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Hydrolysis

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Description of key information

In a non-guideline study to compare hydrolysis rates of four cyclic methylsiloxane compounds at pH7, a hydrolysis rate constant was established (reliability 2 study). A hydrolysis half-life of 2.2 minutes at pH 7 and 22.5°C was determined. The half-life refers to degradation of parent substance by ring-opening; full hydrolysis takes longer (approximately 1 day).

Key value for chemical safety assessment

Half-life for hydrolysis:
2.2 min
at the temperature of:
22.5 °C

Additional information

In the document attached to the IUCLID endpoint summary, a full discussion including reaction schema and graphical presentation of data are presented.

The studies for this endpoint are summarised as follows:

·      The key study; a non-standard study conducted according to generally accepted scientific principles, which measured the hydrolysis rate at pH 7 of the registration substance, HD4.

·      A QSAR prediction for the hydrolysis rate at pH 4, 7 and 9 for the registration substance, HD4.

·      A measured hydrolysis at pH 7 and a QSAR prediction at pH 4, 7 and 9 for the read-across substance HD5 (CAS 6166-86-5). These are presented as supporting data for read-across arguments for other endpoints.

·      Measured hydrolysis studies for D4 (CAS 556-67-2) at pH 4, 7 and 9 and also at pH 5, 7 and 9.

·      Measured hydrolysis study for D5 (CAS 541-02-6) at pH 4, 5.5, 7, 8 and 9.

·      QSAR predictions of the hydrolysis rates at pH 4, 7 and 9 for the intermediates of HD4 and HD5.

The results are discussed further below.

 

1. Hydrolysis study with HD5 (2,4,6,8,10-pentamethylpentasiloxane, CAS No. 6166-86-5) and HD4 (2,4,6,8-Tetramethylcyclotetrasiloxane, CAS No. 2370-88-9)

The key hydrolysis study was a non-standard study designed to measure the hydrolysis rates of tetramethylcyclotetrasiloxane (HD4 or H4D4, CAS No: 2370-88-9) relative to octamethylcyclotetrasiloxane (D4, CAS No: 556-67-2), and pentamethylcyclopentasiloxane (HD5 or H5D5, CAS No: 6166-86-5) relative to decamethylcyclopentasiloxane (D5, CAS No: 541-02-6) in pH 7 imidazole buffer containing 20% acetonitrile co-solvent at nominal 25°C. Initial test substance concentrations were approximately 3 ppm. Due to the low water solubility and high air/water partitioning of methylcyclosiloxanes, the co-solvent allowed for increased initial concentrations of the parent compounds, and decreased volatilization from solution, than could be achieved with 100% aqueous buffer alone. This is considered to be in line with the recommendation of OECD 111 standard test method for hydrolysis.

The extent of hydrolysis was determined by measuring disappearance of each parent compound in solution as a function of time using a solvent extraction method, followed by analytical determination using gas chromatography with flame ionization detection (GC-FID). While hydrolysis products of the compounds could not be observed in the GC-FID chromatograms because of poor extraction of the degradates, ICP analysis of the hydrolysis samples confirmed conservation of silicon, which was evidence for hydrolysis over other possible loss mechanisms (e.g., volatilization).

The hydrolysis rates of HD4, HD5, D4, and D5 were observed to follow pseudo first-order kinetics. Half-lives at pH 7 for loss of parent substance were determined as 4.2 minutes for HD5 and 2.2 minutes for HD4. Under identical conditions (the modified test condition), the half-lives of 44.4 days for D4 and 50.6 days for D5, were considerably slower than half-lives of HD4 and HD5. Under the modified test conditions (i.e. aqueous-organic buffer containing 20% acetonitrile), the hydrolysis half-life of the positive control substance was substantially longer than under the reference condition (i.e., 100% aqueous), suggesting that the measured half-lives for HD5 and HD4 may be conservative.

Headspace analysis for hydrogen gas was used to obtain information on the mechanism of hydrolysis. Theoretically, there are two possible first steps in the hydrolysis of HD5 and HD4: hydrolysis of a silicon-oxygen bond, resulting in ring-opening; or breaking of a silicon hydrogen-bond to give hydrogen and a silanol (Si-OH) group. Headspace analysis of hydrolysis samples demonstrated hydrogen gas did not begin to form until after over 5 hydrolysis half-lives of HD4 and HD5 occurred. After 16 half-lives, only 5% of the theoretical maximum of hydrogen gas had formed. It took approximately 20 hours for close to 80% of the hydrogen gas to form which corresponds to over 285 half-lives for the hydrolysis of HD4 and HD5. This strongly suggested that the mechanism of hydrolysis for HD4 and HD5 began with ring opening, as has been shown to occur for D4 and D5, followed by a slower rate of hydrolysis of the Si-H groups. The quantitative evolution of hydrogen gas also further supports that mass balance was conserved under the test conditions.

Therefore, the following conclusions can be drawn from this study:

·      Measured half-lives for HD5 and HD4 at pH 7 and 22.5°C are 4.2 minutes and 2.2 minutes respectively.

·      The first-step in the hydrolysis is ring-opening to give an α-ω-siloxanediol.

·      The half-life for breakdown of the Si-H bonds to give hydrogen is approximately 6-8 hours.

·      The final hydrolysis product relevant to CSA is methylsilanetriol. Further degradation in the environment, e.g. to silicate, is thought on grounds of chemical properties, to be possible in the long-term.

2. Hydrolysis studies with D4 (octamethylcyclotetrasiloxane, CAS No. 556-67-2) and D5 (decamethylcyclopentasiloxane, CAS No: 541-02-6)

D4 is a cyclic siloxane with four silicon and four oxygen atoms in the ring. Each silicon atom is bound to two methyl groups. HD4 is a structural analogue in which one methyl group on each silicon is replaced with hydrogen. D5 is a cyclic siloxane with five silicon and five oxygen atoms in the ring. Each silicon atom is bound to two methyl groups. HD5 is a structural analogue in which one methyl group on each silicon is replaced with hydrogen.

The hydrolysis rates of D5 and D4 have been measured in studies conducted according to OECD TG 111 and in compliance with GLP. The following hydrolysis half-lives at 25°C were determined:

·      D5: 9.3 h at pH 4, 351 at pH 5.5, 1590 h (66 d) at pH 7, 214 h at pH 8, 24.8 to 31.6 h at pH 9.

·      D4: 1.8 h at pH 4, 69 -144 h (average 3.9 days) at pH 7, 0.9 - 1 h at pH 9.

The reaction pathway proposed by the study authors (Durham 2006) for hydrolysis of D5 is ring-opening to give 1,1,3,3,5,5,7,7,9,9-decamethylpentasiloxane-1,9-diol (H(OSiMe2)5OH) followed by progressive shortening of the siloxane chain to give H(OSiMe2)4OH, H(OSiMe2)3OH, H(OSiMe2)2OH and finally HOSiMe2OH (dimethylsilanediol, DMSD). The reaction pathway for hydrolysis of D4 (Durham 2005) is similar, with ring-opening to give 1,1,3,3,5,5,7,7-octamethyltetrasiloxane-1,7-diol (H(OSiMe2)5OH) followed by progressive shortening of the siloxane chain to give H(OSiMe2)3OH, H(OSiMe2)2OH and then HOSiMe2OH (dimethylsilanediol, DMSD). Further degradation in the environment, e.g. to silicate, is thought on grounds of chemical properties, to be possible.

The studies used14C-labelled test substance and the reaction was followed using HPLC-LSC. The number of intermediates, their order of initial appearance in the time series, and their decreasing retention times (i.e. increasing polarity) were consistent with the proposed series of dimethylsiloxanediol oligomers, H(OSiMe2)nOH (n = 1-5 for D5 and n=1-4 for D4), the anticipated intermediates and final product of D5 and D4 hydrolysis. The hydrolysis product dimethylsilanediol was observed, but not confirmed analytically. The first reaction step (ring-opening) was found to be reversible to a small extent for D4 under neutral and basic conditions; the other steps were found to be irreversible under the conditions of the test.

Therefore, the following conclusions can be drawn from these studies:

·      The first step in the hydrolysis of D4 and D5 is ring-opening.

·      This is followed in each case by progressive shortening of the dimethylsiloxanediol chain.

·      The final hydrolysis product relevant to CSA for both substances is dimethylsilanediol.

These two substances are close structural analogues of HD5 and HD4, so it is reasonable to assume that HD5 and HD4 follow a similar reaction pathway. The proposed reaction pathway is described in the document attached to the IUCLID EPS.

3. QSAR predictions for the hydrolysis of intermediates for HD5 and HD4

The hydrolysis half-lives at pH 7 and 20-25°C of the intermediate products of siloxane hydrolysis for D4 and D5 have been predicted using a validated QSAR method (PFA, 2014a). Further details are given in the QMRF and QPRF attached to the IUCLID dataset. The substances are predicted to hydrolyse rapidly to methylsilanediol, which then hydrolyses further to methylsilanetriol.

Table 1: Predicted half-lives for HD5, HD4 and their intermediate hydrolysis products

Fate of HD5

Fate of HD4

Compound

Predicted half-life at pH 7 and 25°C

Compound

Predicted half-life at pH 7 and 25°C

HD5

3 minutes (4.2 min measured at pH 7)

HD4

1 minute (2.2 min measured at pH 7)

H(OSi(H)Me)5OH, H5L5-diol

4.2 minutes

H(OSi(H)Me)4OH, H4L4-diol

12 minutes

H(OSi(H)Me)4OH, H4L4-diol

12 minutes

H(OSi(H)Me)3OH, H3L3-diol

24 minutes

H(OSi(H)Me)3OH, H3L3-diol

24 minutes

H(OSi(H)Me)2OH, H2L2-diol

<60 minutes#

H(OSi(H)Me)2OH, H2L2-diol

<60 minutes#

#It is noted that this prediction is likely to be conservative. In a non-standard hydrolysis study with the substance H2-L2 (Dow Corning Corporation, 2012), a half-life of ≤11.3 minutes at pH 7 and 25°C was reported for the hydrolytic degradation of parent substance (breaking of the Si-O bond) to form dimethylsilanol. Therefore, the hydrolysis half-life for H2L2-diol is anticipated to be <60 minutes.

4. QSAR predictions for the hydrolysis at different pHs and temperatures

Hydrolysis half-lives at pH 4 and pH 9 have been predicted using a validated QSAR method. Further details are given in the QMRF and QPRF attached to the IUCLID dataset.

 

As the hydrolysis reaction may be acid or base catalysed, the rate of reaction will 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.

kobs= k0+ kH3O+[H3O+] + kOH-[OH-] + ka[acid] + kb[base]

 

At extremes of pH and under standard hydrolysis test conditions, the rate of hydrolysis is dominated by either the hydronium or hydroxide catalysed mechanism.

Therefore, at low pH:

kobs≈kH3O+ [H3O+]

 

At pH 4 [H3O+] = 10-4mol dm-3and at pH2 [H3O+] = 10-2mol dm-3; therefore, kobsat pH 2 should be approximately 100 times greater than kobsat pH 4.

 

The half-life of a substance at pH 2 is calculated based on:

t1/2(pH 2) = t1/2(pH 4) / 100

 

However, 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, where a half-life is predicted to be less than 5 seconds, the half-life is reported as ≤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.

 

The predicted half-lives for HD5 and HD4 and their intermediate hydrolysis products are reported in the table below.

Table 2: Hydrolysis half-lives at different pH and temperature

 

Half-life

Compound

pH 7, 25°C

pH 9, 25°C

pH 4, 25°C

pH 2, 25°C

pH 2, 37.5°C

pH 7, 37.5°C

HD5

4.2 min

9 s

1.7 min

≤5 s

≤5 s

1.5 min

HD4

2.2 min

≤5 s

1.2 min

≤5 s

≤5 s

47 s

H(OSi(H)Me)5OH

4.2 min

9 s

1.7 min

≤5 s

≤5 s

1.5 min

H(OSi(H)Me)4OH

10 min

19 s

3 min

≤5 s

≤5 s

4 min

H(OSi(H)Me)3OH

26 min

41 s

4 min

≤5 s

≤5 s

10 min

H(OSi(H)Me)2OH

63 min

1.5 min

7 min

≤5 s

≤5 s

23 s

 

No information is available to indicate how the half-life for breakdown of the Si-H bonds will vary with pH.

 

 

Hydrolysis of the read-across substance dichloro(methyl)silane (CAS 75-54-7)

Data for some endpoints are read-across from the analogue substance dichloro(methyl)silane (CAS 75-54-7). The hydrolysis of the two substances is relevant to this read-across as discussed in the appropriate endpoint summaries.

The half-life at pH 4, 7 and 9 for dichloro(methyl)silane is <1 minute at pH 4, 7 and 9 and 25°C based on read-across within the category of chlorosilanes (PFA, 2013ab).

Dichloro(methyl)silane hydrolyses to methylsilanediol (1 mole) and hydrogen chloride (2 moles). Methylsilanediol then reacts further to give methylsilanetriol and hydrogen.

Hydrolysis of the read-across substance trimethoxy(methyl)silane (CAS 1185-55-3)

Data for some endpoints are read-across from the analogue substance trimethoxy(methyl)silane (CAS 1185-55-3). The hydrolysis of the two substances is relevant to this read-across as discussed in the appropriate endpoint summaries.

Hydrolysis half-lives for trimethoxy(methyl)silane at 25°C of <0.033 h at pH 4, 2.2 h at pH 7 and 0.11 h at pH 9 were determined in a reliable study conducted according to an appropriate test protocol, and in compliance with GLP (Miller JA 2004). The half-life at pH 2 and 37.5°C may be calculated in the same way as for the submission substance above. This gives a half-life of approximately 5 seconds.

Trimethoxy(methyl)silane hydrolyses to methylsilanetriol (1 mole) and methanol (3 moles).

References:

Dow Corning Corporation 2012: Comparison of Hydrolysis Rates of 1,1,3,3-Tetramethyldisiloxane and Hexamethyldisiloxane in pH 7 Imidazole Buffer containing 10% Acetonitrile (study report), Testing laboratory: Health and Environmental Sciences Dow Corning Corporation 2200 West Salzburg Road Auburn, MI 48611, Owner company; ReachCentrum SPRL Avenue Edmond van Nieuwenhuyse 6 B-1160 Bruxelles, BELGIUM, Study number: 11749-116, Report date: Jan 24, 2012