[3-(2,3-epoxypropoxy)propyl]triethoxysilane

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2001-06-15 to 2002-06-03

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)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

no

Buffers:

- pH: 4
- Type and final molarity of buffer: Biphthalate (Baker, Art. No. 5657)

- pH: 7
- Type and final molarity of buffer: Phosphate (Backer Art. No. 5656)

- pH: 9
- Type and final molarity of buffer: Borate (Baker Art. No. 7145)

The buffer solutions were sterilized for 25 mins in an autoclave prior to first use. Nitrogen was passed through the buffer solutions for 3 mins except when freshly sterilized.

Details on test conditions:

Initial concentration of test substance in test solution: ca. 1 mg/ml (ca. 0.004 M).

Number of replicates:

Each test was performed in duplicate.

Preliminary study:

The preliminary study was performed at 50.0°C±0.4°C at pH 4.0, pH 7.0 and pH 9.0.
pH 4: The test substance was not soluble.
pH 7: The test substance was unstable (24% hydrolysis in 2.4 h; 100% hydrolysis in 5 days).
pH 9: The test substance was very unstable (100% hydrolysis in 2.4 h).

Transformation products:

no

pH:

4

Temp.:

50 °C

Remarks on result:

other: The solubility was too low to follow the degradation.

pH:

9

Temp.:

50 °C

DT50:

< 2.4 h

Remarks on result:

other: The substance starts to hydrolyse immediately after being dissolved in the buffer.

pH:

9

Temp.:

25 °C

DT50:

< 1 d

Remarks on result:

other: Estimate based on results at 50°C; no further testing was carried out.

pH:

7

Temp.:

50 °C

DT50:

5 h

Type:

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

pH:

7

Temp.:

35 °C

DT50:

14 h

Type:

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

pH:

7

Temp.:

25 °C

DT50:

38 h

Type:

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

Remarks on result:

other: Based on the test at 25°C.

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0.019 h-1

DT50:

36 h

Type:

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

Remarks on result:

other: Based on calculation of the activation energy using the results at all temperatures.

Other kinetic parameters:

The data were plotted as In c, versus t. The linear plots prove that the hydrolysis reaction is pseudo first order. The rate constant k is the slope of a plot of In c, versus t. The half-life was calculated from t1/2 = 0.693 / k.

The rate constant, k at 25°C and pH 7 was calculated using the Arrhenius equation, based on the data measured at pH and 25, 35 and 50°C.

Table 1: Results of hydrolysis at pH 7

		Sample 1	Sample 1	Sample 2	Sample 2
Temperature / °C	Time / hours	Measured concentration / µg/ml	Hydrolysis / %	Measured concentration / µg/ml	Hydrolysis / %
50	0.0	1012.4	0	1029.2	0
50	2.0	790.2	22	820.7	20
50	3.0	650.1	36	683.5	34
50	4.0	531.5	48	576.8	44
50	5.0	504.8	50	471.8	54
50	6.5	428.7	58	430.4	58
50	8.0	321.8	68	310.9	70
50	9.0	299.6	70	276.5	73
50	10.0	248.8	75	237.3	77
35	0.0	1011.7	0	1048.8	0
35	4.8	830.3	18	849.3	19
35	6.3	793.8	22	798.4	24
35	8.0	707.7	30	708.1	32
35	10.0	660.4	35	637.6	39
35	20.8	391.2	61	388.6	63
35	22.3	359.1	65	356.3	66
35	23.8	341.6	66	322.7	69
35	25.3	316.1	69	317.4	70
25	0	1011.6	0	1049.2	0
25	8.3	814.5	19	868.8	17
25	11.3	777.8	23	740.3	29
25	14.3	676.7	33	698.8	33
25	17.3	652.6	35	677.0	35
25	32.3	523.6	48	511.8	51
25	35.3	494.6	51	482.9	54
25	38.3	447.8	56	458.1	56
25	41.3	431.8	57	422.7	60
25	56.5	307.4	70	305.4	71
25	60.5	298.6	70	295.5	72

The first order rate constant and half life were calculated from the values where the degradation was between 20% and 70%.

 

Table 2: Calculation of first order rate constant and half-life time at pH 7.0

	50°C	50°C	35°C	35°C	25°C	25°C
	Sample 1	Sample 2	Sample 1	Sample 2	Sample 1	Sample 2
Slope = (-k_ in [1/h]=	-0.13500	-0.15429	-0.04799	-0.04869	-0.01890	-0.01829
y-axis intercept = ln c(0) =	6.89	6.99	6.96	6.96	6.83	6.82
Coefficient of regression (r)	-0.991	-0.991	-1.000	-0.999	-0.995	-0.999
0.693/k = t1/2 in [h] =	5	4	14	14	37	38

 

Table 3: Calculation of the first order rate constant of the hydrolysis reaction at pH 7.0 according to the Arrhenius equation by regression analysis

Temp. / °C	k / 1/h	E / kJ/mol	K at 25°C / 1/h	t1/2 at 25°C / days	Slope = (-E/R)	y-axis intercept = ln A	Coefficient of regression
50.0	0.135	65.3	0.0193	1	-7859	22.4	-0.997
50.0	0.154
35.0	0.0480
35.0	0.0487
25.0	0.0189
25.0	0.0183

 

Conclusions:

A half-life at pH 7 and 25°C of 36 h was determined in a reliable study conducted according to OECD Guideline 111 and in compliance with GLP.

Reference 2

Endpoint:

hydrolysis

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

See attached QMRFs/QPRFs

Principles of method if other than guideline:

The result was obtained using an appropriate QSAR method (see attached QMRF and QPRF for details).

The model for hydrolysis at pH 7 has been developed for, and applies specifically to di- and tri-alkoxysilanes. It is a multiple linear regression based model with descriptors representing (i) steric effects of the alkoxy group, (ii) steric effects of the side-chain(s), and (iii) electronic effects of the side-chain(s).

The models for hydrolysis at pH 4, 5 and 9 have been developed for, and apply specifically to organosilicon compounds. They are linear regression based models where the descriptor is the half-life at pH 7.

Transformation products:

yes

No.:

#1

No.:

#2

pH:

4

DT50:

0.6 h

Remarks on result:

other: 20-25°C

pH:

5

DT50:

0.6 h

Remarks on result:

other: 20-25°C

pH:

7

DT50:

25.1 h

Remarks on result:

other: 20-25°C

pH:

9

DT50:

0.4 h

Remarks on result:

other: 20-25°C

Conclusions:

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 using an accepted calculation method. The result is considered to be reliable.

Description of key information

Hydrolysis half-life: 12 – 36 h at pH 7 and 25°C (OECD 111).

Additional information

A hydrolysis half-life of 36 hours 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 could reflect rapid hydrolysis followed by polymerisation of the hydrolysis product.

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-lives of approximately 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 hydrolysis of the alkoxysilane (ethoxy) functional group using validated QSAR estimation methods.

For comparison, the hydrolysis half-life of the epoxy group of glycidyl alcohol (a much more soluble substance) was 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).

 

Given the uncertainties in the experimental study conducted with the registration substance, these results are taken together as weight of evidence.

 

As the 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 uncatalyzed 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 [3-(2,3-epoxypropoxy)propyl]triethoxysilane at pH 2 is therefore 0.006 hours (approximately 22 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]triethoxysilane the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is 4 – 13 hours. At 37.5ºC and pH 2 (relevant for conditions in the stomach following oral exposure), the hydrolysis half-life is approximately 7 seconds.

The ultimate hydrolysis products will be 2,3-dihydroxypropoxypropylsilanetriol and ethanol.

Hydrolysis of the read-across substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8)

Data for the substance[3-(2,3-epoxypropoxy)propyl]trimethoxysilane(CAS 2530-83-8) are read-across to the submission substance [3-(2,3-epoxypropoxy)propyl]triethoxysilane for appropriate endpoints (see Section 1.4 of the CSR). 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 Sections of the CSR for each endpoint.

For [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, hydrolysis half-lives at 24.5°C of 0.15 h at pH 5, 6.5 h at pH 7 and 0.13 h at pH 9 were determined in accordance with OECD 111 (Kozerski G, Ziemelis M, Gallavan R 2001). 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.

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 <0.0015 h (<5.4 seconds) at pH 2 and 25°C and 2.4 h at pH 7 and 37.5°C. 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 for the substance at pH 2 and 37.5°C is approximately 5 seconds.

The hydrolysis products are2,3-dihydroxypropoxypropylsilanetrioland methanol.

 

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

Data for the substance 2-(3,4-epoxycyclohexyl)ethyltriethoxy silane (CAS 10217-34-2) are read-across to the submission substance[3-(2,3-epoxypropoxy)propyl]triethoxysilanefor appropriate endpoints (see Section 1.4 of the CSR).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 Sections of the CSR for each endpoint.

For 2-(3,4-epoxycyclohexyl)ethyltriethoxy silane, hydrolysis half-lives at 25°C of 0.7 h at pH 4, approximately 31 h at pH 7 and 0.4 h at pH 9 were determined using a validated QSAR estimation method.

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 0.007 h (25 seconds) at pH 2 and 25°C, 0.0026 h (9 seconds) at pH 2 and 37.5°C and 11 h at pH 7 and 37.5°C.

The hydrolysis products are trihydroxy[2-(7-oxabicyclo[4.1.0]hept-3-yl)ethyl]silane and ethanol.