Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Gene mutation (Bacterial reverse mutation assay / Ames test): negative with and without metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA 1538 and Escherichia coli WP2 uvrA (equivalent to OECD TG 471) (Microbiological Associates, 1992).
Cytogenicity in mammalian cells: not required: in vivo micronucleus result available.
Mutagenicity in mammalian cells: negative with and without metabolic activation in L5178Y cells (OECD TG 476) (BSL Bioservice, 2012).

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992-09-21 - 1992-11-23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The restrictions are that the only positive control used with metabolic activation was 2-aminoanthracene.
Qualifier:
equivalent or similar to
Guideline:
other: US EPA Standards 40 CFR 792 and 340 CFR 160
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
yes
Remarks:
the only positive control used with metabolic activation was 2-aminoanthracene
GLP compliance:
yes
Type of assay:
bacterial reverse mutation assay
Target gene:
Histidine operon (Salmonella) tryptophan operon (E. coli)
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Species / strain / cell type:
S. typhimurium TA 1538
Species / strain / cell type:
E. coli WP2 uvr A
Metabolic activation:
with and without
Metabolic activation system:
Aroclor induced rat liver S9
Test concentrations with justification for top dose:
100, 333, 1000, 3333 and 5000 µg/plate
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: Acetone
- Justification for choice of solvent/vehicle: the test article formed a solution in acetone
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
other: 2-aminoanthracene, all TA strains at 1.0 µg/plate, WP2 uvrA at 10 µg/plate
Remarks:
TA98, TA100, TA1535, TA1537, TA1538, WP2 uvrA with metabolic activation
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
2-nitrofluorene
Remarks:
TA98 without metabolic activation 1.0 µg/plate
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
sodium azide
Remarks:
TA1535 without metabolic activation 1.0 µg/plate
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
9-aminoacridine
Remarks:
TA1537 without metabolic activation 75 µg/plate
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
2-nitrofluorene
Remarks:
TA1538 without metabolic activation 1.0 µg/plate
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
methylmethanesulfonate
Remarks:
WP2 uvrA without metabolic activation 1000 µg/plate
Details on test system and experimental conditions:
METHOD OF APPLICATION: in agar (plate incorporation)

ACTIVATION: S9 mix contained 10% S9 and glucose-6-phosphate and NADP as co-factors. 500 µl of S9 mix was added to 2 ml top agar giving a final concentration of approximately 2% S9.

DURATION

- Exposure duration: 48 hours at 37+/- 2ºC

SELECTION AGENT (mutation assays): histidine deficient agar

NUMBER OF REPLICATIONS: triplicate plates, experiment repeated

DETERMINATION OF CYTOTOXICITY
- Method: other: condition of background lawn


OTHER:
Evaluation criteria:
For the test article to be evaluated positive, it must cause a dose-related increase in the mean revertants per plate of at least one tester strain with a minimum of two increasing concentrations of test article. Data sets for strains TA1535, TA1537 and TA 1538 will be judged positive if the increase in mean revertants is equal to or greater than three times the mean vehicle control value. Data sets for strains TA98, TA100 and WP2 uvrA will be judged positive if the increase in mean revertants is equal to or greater than two times the mean vehicle control value.
Key result
Species / strain:
S. typhimurium, other: TA98, TA100, TA1535, TA1537, TA1538
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Remarks:
Precipitate but no appreciable toxicity was observed
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Key result
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Remarks:
Precipitate but no appreciable toxicity was observed
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
TEST-SPECIFIC CONFOUNDING FACTORS

- Precipitation: occurred between 1000 and 5000 µg/plate, did not interfere with test.

RANGE-FINDING/SCREENING STUDIES:

COMPARISON WITH HISTORICAL CONTROL DATA: yes

ADDITIONAL INFORMATION ON CYTOTOXICITY: cytotoxicity was not evident at any concentration

Summary of results – Experiment I Revertants per plate (mean of 3 plates)

 

Dose µg/ml

+/- metabolic activation

Average revertants per plate

TA98

TA100

TA1535

TA1537

TA1538

WP2 uvrA

Solvent control

-

14

161

10

4

6

19

100

-

17

151

7

5

7

14

333

-

14

158

11

4

8

14

1000

-

15

164

10

4

8

13

3333

-

16

162

9

3

9

16

5000

-

16

158

8

6

6

15

Positive control

-

195

707

355

224

279

150

Solvent control

+

28

177

11

8

11

20

100

+

24

189

11

7

8

19

333

+

20

185

14

5

11

18

1000

+

21

186

8

8

14

18

3333

+

22

184

12

5

12

16

5000

+

26

174

10

7

13

11

Positive control

+

1948

1269

37

39

228

374

 

Summary of results – Experiment II

 

 

Dose µg/ml

+/- metabolic activation

Average revertants per plate

TA98

TA100

TA1535

TA1537

TA1538

WP2 uvrA

Solvent control

-

11

123

6

5

7

15

100

-

12

111

11

4

7

15

333

-

8

113

5

4

5

12

1000

-

14

120

7

4

6

10

3333

-

9

121

10

4

5

15

5000

-

15

151

12

5

8

10

Positive control

-

123

386

297

301

295

145

Solvent control

+

19

137

14

4

13

20

100

+

18

139

12

7

10

15

333

+

19

144

7

6

14

19

1000

+

23

139

11

6

14

14

3333

+

20

143

10

6

7

10

5000

+

22

150

13

9

14

15

Positive control

+

817

814

51

95

818

410

 

Conclusions:
1,1,3,3-Tetramethyl-1,3-divinyldisiloxane has been tested for mutagenicity to bacteria in a reliable study which was conducted according to a protocol that is equivalent to OECD TG 471, and in compliance with GLP. No evidence of a test-substance related increase in the number of revertants was observed with or without metabolic activation in the initial or the repeat experiments using Salmonella typhimurium strains TA 98, 100, 1535, 1537 and 1538, and E.coli WP2uvrA. It is concluded that the test substance is negative for mutagenicity to bacteria under the conditions of the test.
Endpoint:
in vitro gene mutation study in mammalian cells
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.17 (Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.5300 - In vitro Mammalian Cell Gene Mutation Test
Deviations:
no
Qualifier:
according to
Guideline:
other: IWGT Recommendations
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
(Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Germany)
Type of assay:
mammalian cell gene mutation assay
Target gene:
Thymidine kinase
Species / strain / cell type:
mouse lymphoma L5178Y cells
Details on mammalian cell type (if applicable):
- Type and identity of media: RPMI
- Properly maintained: Yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically "cleansed" against high spontaneous background: yes
Metabolic activation:
with and without
Metabolic activation system:
Liver S9 of Wistar Phenobarbital and ß-Naphthoflavone-induced rat liver S9 mix
Test concentrations with justification for top dose:
Pre-experiment: 0.1, 0.5, 2.5, 5.0, 7.5 and 10.0 mM (+/-S9); Experiment I: 0.2, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 mM (+/-S9); Experiment II: 0.5, 1.5, 3.0, 5.0, 7.0, 8.5, 9.5, 10.0 mM (+S9); 0.2, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 mM (-S9)
Vehicle / solvent:
THF (0.25% v/v final concentration in the samples)
Untreated negative controls:
yes
Remarks:
treatment medium
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
benzo(a)pyrene
Remarks:
with metabolic activation : 2.5 µg/ml
Untreated negative controls:
yes
Remarks:
treatment medium
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
ethylmethanesulphonate
Remarks:
without metabolic activation 200 and 300 µg/ml
Untreated negative controls:
yes
Remarks:
treatment medium
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
methylmethanesulfonate
Remarks:
without metabolic activation 10 µg/ml
Details on test system and experimental conditions:
METHOD OF APPLICATION: suspended in medium
DURATION: 4 h (short-term exposure), 24 h (long-term exposure)
Expression time (cells in growth medium): 48 h
Selection time (if incubation with selection agent): about 14 days

SELECTION AGENT (mutation assay) 5 µg/ml trifluorothymidine
NUMBER OF REPLICATIONS: two separate experiments (I+II) with single exposure; cells were seeded in 4 plates and evaluated
NUMBER OF CELLS SEEDED: 2000 cells per well
DETERMINATION OF CYTOTOXICITY: relative total growth (RTG)
Evaluation criteria:
The test item is considered mutagenic if following criteria are met:
-The induced mutant frequency meets or exceeds the Global Evaluation factor (GEF) of 126 per 10^6 cells
- A dose-dependent increase in mutant frequency is detected.

Besides, combined with a positive effect in the mutant frequency, an increased occurrence of small colonies (≥40% of total colonies) is an indication for potential clastogenic effects and/or chromosomal aberrations.
According to the OECD guideline, the biological relevance is considered first for the interpretation of results. Statistical methods might be used as an aid in evaluation the test result.
A test item is considered to be negative if the induced mutant frequency is below the GEF and the trend test is negative.

Statistics:
The non-parametric Mann-Whitney test is applied to the mutation data to prove the dose groups for any significant difference in mutant frequency compared to the negative /solvent controls.
Key result
Species / strain:
mouse lymphoma L5178Y cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Remarks:
RTG 40.6% at 8 mM and 43.4% at 10 mM, 24 h treatment without metabolic activation
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid

Summary: Experiment I and II with and without metabolic activation

 

Dose level (mM)

RCE

%

RTG

%

MF (mutants/10x6 cells)

IMF (mutants/10x6 cells)

GEF exceeded

Statistical significance

Precipitate

Exp 1 with S9

Negative controls

100.0

92.8

115.1

/

/

/

-

114.0

109.1

/

/

/

-

Solvent controls

100.0

100.0

109.6

/

/

/

-

/

/

/

-

0.2

121.1

130.3

92.1

-17.0

-

-

-

0.5

95.7

97.6

123.1

13.6

-

-

-

1.0

102.9

104.9

122.8

13.3

-

-

-

2.0

119.3

127.0

109.1

-0.4

-

-

-

4.0

95.7

99.9

134.2

24.6

-

-

-

6.0

112.3

108.1

105.0

-4.5

-

-

+

8.0

104.4

107.1

113.0

3.5

-

-

+

10.0

102.9

105.0

139.3

29.8

-

-

+

Positive control

91.7

78.4

545.2

435.6

+

+

-

 

Exp II with S9

Negative controls

84.9

82.8

75.0

/

/

/

-

94.1

100.9

/

/

/

-

Solvent controls

100

100.0

76.1

/

/

/

-

/

/

/

-

0.5

79.1

62.8

63.1

-13.0

-

-

-

1.5

84.9

74.5

90.5

14.4

-

-

-

3.0

94.1

85.1

89.1

12.9

-

-

-

5.0

90.0

87.8

114.4

38.2

-

+

-

7.0

80.2

62.7

70.1

-6.1

-

-

+

8.5

86.2

63.1

91.0

14.8

-

-

+

9.5

86.2

55.5

102.2

26.1

-

-

+

10.0

73.6

48.6

70.7

-5.4

-

-

+

Positive control

68.6

53.4

644.7

568.6

+

+

-


 

 

Dose level (mM)

RCE

%

RTG

%

MF (mutants/10x6 cells)

IMF (mutants/10x6 cells)

GEF exceeded

Statistical significance

Precipitate

Exp 1 without S9

Negative controls

114.2

127.5

111.6

/

/

/

-

100.0

107.1

/

/

/

-

Solvent controls

100.0

100.0

95.9

/

/

/

-

/

/

/

-

0.2

95.8

108.4

86.8

-9.1

-

-

-

0.5

83.0

90.7

155.8

59.9

-

+

-

1.0

86.7

89.6

120.6

24.7

-

-

-

2.0

95.8

107.7

137.0

41.1

-

+

-

4.0

84.2

87.0

110.4

14.5

-

-

-

6.0

98.6

102.1

90.3

-5.5

-

-

+

8.0

98.6

95.6

98.2

2.3

-

-

+

10.0

102.9

109.7

88.9

-7.0

-

-

+

Positive control 1

78.5

68.4

689.9

594.0

+

+

-

Positive control 2

64.2

51.3

527.7

431.8

+

+

-

 

Exp II withoutS9

Negative controls

102.9

107.8

138.1

/

/

/

-

92.8

92.4

/

/

/

-

Solvent controls

100.0

100.0

114.7

/

/

/

-

/

/

/

-

0.2

98.4

77.9

125.4

10.7

-

-

-

0.5

109.3

108.9

125.4

10.7

-

-

-

1.0

95.6

70.9

141.5

26.8

-

-

-

2.0

94.2

87.1

154.6

39.9

-

+

-

4.0

104.4

94.1

137.1

22.4

-

-

-

6.0

80.4

60.0

219.6

104.9

-

+

+

8.0

106.0

40.6

122.1

7.4

-

-

+

10.0

79.3

43.4

172.9

58.3

-

+

+

Positive control 1

39.9

19.6

3112.8

2998.1

+

+

-

Positive control 2

42.7

26.0

1509.2

1394.5

+

+

-


 

 

Conclusions:
1,1,3,3-Tetramethyl-1,3-divinyldisiloxane has been tested in an in vitro mammalian cell gene mutation assay (thymidine kinase locus) in mouse lymphoma L5178Y cells. The study was conducted according to OECD TG 476 and in compliance with GLP conditions. No evidence of increase in mutant frequency was observed when tested with and without metabolic activation up to limit concentrations. Appropriate positive and solvent controls were included and gave expected results. It is concluded that the test substance is negative for mutagenicity to L5178Y cells under the conditions of the test.
Executive summary:

The test item 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane was assessed for its potential to induce mutations at the mouse lymphoma thymidine kinase locus using the cell line L5178Y.

The selection of the concentrations used in the main experiments was based on data from the pre-experiment. In Experiments I and II 10.0 mM (with and without metabolic activation) was selected as the highest concentration. Experiment I with and without metabolic activation and Experiment II with metabolic activation were performed as a 4 h short-term exposure assay. Experiment II without metabolic activation was performed as a 24 h long-term exposure assay.

The test item was investigated at the following concentrations:

Experiment I

with and without metabolic activation:

0.2, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 mM

Experiment II

with metabolic activation:

0.5, 1.5, 3.0, 5.0, 7.0, 8.5, 9.5, 10.0 mM

and without metabolic activation:

0.2, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 mM

Precipitation of the test item was noted in the pre-experiment (with and without metabolic activation)at concentrations of 5 mM and higher, in Experiment I (with and without metabolic activation)at concentrations of 6 mM and higher and in Experiment II with metabolic activationat 7 mM and higher, and in Experiment II without metabolic activation at 6 mM and higher.

Growth inhibition was observed in Experiment II with and without metabolic activation.

In Experiment I with metabolic activation the relative total growth (RTG) was 105.0% for the highest concentration (10.0 mM) evaluated. The highest concentration evaluated without metabolic activation was 10.0 mM with a RTG of 109.7%. In Experiment II with metabolic activation the relative total growth (RTG) was 48.6% for the highest concentration (10.0 mM) evaluated. The highest concentration evaluated without metabolic activation was 10.0 mM with a RTG of 43.4%.

In Experiment I and II no biologically relevant increase of mutants was found after treatment with the test item (with and without metabolic activation).The Global Evaluation Factor of 126 was not exceeded by the induced mutant frequency at any concentration (GEF; defined as the mean of the negative/vehicle mutant frequency plus one standard deviation; data gathered from ten laboratories).

No dose-response relationship was observed.

Additionally, in Experiment I and II colony sizing showed no clastogenic effects induced by the test item under the experimental conditions (with and without metabolic activation).

EMS, MMS and B[a]P were used as positive controls and showed distinct and biologically relevant effects in mutation frequency. Additionally, MMS and B[a]P significantly increased the number of small colonies, thus proving the efficiency of the test system to indicate potential clastogenic effects. This study is classified as acceptable. This study satisfies the requirement for Test Guideline OPPTS 870.5300, OECD 476 for in vitro mutagenicity (mammalian forward gene mutation) data.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

Micronucleus assay (oral gavage administration): negative (OECD TG 474) (Bioreliance, 2012).

Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
micronucleus assay
Species:
mouse
Strain:
ICR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan, Frederick, MD
- Age at study initiation: 6 weeks old
- Weight at study initiation: 27.7 - 34.9 grams for males and 24.4 -29.5 grams for females
- Assigned to test groups randomly: [yes, under following basis: ] 5 males and 5 females per test group
- Fasting period before study: no
- Housing: 5 mice per sex per approved Micro-Barrier cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 ± 3°F
- Humidity (%): 50 ± 20%
- Air changes (per hr): 10 per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: 6 weeks of age on 11th April 2012 To: 26th April 2012
Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil
- Justification for choice of solvent/vehicle: based on Sponsor information
- Concentration of test material in vehicle:
- Amount of vehicle (if gavage or dermal): 80%
- Type and concentration of dispersant aid (if powder):
- Lot/batch no. (if required):
- Purity:
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: appropriate amount of test substance weighed and combined with 80% target volume of vehicle. After vortexing, remaining volume of vehicle was added. Dosing solutions were 100, 200 and 400 mg/ml
Duration of treatment / exposure:
Negative and positive controls and all treatment groups - 24 hour. Negative control and highest treatment group - 48 hours.
Frequency of treatment:
Test compound and controls were dosed once by oral gavage.
Post exposure period:
The negative and positve controls and treatment groups were sacrificed 24 hours after administration of test substance. The negative control and highest treatment group were sacrificed 48 after administration of test substance.
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
dosing formulations were analysed: 200 and 400 mg/ml solutions met acceptance criteria (85-115% of target concentration; 100 mg/ml solution was below this range (~84.5%)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
dosing formulations were analysed: 200 and 400 mg/ml solutions met acceptance criteria (85-115% of target concentration; 100 mg/ml solution was below this range (~84.5%)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
Remarks:
dosing formulations were analysed: 200 and 400 mg/ml solutions met acceptance criteria (85-115% of target concentration; 100 mg/ml solution was below this range (~84.5%)
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes, concurrent vehicle
Positive control(s):
- positive control substance: cyclophosphamide
- Justification for choice of positive control(s): standard guideline positive control
- Route of administration: oral gavage
- Doses / concentrations: 50 mg/kg
Tissues and cell types examined:
Bone marrrow was collected from all treatment groups and polychromatic erythrocytes (PCE's), 2000 were scored per animal thus 10,000 per treatment group, and normochromatic erythrocytes (NCE's) were examined for micronuclei.
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: dose limit

TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): no further information

DETAILS OF SLIDE PREPARATION: Following euthanasia, the femurs were exposed, and the bone marrow was aspirated into syringe with fetal bovine serum. The bone marrow was centrifuged and the supernatant drawn off. The cell pellet was re-suspended and a small drop of bone marrow suspension was spead onto a clean glass slide (2 slides per mouse). The slides were air dried, fixed in methanol and stained with acridine orange.

METHOD OF ANALYSIS: Slides were coded randomly. Bone marrow cells were evaluated using a flourescent microscope. 2000 PCE's were scored for micronuclei per animal. The corresponding NCE's were scored for micronuclei.


OTHER:
Evaluation criteria:
The test substance is considered to induce a positive response if the incidence of micronucleated polychromatic erythrocytes at one or more doses is statistically elevated elative compared to the vehicle control.
Statistics:
Statistical significance was determined using the Kastenbaum-Bowman tables which are based on the binomial distribution.
Sex:
male/female
Genotoxicity:
negative
Toxicity:
not examined
Remarks:
No mortalities occurred. Diarrhea noted in one male mouse at 1000 mg/kg bw; piloerection noted in some male and all female, and diarrhea noted in 2 males and 2 females in 2000 mg/kg bw group
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid

Summary of Bone Marrow Micronucleus Analysis

Treatment (5 ml/kg bw)

Sex and time (hrs)

Mean of PCE/Total erythrocytes

Mean of MPCE/2000 PCE

Number of MPCE/PCE scored

Solvent control

M - 24

0.538

0.0

0 / 1000

F -24

0.546

0.1

1 / 1000

500 mg/kg bw

M - 24

0.531

0.1

1 / 1000

F - 24

0.566

0.2

2 / 1000

1000 mg/kg bw

M - 24

0.585

0.6

6 / 1000

F - 24

0.561

0.3

3 / 1000

2000 mg/kg bw

M - 24

0.567

0.2

2 / 1000

F - 24

0.574

0.1

1 / 1000

Positive control

M - 24

0.472

23.3

*233 / 1000

F - 24

0.462

15.5

*155 / 1000

Solvent control

M - 48

0.433

0.3

3 / 1000

F - 48

0.544

0.2

2 / 1000

2000 mg/kg bw

M - 48

0.527

0.1

1 / 1000

F - 48

0.581

0.0

0 / 1000

 

* = Statistically significant increase compared to vehicle control

PCE: polychromatic erythrocytes; MPCE; micronucleated PCE

Conclusions:
1,1,3,3-Tetramethyl-1,3-divinyldisiloxane was tested in an in vivo mouse micronucleus assay according to OECD TG 474, in compliance with GLP. No evidence of a test substance related increase in the induction of micronucleus was observed after dosing orally by gavage at 500, 1000 and 2000 mg/kg bw. Appropriate positive and vehicle controls were included and gave expected results. Confirmation of test article exposure was provided by an oral gavage study to determine concentration of test article in the plasma. It is concluded that the test substance is not genotoxic under the conditions of the test.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Information is available from reliable studies on 1,1,3,3-tetramethyl-1,3-divinyldisiloxane from in vitro bacterial and mammalian mutagenicity studies and an in vivo micronucleus assay.

1,1,3,3-Tetramethyl-1,3-divinyldisiloxane has been tested for mutagenicity to bacteria in a reliable study which was conducted according to a protocol similar to OECD Test Guideline 471, and in compliance with GLP ( Microbiological Associates, 1992). No evidence of a test-substance related increase in the number of revertants was observed with or without metabolic activation in the initial or the repeat experiments using Salmonella typhimurium strains TA 98, 100, 1535, 1537 and 1538, and E.coli WP2uvrA. Appropriate positive, medium and solvent controls were included and gave expected results. It is concluded that the test substance is negative for mutagenicity to bacteria under the conditions of the test.

1,1,3,3-Tetramethyl-1,3-divinyldisiloxane has been tested in an in vitro mammalian cell gene mutation assay (thymidine kinase locus) in mouse lymphoma L5178Y cells ( BSL Bioservice, 2012). The study was conducted according to OECD Test Guideline 476 and in compliance with GLP conditions. No evidence of increase in mutant frequency was observed when tested with and without metabolic activation up to limit concentrations. Appropriate positive, medium and solvent controls were included and gave expected results. It is concluded that the test substance is negative for mutagenicity to L5178Y cells under the conditions of the test.

1,1,3,3-Tetramethyl-1,3-divinyldisiloxane was tested in an in vivo mouse micronucleus assay according to OECD Test Guideline 474 and in compliance with GLP (BioReliance, 2012). No evidence of a test substance related increase in the induction of micronucleus was observed. Appropriate positive and vehicle controls were included and gave expected results. Confirmation of test article exposure was provided by an oral gavage study to determine concentration of test article in the plasma. It is concluded that the test substance is not genotoxic under the conditions of the test.


Justification for classification or non-classification

Based on the available in vitro and in vivo genotoxicity data, 1,1,3,3-tetramethyl-1,3-divinyldisiloxane is not classified for mutagenicity according to Regulation (EC) No. 1272/2008.