N-(3-(trimethoxysilyl)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:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

GLP compliance:

no

Specific details on test material used for the study:

5E-02 M stock solutions of test material in acetonitrile were prepared in a nitrogen-purged glove bag. Sample vials were stored over anhydrous calcium sulphate in secondary airtight containers

Analytical monitoring:

yes

Details on sampling:

direct sample infusion

Buffers:

Ammonium acetate/acetic acid and imidazole/imidazole hydrochloric acid buffers of varying concentrations between 5-50 mM and 5-25 mM, respectively. All buffer solutions were purged with argon gas for at least 15 mins to exclude oxygen and carbon dioxide.

Details on test conditions:

pH range 3.8-7.1
temperature range 10.3-35.1 °C, thermostatted to ± 1 °C using a circulating water bath

pH:

4

Temp.:

24.7 °C

pH:

5

Temp.:

24.7 °C

pH:

7

Number of replicates:

multiple at pH and temperature of interest.

Statistical methods:

Unconstrained nonlinear regression analysis was used to obtain estimates for the rate constants by fitting the dataset to multiple equation kinetic models. Analysis using Origin® 6.0 data analysis software (Microcal Software, Inc.) employing the Levenburg-Marquardt minimization algorithm.
After supplying the data and kinetic model, each model parameter was initially estimated from linear regression of the natural log transformed (EDA-Pr)Si(OMe)3 intensities vs time.

Preliminary study:

No data

Transformation products:

yes

No.:

#1

No.:

#2

Key result

pH:

4

Temp.:

24.7 °C

DT50:

0.1 h

Remarks on result:

other: calulated using the Arrhenius parameters, as a function of pH and temperature at zero buffer concentration

Key result

pH:

5

Temp.:

24.7 °C

DT50:

0.32 h

Remarks on result:

other: calulated using the Arrhenius parameters, as a function of pH and temperature at zero buffer concentration

Key result

pH:

7

Temp.:

24.7 °C

DT50:

0.025 h

Remarks on result:

other: calulated using the Arrhenius parameters, as a function of pH and temperature at zero buffer concentration

 Table 1. Results calulated using the Arrhenius parameters, as a function of pH and temperature at zero buffer concentration

pH	Temperature (°C)	Half-life (hr)
4	10.0	0.23
4	24.7	0.10
4	37.0	0.066
5	10.0	1.5
5	24.7	0.32
5	37.0	0.26
7	10.0	0.10
7	24.7	0.025
7	37.0	0.0090

 

 

Table 2. Observed Rate Constants for Hydrolysis Reactions of DAPMS Used For Modelling the Effect pH and Buffer Concentration at 25 °C.

 

Run	pH	[buffer], mM^a	k1 x 10^3, s^-1	k2 x 10^3, s^-1	k3 x 10^3, s^-1
19	3.78	10.6	3.32(0.08)^b	7.00(0.75)	17.2(9.2)
7	4.14	5.3	1.59(0.04)	3.33(0.41)	10.8(4.5)
8	4.02	53	3.13(0.08)	6.31(0.90)	12.6(3.7)
18	4.69	26.5	0.974(0.026)	2.04(0.31)	6.23(5.16)^c
24	4.97	26.5	0.728(0.018)	1.50(0.19)	2.67(0.85)
6	5.21	5.3	0.493(0.028)	0.974(0.146)	1.19(1.11)^c
5	5.11	26.5	0.524(0.017)	0.876(0.089)	3.92(3.73)^c
9	6.15	10	1.88(0.07)	1.29(0.12)	2.87(0.72)
13	6.07	25	1.71(0.04)	1.23(0.11)	2.23(1.47)
17	6.44	10	3.48(0.11)	1.86(0.14)	3.78(1.18)
14	6.4	25	3.48(0.12)	1.93(0.22)	4.93(3.87)
15^d	6.39	25	3.50(0.12)	2.42(0.31)	4.89(5.99)^c
16^e	6.42	25	4.05(0.22)	2.96(0.60)	7.53(11.0)^c
10	6.79	10	4.45(0.21)	2.89(0.25)	5.04(1.32)
25	6.7	25	5.73(0.31)	2.56(0.37)	5.06(4.29)^c
29	7.08	5	7.98(0.19)	5.11(0.23)	8.17(1.95)
30	7.08	5	8.35(0.19)	5.13(0.23)	8.10(1.93)

^a pH 3.8-5.2: HOAc/NH4OAc; pH>6: Imidazole/Imidazole-HCl.

^b Uncertainties in parenthesis reflect 95% confidence interval (CI) from non-linear regression analysis.

^c Wide 95% CI approaching or exceeding 100% relative to value of k₃

^d Initial silane concentration= 2.56x10^-5 M

^e Initial silane concentration= 2.04x10^-4 M

 

Between pH 3.8 and 5.2, it was observed exclusively that k₁ < k₂ < k₃ as expected, while above pH 6.0 the general trend k₂< k₁ ≈ k₃

 

Table 3. Calculated^f Half-lives for Observed Hydrolysis Reaction of DAPMS for the Rate Limiting Step at 25 °C

 

Run	pH	[buffer], mM	t1/2, h
19	3.78	10.6	0.752
8	4.02	53	0.797
7	4.14	5.3	1.569
18	4.69	26.5	2.562
24	4.97	26.5	3.428
5	5.11	26.5	4.762
6	5.21	5.3	5.062

 

Table 4. Calculated^f Half-lives for Observed Hydrolysis Reaction of DAPMS for the Rate Limiting Step at 25 °C

Run	pH	[buffer], mM	t1/2, h
13	6.07	25	2.029
9	6.15	10	1.934
15	6.39	25	1.031
14	6.40	25	1.293
16	6.42	25	0.843
17	6.44	10	1.342
25	6.70	25	0.975
10	6.79	10	0.863
29	7.08	5	0.488
30	7.08	5	0.486

 

^fcalculated by the study reviewer

 

Table 5. Results of Multiple Linear Regression Analysis of DAPMS Kinetic Experiments in pH Range 3.8-5.2 at 25 °C

Constant (units)	1^st hydrolysis step	2^nd hydrolysis step	3^rd hydrolysis step
kH3O+ (M^-1 s^-1)	16.8	36.0	75.0
kNH3 (s^-1)	1.36x10^-2	5.24x10^-3	N/A (a)
k0, est. (s-1)	2.7x10^-4	5.2x10^-4	5.1x10^-3

(a)  Data not sufficiently precise for pH>6.4 to yield reliable estimate

 

 

Table 6. Arrhenius Parameters for the Hydronium and Hydroxide Ion Catalyzed Hydrolysis Reactions of DAPMS.

	A, s^-1	Ea, kJ/mol	r^2
k^1H3O+	3.30E+03	34.1	0.9986
k^2H3O+	-	-	0.9536
k^3H3O+	-	-	0.9502
k^1NH	9.19E+08	65.1	0.9998
k^2NH	1.57E+08	62.1	0.9978
k^3NH	6.11E+11	80.4	0.9998

Conclusions:

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 a reliable study conducted according to an appropriate test protocol, but not in compliance with GLP.

Description of key information

Hydrolysis half-lives: 0.1 h at pH 4, 0.32 h at pH 5, 0.025 h at pH 7 and 24.7°C (OECD 111)

Key value for chemical safety assessment

Half-life for hydrolysis:

0.025 h

at the temperature of:

24.7 °C

Additional information

Measured half-life values of 0.1 h at pH 4 and 24.7°C, 0.025 h at pH 7 and 24.7°C, and 0.32 h at pH 5 and 24.7°C were determined for the substance in accordance with OECD 111. The result is considered to be reliable and has been assigned as key study. 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 0.4 h at 25°C was reported, information on the pH was not stated.

 

In addition, hydrolysis in soil conditioned 0.01 M CaCl₂ solution and in wet soil was investigated in preparation for an adsorption/desorption study (see IUCLID dossier Section 5.4.1, Landsberg 2017). The measured half-lives in soil conditioned 0.01 M CaCl₂ solution were as follows: Eurosoil 2 (pH 7.9) 0.015 h, Eurosoil 3 (pH 6.0) 0.084 h, Eurosoil 4 (pH 7.5) 0.021 h, LUFA 2.4 (pH 7.8) 0.015 h, LUFA 5M (pH 7.7) 0.015 h. Concentrations in soil samples were found to decrease within 5 minutes, indicating that the substance is unstable; half-lives were not determined.

 

The complete hydrolysis of CAS No. 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 intramolecular catalysis mechanism caused by free amine groups has been identified for this substance which speeds up the hydrolysis at pH 7 relative to that observed for similar alkoxysilanes. However, still with the similar general pH-dependent behaviour observe for alkoxysilane hydrolysis. This different mechanism is proposed as the cause of a minimum rate at pH < 7 (at pH ≥ 5.21 < 6.07).

 

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]

 

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-(trimethoxysilyl)propyl)ethylenediamine at pH 2 is therefore 0.001 hours (3.6 seconds). However, it is not appropriate or necessary to attempt to predict accurately when the half-life is less than 5-10. As a worst-case it can therefore be considered that the half-life for the substance at pH 2 and 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 N-(3-(trimethoxysilyl)propyl)ethylenediamine the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is 0.0089 hours (32 seconds). 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-(trihydroxysilyl)propyl)ethylenediamine and methanol.