Trimethoxy(methyl)silane

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2017-01-12 to 2017-07-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Principles of method if other than guideline:

The study was designed to investigate the hydrolytic stability of methyltrimethoxysilane applied in corn oil under conditions mimicking the stomach of a rat.

The hydrolysis of methyltrimethoxysilane was studied in the dark in Gastric Fluid simulation buffer at a pH of 3.0±0.1 at 37±1°C on a shaking water bath set to 100 rpm.

Samples were produced in triplicate and analysed for the test compound and degradation product methanol. Both the corn oil and aqueous layers were analysed.

The design of the study was based on the following test guidelines:
OECD (2004), OECD Guideline for the Testing of Chemicals, Test Guideline 111, ‘Hydrolysis as a Function of pH’.
EFSA Note For Guidance (2008), Food Contact Materials, Annex 1 to Chapter III, Measurement of Hydrolysis of Plastic Monomers and Additives.

GLP compliance:

no

Remarks:

GLP regulations are not applicable to studies of this kind and no claim of GLP compliance is made. The study was conducted in a GLP compliant facility and the practices and procedures adopted during its conduct were consistent with the Principles of GLP.

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent/transformation products: Triplicate samples
- Sampling method: Complete treated samples were removed at each sampling time.
- Sampling methods for the volatile compounds, if any: N/A
- Sampling intervals/times for pH measurements: N/A
- Sampling intervals/times for sterility check: N/A
- Sample storage conditions before analysis: Samples were transferred directly to the system.
- Other observation, if any (e.g.: precipitation, colour change etc.): N/A

Buffers:

Hydrolysis was performed at pH 3 in Gastric Fluid simulation buffer solution. Gastric Fluid simulation buffer solution was prepared using reagent grade chemicals and Milli-Q water, sterilised by vacuum filtration, then sparged with nitrogen to reduce dissolved oxygen concentration. The pH was checked at 37±1°C. The solution was prepared by adjusting 2g/L sodium chloride to pH 3.0±0.1 with hydrochloric acid.

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: Amber glass vials with rubber septa and crimp-top.
- Sterilisation method: Amber glass vials sterilised by autoclave, buffer solutions filtered.
- Lighting: Dark
- Measures taken to avoid photolytic effects: Test conducted in the dark.
- Measures to exclude oxygen: N/A
- Details on test procedure for unstable compounds: N/A
- Details of traps for volatile, if any: Sealed vessels, no collection of volatiles
- If no traps were used, is the test system closed/open: Closed
- Is there any indication of the test material adsorbing to the walls of the test apparatus? No
TEST MEDIUM
- Volume used/treatment: 3.2 mL (0.5 mL Corn Oil dosing solution, 2.7 mL gastric fluid simulation buffer)
- Kind and purity of water: Milli-Q water
- Preparation of test medium: N/A
- Renewal of test solution: N/A
- Identity and concentration of co-solvent: N/A
OTHER TEST CONDITIONS
- Adjustment of pH: Buffer solution at pH 3.0
- Dissolved oxygen: N/A
Methyltrimethoxysilane was prepared in corn oil to create a dosing solution at 50 mg/mL. Dosing solution was then spiked in to gastric fluid simulation buffer in ca 3.7mL test vessels.
For the tests carried out, samples were placed in a shaking water baths maintained at 37 ±1°C and 100 rpm in the dark. The temperature was monitored and recorded at every sampling time point using a certified thermometer.

Duration:

60 min

pH:

3

Temp.:

37 °C

Number of replicates:

Three

Positive controls:

no

Negative controls:

no

Statistical methods:

The rate of hydrolysis is a pseudo-first order reaction and is described as follows: kobs=1/T Ln C0/CT
where
C0 is the concentration of the applied test item,
CT is the concentration of the test item at time T, and
kobs is the observed rate constant.

Preliminary study:

The preliminary study was not required because methyltrimethoxysilane is known to be unstable in water.

Transformation products:

yes

No.:

#1

Details on hydrolysis and appearance of transformation product(s):

The decrease in concentration with time of methyltrimethoxysilane and the increase of concentration with time of methanol with time were followed (see Figure 1 and Figure 2 attached). The anticipated reaction scheme is presented in the attachments section.

% Recovery:

>= 87.5 - <= 104

pH:

3

Temp.:

37 °C

Duration:

1 h

Remarks on result:

other: A molar recovery based on the quantity of methyltrimethoxysilane and molar equivalents of its hydrolysis product methanol (3 moles of methanol were assumed per mole of methyltrimethoxysilane) was between 87.5 and 104% at each time point

Key result

pH:

3

Temp.:

37 °C

Hydrolysis rate constant:

0.021 min-1

DT50:

33.3 min

Type:

(pseudo-)first order (= half-life)

Results gathered from this study are presented in Table 1 to Table 3. Figure 1 shows a plot of natural log of methyltrimethoxysilane concentration against time. Figure 2 shows a plot of concentration of methanol in the whole system against time.

 

Methyltrimethoxysilane was seen to hydrolyse in a significant manner (>10% degradation over the one hour time period), with ca. 80% degradation of the sample seen over the hour long test period (Table 1).

When methanol concentration (Table 2) is combined with the concentration of methyltrimethoxysilane in mole equivalents of methyltrimethoxysilane (3 moles of methanol per mole of methyltrimethoxysilane are assumed) recoveries ranged from 87.5 to 104% across 3 replicates (Table 3). Methanol content in the samples increases proportionally to the decrease in methyltrimethoxysilane in the system. This indicates that methanol is a product of this hydrolysis reaction.

Across the time points, the vast majority of the methyltrimethoxysilane was present in the corn oil with only trace amounts present in the simulated gastric juice layer. Conversely, the majority of the degradation product methanol was present in the gastric juice layer with very small amounts present in the corn oil layer. This suggest that hydrolysis rapidly occurs once methyltrimethoxysilane is in contact with the aqueous layer and the rate determining step is the transfer of the methyltrimethoxysilane from the corn oil to the water.

Table 1: Hydrolysis of Samples Prepared in Gastric fluid simulation buffer (Methyltrimethoxysilane)

Medium	Sample Name	Applied Mass (µg)	Calculated Concentration in Gastric Juice (µg/mL)**	Calculated Concentration in Corn Oil (µg/mL)	Average Total Mass (µg)	Mean Recovery (% Applied)
Gastric Fluid Simulation Buffer	0 min Rep 1	25000	7.17	844.2	19083	76.3
	0 min Rep 2		N/D	N/D
	0 min Rep 3		N/D	1062.
	5 min Rep 1		7.33	956.9	18337	73.3
	5 min Rep 2		N/D	903.4
	5 min Rep 3		5.08	887.7
	10 min Rep 1		7.76	701.0	14021	56.1
	10 min Rep 2		8.82	724.9
	10 min Rep 3		5.38	674.2
	20 min Rep 1		8.95	7.42*	12095	48.4
	20 min Rep 2		9.15	631.0
	20 min Rep 3		5.51	576.4
	30 min Rep 1		8.50	545.0	11171	44.7
	30 min Rep 2		9.65	483.0
	30 min Rep 3		7.12	644.1
	60 min Rep 1		9.17	275.7	5401	21.6
	60 min Rep 2		9.73	107.1*
	60 min Rep 3		7.53	262.0

*result likely from analytical error and not included in further calculations

**all of these samples are below the LOQ and assay range (10-1250 µg/mL) for this assay. They have still been included in further calculations

N/D= Not detected

Table 2: Methanol Produced as a Function of Hydrolysis

Medium	Sample Name	Applied Mass (µg)	Calculated Concentration in Gastric Juice (µg/mL)	Calculated Concentration in Corn Oil (µg/mL)	Average Total Mass (µg)
Simulated Gastric Juice	0 min Rep 1	0	75.5	20.2**	2121
	0 min Rep 2		50.7	8.92**
	0 min Rep 3		82.9	6.73**
	5 min Rep 1		101	15.8**	3191
	5 min Rep 2		96.2	16.2**
	5 min Rep 3		116	23.7**
	10 min Rep 1		176	39.7	5536
	10 min Rep 2		181	27.8
	10 min Rep 3		184	32.6
	20 min Rep 1		376	14.7**	8747
	20 min Rep 2		292	30.5
	20 min Rep 3		250	27.5
	30 min Rep 1		336	45.2	9503
	30 min Rep 2		401	29.0
	30 min Rep 3		241	30.9
	60 min Rep 1		N/D*	42.2	14649
	60 min Rep 2		618	19.3**
	60 min Rep 3		420	33.8

Table 3: Molar Recovery

Timepoint (minutes)	Mass of Methanol (µg)	Molar Equivalent	Mass of MTMS (µg)	Molar Equivalent	Total Molar Equivalent	Moles of MTMS applied	Molar Recovery (%)
0	2121	22.1	19083	140	162	184	88.0
5	3191	33.2	18337	135	168	184	91.3
10	5536	57.6	14021	103	161	184	87.5
20	8747	91.0	12095	88.8	180	184	97.8
30	9503	98.9	11171	82.0	181	184	98.4
60	14649	152	5401	39.6	192	184	104

Validity criteria fulfilled:

yes

Conclusions:

The hydrolysis of methyltrimethoxysilane was investigated under conditions designed to mimic the rat stomach after dosing the substance in corn oil. The half-life for disappearance of methyltrimethoxysilane applied in corn oil to gastric simulation buffer was 33 mins at pH 3 and 37°C and appears to be determined by phase transfer. The data suggest that, in the investigated system, hydrolysis occurs rapidly once methyltrimethoxysilane comes into contact with the aqueous layer and the rate determining step is the transfer of the methyltrimethoxysilane from the corn oil to the water. Combined recoveries of methyltrimethoxysilane and methanol (in mole equivalents of methyltrimethoxysilane; 3 moles methanol to 1 mole methyltrimethoxysilane assumed) were 87.5 to 104% and methanol content increased proportionally to the decrease in methyltrimethoxysilane. The study was conducted according to an appropriate test protocol and is considered reliable.

Reference 2

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003-10-13 to 2004-09-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

GLP compliance:

yes

Buffers:

The test system specified in the guideline requires distilled water, however, as the selected analytical method was 1H-NMR, it was necessary to use deuterated water to prepare the buffers. The relationship between pH and pD scales was established by Glasoe and Long. For solutions of comparable acidity of basicity the pH meter reading in D20 solution is 0.40 pH units lower than in H20 solution when calibrated against aqueous buffer standards. In this case: pD = pH meter reading + 0.40.
0.05 M buffer solutions were prepared to target pH 3.6, 6.6 and 8.6 by titration of formic acid (96%), sodium phosphate monobasic (99.0%) and boric acid (99.5%) solution, respectively, with sodium hydroxide (99.998%) solution. The formic acid, sodium phosphate monobasic, boric acid and sodium hydroxide were not deuterated.
Constant ionic strength was maintained for buffers by the addition of sodium chloride (99.999%). The ionic strength was not measured, but calculated based on buffer concentration/pH. Buffer solutions were made to known final volumes in polypropylene volumetric flasks with D2O. If necessary, final pH adjustments were made by dropwise addition of a concentrated sodium hydroxide or hydrochloric acid solution (prepared in D2O). The pH of each buffer solution was measured with a calibrated pH meter at the appropriate temperature and then converted to pD. Prior to use, the buffer solutions were sparged with argon gas for at least 5 min to exclude oxygen and sterilised through a 0.2µm filter.

Details on test conditions:

Kinetics experiments were conducted at the targeted pD 4, 7, and 9 at 25°C, pD 4 and 9 at 35°C and pD 4 and 9 at 10°C with buffer concentrations of 0.05M.
The experiment for pD 9 at 35°C was run in duplicate for repeatability purposes.
Buffers were thermostatted to ±0.1°C.
The test system consisted of buffered deuterated water (99.9 atom% D).
Due to the hydrolytically unstable nature of the test substance, the water miscible solvent ACN-d3 was used for application and distribution of the test substance in the test system. The acetonitrile was <1% (v/v) as allowed per the guideline.
Test systems: formic acid/NaOH for pD 4, sodium phosphate monobasic/NaOH for pD 7, and boric acid/NaOH for pD 9
Nominal initial concentration = 1x10-3 M (~150 mg/L). 
The hydrolysis reaction was initiated by adding an aliquot (95 µl) of the test substance solution (0.1 M MTMS in ACN-d3) to 10 ml of buffer (thermostatted to the appropriate temperature) using a gas tight volumetric syringe. The sample was immediately capped and inverted one time for mixing. Approximately 800 µl of the resulting sample was quickly transferred to an NMR tube and the 1H-NMR spectrum measured. The time between addition of the MTMS to the buffer and the first acquired spectrum was measured and recorded. To ensure the integrity of methyltrimethoxysilane, the test substance solution was analyzed by 1H-NMR before and after each set of hydrolysis kinetic experiments.

Number of replicates:

The experiment at pD 9 and 35°C was run in duplicate. The observed rate constants were 17.1420 and 18.3114 h-1 with a deviation of 3.3%. The deviation is slightly higher than the target 2.5% indicated in the OECD guideline because the NMR shims, resulting peak shape and resolution were better for replicate II than replicate I.

Statistical methods:

The hydrolysis of MTMS in dilute aqueous solution was observed to follow first-order kinetics for pD 7 and 9. The natural logarithm of the concentration (as peak intensity) was plotted as a function of reaction time. The observed rate constant, k, for the hydrolysis reaction is equal to the slope of a first-order regression line fitted to the data. The half-life of the hydrolysis reaction was calculated from the estimated rate constant according to the following equation: t1/2 = ln 2/k, where k is the reaction rate constant and t1/2 is the half-life of the test substance. Descriptive statistics such as average, average deviation, percent, and linear regression analysis were also performed.

Preliminary study:

The preliminary test at 50°C was not conducted since MTMS is considered hydrolytically unstable (t1/2 < 1 year).

Transformation products:

yes

No.:

#1

No.:

#2

Details on hydrolysis and appearance of transformation product(s):

Degradation products: Methylsilanetriol and methanol (CAS No. 67-56-1)
The hydrolysis product, methanol, was observed in  this study.  Based on the chemical structure of MTMS, this hydrolysis is
expected to produce 3 moles of methanol and 1 mole of methylsilanetriol  (SEHSC (2008) Communication from T Hill, Scientific Programs Manager 
Silicones Environmental, Health and Safety Council.)

Key result

pH:

4

Temp.:

10 °C

DT50:

< 0.034 h

Remarks on result:

other: <2 min; hydrolysis too rapid to determine rate constant

Key result

pH:

4

Temp.:

25 °C

DT50:

0 - < 0.033 h

Remarks on result:

other: <2 min; hydrolysis too rapid to determine rate constant

Key result

pH:

4

Temp.:

35 °C

DT50:

< 0.021 h

Remarks on result:

other: <2 min; hydrolysis too rapid to determine rate constant

Key result

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0.32 h-1

DT50:

2.2 h

Type:

(pseudo-)first order (= half-life)

Key result

pH:

9

Temp.:

10 °C

Hydrolysis rate constant:

1.86 h-1

DT50:

0.37 h

Type:

(pseudo-)first order (= half-life)

Key result

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

6.04 h-1

DT50:

0.11 h

Type:

(pseudo-)first order (= half-life)

Key result

pH:

9

Temp.:

35 °C

Hydrolysis rate constant:

17.7 h-1

DT50:

0.039 h

Type:

(pseudo-)first order (= half-life)

Remarks on result:

other: Average rate constant (rep I 17.1 h-1, rep II 18.3 h-1)

Conclusions:

Hydrolysis half-lifes at 25°C of <0.033 h, 2.2 h and 0.11 h were determined at pH 4, 7 and 9, respectively, in a reliable study conducted according to an appropriate test protocol, and in compliance with GLP.

Executive summary:

MTMS hydrolysis was followed by measuring its disappearance as a function of time by 1H-NMR spectroscopy. The hydrolysis was observed to follow pesudo-first order kinetics for pD 7 and 9, was pH dependent (faster at pH 4 and 9 than pH 7), and accelerated at higher temperature. The hydrolysis of MTMS for pD 4 was so rapid that insufficient data was obtained to determine the hydrolysis rate, however, the data were adequate for estimating the upper limit of t1/2.

According to the definition put forth in the test guidelines, the test substance was observed to be hydrolytically unstable (t1/2 <1 year) over a range of environmentally relevant pD conditions at 10.0, 25.0, and 35.0°C.

Description of key information

Hydrolysis half-lives: <0.033 h at pH 4, 2.2 h at pH 7 and 0.11 h at pH 9 and 25°C (OECD 111)

Key value for chemical safety assessment

Half-life for hydrolysis:

2.2 h

at the temperature of:

25 °C

Additional information

Hydrolysis half-lives at 25°C of <0.033 h at pH 4, 2.2 h at pH 7 and 0.11 h at pH 9 were determined for the substance in accordance with OECD 111 and in compliance with GLP. The result is considered to be reliable and selected as key study.

In a supporting reliable study, the stability of the substance in aqueous media under physiological conditions was investigated. The rates of hydrolysis of 1000 ppm trimethoxy(methyl)silane were determined in water at  pH 5.7, 0.15 molar (M) sodium-phosphate buffer (PBS), and 10% rat  serum in 0.15M PBS at pH 7.4 and 37.4°C in soft glass reactors. In this study, the substance was hydrolysed in water, PBS, and PBS plus 10% rat serum at pH 7.4 and 37°C with half-lives of 24, 6.7 and 8.6 minutes respectively. This is also supported by a result in secondary literature of non assignable reliability, which reports a half-life of 23 minutes at pH 5.7 and 37.4°C.

In another supporting study (CRL 2017), the hydrolysis of trimethoxy(methyl)silane was investigated under conditions designed to mimic the rat stomach after dosing the substance in corn oil. The half-life for disappearance of trimethoxy(methyl)silane applied in corn oil to gastric simulation buffer was 33 mins at pH 3 and 37°C and appears to be determined by phase transfer. The data suggest that, in the investigated system, hydrolysis occurs rapidly once trimethoxy(methyl)silane comes into contact with the aqueous layer and the rate determining step is the transfer of the trimethoxy(methyl)silane from the corn oil to the water. Combined recoveries of trimethoxy(methyl)silane and methanol (in mole equivalents of trimethoxy(methyl)silane; 3 moles methanol to 1 mole trimethoxy(methyl)silane assumed) were 87.5 to 104% and methanol content increased proportionally to the decrease in trimethoxy(methyl)silane. The study was conducted according to an appropriate test protocol and is considered reliable.

As the hydrolysis reaction may be acid or base-catalysed, the rate of reaction is expected to be slowest at around pH 7 and increase as the pH is raised or lowered. For an acid-base catalysed reaction in buffered solution, the measured rate constant is a linear combination of terms describing contributions from the uncatalysed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.

k_obs = k₀+ k_H3O+[H3O⁺] + k_OH^-[OH^-] + k_a[acid] + k_b[base]

At extremes of pH and under standard hydrolysis test conditions, it is reasonable to suggest that the rate of hydrolysis is dominated by either the hydronium or hydroxide catalysed mechanism.

Therefore, at low pH:

k_obs≈k_H3O+[H3O⁺]

At pH 4 [H₃O⁺] = 10^-4 mol dm^-3 and at pH 2 [H₃O⁺] = 10^-2 mol dm^-3; therefore, k_obs at pH 2 should be approximately 100 times greater than k_obs at pH 4.

The half-life of a substance at pH 2 is calculated based on:

t_1/2(pH 2) = t_1/2(pH 4) / 100

The calculated half-life of the substance at pH 2 is therefore less than 2 seconds at 25°C. However, it is not appropriate or necessary to attempt to predict accurately when the half-life is less than 5-10 seconds. As a worst-case it can therefore be considered that the half-life for trimethoxy(methyl)silane at pH 2 and 20-25°C is approximately 5 seconds.

 

Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Under ideal conditions, hydrolysis rate can be recalculated according to the equation:

DT₅₀(XºC) = DT₅₀(T) x e^(0.08.(T-X))

Where T = temperature for which data are available and X = target temperature.

Thus, for trimethoxy(methyl)silane the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is 0.8 hours. At 37.5ºC and pH 2 (relevant for conditions in the stomach following oral exposure), it is not appropriate to apply any further correction for temperature to the limit value and the hydrolysis half life is therefore approximately 5 seconds.

 

The hydrolysis products for the registered substance are methylsilanetriol and methanol.

 

The hydrolysis data for substances used in this dossier for read-across purposes for other endpoints are now discussed.

Hydrolysis of the read-across substance trimethoxy(propyl)silane (CAS: 1067-25-0)

Data for the substance, trimethoxy(propyl)silane (CAS 1067-25-0) are read-across to the submission substance trimethoxy(methyl)silane for the biodegradation in water endpoint. The silanol hydrolysis product and the rate of hydrolysis of the two substances are relevant to this read-across, as discussed in the appropriate section for the endpoint.

For trimethoxy(propyl)silane, hydrolysis half-lives at 20-25°C of 0.2 h at pH 4, 2.6 h at pH 7 and 0.1 h at pH 9 were predicted for the substance using validated QSAR estimation methods.

The hydrolysis products are propylsilanetriol and methanol.

Hydrolysis of the read-across substance triethoxy(methyl)silane (CAS 2031-67-6)

Data for the substance, triethoxy(methyl)silane (CAS 2031-67-6) are read-across to the submission substance trimethoxy(methyl)silane for the developmental toxicity endpoint. For short-term toxicity to fish, short-term toxicity to aquatic invertebrates and toxicity to aquatic algae endpoints, the studies for triethoxy(methyl)silane is used as supporting studies. The formation of the same silanol hydrolysis product, methylsilanetriol by both substances is relevant to this read-across as discussed in the appropriate sections for each endpoint.

For triethoxy(methyl)silane, hydrolysis half-lives at 20-25°C of 0.3 h at pH 4, 5.5 h at pH 7 and 0.1 h at pH 9 were determined for the substance in using validated QSAR estimation methods.

The half-lives at pH 2 and 25°C, at pH 7 and 37.5°C and at pH 2 and 37.5°C may be calculated in the same way as for the registration substance above. This gives a half-life of 0.003 h (11 seconds) at pH 2 and 25°C and 2.0 h at pH 7 and 37.5°C. However, it is not appropriate or necessary to attempt to predict accurately when the half-life is less than 5-10 seconds. As a worst-case it can therefore be considered that the half-life for the substance at pH 2 and 37.5°C is approximately 5 seconds.

The hydrolysis products are methylsilanetriol and ethanol.