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EC number: 245-659-7 | CAS number: 23432-62-4
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Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2014-08-13 to 2014-09-23
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- Results of dose range finding test are in contrast to the results observed in the main study.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Version / remarks:
- (1997)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian cell gene mutation tests using the thymidine kinase gene
Test material
- Reference substance name:
- Methyl [3-(trimethoxysilyl)propyl]carbamate
- EC Number:
- 245-659-7
- EC Name:
- Methyl [3-(trimethoxysilyl)propyl]carbamate
- Cas Number:
- 23432-62-4
- Molecular formula:
- C8H19NO5Si
- IUPAC Name:
- methyl N-[3-(trimethoxysilyl)propyl]carbamate
- Details on test material:
- - Name of test material (as cited in study report): Methyl [3-(trimethoxysilyl)propyl]carbamate
- Physical state: liquid
- Stability under test conditions: stable
- Storage condition of test material: at RT, protect from light, avoid humidity
Constituent 1
Method
- Target gene:
- TK locus
Species / strain
- Species / strain / cell type:
- mouse lymphoma L5178Y cells
- Details on mammalian cell type (if applicable):
- Type and identity of media:
- Basic medium: RPMI 1640 Hepes buffered medium containing penicillin/streptomycin (50 U/ml and 50 μg/ml, respectively), 1 mM sodium pyruvate and 2 mM L-glutamine
- Growth medium: Basic medium, supplemented with 10% (v/v) heat-inactivated horse serum (=R10 medium)
- Exposure medium: for 3 hour exposure: cells were exposed to the test substance in basic medium supplemented with 5% (v/v) heat-inactivated horse serum (R5-medium); for 24 hour exposure:
cells were exposed to the test substance in basic medium supplemented with 10% (v/v) heat-inactivated horse serum (R10-medium).
- Selective medium: Selective medium consisted of basic medium supplemented with 20% (v/v) heat-inactivated horse serum and 5 µg/ml trifluorothymidine (TFT)
- Properly maintained: yes - Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- co-factor supplemented post-mitochondrial fraction (S9 mix), prepared from the livers of Sprague Dawley rats treated with a suspension of phenobarbital (80 mg/kg body weight) and ß-naphthoflavone (100 mg/kg).
- Test concentrations with justification for top dose:
- Experiment 1:
- 1.7, 5.4, 17, 52, 164, 512, 1600, 2373 µg/ml with and without metabolic activation (3 h)
Experiment 2:
- 1.7, 5.4, 17, 52, 164, 512, 1600, 2373 µg/ml without metabolic activation (24 h) - Vehicle / solvent:
- - Vehicle solvent used: DMSO; 1% (v/v)
- Justification for choice of solvent/vehicle: Due to the limited solubility of the test substance in water, DMSO was selected as the vehicle
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: - Methyl methanesulfonate: 15 µg/ml (3 h) and 5 µg/ml (24 h) in DMSO without S9-mix - Cyclophosphamide: 7.5 µg/ml in HBSS (3, 24 h) with S9-mix
- Details on test system and experimental conditions:
- METHOD OF APPLICATION:
- in suspension
DURATION:
1st experiment: 3 h exposure with and without S9 mix
2nd experiment: 24 h exposure without S9 mix
- Expression time (cells in growth medium): 2 days after the end of the treatment, cells were plated for determination of the cloning efficiency and the mutation frequency in 96-well microtiter plates containing TFT selective medium. The microtitre plates were incubated for 11 or 12 days.
- Selection time: 11-12 days
- Fixation time (start of exposure up to fixation or harvest of cells): 14-15 days
SELECTION AGENT (mutation assays):
- 5 µg/ml trifluorothymidine (TFT)
NUMBER OF REPLICATIONS:
- two
DETERMINATION OF CYTOTOXICITY:
- Method: cloning efficiency and relative total growth
OTHER:
- Small and large colonies were differentiated, as small colonies are capable to indicate chromosomal mutations. - Evaluation criteria:
- The test item is considered mutagenic if the following criteria are met:
- The induced mutant frequency meets or exceeds the Global Evaluation factor (GEF) of 126 mutants per 10E6 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. - Statistics:
- The global evaluation factor (GEF) has been defined by the IWGT as the mean of the negative/solvent MF distribution plus one standard deviation. For the micro well version of the assay the GEF is 126.
A test substance is considered positive (mutagenic) in the mutation assay if it induces a MF of more than MF(controls) + 126 in a dose-dependent manner. An observed increase should be biologically relevant and will be compared with the historical control data range.
A test substance is considered equivocal (questionable) in the mutation assay if no clear conclusion for positive or negative result can be made after an additional confirmation study.
A test substance is considered negative (not mutagenic) in the mutation assay if none of the tested concentrations reaches a mutation frequency of MF(controls) + 126.
Results and discussion
Test resultsopen allclose all
- Species / strain:
- mouse lymphoma L5178Y cells
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- at > 52 µg/ml with metabolic activation (3 h)
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- Cytotoxicity was only observed in the presence of S9-mix (at > 512 µg/ml), resulting in a relative total growth of 40%.
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- mouse lymphoma L5178Y cells
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RANGE-FINDING/SCREENING STUDIES:
In the dose range finding test, L5178Y mouse lymphoma cells were treated with a test substance concentration range of 52 to 2373 µg/ml in the absence and presence of S9-mix with a 3 hour treatment period and at 10 to 475 µg/ml in the absence of S9-mix with a 24 hour treatment period. No toxicity in the suspension growth was observed up to and including the highest test substance concentration of 2373 μg/ml compared to the suspension growth of the solvent control both in the absence and presence of S9-mix.
COMPARISON WITH HISTORICAL CONTROL DATA:
The spontaneous mutation frequencies in the solvent-treated control cultures were between the minimum and maximum value of the historical control data range and within the acceptability criteria of this assay.
Any other information on results incl. tables
Experiment 1: Cytotoxic and mutagenic response of methyl-N- [3-(trimethoxysilyl)propyl]carbamate in the mouse lymphoma L5178Y test system
Dose (µg/ml) |
RSG (%) |
CEday2 (%) |
RSday2 (%) |
RTG (%) |
Mutation frequency per 106 survivors |
||
total |
small |
large |
|||||
without metabolic activation 3 hours treatment |
|||||||
SC1 |
100 |
102 |
100 |
100 |
81 |
63 |
16 |
SC2 |
84 |
106 |
84 |
19 |
|||
1.7 |
88 |
86 |
93 |
82 |
87 |
66 |
18 |
5.4 |
95 |
81 |
88 |
83 |
76 |
60 |
14 |
17 |
88 |
93 |
100 |
86 |
102 |
80 |
19 |
52 |
93 |
63 |
68 |
63 |
125 |
106 |
17 |
164 |
91 |
72 |
78 |
71 |
79 |
55 |
22 |
512 |
81 |
90 |
97 |
79 |
111 |
71 |
35 |
1600 |
84 |
79 |
85 |
72 |
107 |
83 |
21 |
2373 |
85 |
81 |
88 |
74 |
109 |
78 |
27 |
MMS |
60 |
55 |
59 |
36 |
1084 |
792 |
184 |
with metabolic activation 3 hours treatment |
|||||||
SC1 |
100 |
81 |
100 |
100 |
62 |
27 |
33 |
SC2 |
69 |
88 |
32 |
53 |
|||
1.7 |
88 |
83 |
110 |
97 |
75 |
34 |
39 |
5.4 |
83 |
97 |
128 |
107 |
89 |
47 |
38 |
17 |
102 |
105 |
140 |
143 |
75 |
31 |
41 |
52 |
135 |
99 |
132 |
178 |
82 |
37 |
41 |
164 |
90 |
89 |
118 |
105 |
130 |
69 |
54 |
512 |
74 |
77 |
102 |
76 |
379 |
182 |
143 |
1600 |
61 |
61 |
81 |
50 |
604 |
258 |
237 |
2373 |
52 |
58 |
76 |
40 |
714 |
366 |
212 |
CP |
47 |
19 |
26 |
12 |
2839 |
1426 |
1033 |
Experiment 2: Cytotoxic and mutagenic response of methyl-N-[3-(trimethoxysilyl)propyl]carbamate in the mouse lymphoma L5178Y test system
Dose (µg/ml) |
RSG (%) |
CEday2 (%) |
RSday2 (%) |
RTG (%) |
Mutation frequency per 106 survivors |
||
total |
small |
large |
|||||
without metabolic activation 24 hours treatment |
|||||||
SC1 |
100 |
89 |
100 |
100 |
62 |
24 |
36 |
SC2 |
90 |
77 |
32 |
42 |
|||
1.7 |
87 |
78 |
87 |
76 |
57 |
15 |
41 |
5.4 |
91 |
88 |
98 |
89 |
68 |
18 |
48 |
17 |
95 |
85 |
95 |
90 |
80 |
21 |
57 |
52 |
103 |
79 |
89 |
91 |
83 |
19 |
62 |
164 |
99 |
93 |
104 |
102 |
69 |
21 |
47 |
512 |
94 |
105 |
118 |
110 |
53 |
17 |
35 |
1600 |
90 |
80 |
90 |
81 |
103 |
49 |
50 |
2373 |
89 |
81 |
91 |
81 |
80 |
33 |
45 |
MMS |
88 |
77 |
86 |
76 |
687 |
234 |
367 |
Note: All calculations were made without rounding off
RSG= Relative Suspension Growth; CE= Cloning Efficiency: RS= Relative Survival; RTG= Relative Total Growth; SC= Solvent control= dried dimethyl sulfoxide; MMS= Methylmethanesulfonate; CP= Cyclophosphamide
Historical control data of the spontaneous mutation frequencies of the solvent controls for the mouse lymphoma assay
|
Mutation frequency per 106survivors |
||
|
- S9-mix |
+ S9-mix |
|
|
3 hour treatment |
24 hour treatment |
|
Range |
[50 – 119] |
[50 – 150] |
[50 – 167] |
Mean |
73 |
70 |
81 |
SD |
16 |
19 |
25 |
n |
152 |
132 |
283 |
Historical control data of the mutation frequencies of the positive controls for the mouse lymphoma assay
|
|
Mutation frequency per 106survivors |
||
|
|
- S9-mix |
+ S9-mix |
|
|
|
3 hour treatment |
24 hour treatment |
|
Range |
[501 – 3165] |
[504 – 1445] |
[593 – 4356] |
|
Mean |
902 |
750 |
1377 |
|
SD |
367 |
198 |
593 |
|
n |
78 |
67 |
141 |
SD = Standard deviation
n = Number of observations
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results: negative without metabolic activation
positive with metabolic activation after 3 h
The in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells performed according to OECD guideline 476 and in compliance with GLP, employing doses of up to 2373 µg/ml, revealed that the test substance does not show mutagenic potential without metabolic activation. In contrast, the test material is mutagenic under the given experimental conditions with metabolic activation. In summary, the mutagenic activity is confined only to incubations with metabolic activation.
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