Tetrakis(2-butoxyethyl) orthosilicate

Endpoint summary

Additional information

Summary and discussion of toxicokinetics

There are no in vitro or in vivo data on the toxicokinetics of tetrakis(2-butoxyethyl) orthosilicate.

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 comparisons 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, other known or predicted physicochemical properties of tetrakis(2-butoxyethyl) orthosilicate reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

Tetrakis(2-butoxyethyl) orthosilicate has a predicted water solubility of 6.6 mg/l, a predicted log Kow of 4.3 and a molecular weight of 496.8.

In contact with water, tetrakis(2-butoxyethyl) orthosilicate hydrolyses rapidly (half-life of approximately 4 hours at pH 7, 1.7 hours at pH 4, 1.7 hours at pH 9 and 20 -25°C) to generate monosilicic acid. Monosilicic acid undergoes reversible condensation reactions in water and a dynamic equilibrium is established. Above approximately 100 -150 mg/l as SiO2, an amorphous precipitate (polysilicic acid or SAS or insoluble silica) is formed. The solubility of monosilicic acid (soluble silica) in aqueous media is therefore limited to 100 -150 mg/l. It has a predicted log Kow of -4 and a molecular weight of 96.1.

The non-silanol product of hydrolysis is 2-butoxyethanol. 2 -butoxyethanol is miscible with water and has a log Kow of 0.8 and a molecular weight of 118.2.

Relevant human exposure is to the parent substance and can occur via the inhalation or dermal routes.

The toxicokinetics of 2-butoxyethanol have been reviewed in other major reviews (OECD SIDS, 1997) and are only considered briefly here to support the reduction of assessment factors in the DNEL derivation.

 

Absorption

Oral

Significant oral exposure is not expected for this substance.

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 must 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).

Due to the molecular weight (497 g/mol) and low water solubility (6.6 mg/L) of tetrakis(2-butoxyethyl) orthosilicate should oral exposure occur significant systemic exposure to the parent substance is unlikely.  The available physical chemical data indicates that tetrakis(butoxyethoxy)silane is rapidly hydrolysed in the stomach following oral exposure (at 37.5ºC and pH 2, the hydrolysis half -life is approximately 30 seconds). The non-silicon hydrolysis product, 2-butoxyethanol, has physicochemical properties favourable for absorption (moderate log Kow and high water solubility). 2 -Butoxyethanol is readily absorbed (100% assumed) following oral exposure (EU SCHER, 2008).

The physicochemical properties of monosilicic acid are less favourable for absorption (very log Kow, limited solubility in water). However, some monosilicic acid may be absorbed from the gut. Absorption of insoluble silica will be insignificant as compared to the absorption of the soluble species (Carlisle, 1986); the high molecular weight and lack of solubility of the condensed silica species make their absorption unfavourable.

The repeated dose toxicity study via the oral route (Eurofins (2016)) does show evidence of absorption, as systemic effects were observed.

 

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 log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

Tetrakis(2-butoxyethyl) orthosilicate has a log K_ow value (4.3) above the favourable range and low water solubility (6.6 mg/L) therefore absorption across the skin is not likely to occur and significant systemic exposure following dermal exposure is unlikely.

The hydrolysis product, 2-butoxyethanol is known to be well absorbed following dermal exposure (EU SCHER, 2008).

The silicon-containing hydrolysis product, silicic acid, does not have favourable properties for dermal absorption (very low log Kow, limited water solubility). The substance is likely to be too hydrophilic to cross the lipid rich environment of the stratum corneum.

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 coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for tetrakis(2-butoxyethyl) orthosilicate results in a blood:air partition coefficient of approximately 36:1 meaning that if lung exposure occurred there would be some uptake into the systemic circulation. When monosilicic acid is produced by hydrolysis, it may be retained in the lining of the respiratory tract as it is very polar. Absorption is likely to be low. The low solubility of the parent (6.6 mg/l) and the relatively slow hydrolysis (t1/2 88 mins at pH 7 and 37.5) means that concentrations of silicic acid in the lung are unlikely to be high enough to result in formation of insoluble silica via condensation reactions (monosilicic acid is soluble to about 100-150 mg/l).

The hydrolysis product, 2 -butoxyethanol is known to be well absorbed following inhalation, with absorption of 55 -60% measured in human volunteer inhalation studies (EU SCHER, 2008). The physicochemical properties are favourable for uptake via the lungs.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jongh 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 this value for tetrakis(2-butoxyethyl) orthosilicate predicts that, should systemic exposure to parent occur, distribution would primarily be into fat, with potential slight distribution into liver, muscle, brain and kidney.

Table: tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
tetrakis(2-butoxyethyl) orthosilicate	4.3	19952	8.6	5.3	113.3	9.6	5.8

 

Tetrakis(2-butoxyethyl) orthosilicate which is absorbed may be expected to undergo hydrolysis within the blood.

Experimental animal studies have shown the hydrolysis product 2-butoxyethanol is rapidly and widely distributed to all tissues following oral and dermal exposure (OECD SIDS, 1997 - publications cited).

Silicic acid is a small molecule and therefore has the potential to be widely distributed but its hydrophilic nature will limit diffusion across membranes and accumulation in fatty tissues. Human blood contains 1 mg SiO₂/l of monosilicic acid (Iler, R. K., 1979).

Metabolism

Data on the metabolism of tetrakis(2-butoxyethyl) orthosilicate are not available, but initial hydrolysis leads to the formation of the non-silanol hydrolysis product, 2-butoxyethanol and monosilicic acid. 2-Butoxyethanol is rapidly metabolised (plasma half-life of less than one hour) to form 2 -butoxy-acetic acid (BAA). This metabolsim is catalysed by alcohol dehydrogenase and aldehyde dehydrogenase and is followed by formation of glucuronide conjugates of BAA. A significant proportion of 2 -butoxyethanol remains unmetabolised (EU SCHER, 2008).

In animals, smaller amounts of the glucuronide and sulfate conjugates and ethylene glycol can be formed by other metabolic pathways, following exposure at high doses. In human studies, the glutamine conjugate of BAA has been detected in urine following exposure to 2-butoxyethanol, and suggests an additional detoxification pathway in humans (Rettenmeier et al., 1993 in OECD SIDS, 1997 - publication not found). Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for tetrakis(2-butoxyethyl) orthosilicate. 

Silicon is an essential trace element participating in the normal metabolism of higher animals. It is required in bone, cartilage and connective tissue formation as well as participating in other important metabolic processes. The silicon is present almost entirely as free, soluble monosilicic acid (Carlisle 1986).

 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by De Jonghet 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 tetrakis(2-butoxyethyl) orthosilicate in blood is <1% and is therefore unlikely to be eliminated via the kidneys in urine. In the available repeat dose toxicity studies, adverse effects including tubular hemosiderin deposits and tubulo-interstitial inflammation were noted in the kidneys. The main route of elimination of 2-butoxyethanol in experimental animals and humans is rapid excretion via the urine as BAA (80 to 90% as BAA). The plasma half-life of metabolites is four hours. About 10-20% of BAA is eliminated as CO₂ in expired air (EU SCHER, 2008; OECD SIDS, 1997 - publication given).

There is a PBPK model for 2-butoxyethanol, which is sufficiently well developed to justify its used to derive animal to man toxicokinetic extrapolation factors for the inhalation route. These factors are based on the toxicokinetics of BAA since this is the metabolite that causes the critical toxic effects (EU Risk Assessment, 2008).

 

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.

EU Risk Assessment Report on 2 -butoxyethanol (EGBE), CAS 111 -76 -2, Human Health Part, 2008.

SCHER Opinion on the risk assessment report on the risk assessment report on 2 -butoxyethanol (EGBE), CAS 111 -76 -2, Human Health Part, 12 March 2008.

OECD (1997): SIDS Initial Assessment Report for SIAM 6, Paris, 9-11 June 1997,2-butoxyethanol, CAS 111-76-2.

Iler, Ralph K. (1979) The Chemistry of Silica: Solubility, Polymerization, Colloid and Surface Properties and Biochemistry of Silica, Wiley, p. 13.