3-(trimethoxysilyl)propyl isocyanate

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:

2012-12-11 to 2012-12-17

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

Samples were taken at test start and at a minimum of 8 spaced points, normally between 10 and 90% of hydrolysis, at each test temperature. All test item containing samples were analysed immediately (max. 1% of total incubation time until start of analyses) via LC-MS/MS. Beginning of derivatisation was defined as start of analysis.

Buffers:

Buffer solution pH 4: 45 mL of 0.1 mol/L NaOH were mixed with 250 mL 0.1 mol/L monopotassium citrate and diluted to 500 mL with double distilled water.

Buffer solution pH 7: 148.15 mL of 0.1 mol/L NaOH were mixed with 250 mL 0.1 mol/L KH2PO4 and diluted to 500 mL with double distilled water.

Buffer solution pH 9: 106.5 mL of 0.1 mol/L NaOH were mixed with 2500 mL 0.1 mol/L H3BO3 in 0.1 mol/L KCl and diluted to 500 mL with double distilled water.

Buffers were prepared from chemicals with analytical grade or better quality. Buffers were purged with nitrogen for 5 min. Then the pH was checked to a precision of at least 0.1 at the required temperature.

Details on test conditions:

Co-solvent: Acetonitrile, 10 % (v/v)
Initial test concentration: 100 µg/L
Test vessels: HPLC vials, volume: 4 mL
Test volume: 2 mL
Temperatures (measured every minute): 10.1 ± 0.04, 20.1 ± 0.04 and 30.0 ± 0.05 °C

Duration:

40 min

pH:

4

Temp.:

10

Initial conc. measured:

115 µg/L

Duration:

60 min

pH:

4

Temp.:

20

Initial conc. measured:

110 µg/L

Duration:

8 min

pH:

4

Temp.:

30

Initial conc. measured:

123 µg/L

Duration:

40 min

pH:

7

Temp.:

10

Initial conc. measured:

117 µg/L

Duration:

60 min

pH:

7

Temp.:

20

Initial conc. measured:

125 µg/L

Duration:

9 min

pH:

7

Temp.:

30

Initial conc. measured:

128 µg/L

Duration:

36 min

pH:

9

Temp.:

10

Initial conc. measured:

109 µg/L

Duration:

8 min

pH:

9

Temp.:

20

Initial conc. measured:

103 µg/L

Duration:

5 min

pH:

9

Temp.:

30

Initial conc. measured:

116 µg/L

Number of replicates:

1 replicate each per pH, temperature, and sampling time

Positive controls:

no

Negative controls:

no

Preliminary study:

No preliminary study was performed since hydrolytic lability was known.

Transformation products:

not measured

Key result

pH:

4

Temp.:

10 °C

Hydrolysis rate constant:

0.086 min-1

DT50:

8.08 min

Type:

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

Remarks on result:

other: Confidence interval: 7.42 to 8.71 min

Key result

pH:

4

Temp.:

20 °C

Hydrolysis rate constant:

0.182 min-1

DT50:

3.81 min

Type:

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

Remarks on result:

other: Confidence interval: 3.4 to 4.21 min

Key result

pH:

4

Temp.:

30 °C

Hydrolysis rate constant:

0.276 min-1

DT50:

2.51 min

Type:

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

Remarks on result:

other: Confidence interval: 2.18 to 2.85 min

Key result

pH:

7

Temp.:

10 °C

Hydrolysis rate constant:

0.057 min-1

DT50:

12.1 min

Type:

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

Remarks on result:

other: Confidence interval: 11.9 to 12.3 min

Key result

pH:

7

Temp.:

20 °C

Hydrolysis rate constant:

0.142 min-1

DT50:

4.88 min

Type:

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

Remarks on result:

other: Confidence interval: 4.41 to 5.34 min

Key result

pH:

7

Temp.:

30 °C

Hydrolysis rate constant:

0.322 min-1

DT50:

2.15 min

Type:

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

Remarks on result:

other: Confidence interval: 2.0 to 2.3 min

Key result

pH:

9

Temp.:

10 °C

Hydrolysis rate constant:

0.12 min-1

DT50:

5.78 min

Type:

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

Remarks on result:

other: Confidence interval: 5.3 to 6.26 min

Key result

pH:

9

Temp.:

20 °C

Hydrolysis rate constant:

0.36 min-1

DT50:

1.93 min

Type:

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

Remarks on result:

other: Confidence interval: 1.73 to 2.12 min

Key result

pH:

9

Temp.:

30 °C

Hydrolysis rate constant:

0.26 min-1

DT50:

0.74 min

Type:

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

Remarks on result:

other: Confidence interval: 0.72 to 0.76 min

 

pH 4
	10°C	20°C	30°C
Regression equation	-0.0858x + 3.99	-0.182x + 3.87	-0.276x + 4.00
Correlation factor [r^2]	0.995	0.993	0.955
Reaction rate constant kobs [1/min]	8.58 x 10^-2	1.82 x 10^-1	2.76 x 10^-1
Half life T½ [min]	8.08	3.81	2.51
Confidence interval of half lifeT½ [min]	7.42 to 8.71	3.40 to 4.21	2.18 to 2.85
pH 7
	10°C	20°C	30°C
Regression equation	-0.0574x + 4.04	-0.142x + 3.97	-0.322x + 4.06
Correlation factor [r^2]	0.999	0.993	0.993
Reaction rate constant kobs [1/min]	5.74 x 10^-2	1.42 x 10^-1	3.22 x 10^-1
Half lifeT½ [min]	12.1	4.88	2.15
Confidence interval of half lifeT½ [min]	11.9 to 12.3	4.41 to 5.34	2.00 to 2.30

 

pH 9
	10°C	20°C	30°C
Regression equation	-0.120x + 3.96	-0.360x + 3.76	-0.0156x + 4.06
Correlation factor [r^2]	0.994	0.986	0.999
Reaction rate constant kobs [1/min]	1.20 x 10^-1	3.60 x 10^-1	2.60 x 10^-4
Half lifeT½ [min]	5.78	1.93	0.74
Confidence interval of half lifeT½ [min]	5.30 to 6.25	1.73 to 2.12	0.72 to 0.76

 

Validity criteria fulfilled:

yes

Conclusions:

The hydrolysis of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diisocyanate was studied according to OECD Test Guideline 111 (2004) and Council Regulation (EC) No. 440/2008, Method C.7 with a test item concentration of 100 µg/L in buffer solutions of pH 4, 7 and 9 at temperatures of 10, 20 and 30 °C. Rapid hydrolysis following pseudo-first order kinetics with the following half-lives was observed:
pH 4: 8.08 min (10°C), 3.81 min (20°C), 2.51 min (30°C)
pH 7: 12.1 min (10°C), 4.88 min (20°C), 2.15 min (30°C)
pH 9: 5.78 min (10°C), 1.93 min (20°C), 0.74 min (30°C)

Apparently, the base catalysed hydrolysis is the fastest hydrolysis process.

Executive summary:

The hydrolysis of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diisocyanate was studied according to OECD Test Guideline 111 (2004) and Council Regulation (EC) No. 440/2008, Method C.7 with a test item concentration of 100 µg/L in buffer solutions of pH 4, 7 and 9 at temperatures of 10, 20 and 30 °C. Rapid hydrolysis following pseudo-first order kinetics with the following half-lives was observed:

pH 4: 8.08 min (10°C), 3.81 min (20°C), 2.51 min (30°C)

pH 7: 12.1 min (10°C), 4.88 min (20°C), 2.15 min (30°C)

pH 9: 5.78 min (10°C), 1.93 min (20°C), 0.74 min (30°C).

Apparently the base catalysed hydrolysis is the fastest hydrolysis process.

Reference 2

Endpoint:

hydrolysis

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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 QMRF/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

Key result

pH:

4

DT50:

0.2 h

Remarks on result:

other: 20-25°C

Key result

pH:

5

DT50:

0.3 h

Remarks on result:

other: 20-25°C

Key result

pH:

7

DT50:

2.8 h

Remarks on result:

other: 20-25°C

Key result

pH:

9

DT50:

0.1 h

Remarks on result:

other: 20-25°C

Conclusions:

Hydrolysis half-life values at 20-25°C of 0.2 h at pH 4, 2.8 h at pH 7 and 0.1 h at pH 9 were obtained using an accepted calculation method. The result is considered to be reliable.

Reference 3

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2003-09-04 to 2003-09-10

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

The study was conducted according to an appropriate OECD test guideline, with acceptable restrictions. The restrictions were that the study was not carried out according to the most up-to-date guideline and the substance was determined only to be unstable at pH 4, 7 and 9 and 50°C; no precise value of the half-life at 25°C was determined.

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Version / remarks:

May 12, 1981

Deviations:

no

Remarks:

NB: According to the most recent version of this test guideline a higher-tier study should be carried out for substances that are found to be unstable in the preliminary study. This was not done as it was not required under the 1981 guideline.

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

December 1992

Deviations:

no

GLP compliance:

yes

Radiolabelling:

no

Analytical monitoring:

yes

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.

Preliminary study:

Only the preliminary study was carried out as the substance was found to be unstable at pH 4, 7 and 9. The results are discussed below.

Transformation products:

not measured

Key result

pH:

4

Temp.:

50 °C

DT50:

< 2.4 h

Remarks on result:

other: The test substance could not be detected immediately after sample preparation; therefore, hydrolysis is very rapid.

Key result

pH:

7

Temp.:

50 °C

DT50:

< 2.4 h

Remarks on result:

other: The test substance was about 50% hydrolysed in the t0 sample and could not be detected after 2.4 h; therefore, hydrolysis is rapid.

Key result

pH:

9

Temp.:

50 °C

DT50:

< 2.4 h

Remarks on result:

other: The test substance could not be detected immediately after sample preparation; therefore, hydrolysis is very rapid.

Key result

pH:

4

Temp.:

25 °C

DT50:

< 1 d

Remarks on result:

other: Estimate based on results at 50°C.

Key result

pH:

7

Temp.:

25 °C

DT50:

< 1 d

Remarks on result:

other: Estimate based on results at 50°C.

Key result

pH:

9

Temp.:

25 °C

DT50:

< 1 d

Remarks on result:

other: Estimate based on results at 50°C.

At pH 4.0 and 9.0, no test substance could be detected immediately after dissolution in the buffer; indicating that the substance is very unstable in aqueous test solutions at pH 4 and 9.

At pH 7.0, approximately 50% of the test substance was degraded at t0. No test substance was detected after 2.4 h of incubation.

It was concluded that the estimated half-lives under representative conditions (25°C) are less than one day at pH 4, 7 and 9.

No further testing was carried out because the substance was unstable at all pH values.

Table 1: Results of the preliminary study at 50°C

	Initial measured concentration / µg/ml	Measured concentration after 2.4 h incubation / µg/ml	Measured concentration after 5 days incubation / µg/ml	Hydrolysis reaction after 5 days incubation
pH 4.0	n.d	n.d	n.d	100
pH 4.0	n.d	n.d	n.d	100
pH 7.0	31.16*	n.d	n.d	100
pH 7.0	31.52*	n.d	n.d	100
pH 9.0	n.d	n.d	n.d	100
pH 9.0	n.d	n.d	n.d	100

n.d. – not detected

* Already partially hydrolysed; theoretical initial concentrations based on preparation of the solutions should be ca. 57 mg/l, which corresponds to half the water solubility.

Conclusions:

The hydrolysis half-life of the substance was found to be much less than 2.4 h at pH 4, 7 and 9 and 50°C. Therefore, the half-lives at 25°C and pH 4, 7 and 9, were estimated to be <1 day. The study was conducted according to OECD Guideline 111 (1981) and in compliance with GLP; the results are considered to be reliable.

Description of key information

Hydrolysis half-life (isocyanate group): 3.81 min at pH 4, 4.88 min at pH 7 and 1.93 min at pH 9 and 20°C (OECD 111) based on read-across from 2,2,4(or 2,4,4)-trimethylhexane-1,6-diisocyanate

Hydrolysis half-life (trimethoxysilane group): 0.2 h at pH 4, 2.6 h at pH 7, and 0.1 h at pH 9 and 20-25°C (QSAR)

Key value for chemical safety assessment

Half-life for hydrolysis:

4.88 min

at the temperature of:

20 °C

Additional information

The substance, 3-(trimethoxysilyl)propyl isocyanate has two types of hydrolysable group, trimethoxy (-OCH₃) and isocyanate (-N=C=O). The isocyanate group is expected to hydrolyse very rapidly in contact with water, for example the hydrolysis half-lives of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diisocyanate (CAS 32052-51-0) were measured in accordance with OECD 111 test method and in compliance with GLP (Lange 2013). Very rapid hydrolysis following pseudo-first order kinetics with the following half-lives was determined:

pH 4 - 8.08 min at 10°C, 3.81 min at 20°C and 2.51 min at 30°C

pH 7 - 12.1 min at 10°C, 4.88 min at 20°C and 2.15 min at 30°C

pH 9 - 5.78 min at 10°C, 1.93 min at 20°C and 0.74 min at 30°C

Similarly, n-butyl isocyanate (CAS 111-36-4) was reported to undergo complete hydrolysis in water within a few minutes at 20°C (OECD 2005).

However, the hydrolysis half-life of the submission substance was found to be much less than 2.4 h at pH 4, pH 7 and pH 9 and 50°C. Therefore, the half-lives at 25°C and pH 4, pH 7 and pH 9, were estimated to be <1 day, which is consistent with the expected behaviour. The study was conducted according to OECD Guideline 111 (1981) and in compliance with GLP; the results are considered reliable. Although according to the most recent version of the test guideline, a higher-tier test should be carried out if a substance is found to be unstable in the preliminary test, this was not done in this study. In view of the extreme instability of the isocyanate group as discussed above, in practice it may not be technically feasible to do so and obtaining a more accurate half-life value would be of limited use.

Therefore, based on available hydrolysis data for the isocyanate group present in the submission substance, this means very rapid hydrolysis to form 3-(trimethoxysilyl)propylamine (CAS 13822-56 -5), as an intermediate hydrolysis product and carbon dioxide. The hydrolysis half-lives of 3-(trimethoxysilyl)propylamine have been predicted using a validated QSAR estimation method to be 0.2 h at pH 4, 0.3 h at pH 5, 2.6 h at pH 7, and 0.1 h at pH 9 and 20-25°C.

Hydrolysis reactions of alkoxysilanes can be catalysed by both acid and base. The rate of hydrolysis is slowest close to pH 7 and increases 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. This is supported by studies for various organosilicon compounds in which calculation of k_H3O⁺ and k_OH^- from the experimental results at pH 4 and 9, respectively, resulted in reasonable estimates of the half-life at pH 7.

 

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-(trimethoxysilyl)propylamine at pH 2 and 20 - 25°C is therefore 0.004 hours (approximately 14 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 3-(trimethoxysilyl)propylamine the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is approximately 1 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 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 (0.1 - 1 h).

The ultimate product of the hydrolysis reaction under dilute condition is 3-aminopropylsilanetriol. The other hydrolysis products are methanol and carbon dioxide.

Hydrolysis of the read-across substance triethoxy(3-isocyanatopropyl)silane (CAS 24801-88-5)

Data for the substance triethoxy(3-isocyanatopropyl)silane (CAS 24801-88-5) are read-across to the submission substance 3-(trimethoxysilyl)propyl isocyanate for the biodegradation in water and toxicity to microorganims endpoints. The silanol hydrolysis product and the rate of hydrolysis of the two substances are relevant to this read-across, as discussed in the appropriate sections for each endpoint.

 

For triethoxy(3-isocyanatopropyl)silane, the isocyanate group is expected to hydrolyse very rapidly to form 3-aminopropyl(triethoxy)silane (CAS 919-30-2) as an intermediate hydrolysis product and carbon dioxide. The hydrolysis half-lives of 3-aminopropyl(triethoxy)silane have been measured in accordance with OECD 111 to be 0.8 h at pH 5, 8.5 h at pH 7, and 0.15 h at pH 9 and 24.7°C. In addition, hydrolysis half-lives of 0.4 h at pH 4 and 0.1 h at pH 9 were predicted for 3-aminopropyltriethoxysilane using a validated QSAR estimation method.

 

The ultimate products of the hydrolysis reaction of triethoxy(3-isocyanatopropyl)silane under dilute conditions are 3-aminopropylsilanetriol, ethanol and carbon dioxide. For the registered substance, the ultimate hydrolysis products are 3-aminopropylsilanetriol, methanol and carbon dioxide.

Hydrolysis of the read-across substance 3-aminopropyl(triethoxy)silane (CAS 919-30-2)

Data for the substance 3-aminopropyl(triethoxy)silane (CAS 919-30-2) are read-across to the submission substance 3-(trimethoxysilyl)propyl isocyanate for the for the short-term toxicity to fish, short-term toxicity to invertebrates, toxicity to algae and eye irritation endpoints. The silanol hydrolysis product and the rate of hydrolysis of the two substances are relevant to this read-across, as discussed in the appropriate sections for each endpoint.

 

The hydrolysis half-lives of 3-aminopropyl(triethoxy)silane have been measured in accordance with OECD 111 to be 0.8 h at pH 5, 8.5 h at pH 7, and 0.15 h at pH 9 and 24.7°C. In addition, hydrolysis half-lives of 0.4 h at pH 4 and 0.1 h at pH 9 were predicted for the intermediate hydrolysis product, 3-aminopropyl(triethoxy)silane using a validated QSAR estimation method.

 

The half-lives at pH 7 and 37.5°C and at pH 2 and 37.5°C may be calculated in the same way for 3-aminopropyl(triethoxy)silane as for the intermediate hydrolysis product of the registration substance, as described above. This gives a half-life of approximately 5 seconds at pH 2 and 37.5°C, and approximately 3 hours at pH 7 and 37.5°C. At 37.5ºC and pH 5.5 (relevant for dermal exposure), the hydrolysis half -life will be in between the half-lives at pH 4 and pH 7 at 37.5ºC (0.15 – 3 hours).

The ultimate products of the hydrolysis reaction of 3-aminopropyl(triethoxy)silane are 3-aminopropylsilanetriol and ethanol.

For the registered substance, the ultimate hydrolysis products are 3-aminopropylsilanetriol, methanol and carbon dioxide.

The Table below summarises all relevant hydrolysis half-lives used in this chemical safety assessment

Table: Summary of relevant hydrolysis half-lives

Name	CAS	Half-lives at 20-25°C	Half-lives at 20-25°C	Half-lives at 20-25°C	Half-lives at 20-25°C	Half-lives at 37.5°C	Half-lives at 37.5°C	Half-lives at 37.5°C
		pH 4	pH 5	pH 7	pH 9	pH 2	pH 5.5	pH 7
2,2,4 (or 2,4,4)-Trimethylhexane-1,6-diisocyanate (isocyanate group)	32052-51-0	3.81 minute*	-	4.88 minute*	1.93 minute*	-		-
3-(Trimethoxysilyl)propyl isocyanate (trimethoxysilane group)	15396-00-6	0.2 hour**	0.3 hour**	2.8 hour**	0.1 hour**	-		-
3-(trimethoxysilyl)propylamine (trimethoxysilane group)	13822-56-5	0.2 hour**	0.3 hour**	2.6 hour**	0.1 hour**	5 seconds	0.1 – 1 hour	1 hour
3-Aminopropyl(triethoxy)silane (triethoxysilane group)	919-30-2	0.4 hour**	0.8 hour*	8.5 hour*	0.15 hour*	14 seconds	0.15 – 3 hour	3 hours

*measured

**predicted

-not calculated

References:

Lange (2013).Lange, J. (2013). Vestanat TMDI - hydrolysis as a function of pH. Dr. U. Noack-Laboratorien, Sarstedt (Germany). Test report. Testing laboratory: Dr. U. Noack-Laboratorien, Sarstedt (Germany). Report no.: CPH14411. Owner company: Evonik lndustries AG. Report date: 2013-01-21.

OECD (2005). SIDS Initial Assessment Report for SIAM 21, Washington, 18-21 October 2005, n-Butyl isocyanate, CAS 111-36-4.