N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP. In addition, the following acceptable restrictions are identified: No evidence of replicates or checks against well established references, Loading Concentrations may be approximate, and there are no uncertainties quoted, and LOQ is not stated.

Principles of method if other than guideline:

Screening method based on 1H-NMR spectroscopy. The formation of the product methanol was observed.

GLP compliance:

no

Buffers:

pH 4: citrate buffer, pH 7: phosphate buffer and pH 9: borate buffer

Preliminary study:

No preliminary study was carried out.

Transformation products:

yes

No.:

#1

No.:

#2

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

The formation of methanol and the formation and decay of the mono-methoxy intermediate were followed during the reaction.

Key result

pH:

4

DT50:

< 3 min

Remarks on result:

other: At room temperature

Key result

pH:

7

DT50:

15 min

Remarks on result:

other: At room temperature

Key result

pH:

9

DT50:

< 3 min

Remarks on result:

other: At room temperature

Other kinetic parameters:

None determined.

The NMR experiment allowed the loss of the first methoxy group to be followed and the formation of the monomethoxy-intermediate, which is eventually also hydrolysed. All methoxy groups are ultimately converted to methanol.

Taking into account only the original test substance and final products, a formal half-life of 15 mins was calculated. This corresponds to the slope of the regression line in the Arrhenius plot. It was noted that the axis intercept for this plot was at ca. 70% rather than being close to 100% at time zero. The authors of the report concluded that this probably resulted from fast hydrolysis of the original silane to the mono-methoxy-intermediate, which then hydrolyses more slowly. This behaviour was not investigated in more detail because it was clear that hydrolysis was very rapid.

Conclusions:

Hydrolysis half-lives of <3 min at pH 4, 15 min at pH 7 and <3 min at pH 9 were determined at room temperature in a non-guideline study conducted according to generally accepted scientific principles, but not in compliance with GLP. The half-lives relate to formation of the final product from the test substance.

Description of key information

Hydrolysis half-lives: <3 minutes at pH 4, 15 minutes at pH 7 and <3 minutes at pH 9 at 20 - 25°C (measured data)

Key value for chemical safety assessment

Half-life for hydrolysis:

15 min

Additional information

Hydrolysis half-lives of <3 minutes at pH 4, 15 minutes at pH 7 and <3 minutes at pH 9 were determined at room temperature in a non-guideline study conducted according to generally accepted scientific principles, but not in compliance with GLP. The hydrolysis reaction involves two steps for consecutive loss of the two methoxy groups. The half-lives were determined based on data for the loss of the parent substance and formation of the final products. Therefore, they are half-lives for formation of N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine from N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine (not half-lives for the initial degradation of N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine by loss of the first methoxy group).

The hydrolysis reactions of alkoxysilanes are generally acid or base catalysed; the rate of reaction is slowest at around pH 7 and increases as the pH is raised or lowered. For diamine substances, an additional intramolecular catalysis mechanism has been identified and results in the hydrolysis at pH 7 being faster than that observed for similar alkoxysilanes. The degree of intramolecular catalysis is pH-dependent (less important at acid pH) because it depends on the ionisation state of the diamine group (Dow Corning Corporation 2001b).

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, general acids or bases, and the intramolecular catalysis.

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

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 N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine at pH 2 is therefore 0.03 minutes (1.8 seconds). 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 of the substance 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) * e^(0.08.(T-X))

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

Thus, for N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is 0.09 hours (324 seconds). At pH 4 and 37.5ºC, the calculated half-life is <1 minute. 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 products of hydrolysis are N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine (1 mole) and methanol (2 moles).

The hydrolysis half-lives of substances used for read-across in other areas are discussed below:

Hydrolysis of the read-across substance, N-[3-(trimethoxysilyl)propyl]ethylenediamine (CAS 1760-24-3)

Data for the substance, N-[3-(trimethoxysilyl)propyl]ethylenediamine (CAS 1760-24-3) are read-across to the submission substance N-[3-(dimethoxy(methyl)silyl)propyl]ethylenediamine for various endpoints. The hydrolysis half-lives and the silanol hydrolysis products of the two substances are relevant to this read-across, as discussed in the appropriate sections for each endpoint.

For N-[3-(trimethoxysilyl)propyl]ethylenediamine, hydrolysis half-lives at 24.7°C of 0.1 h at pH 4, 0.32 h at pH 5, and 0.025 h at pH 7 were determined in accordance with OECD 111 (Dow Corning Corporation 2001b). At pH >7, the half-life became too rapid (<90 s) to measure using the methodology of this study. In other secondary sources to which reliability could not be assigned, a hydrolysis half-life of 0.016 h at pH 7 and 24.7°C was reported. Also, a hydrolysis half-life of 24.1 h at 25°C was reported, information on the pH was not stated.

The complete hydrolysis of CAS 1760-24-3 involves consecutive removal of the three methoxy groups; it is therefore a three-step process. The quoted half-lives refer to degradation of parent substance. In addition, separate rate constants for the three consecutive hydrolysis reactions have been measured. For the acid catalysed rate constants, the second and third reaction steps were found to be approximately twice as fast as the previous step (k₁<k₂<k₃). For the base catalysed rate constants, the second step was found to be approximately 1.5-fold slower than the first step which was about the same as the third step (k₂<k₁˜k₃). Therefore, rapid formation of the final product is expected across the pH range.

It is noted that the half-life is slower at pH 5 than at pH 7 and pH 4. In general, alkoxysilane hydrolysis is slowest at around pH 7 and faster as the pH is raised or lowered. However, a possible intermolecular catalysis mechanism has been identified for this substance which speeds up the hydrolysis at pH 7 relative to that observed for similar alkoxysilanes. This mechanism is proposed as the cause of the different pH-dependent behaviour. The acid-catalysed mechanism is believed to dominate under acid conditions, therefore, the calculation of the pH 2 half-life discussed above is valid.

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 0.001 h (3.6 seconds) at pH 2 and 25°C, and 0.0089 h (32 seconds) at pH 7 and 37.5°C. 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 of the substance at pH 2 and 37.5°C is approximately 5 seconds.

The hydrolysis products are N-(3-(trihydroxysilyl)propyl)ethylenediamine (1 mole) and methanol (3 moles).