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Hydrolysis

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Reference
Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The study was conducted according to an appropriate OECD test guideline. It was not compliant with GLP.
Qualifier:
according to
Guideline:
OECD Guideline 111 (Hydrolysis as a Function of pH)
GLP compliance:
no
Radiolabelling:
no
Analytical monitoring:
yes
Details on sampling:
Individual kinetic experiments were conducted in one of two modes, depending on the expected half-life of the parent substance. The first mode was used for half-life < ca. 1h and involved a separate reaction aliquot for each unique reaction time to be sampled. Immediately prior to analysis of a particular sample, the hydrolysis reaction was quenched by rapid adjustment to pH 6.5-7.5 by addition of acid or base. The final pH of a subset of samples was verified. The second mode was used for pH 7 and 7.6 and involved up to four staggered reaction solutions. The separate reactions were repeatedly sampled in alternating fashion over three to four hours to collect hydrolysis data spanning 2-3 half-lives of the parent substance.
Buffers:
Buffer solutions of known pH and concentration were prepared by titration of 1M glacial acetic acid or tris(hydroxymethyl)-aminomethane (99.9%) solution with 1M sodium hydroxide (99.998%) or hydrochloric acid solution (37 wt%), respectively. A constant ionic strength of 0.20 M was maintained by addition of an appropriate volume of 2M sodium chloride solution. Buffer solutions were made to known final volume in polypropylene volumetric flasks with deionized water (>18 MO cm). If necessary, final pH adjustments were made by dropwise addition of sodium hydroxide or hydrochloric acid using a calibrated pH meter. Prior to use all buffer solutions were sparged with argon for at least 15 min. The pH of each buffer solution was measured again just prior or during the kinetic experiment for which it was used.
Details on test conditions:
5*10-2 M stock solutions of the test material in acetonitrile were prepared in a nitrogen-purged glove bag and stored in 22 ml plastic vials having septum lined open-top caps. When not in use, the vials were stored in a secondary airtight container filled with Drierite.
Kinetic experiments were conducted over the pH range 5-9 with buffer concentrations varying from 0.005 to 0.07 M for acetic acid/sodium acetate and 0.002 to 0.2 for Tris-HCl/Tris. As the hydrolysis reactions were expected to show general base catalysis, buffer concentrations were selected to give particular concentrations of the conjugate base over the range of pH covered by each buffer.
Experiments were conducted at 10.1 to 36.9°C, thermostatted to ±0.1°C.
The starting concentration was not varied as previous studies have demonstrated that the reaction rate in dilute aqueous solution is first order in silane concentration.
Statistical methods:
The changes in peak area associated with each of the four components of the reaction mixture (parent, intermediates and product) over time contain kinetic information pertaining to the rates of the three consecutive hydrolysis reactions. Unconstrained nonlinear regression analysis was used to obtain estimates for the rate constants k1, k2 and k3 by simultaneously fitting the dataset to a kinetic model based on pseudo-first order kinetics for each reaction. A parameter was added to account for the varying sensitivity of the instrument to each component. The initial silane concentration was treated as a fixed parameter.
The analysis was performed using Origin 6.0 data analysis software, which employs the Levenburg-Marquardt minimization algorithm. The software varied the software parameters iteratively. The tolerance was set at 0.01%. Convergence was typically reached in 3 iterations, although occasionally 6 or 7 iterations were required.
Transformation products:
not measured
Details on hydrolysis and appearance of transformation product(s):
Trialkoxysilanes undergo hydrolysis in dilute aqueous solution via a series of consecutive pseudo first order reactions:
RSi(OR')3 ¿ RSi(OR')2(OH) ¿ RSi(OR')(OH)2 ¿ RSi(OH)3

The signal associated with the parent silane followed a simple exponential decrease over time. Those of the intermediate products appeared early and reached maxima part way through the hydrolysis process, followed by a slow decrease that continued until completed hydrolysis was nearly reached. The final product response initially increased slowly, followed by a period of accelerated, almost linear, growth. Later in the reaction, the rate of product formation gradually began to decrease, approaching complete hydrolysis in an asymptotic manner.
Key result
pH:
5
Temp.:
24.5 °C
DT50:
0.15 h
Key result
pH:
7
Temp.:
24.5 °C
DT50:
6.5 h
Key result
pH:
9
Temp.:
24.5 °C
DT50:
0.13 h
Key result
pH:
5
Temp.:
10 °C
DT50:
0.29 h
Key result
pH:
7
Temp.:
10 °C
DT50:
18 h
Key result
pH:
9
Temp.:
10 °C
DT50:
0.11 h
Key result
pH:
5
Temp.:
37 °C
DT50:
0.087 h
Key result
pH:
7
Temp.:
37 °C
DT50:
3.3 h
Key result
pH:
9
Temp.:
37 °C
DT50:
0.053 h
Other kinetic parameters:
In general, very good agreement between the experiment data and the fitted curves was observed for all components. The only systematic deviation is early in the reaction where the apparent concentration of the first intermediate is greater than that predicted by the kinetic model. This is thought to be likely due to the procedure used to quench the reaction via pH neutralization. The effect is not large and is not believed to significantly bias the estimation of k2 and k3.

The rate constants exclusively follow the trend k1

Nominal initial concentration = 5x10-4 M (~110 mg/L). The concentration was not directly measured; rate constants were extracted from changes in analytical response for each component.

Table 1.  Kinetic Constants for Hydronium, Hydroxide, and Solvent (H2O) Catalyzed Hydrolysis Reactions of
[3-(2,3-epoxypropoxy)propyl]trimethoxysilane at 24.5 °C

Constant (units)

1sthydrolysis step

2ndhydrolysis step

3rdhydrolysis step

kH3O+(M-1s-1)

131

310

354

k-OH(M-1s-1)

143

957

1850

k0(s-1)

2.2 x 10-6

1.3 x 10-5

1.8 x 10-5


Over the pH range investigated, the intermediate silanol products (the mono- and di-ol) were observed to hydrolyse more rapidly than
the original tri-alkoxysilane.  Consequently, these breakdown products can be considered transient.  The stability of the methanol
co-product was not considered, but is probably stable under these conditions.

Conclusions:
Hydrolysis half-lives at pH 5, 7 and 9 (24.5°C) of 8.8, 390 and 8.1 min (0.15, 6.5 and 0.13 h), respectively were determined in a reliable study according to an appropriate test protocol but not under GLP.
Executive summary:

The acid-base catalysed stepwise hydrolysis kinetics of 3 -glycidoxypropyltrimethoxysilane were determined using high performance liquid chromatography (HPLC) and inductively coupled plasma optical emission spectroscopy (ICP-OES). The hydrolysis reactions were monitored by sampling kinetic solutions at various times and performing a chromatographic separation of the parent silane, the intermediate hydrolysis products (the mono-ol and di-ol), and the final silanetriol. The column effluent was directed into the ICP-OES for on-line monitoring of atomic emission to give a series of silicon chromatograms for the kinetic run. The systematic changes in peak area for each of the chemical species as a function of reaction time provide information from which the rate constants of the consecutive hydrolysis reactions, k1, k2 and k3, were obtained. A series of rate constants were measured over a range of pH and buffer concentration, permitting calculation of the catalytic constants, kH3O+ and k-OH for each hydrolysis step. The temperature dependence of each of these catalytic pathways was also determined through additional experiments at the extremes of pH. In the absence of other catalytic species, the predicted half-life, t1/2, of GPTMS at pH 5, 7 and 9 (24.5°C) was 8.8, 390 and 8.1 min, respectively, with the rate minimum occurring at pH 7.0. Extrapolating of 0°C, the maximum value of t1/2 was predicted as 36 h at pH 7.2. These results are consistent with published data pertaining to the initial hydrolysis step and confirm that over a wide range of conditions the first hydrolysis step is rate limiting.

Description of key information

Hydrolysis half-life (methoxy group): 0.15 h at pH 5, 6.5 h at pH 7 and 0.13 min at pH 9 and 24.5°C (OECD 111)

Key value for chemical safety assessment

Half-life for hydrolysis:
6.5 h
at the temperature of:
24.5 °C

Additional information

The submission substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane contains two types of hydrolysable groups; three methoxy groups (which react to the corresponding silanol and methanol) and one epoxide ring (which has the potential to react to the corresponding diol). The chemical safety assessment of the substance assumes that these reaction processes will proceed independently based on their rate under relevant conditions.

Hydrolysis of the methoxysilane groups:

A hydrolysis half-lives for the methoxy group of 0.15 h at pH 5, 6.5 h at pH 7 and 0.13 h at pH 9 and 24.5°C were determined according to OECD 111 but not in compliance with GLP. At 10°C, hydrolysis half-lives were 0.29 h at pH 5, 18 h at pH 7 and 0.11 h at pH 9. Also, at 37°C, half-lives of 0.087 h at pH 5, 3.3 h at pH 7 and 0.053 h at pH 9 were determined for the substance. The result is considered to be reliable and is selected as key study. The hydrolysis half-life at pH 4 is expected to be faster than at pH 5. Therefore, at pH 4, a conservative half-life of <0.15 h is used.

In another study which uses Gel Permeation Chromatography (GPC) to determine the relative molecular weight distribution of the hydrolysis and condensation products. Characterisation was determined via NMR and ESI-MS and analysis was carried out at 1 h and 4 h. The test temperature was at 22°C. The qualitative result of the analysis indicates that cyclic and linear condensation products were detected at the 1 h and 4 h period. The intensities of the hydrolysis products decreased over time as a result of continuous condensation reactions.

In a secondary source to which reliability could not be assigned, hydrolysis half-lives of 5 min at pH 5, 52.5 min at pH 7 and 11.6 min at pH 9 and 25°C were reported for the substance.

Hydrolysis of the epoxide ring:

Very limited evidence of the hydrolysis of the epoxide ring is available. The hydrolysis half-life of the epoxy group of glycidyl alcohol (a much more soluble substance) is reported to be 12 hours at 25°C and pH 7 (HSDB citing Mabey W, Mill T J Phys Chem Ref Data 7: 383-415 (1978). In the case of the submission substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane , it is considered that the epoxide ring opening is not significant for the exposure assessment at any relevant pH. Therefore, where the chemical safety assessment considers hydrolysis products; these are identified as [3-(2,3-epoxypropxy)propyl]silanetriol and methanol. This is a conservative position in the absence of clear evidence, as the epoxide structural feature is likely to be more toxic than the corresponding diol.

As the alkoxysilane group hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at 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.

 

kobs= k0+ kH3O+[H3O+] + kOH-[OH-] + ka[acid] + kb[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:

kobs˜kH3O+[H3O+]

 

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

 

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

t1/2(pH 2) = t1/2(pH 4) / 100

The calculated half-life of [3-(2,3-epoxypropoxy)propyl]trimethoxysilane at pH 2 and 24.5°C is therefore 0.0015 hours (approximately 5 seconds). However, it is likely that factors such as diffusion become rate-determining when the half-life is less than 5-10 seconds. As a worst-case it can therefore be considered that the half-life of the substance at pH 2 and room temperature 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) * e(0.08.(T-X))

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

Thus, for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is 2.3 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. At 37.5ºC and pH 5.5 (relevant for dermal exposure), the hydrolysis half -life will be in between the half-lives at pH 5 and pH 7 at 37.5ºC.

The hydrolysis products are [3-(2,3-epoxypropoxy)propyl]silanetriol and methanol.

The hydrolysis of other substances used for read-across in other endpoints are discussed below:

Hydrolysis of the read-across substance 2-(3,4-epoxycyclohexyl)ethyltriethoxysilane (CAS 10217-34-2)

Data for the substance 2-(3,4-epoxycyclohexyl)ethyltriethoxysilane (CAS 10217-34-2) are read-across to the submission substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane for repeated dose toxicity:oral endpoint. The structural similarity, hydrolysis half-life and the silanol hydrolysis product of the two substances is relevant to this read-across, as discussed in the appropriate section for the endpoint.

 

For 2-(3,4-epoxycyclohexyl)ethyltriethoxy silane, hydrolysis half-lives for reaction of the ethoxy groups of 0.7 h at pH 4, 0.7 h at pH 5, 30.7 h at pH 7 and 0.4 h at pH 9 at 20-25°C were determined using a validated QSAR estimation method. The half-life at pH 7 is supported by a reliable OECD 111 study result of 28.6 h and 30.3 h at pH7 and 25°C for the two isomers present. It is not clear in the study which groups were hydrolysing but the half-life is consistent with expectation for the rate of reaction of the ethoxy groups.

 

The half-lives for the reaction of the ethoxy groups 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 0.007 h (25 seconds) at pH 2 and 25°C and approximately 11 h at pH 7 and 37.5°C. At pH 2 and 37.5°C, the hydrolysis half-life is 0.0026 h (approximately 9 seconds). However, it is likely that factors such as diffusion become rate-limiting when the half-life is less than 5-10 seconds. As a worst-case it can therefore be considered that the half-life at pH 2 and 37.5°C is approximately 5 seconds

 

The hydrolysis products for the read-across substance are 2-(3,4-epoxycyclohexyl)ethylsilanetriol and ethanol.

Hydrolysis of the read-across substance [3-(2,3-epoxypropoxy)propyl]triethoxysilane (CAS 2602-34-8)

Data for the substance [3-(2,3-epoxypropoxy)propyl]triethoxysilane (CAS 2602-34-8) are read across to the submission substance 3-(2,3-epoxypropoxy)propyltrimethoxysilane for the in vitro genetic toxicity endpoint. The structural similarity and the silanol hydrolysis product of the two substances is relevant to this read-across, as discussed in the appropriate section for each endpoint.

A hydrolysis half-life of 36 h at pH 7 and 25°C was determined in a reliable study conducted in accordance with OECD 111 and in compliance with GLP. At pH 9.0, the half-life was found to be <2.4 h at 50°C and estimated to be <1 day at 25°C. At pH 4.0, the test substance was found to be insoluble. The authors of this summary consider that this observation could be due to rapid hydrolysis followed by polymerisation of the hydrolysis product rather than insolubility of the parent substance. The hydrolysis study focuses on removal of parent. The products were not identified in the study and it is unclear which reaction(s) the stated half-lives relate to.

Hydrolysis half-life values of 0.6 h at pH 4, 0.6 h at pH 5, 25.1 h at pH 7 and 0.4 h at pH 9 and 20-25°C were obtained for the hydrolysis of the alkoxysilane (ethoxy) functional group using an accepted QSAR validation method.

The hydrolysis products for the read-across substance are [3-(2,3-epoxypropoxy)propyl]silanetriol and ethanol.