1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-09-05 to 2013-09-10

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted using an acceptable screening method and in compliance with a known quality system (ISO 9001:2008)

Qualifier:

according to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

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

Remarks:

ISO 9001:2008

Details on sampling:

For 1H NMR measurement 850 µl of the buffer solutions containing about 5 µl GENIOSIL GF 69 (pH 4.0, pH 7.0, pH 9.0, respectively) were mixed with 150 µl of deuterated dimethylsulfoxide (DMSO-d6) as shift and internal standard in a 5 mm NMR sample tube.

1H-NMR measurements were started immediately after mixing the sample and transferring the sample in tube in the spectrometer. This takes about 2 minutes. Then every 10 to 40 sec a 1H NMR spectrum was acquired. Experiments were performed at 298K (25°C).

Buffers:

pH 4.0: CertiPur Potassium hydrogen phthalate; company Merck
pH 7.0: CertiPur Potassium dihydrogen phosphate / disodiumhydrogen phosphate; company Merck
pH 9.0: CertiPur, Boron acid / potassium chloride / NaOH, company Merck

Preliminary study:

No preliminary study was carried out.

Transformation products:

yes

No.:

#1

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

At all pH values decreasing signals of methoxysilyl groups and increasing signals of methanol could be observed.

Key result

pH:

4

Temp.:

25 °C

Hydrolysis rate constant:

0.138 min-1

DT50:

5 min

Type:

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

Key result

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

0.006 min-1

DT50:

111.3 min

Type:

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

Key result

pH:

9

Temp.:

25 °C

Hydrolysis rate constant:

0.155 min-1

DT50:

4.5 min

Type:

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

The evaluation is based on the sum of the nine methoxysilyl groups. Only the first hydrolytic step could be detected separately. Its half-life times are equal to or below the values from the cumulative evaluation.

The 1H-NMR spectra for pH 4, pH 7 and pH 9 are attached.

The experiment/time at pH 4, pH 7 and pH 9 are also attached in Tables 3 to 5

Conclusions:

Hydrolysis half-lives of 5 min at pH 4, 111.3 min at pH 7 and 4.5 min at pH 9 and 25°C were determined for the substance using a relevant test method and in compliance with a known quality system. The result is considered to be reliable.

Description of key information

Hydrolysis half-life: 5 minutes at pH 4, 111.3 minutes at pH 7 and 4.5 minutes at pH 9 and 25°C (EU Method C.7)

Key value for chemical safety assessment

Half-life for hydrolysis:

111.3 min

at the temperature of:

25 °C

Additional information

Hydrolysis half-lives of 5 minutes (0.083 hours) at pH 4, 111.3 minutes (1.86 hours) at pH 7 and 4.5 minutes (0.075 hours) at pH 9 and 25°C were determined for the substance using a relevant test method and in compliance with a known quality system (ISO 9001:2008). The result is considered to be 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 0.0008 hours (approximately 3 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 of 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°C) * e^(0.08.(T-X))

 

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

 

Thus, for the submission substance, the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is approximately 0.68 hour. At 37.5ºC and pH 2 (relevant for conditions in the stomach following oral exposure), the half-life is approximately 5 seconds.

 

The hydrolysis products in this case are tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione and methanol.