Amino functional alkoxysilanes

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no in vivo data on trimethoxy(methyl)silane and its reaction products with 3-aminopropyltriethoxysilane and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (EC 701 -410 -9) , or its constituent silanes. The kinetics of other constituents, methanol and ethanol, have been studied in detail and will not be discussed further here.

The major constituent, trimethoxy(methyl) silane (MTMS; CAS 1185-55-3; Block A) and one of the aminofunctional silanes, 3-aminopropyl(triethoxy)silane (CAS 919-30-2; Block B) will be discussed. MTMS is considered to represent the alkoxysilane constituents of the mixture and 3-aminopropyl(triethoxy)silane represents the aminofunctional silanes in the mixture.

The following summary has been prepared based on the physicochemical properties of MTMS and 3-aminopropyl(triethoxy)silane themselves and their hydrolysis products and using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. The main input variable for the majority of these algorithms is log K_ow so by using this, and where appropriate other, known or predicted physicochemical properties of MTMS and 3-aminopropyl(triethoxy)silane, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

MTMS hydrolyses in contact with water (half-life 2.2 hours at pH 7), generating methanol and methylsilanetriol. 3-Aminopropyl(triethoxy)silane hydrolyses in contact with water (half-life of 8.5 hours at pH7), generating the hydrolysis products ethanol and 3-aminopropylsilanetriol.

Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent substance and hydrolysis products.

Absorption

Oral

Significant oral exposure is not expected for trimethoxy(methyl)silane and its reaction products with 3 -aminopropyltriethoxysilane and [3 -(2,3 -epoxypropoxy)propyl]trimethoxysilane.

However, oral exposure to the hydrolysis products methylsilanetriol and 3-aminopropylsilanetriol is possible via the environment.

When oral exposure takes place it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. 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).

Both of the hydrolysis products have molecular weights under 200 and are very soluble (1E+06 mg/ml) so should oral exposure occur then systemic exposure is very likely. Systemic effects were noted in a repeat dose oral toxicity study with MTMS (Dow Corning Corporation, 2005) and an acute toxicity study with 3-aminopropyl(triethoxy)silane (Bushy Run Research Center, 1989) indicating that absorption of test substance-related material had occurred.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_ow values. Substances with a log K_ow value between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

 

The water solubility (9.1E+04 mg/L) of MTMS is favourable for dermal absorption but the log K_ow (0.7) is below the favourable range so systemic exposure resulting from dermal absorption is likely to be limited. Furthermore, after or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. MTMS is volatile (VP 10680 Pa) so this would further reduce the potential for dermal absorption. Although the water solubility of the hydrolysis product, methylsilanetriol, is favourable for absorption, the log K_ow of -2.4 is not, so it is considered too hydrophilic to cross the lipid-rich stratum corneum. Therefore, dermal uptake is likely to be minimal.

An acute dermal toxicity study with MTMS showed no indication of systemic toxicity at a dose of 10 ml/kg (Mellon Institute, 1963b). Since clear evidence of systemic toxicity was observed via the oral (Mellon Institute, 1963a) and inhalation (Dow Corning Corporation, 2006) routes, this supports the conclusion that there is very little to no dermal absorption of trimethoxy(methyl)silane.

The water solubility and log K_ow of 3-aminopropyl(triethoxy)silane are both favourable for absorption and the low vapour pressure (2 Pa) is unlikely to be a major factor limiting dermal absorption, therefore systemic exposure via this route is considered likely. Furthermore, since this substance is corrosive to the skin, damage to the skin might increase penetration. Although the water solubility of the hydrolysis product, 3-aminopropylsilanetriol, is favourable for absorption, the log K_ow of -2.9 is not; therefore it is considered too hydrophilic to cross the lipid-rich stratum corneum and dermal uptake is likely minimal.

An acute dermal toxicity study with 3-aminopropyl(triethoxy)silane (Bushy Run Research Center, 1989b) shows evidence of dermal absorption, although some or all of the effects could be secondary to corrosive effects. Skin irritation/corrosion studies (Bushy Run Research Center, 1990) did not report any signs of systemic toxicity.

Inhalation

There is a Quantitative Structure-Property Relationship (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 coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

The predicted hydrolysis half-life for trimethoxy(methyl)silane at 37.5ºC and pH 7 (relevant for lungs and blood) is approximately 0.8 hours. This prediction is based on a weight of evidence of data from validated QSAR estimation method and measured data. 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 uncatalyzed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.

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

This chemical reaction is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of trimethoxy(methyl)silane will be present in the airway surface liquid, without significant variation between individuals. Proving the hydrolysis rate in the lungs of experimental animals in vivo would present many complicated (possibly insurmountable) technical difficulties, and therefore the presence of parent and hydrolysis product is assumed as a worst-case scenario.

Using these values for MTMS results in a blood:air partition coefficient of approximately 23:1, meaning that if lung exposure were to occur there would be uptake into the systemic circulation. The high water solubility of the hydrolysis product, methylsilanetriol, results in a very high blood:air partition coefficient (approximately 7.9E+07:1) so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake would be expected into the systemic circulation. However, the high water solubility of methylsilanetriol could lead to some of it being retained in the mucus of the lungs so absorption is then likely to slow down.

Available acute and repeated dose toxicity inhalation studies (Dow Corning Corporation, 2006 and 2008) on trimethoxy(methyl)silane suggest that this substance is absorbed across the lungs, as adverse systemic effects were observed.

Using these values for 3-aminopropyl(triethoxy)silane results in a high blood:air partition coefficient of approximately 1.4E+04:1 meaning that if lung exposure occurred there would be uptake into the systemic circulation. The high water solubility of the hydrolysis product, 3-aminopropylsilanetriol, results in a very high blood:air partition coefficient (approximately 3.2E+10:1) so once hydrolysis has occurred, as would be expected to in the lungs, then significant uptake would be expected into the systemic circulation. However, the high water solubility of 3-aminopropylsilanetriol could lead to some of it being retained in the mucus of the lungs so absorption is then likely to slow down.

As with dermal exposure, damage to membranes caused by the corrosive nature of the substance might enhance the uptake. An acute inhalation toxicity study (Bushy Run Research Center, 1982) showed local signs but no definite systemic effects.

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. Using these values predicts that distribution of MTMS and 3-aminopropyl(triethoxy)silane will be limited and primary into fat while for the hydrolysis products, distribution will be minimal.

Table 5.1.1: tissue:blood partition coefficients

 

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Trimethoxy(methyl)silane	0.7	5.01	0.8	0.8	3.9	1.0	0.9
3 -Aminopropyltriethoxysilane	1.7	50.12	1.8	1.4	32.3	1.5	1.2
3 -Aminopropylsilanetriol	-2.9	0.0013	0.6	0.7	0.0	0.7	0.8
Methylsilanetriol	-2.4	0.004	0.6	0.7	0.0	0.7	0.8

 

Repeated dose studies on MTMS (Dow Corning Corporation, 2005 and 2008) and 3-aminopropyl(triethoxy)silane (WIL Research, 2001a) showed signs of adverse effects on various organs, indicating systemic exposure of test item-related material.

Metabolism

There are no data on the metabolism of trimethoxy(methyl)silane. However, it will hydrolyse to form methanol and methylsilanetriol once absorbed into the body. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Trimethoxy(methyl)silane is in an analogue group of substances for which, in general, there is no evidence of any significant biodegradation once hydrolysis and subsequent biodegradation of alkoxy/acetoxy groups has been taken into account (PFA, 2013f). In a ready biodegradation study with the structurally related substance trimethoxy(propyl)silane, the biodegradation observed is attributable to the non-silanol hydrolysis product (methanol). Mass-balance calculation has been undertaken to determine the percentage by weight of the parent substance that is associated with the biodegradable by-product. Once the biodegradation of the hydrolysed methoxy- groups is taken into account, there is no evidence of any biodegradation of the silanol hydrolysis product, propylsilanetriol. This observation is supported by studies with silanols that are structurally similar to propylsilanetriol. Studies with hydroxytrimethylsilane (CAS 1066-40-6) and dimethylsilanediol (CAS 1066-42-8) show no evidence of biodegradation (Clarke, 2008; Dow Corning Corporation, 1984).

It is therefore concluded that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

There are no data on the metabolism of 3-aminopropyl(triethoxy)silane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QSPRs 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 this algorithm, the soluble fraction of MTMS and 3-aminopropyl(triethoxy)silane in blood is approximately 97% and 74% respectively. The corresponding figure for the hydrolysis products is >99.9%. Therefore all will be effectively eliminated via the kidneys in urine and accumulation is very unlikely.

In conclusion, rapid absorption into the blood and fast elimination from the blood via urine support the hypothesis that after hydrolysis a water-soluble silanol is formed (supported by log Kow calculation) which is rapidly excreted from the body. Since, this hydrolysis occurs without enzymatic involvement it is appropriate to reduce the intraspecies assessment factor from 5 to 2.2 for workers and from 10 to 3.2 for the general population, by exclusion of the toxicokinetic element of this assessment factor.

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.

Dow Corning Corporation (1984) Twenty Day Biochemical Oxygen Demand of Dimethylsilanediol with Bacterial Isolates Previously Exposed to Silicones

Clarke, N (2008). Trimethylsilanol (CAS No. 1066-40-6) Assessment of Ready Biodegradability; CO2 in Sealed Vessels (CO2 Headspace Test). Safepharm Laboratories Limited, Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD. Report number: 2581/0002. Report date: 2008-10-14.