication of skin sensitisation
Remarks:
sensitization incidence index 0%
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
10% TM in acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 1
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
10% of TM in acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0.7
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
100% acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0.8
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
100% in acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Irritation severity index 0.2
Remarks on result:
no indication of skin sensitisation

Challenge Phase: The 10% formulation of the hydrolysis product in acetone applied to 20 sites induced one moderate and 19 slight dermal reactions at the 24-hour observation. Only six sites displayed slight reactions at the 48-hour evaluation. On the vehicle (acetone) control sites, 12 had slight reactions at 24-hours post-exposure and a single site had a slight reaction present at 48 hours. For the Negative Control-I Group animals, the 10% hydrolysis product solution induced six slight dermal reactions at both the 24 and 48-hour observation. Two of the vehicle control sites on the Negative Control-I Group animals were noted with slight dermal reactions at the 24-hour observation. All irritation completely subsided by 48 hours. The positive control material, 0.1% dinitrochlorobenzene (DNCB), induced six slight, two moderate and two severe reactions at 24 hours after challenge dosing. By 48 hours, the responses had increased to two slight, six moderate and Mo severe reactions. In addition, eschar was present at all sites at 48 hours post-exposure. Yellow staining was observed for all positive control sites at both 24 and 48 hours. There were no skin reactions present on the vehicle control animals treated with 80% ethanol.

Rechallenge Phase: There were 20 very slight reactions for Test Group guinea pig sites rechallenged with 10% hydrolysis product in acetone at 24 hours. By 48 hours, the number so affected had fallen to eight. Fifteen very slight reactions were observed for sites rechallenged with 100% acetone. Irritation completely subsided for all sites dosed with 100% acetone by 48 hours post-exposure. All sites rechallenged with 10% hydrolysis product had slight reactions noted at 24 hours for the Negative Control-Il Group. Seven of the ten sites had slight dermal reactions at the 48-hour observation. Eight of the vehicle control sites on the Negative Control-II Group were noted with slight dermal reactions at 24 hours. Irritation completely subsided for all but two sites with slight reactions at 48 hours.

Interpretation of results:
GHS criteria not met
Conclusions:
In the skin sensitisation study, conducted according to OECD Test Guideline 406 and in compliance with GLP, based on results obtained following challenge and rechallenge, the test material (hydrolysate) was found to be a not a skin sensitiser.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
GLP compliance:
yes (incl. QA statement)
Type of study:
Buehler test
Justification for non-LLNA method:
The non-LLNA study was already available and a new test was not conducted.
Species:
guinea pig
Strain:
other: Hartley albino
Sex:
male/female
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
Induction 50% w/v in acetone
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
Challenge 10% w/v in acetone
No. of animals per dose:
Positive control - 10
Test item - 20
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10% TM
No. with + reactions:
1
Total no. in group:
20
Clinical observations:
Sensitisation incidence index 5%
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Sensitisation incidence index 5%
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50% HCA in acetone
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
Sensitisation incidence index 90%
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
50% HCA
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
Sensitisation incidence index 90%
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10% TM
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Sensitisation incidence index 0%
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10% TM
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Sensitisation incidence index 0%
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
In the skin sensitisation study, conducted according to EPA OPPTS 870.2600 (Skin Sensitisation) and in compliance with GLP, trimethoxy(vinyl)silane was concluded to be not sensitising.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
29.06.1993 to 19.08.1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
yes (incl. QA statement)
Type of study:
Buehler test
Justification for non-LLNA method:
The non-LLNA study was already available and a new test was not conducted.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH.
- Age at study initiation: 'healthy young adults'
- Weight at study initiation: 500 g
- Housing: Maximum of five per Makrolon type IV cage
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20± 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29.06.1993 To: 19.08.1993
Route:
epicutaneous, occlusive
Vehicle:
other: MEH 56 corn oil
Concentration / amount:
100% in induction exposures
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: MEH 56 corn oil
Concentration / amount:
25% in challenge exposure
No. of animals per dose:
20 animals/test group
10 animals/control group
Details on study design:
1st application: Induction 100 % occlusive epicutaneous
2nd application: Induction 100 % occlusive epicutaneous
3rd application: Induction 100 % occlusive epicutaneous

In the definitive test, a test group of 20 animals was induced with 100% test substance on days 0, 7 and 14 and subsequently challenged with 25% test substance in corn oil on day 28; 25% test article in MEH 56 corn oil was the maximum non-irritating concentration. A control group of 10 animals was induced and challenged with MEH 56 corn oil.
Reading:
other: Overall result
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
30
Group:
test chemical
Dose level:
25% test article-treated animals
No. with + reactions:
13
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
54
Group:
test chemical
Dose level:
25% test article-treated animals
No. with + reactions:
13
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
30
Group:
negative control
Dose level:
vehicle test group
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
54
Group:
negative control
Dose level:
vehicle test group
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
not specified
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
other: Not specified.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
not specified
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
other: not specified

There were no substance related effects or influence on body weight in either test or control animals. Slight erythema
and edema were observed during Induction Phases I, II and III in the test article-treated animals; no skin irritation
was observed in the control animals.  Positive skin reactions were observed in 13/20 test article-treated
animals (30 h or 54 h post administration); animals treated with vehicle alone showed no skin reaction (0/10).

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
In the skin sensitisation study, conducted according to OECD Test Guideline 406 and in compliance with GLP, trimethoxy(vinyl)silane was concluded to be sensitising to skin.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

There are five existing in vivo skin sensitisation studies in guinea pigs conducted according to the Buehler and Guinea Pig Maximisation Test protocols that form a weight of evidence for the skin sensitising potential of trimethoxy(vinyl)silane.

Three Guinea Pig Maximisation Tests and one Buehler test gave clear negative results (WIL Laboratories, 1999; Huls, 1994; WIL Laboratories, 1996 and WIL Laboratories, 2000). A second Buehler test gave a positive result (Huls, 1993).

The most recent test conducted for skin sensitising potential of trimethoxy(vinyl)silane found the test material not sensitising in a Guinea Pig Maximisation Test, was conducted according to current OECD Test Guideline 406 and in compliance with GLP (WIL Laboratories, 2000). The reported sensitisation incidence index for the test group was 0% (0/20) following challenge. The study concluded that the test material is not a skin sensitiser in the guinea pig.

A second reliable Guinea Pig Maximisation Test with the registered substance (Huls, 1994) showed irritant reactions evident at induction; however, no skin reactions were present at challenge and the study concluded the test material not to be a sensitiser under the conditions of the test.

In the third reliable Guinea Pig Maximisation Test with the hydrolysis product of trimethoxy(vinyl)silane, vinylsilanetriol (WIL Laboratories, 1996) the sensitization incidence index for the test group was calculated to be 5% (1/20) following challenge with 10% test material in acetone. There were no sensitization reactions in the test group following rechallenge with 10% test material. The sensitization incidence index for the test group was 0%. Vehicle control sites on the test group animals treated with 100% acetone displayed no evidence of sensitization at challenge. The study concluded the test substance to be a non-sensitiser. Due to the rapid hydrolysis of trimethoxy(vinyl)silane (half-life less than 0.1 hour at physiological pH) testing of the hydrolysis product is considered representative of the skin sensitisation potential of trimethoxy(vinyl)silane.

In a reliable Buehler test (WIL Laboratories, 1999) which was conducted according to current guideline and in compliance with GLP, at the first challenge, 1/20 animals showed a reaction in response to the test material. However, at rechallenge, no reactions were evident. The test material was concluded to be non-sensitising under the conditions of the study.

In a second reliable Buehler Test (Huls, 1993) the registered substance (but not controls) showed irritant reactions evident at induction, and positive skin reactions were present at challenge in 13/20 test animals and 0/10 control animals. The study concluded the test material to be a sensitiser under the conditions of the test.

The weight of evidence from five in vivo skin sensitisation studies in guinea pigs according to the Buehler and the maximisation test protocol suggests that trimethoxy(vinyl)silane should not be classified as skin sensitiser. This is due to the consistent absence of a skin sensitisation potential of trimethoxy(vinyl)silane in four animal studies: three GPMTs and one Buehler assay; versus a positive finding in a single Buehler test.

In addition to the in vivo experimental animal data, three manufacturers of trimethoxy(vinyl)silane have provided statements which confirm that there have been no cases of skin sensitisation amongst workers during more than 40 years of manufacture (Wacker, 2017; Momentive, 2017, Evonik Degussa, 2017).

These data included internal information from: relevant plants, number of employees, exposure description; medical surveillance, regular health checks (especially concerning skin status) already performed on employees of the relevant plants, information from the Network of Departments of Dermatology for the surveillance and scientific evaluation of contact allergies, information from Employer's liability insurance association (BG Bau), information from customer and a comprehensive literature search there have been no cases of skin sensitisation during more than 20 years of production, handling and use of trimethoxy(vinyl)silane.

There is therefore no evidence that this substance causes skin sensitisation under relevant exposures in workers.

Additional testing to further confirm the negative conclusion is not required as there are already four reliable in vivo tests showing negative results compared with one positive result. When comparing outcomes from a Buehler test with those of the GPMT, the intradermal induction step increases the GPMT’s effectiveness in triggering a sensitisation response and makes, along with the longer induction patch application (48 hrs in the GPMT vs 6 hrs in the Buehler assay), the GPMT is more sensitive compared to the Buehler test. This is scientifically widely recognised and the reason why the regulatory community prefers the GPMT over the Buehler test for skin sensitisation hazard identification purposes. This added sensitivity gives extra weight to the negative findings in the three GPMTs.

There is also a question regarding the reliability of the LLNA for silicon-based substances, which means that conducting such a study will not add weight to the database for a positive or negative outcome and therefore will not make any contribution to the protection of human health. The current accepted and preferred method for skin sensitisation testing according to the REACH legislation (EC no 1907/2006) and CLP Regulation (EC No 1272/2008) is the murine local lymph node assay (LLNA). A validated test method, OECD TG 429 (OECD 2010) is available for the LLNA. The guideline acknowledges the limits of the LLNA, and states that there are instances where ‘test substance classes or substances containing functional groups shown to act as potential confounders’ make the use of guinea pig tests more appropriate. It is concluded that the LLNA is not applicable where the properties of the test material cause interference in the accuracy of the LLNA (OECD 2010). The statement in the OECD TG 429 is given with reference to the findings of Basketter et al. (2009a), who demonstrated false positives in silicone based substances which had previously been demonstrated to be non-sensitisers in the guinea pig maximisation test (GPMT). The importance of available evidence from guinea pig results, consideration of chemical reactivity, epidermal bioavailability and clinical and experimental human data are emphasised as central to reaching appropriate regulatory decisions for substances which have been shown to fall outside the specificity of the LLNA (Basketter et al., 2009b). The non-applicability of the LLNA for silicone based substances has also been demonstrated by Petry et al.(2012). The sensitisation potential of polyfunctional silicone materials was tested in a comparative study investigating the GPMT and the LLNA assays, which found the five tested substances to be negative in the GPMT whereas they were concluded to be weak to moderate skin sensitisers in the LLNA (Petry et al., 2012).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The weight of evidence from five in vivo skin sensitisation studies in guinea pigs conducted according to the Buehler and Guinea Pig Maximisation Test protocols, together with over 20 years of occupational medical data, literature search results and data from an insurance association, suggests that trimethoxy(vinyl)silane does not require classification according to Regulation (EC) 1272/2008.