Amino functional alkoxysilanes

Endpoint summary

Additional information

There are no measured toxicokinetic data on the registration substance itself, trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine, or on the constituents of the registration substance, trimethoxy(methyl)silane (Block A, CAS No. 1185-55-3), 3-aminopropyl(trimethoxy)silane (Block B, CAS No. 13822-56-5), disilyl(cycloalkylamine), penta(methoxy)- (Block C) and trisilyl(alkylamine), octamethoxy-methyl- (Block D). 

The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the constituents of the registered substance and their hydrolysis products. The data have been used in algorithms which are the basis of many physiologically based pharmacokinetic and toxicokinetic (PBTK) prediction models. Although these algorithms provide quantitative outputs, for the purposes of this summary only qualitative statements or predictions will be made because of the remaining uncertainties that are characteristic of prediction models.

The main input variable for the majority of the algorithms is the log K_ow. By using this and, where appropriate, other known or predicted physicochemical properties of the constituents or their hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

In contact with water, all of the constituents of the substance react rapidly (half-life of <12 hours at pH 7) to produce the corresponding silanol hydrolysis products and methanol. Direct exposure of workers and the general population to the parent substance or its hydrolysis products might occur via the inhalation and dermal routes. Exposure of the general population via the environment might occur via the oral route but would be limited to the hydrolysis product due to the rapid hydrolysis.

The toxicokinetics of methanol have been reviewed in other major reviews (OECD SIDS, 2004) and are not considered further here.

 

Absorption

Oral

Direct oral exposure is not expected for this substance. However, oral exposure to the hydrolysis product is potentially possible via the environment.

When oral exposure takes place, it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

The key parameters for each constituent are presented in Table 5.1.1. At pH 2 in the stomach, all constituents are predicted to hydrolyse to the corresponding hydrolysis product within 5 seconds at the temperature of 37.5°C. The parameters for the hydrolysis products are also therefore relevant.

Table 5.1.1: Molecular weight and water solubility values for the constituents and hydrolysis products

Block	Constituent	Molecular weight	Water solubility (mg/L) at 20°C	Hydrolysis product	Hydrolysis product molecular weight	Hydrolysis product water solubility (mg/L) at 20°C
A	Trimethoxy(methyl)silane	136.22	9.1E+04	Methylsilanetriol	94.14	1.0E+06 but condensation possible at 1000 mg/L
B	3-aminopropyl(trimethoxy)silane	179.29	5.7E+05	(3-Aminopropyl)silanetriol	137.21	1.0E+06 but condensation possible at 1000 mg/L
C	Disilyl(cycloalkylamine), penta(methoxy)-	383.59	2.3E+05	5-Oxa-9-aza-1,13-disilatridecane-1,1,1,7,13,13,13-heptol	331.47	1.0E+06 but condensation possible at 1000 mg/L
D	9-{ [Dimethoxy(methyl)silyl]oxy} -3,3,15,15-tetramethoxy-2,7,16-trioxa-11-aza-3,15-disilaheptadecane	519.82	1.7E+04

Therefore, if oral exposure to trimethoxy(methyl)silane (Block A) were to occur, the molecular weight and water solubility of the parent substance would favour absorption. However, rapid hydrolysis under the conditions of the stomach would limit the amount of parent substance available for absorption. The hydrolysis product, methylsilanetriol, has favourable molecular weight and water solubility values for absorption, so systemic exposure to the hydrolysis product would be more likely than to parent substance .

 

Similarly, Block B, 3-aminopropyl(trimethoxy)silane and its hydrolysis product, (3-aminopropyl)silanetriol, have water solubility values and molecular weights favourable for absorption, and therefore, should oral exposure occur systemic exposure is very likely. Due to rapid hydrolysis under the conditions of the stomach, systemic exposure to the hydrolysis product would dominate.

 

Although Blocks C and D, and their hydrolysis product, 5-oxa-9-aza-1,13-disilatridecane-1,1,1,7,13,13,13-heptol, are soluble, their molecular weights are above the favourable range, therefore following oral exposure, absorption and systemic exposure to these substances and hydrolysis products would be limited.

There were no signs of systemic toxicity evident in the acute toxicity (Dow Corning Corporation, 1990a). However, in the oral repeated dose toxicity study (Charles River Laboratories, 2018), conducted with the registration substance there were effects on motor activity at the highest dose (250 mg/kg bw/day), which is evidence of absorption of at least one of the constituents and/or their hydrolysis product(s).

Dermal

If dermal exposure were to occur this would be to the parent constituents as well as their hydrolysis products, as the pH of skin (5.5) would be favourable for hydrolysis of all constituents within 1-2 hours.

The fat solubility and the potential dermal penetration of a substance can be estimated by using the water solubility and log Kow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), particularly if water solubility is high. These values are presented for the blocks/constituents and their associated hydrolysis products in Table 5.1.2:

Table 5.1.2 Water solubility and log K_ow values for the constituents and hydrolysis products

Block	Constituent	Water solubility (mg/L) at 20°C)	Log Kow	Hydrolysis product	Hydrolysis product Log Kow	Hydrolysis product water solubility (mg/L) at 20°C
A	Trimethoxy(methyl)silane	9.1E+04	0.7 at 20°C	Methylsilanetriol	-2.4 at 20°C	1.0E+06 but condensation possible at 1000 mg/L
B	3 -Aminopropyl(trimethoxy)silane	5.7E+05	0.2 at 20°C (unionised) -4 at pH 2, -4 at pH 4, -2.8 at pH 7, -0.8 at pH 9 (ionised values)	(3-Aminopropyl)silanetriol	-2.9 at 20°C (unionised) -4 at pH 2, -4 at pH 4, -4 at pH 7, -3.5 at pH 9 (ionised values)	1.0E+06 but condensation possible at 1000 mg/L
C	Disilyl(cycloalkylamine), penta(methoxy)-	2.3E+05	-0.3 at 20°C (unionised) -4 at pH 2, -4 at pH 4, -3.3 at pH 7, -1.3 at pH 9 (ionised values)	5-Oxa-9-aza-1,13-disilatridecane-1,1,1,7,13,13,13-heptol	-4 at 20°C (unionised) -4 at pH 2, -4 at pH 4, -4 at pH 7, -4 at pH 9 (ionised values)	1.0E+06 but condensation possible at 1000 mg/L
D	9-{ [Dimethoxy(methyl)silyl]oxy} -3,3,15,15-tetramethoxy-2,7,16-trioxa-11-aza-3,15-disilaheptadecane	1.7E+04	-1.2 at 20°C (unionised) -4 at pH 2, -4 at pH 4, -4 at pH 7, -2.2 at pH 9 (ionised values)

 

Although the water solubility of Block A, trimethoxy(methyl)silane, is potentially favourable for dermal absorption, the log Kow is not; therefore, absorption by this route cannot be ruled out but is not likely. Although the hydrolysis product methylsilanetriol is highly soluble, the log Kow value indicates it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the blood is likely to be minimal.

For Blocks 2-4, the predicted water solubility is favourable for absorption across the skin but the log K_ow values of the ionised forms at pH 4-7 are not favourable. Therefore, absorption across the skin is not likely to occur as the substance is likely to be too hydrophilic to cross the lipid-rich environment of the stratum corneum. An acute dermal toxicity study with the registration substance (Dow Corning Corporation 1990b) showed no indication of systemic toxicity.

Inhalation

There is a QSPR to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry’s Law coefficient and the octanol: air partition coefficient (K_oct-air) as independent variables. The blood:air partition coefficients for the Constituents and their hydrolysis products are presented in Table 5.1.3.

 

Table 5.1.3: Blood:air partition coefficients

	Constituent	Blood:air partition coefficient
Block A	Trimethoxy(methyl)silane	100:1
Block B	3-Aminopropyl(trimethoxy)silane	1.1E+06:1
Block C	Disilyl(cycloalkylamine), penta(methoxy)-	6.4E+08:1
Block D	9-{ [Dimethoxy(methyl)silyl]oxy} -3,3,15,15-tetramethoxy-2,7,16-trioxa-11-aza-3,15-disilaheptadecane	1.46E+09:1
Hydrolysis product 1	Methylsilanetriol	4.0E+09
Hydrolysis product 2	(3-Aminopropyl)silanetriol	1.8E+10
Hydrolysis product 3	5-Oxa-9-aza-1,13-disilatridecane-1,1,1,7,13,13,13-heptol	3.3E+18:1

 

All constituents and their hydrolysis products have high blood:air partition coefficients meaning that, if lung exposure occurred there would be uptake in to the systemic circulation. The high water solubility of the constituents and their hydrolysis products might also lead to the substances being partly retained in the mucus of the lungs, slowing any absorption.

Distribution

For blood: tissue partitioning a QSPR algorithm has been developed by DeJongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol: water partition coefficient (K_ow) is described. For the constituents and hydrolysis products of the registration substance, distribution into the main body compartments is predicted to be minimal.

 

Table 5.1.4 Tissue:blood partition coefficients

	Constituent / hydrolysis product	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Block A	Trimethoxy(methyl)silane	0.7	5.01	0.8	0.8	3.9	1.0	0.9
Block B	3 -Aminopropyl(trimethoxy)silane	-2.8 (ionised value)	1.58E-03	0.6	0.7	0	0.7	0.8
Block C	Disilyl(cycloalkylamine), penta(methoxy)-	-3.3 (ionised value)	5.0E=-4	0.6	0.7	0	0.7	0.8
Block D	9-{ [Dimethoxy(methyl)silyl]oxy} -3,3,15,15-tetramethoxy-2,7,16-trioxa-11-aza-3,15-disilaheptadecane	-4 (ionised value)	1.0 E-04	0.6	0.7	0	0.7	0.8
Hydrolysis product 1	methylsilanetriol	-2.4	3.98E-03	0.6	0.7	0.0	0.7	0.8
Hydrolysis product 2	(3-Aminopropyl)silanetriol	-4 (ionised value)	1.0 E-04	0.6	0.7	0	0.7	0.8
Hydrolysis product 3	5-Oxa-9-aza-1,13-disilatridecane-1,1,1,7,13,13,13-heptol	-4 (ionised value)	1.0 E-04	0.6	0.7	0	0.7	0.8

 

Metabolism

There are no data on the metabolism of the registration substance; however, once absorbed into the body, the constituents will hydrolyse to the corresponding hydrolysis products.

In vitro bacterial mutagenicity and mammalian chromosome aberration studies showed no observable differences with and without metabolic activation. However, an in vitro mammalian mutagenicity study in mouse lymphoma L5178Y cells (Charles River Laboratories, 2017) showed a positive result with metabolic activation, negative without, indicating potential for metabolism by hepatic enzymes in vivo. The potential for mutagenicity in vivo therefore requires further investigation.

 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh et al. (1997) using log K_ow as an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

Using the algorithm, the soluble fraction of calculated for all constituents and their hydrolysis products in blood is > 97%. Therefore, once absorbed, the constituents and hydrolysis products are likely to be eliminated via the kidneys in urine, and accumulation is unlikely.

References:

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

OECD (2004): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 18-20 October 2004, Methanol, CAS 67-56-1.