Triethoxy(3-isocyanatopropyl)silane

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of triethoxy(3-isocyanatopropyl)silane.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis products and using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. Although these algorithms provide a numerical value, for the purposes of this summary only qualitative statements or predictions will be made.

The main input variable for the majority of these algorithms is log K_ow so by using this, and other where appropriate, known or predicted physicochemical properties of triethoxy(3-isocyanatopropyl)silane or its hydrolysis products where relevant, reasonable predictions or statements can be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Triethoxy(3-isocyanatopropyl)silane hydrolyses very rapidly, half-life <1 minute at pH 7 to form an intermediate hydrolysis product 3-aminopropyltriethoxysilane and carbon dioxide. 3-Aminopropyltriethoxysilane has a measured hydrolysis half-life of 0.8 h at pH 5, 8.5 h at pH 7, and 0.15 h at pH 9 and 24.7°C. The ultimate products of the hydrolysis reaction are 3-aminopropylsilanetriol and ethanol.

Relevant human exposure would be via the inhalation or dermal routes. However, due to the high reactivity against amine and hydroxyl groups, including water, relevant systemic exposure to triethoxy(3-isocyanatopropyl)silane can be excluded for all routes of exposure. Relevant inhalation exposure would be to the hydrolysis products, primarily to 3-aminopropyltriethoxysilane  (hydrolysis would occur rapidly when inhaled, even if a mixture of parent and hydrolysis products were present in air). The substance would also be expected to hydrolyse rapidly in contact with moist skin. At the local site of contact severe effects can be expected that trigger the hazard classification of the substance. Relevant systemic exposure by inhalation or dermal contact is to the primary and secondary hydrolysis products only.

The parent substance is a respiratory sensitiser and this is the critical health effect for the registered substance.

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

Absorption

Oral

Significant direct oral exposure is not expected for the corrosive parent substance, triethoxy(3-isocyanatopropyl)silane or the corrosive intermediate hydrolysis product 3-aminopropyl(triethoxy)silane. However, oral exposure to the final hydrolysis product 3-aminopropylsilanetriol is 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 water solubility of 3-aminopropyltriethoxysilane favours exposure although its molecular weight is above the ideal range which may limit the extent. 3-aminopropylsilanetriol with high predicted water solubility of 1E+06 mg/l and a molecular weight of 137.21 clearly meets the criteria so should oral exposure occur then systemic exposure is very likely.

Systemic effects were noted in acute oral studies with the parent substance (SafePharm Laboratories, 2003 and Chem Hygiene Fellowship, 1973) and repeat dose oral studies with the hydrolysis product 3-aminopropyltriethoxysilane (WIL, 1999 and 2001), indicating absorption of 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 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.

For the intermediate hydrolysis product 3-aminopropyltriethoxysilane the water solubility (1.7E+04 mg/l) and log K_ow (1.7) are favourable for dermal absorption. Once hydrolysis has occurred absorption is likely to be significantly reduced as les susbtance will be present. However, it is also possible that the damage caused by the corrosive properties of the parent substance and hydrolysis product might increase absorption overall.

The predicted water solubility (1E+06 mg/l) of the (ultimate) hydrolysis product 3-aminopropylsilanetriol is favourable for absorption across the skin but the log K_ow of -2.9 is not. 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.

No systemic effects were noted in an acute dermal study with the parent substance (Chem Hygiene Fellowship, 1973) or a repeat dose dermal study with the hydrolysis product 3-aminopropyltriethoxysilane (BRRC, 1990), only findings attributable to the local corrosive properties of the substances were noted.

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 (Koct:air) as independent variables.

Using these values for the intermediate hydrolysis product 3 -aminopropyltriethoxysilane results in a predicted blood:air partition coefficient of approximately 4.1E+04:1 meaning that significant uptake would be expected into the circulatory system. However, the higher water solubility of 3-aminopropyltriethoxysilane may lead to some of it being retained in the mucus of the lungs so absorption is likely to slow down. It is also possible that the damage caused by the corrosive properties of the parent substance and hydrolysis product might increase absorption overall.

For the final hydrolysis product 3-aminopropylsilanetriol, the QSPR results in a markedly higher blood:air partition coefficient (approximately 3E+10:1) so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake would be expected into the circulatory system. Similarly to the previous hydrolysis product, the high water solubility of 3-aminopropylsilanetriol may lead to some of it being retained in the mucus of the lungs so absorption is likely to slow down.

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 (Kow) is described.

Using this value for the intermediate hydrolysis product 3 -aminopropyltriethoxysilane predicts that there will be some distribution into fat but very little into other tissues. For the final hydrolysis product, 3-aminopropylsilanetriol, distribution into the main body compartments would be minimal with tissue:blood partition coefficients of less than 1 for all major tissues (zero for fat).

Table 1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-amino propyltriethoxysilane	1.7	50.12	1.8	1.4	32.3	1.5	1.2
3-aminopropylsilanetriol	-2.9	1.26E-03	0.6	0.7	0.0	0.7	0.8

Metabolism

There are no data on the metabolism of triethoxy(3-isocyanatopropyl)silane. Genetic toxicity tests with the registered susbtance, or the intermediate hydrolysis product (3-aminopropyltriethoxysilane) 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. QPSRs as developed by DeJongh et al. (1997) using log Kow 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 3-aminopropyltriethoxysilane and 3-aminopropylsilanetriol are 74% and >99% respectively. Therefore the hydrolysis products would be likely to be eliminated via the kidneys in urine and accumulation is unlikely.

References

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

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.

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.