N-[3-(trimethoxysilyl)propyl]butylamine

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility, and log D values it can be expected that the submission substance is likely to be absorbed via the oral, dermal and the inhalation routes, however, the low vapour pressure means that inhalation exposure is likely to be negligible. Dermal absorption is considered to be low. Hydrolysis is expected to occur and thus exposure is expected to both the parent and its hydrolysis products 3-(N-butylamino)propylsilanetriol and methanol. Based on the high water solubility of the parent substance and its hydrolysis product, distribution in the body and a fast excretion via the renal route can be expected. The bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of N-[3-(trimethoxysilyl)propyl]-1-butanamine.

The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the registered substance and its hydrolysis product (see Table below). 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 Kow or in case of N-[3-(trimethoxysilyl)propyl]-1-butanamine the calculated log D value. By using this and, where appropriate, other known or predicted physicochemical properties of N-[3-(trimethoxysilyl)propyl]-1-butanamine or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

N-[3-(trimethoxysilyl)propyl]-1-butanamine hydrolyses in contact with water (measured half-life of 4 hours at pH 7 at 20-25°C), generating 3-(N-butylamino)propylsilanetriol 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 3-(N-butylamino)propylsilanetriol due to hydrolysis.

The toxicokinetics of methanol have been reviewed in other major reviews and are not considered further here.

Table: Physicochemical properties

Physicochemical properties	N-[3-(trimethoxysilyl)propyl]-1-butanamine	3-(N-butylamino)propylsilanetriol
Water solubility	13000 mg/L at 20°C (QSAR)	1.0E+06 mg/L at 20°C (QSAR)
Vapour pressure	4.04 Pa at 25°C (QSAR)	< 0.001 Pa at 25°C (QSAR)
Log D	-6.47 at pH 2, -4.47 at pH 4, -2.79 at pH 5.5, -1.47 at pH 7 and 0.52 at pH 9 (QSAR)	-8.91 at pH 2, -6.91 at pH 4, -5.41 at pH 5.5, -3.91 at pH 7 and -1.95 at pH 9 (QSAR)
Molecular weight (g/mol)	235.4	193.32
Half-life	4 h at pH 7, 0.2 h at pH 4 and 0.07 h at pH 9 at 20-25°C (QSAR)

 

Absorption

Oral

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. Generally, the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. 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 g/mol) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (ECHA, 2017).

Therefore, if oral exposure to the parent did occur, the molecular weight of N-[3-(trimethoxysilyl)propyl]-1-butanamine (235.4 g/mol) is in the favourable range and would favour absorption, so systemic exposure by this route is likely. At pH 2 in the stomach, the parent compound is predicted to hydrolyse very rapidly into the hydrolysis product 3-(N-butylamino)propylsilanetriol within 5 seconds at the temperature of 37.5°C, therefore, the hydrolysis product is the predominant species that will be available for absorption. The molecular weight of 3-(N-butylamino)propylsilanetriol (193.32 g/mol) is in the favourable range for absorption, however, due to its very high water solubility (1.0E+06 mg/L at 20°C) the rate of passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

No signs of systemic toxicity were evident in the available 90-day repeated dose toxicity study with N-[3-(trimethoxysilyl)propyl]-1-butanamine (BSL, 2022). Thus based on the oral repeated dose toxicity study, no prediction of systemic availability is possible. The hydrolysis product is assumed to be rapidly excreted via the renal route. Hence, only minor bioavailability of N-[3-(trimethoxysilyl)propyl]-1-butanamine after oral administration is indicated.

 

Dermal

If dermal exposure were to occur, in practice this would be to the parent compound as well as the hydrolysis product.Substances with log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), particularly if water solubility is high. Values < -1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low.

 

The water solubility of 13000 mg/L, log D of -2.79 at pH 5.5 and molecular weight of 235.4 g/mol of the parent substance suggest that absorption is low. For the hydrolysis product 3-(N-butylamino)propylsilanetriol the water solubility of 1E+06 mg/L, log D of -5.41 at pH 5.5 and molecular weight of 193.32 suggests the substance will also have a low potential to be absorbed by the dermal route. Since the water solubility is above 10000 mg/L and the log D value below 0, the parent substance and hydrolysis product may be too hydrophilic to cross the lipid rich environment of the stratum corneum. QSAR based dermal permeability prediction (DERMWIN V2.02.2012) using molecular weight, log D at pH 5.5 and water solubility, calculated a dermal penetration rate of 0.01427 µg/cm²/event for N-[3-(trimethoxysilyl)propyl]-1-butanamine and 0.03522 µg/cm²/event for 3-(N-butylamino)propylsilanetriol, respectively.

The substance is a skin irritant, thus damage to the skin surface may enhance penetration.

An acute dermal toxicity study (Bushy Run Research Center, 1981) with rabbits revealed strong skin damaging effects of the test material at the doses applied. The dermal LD50 reported was 15200 mg/kg bw, and clinical signs were limited to local effects.

 

Inhalation

N-[3-(trimethoxysilyl)propyl]-1-butanamine has a low vapour pressure of 4.04 Pa at 25°C. Therefore, inhalation exposure of vaporised substance is unlikely.

The pH of the airway surface liquid has been determined to be in the range 6.7-7 (Jayaraman et al., 2000), without significant inter- or intraspecies variation.

The estimated hydrolysis half-life at 20-25 °C and pH 7 (relevant for lungs and blood) is 4 hours. 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]

Hydrolysis is a chemical reaction that is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of N-[3-(trimethoxysilyl)propyl]-1-butanamine 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.

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’s Law coefficient and the octanol: air partition coefficient (Koct: air) as independent variables.

Using these values for N-[3-(trimethoxysilyl)propyl]-1-butanamine predicts a blood: air partition coefficient of approximately 7.1E+03:1 meaning that, in steady state, more or less 100% of this substance will be in blood and very little in air, and therefore if lung exposure occurs the majority of parent substance available would be absorbed. However, hydrolysis is expected. For the hydrolysis product, 3-(N-butylamino)propylsilanetriol, the predicted blood: air partition coefficient is approximately 2.6E+09:1 meaning that systemic exposure is predicted to be even higher. Again, this prediction is based on physicochemical properties and is not expected to vary between individuals.

It is also important to consider the water solubility of N-[3-(trimethoxysilyl)propyl]-1-butanamine and its hydrolysis product with respect to dissolving in the mucous of the respiratory tract. The parent is very soluble, therefore, solubility in the mucous of the respiratory tract is expected to be high. The hydrolysis product is even more soluble in water and therefore also expected to be present in the mucous lining following inhalation of N-[3-(trimethoxysilyl)propyl]-1-butanamine. Therefore, there is potential for passive absorption.

An acute inhalation toxicity study in rats was carried out, using a test atmosphere containing substantially saturated vapour of the test item. Following 6 hours of exposure no deaths occurred, and no signs of toxicity were observed. Moreover, gross pathology revealed no remarkable findings. Thus, a low hazard potential of the substance via the inhalative route can be estimated.

In conclusion, inhalation exposure to N-[3-(trimethoxysilyl)propyl]-1-butanamine is considered to be negligible, due to its low vapour pressure. However, should exposure occur, the parent substance and hydrolysis product 3-(N-butylamino)propylsilanetriol are likely to be absorbed.

Distribution

The low molecular weight, high and very high water solubility of the parent and hydrolysis product, respectively, suggest they will both have the potential to diffuse through aqueous channels, pores and will be widely distributed; however the log D of -1.47 at pH 7 for the parent and of ‐3.91 at pH 7 for the hydrolysis product indicate the substances are unlikely to be distributed into cells. Therefore, the extracellular concentration will be higher than the intracellular concentration.

The high water solubility and the low log D of both the parent and hydrolysis product suggest that accumulation in the body is not likely for both substances.

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 N-[3-(trimethoxysilyl)propyl]-1-butanamine (log D = -1.47 at pH 7) and its hydrolysis product (log D = -3.91 at pH 7) predicts that, should systemic exposure occur, distribution into the main body compartments is predicted to be minimal.

Table: Tissue: blood partition coefficients

	Log D (pH 7)	Kow	Liver	Muscle	Fat	Brain	Kidney
N-[3-(trimethoxysilyl)propyl]-1-butanamine	-1.47	0.034	0.6	0.7	-0.2	0.7	0.8
3-(N-butylamino)propylsilanetriol	-3.91	1.2E-04	0.6	0.7	-0.2	0.7	0.8

 

Metabolism

N-[3-(trimethoxysilyl)propyl]-1-butanamine is a moisture-sensitive liquid that hydrolyses in contact with water (measured half-life less than 4 hours at pH 7 and 25°C), generating methanol and 3-(N-butylamino)propylsilanetriol. There is no data on the metabolism of either of the parent substance N-[3-(trimethoxysilyl)propyl]-1-butanamine nor the hydrolysis product 3-(N-butylamino)propylsilanetriol.

N-[3-(trimethoxysilyl)propyl]-1-butanamine is within 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). This is also demonstrated in the available biodegradation study (Hydrotox, 2004) for N-[3-(trimethoxysilyl)propyl]-1-butanamine, where there is no evidence of any significant biodegradation of the silanol hydrolysis product.

It cannot be excluded, that amine containing compounds underlie multiple metabolic reactions such as N-oxidation or N-dealkylation, but this is considered to be insignificant and would only enhance renal excretion.

Excretion

The low molecular weight (below 300 g/mol) and high to very high water solubility of the parent and hydrolysis product suggest that they are likely to be excreted by the kidneys into urine.

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 N-[3-(trimethoxysilyl)propyl]-1-butanamine and of 3-(N-butylamino)propylsilanetriol in blood is approximately 100%. Therefore, these figures suggest that the parent substance and hydrolysis product is likely to be effectively eliminated via the kidneys in urine.

 

These findings 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:

ECHA (2017). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0. June 2017                                                  

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.

Gerin (2016) Fate of silanols in various aquatic / soil environments: Investigation of dimethylsilanediol (bio)degradation in microcosms

Jayaraman, S.; Song, Y.; Vetrivel, L.; Shankar, L. & Verkman, A. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH Journal of Clinical Investigation, American Society for Clinical Investigation, 2000, 107, 317-324.

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.

PFA, 2013f, Peter Fisk Associates, Biodegradation Main Analogue Group report, PFA.300.005.007