1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

Endpoint summary

Additional information

Summary and discussion of toxicokinetics

There are no data on the toxicokinetics of 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the parent and hydrolysis productsand 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 where appropriate, other known or predicted physicochemical properties of 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

1,3,5 -Tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione is a highly viscous moisture sensitive liquid. In contact with water 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione reacts rapidly (half-life of 111.3 minutes at pH 7 and 25°C) to produce 1,3,5-tris[3-(trihdroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione and methanol. The hydrolysis half-life at 37.5°C and pH 7 (relevant for lungs and blood) is approximately 0.68 hours (approximately 41 minutes). At 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), the calculated half-life is approximately 5 seconds, and at 37.5°C and pH 5.5 (relevant for dermal exposure), the half-life is between 2 minutes and 41 minutes.

For 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione, human exposure can occur via the inhalation or dermal routes. Due to the rapid hydrolysis, relevant dermal and inhalation exposure would be to the parent and hydrolysis products. Significant oral exposure is not expected for this substance. However, oral exposure to humans via the environment may be relevant for the hydrolysis products.

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

Absorption

Oral

Significant oral exposure is not expected for this substance. Oral exposure to the hydrolysis products 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione and methanol is potentially possible via the environment.

When oral exposure takes place, it can be assumed that, 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).

Therefore, if oral exposure to the parent did occur, both the molecular weight of 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione (615.86 g/mol) and the water solubility of 0.014 mg/L are unfavourable for absorption, so exposure by this route is not likely. The hydrolysis product 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione is soluble in water (water solubility 1E+06 mg/L,limited to <100 mg/L by condensation reactions) therefore, although the molecular weight (489.62 g/mol) is above the favourable range, systemic exposure to the hydrolysis product following oral exposure is possible.

Systemic effects were observed in the key acute oral toxicity study (BRRC 1990), indicating that absorption of parent substance or hydrolysis product into the system circulation has occurred following oral exposure.

 

Dermal

Dermal exposure would be to the parent and hydrolysis products.

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.

The predicted log K_ow of 2.4 for 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione is in the favourable range for dermal absorption, however the water solubility of 0.014 mg/L indicates that absorption may be limited by poor solubility. After or during deposition on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. With a vapour pressure of 0.11 Pa at ambient temperature, evaporation of 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione is expected to be insignificant in respect of impact on potential dermal absorption.

The predicted water solubility (1E+06 mg/L) of the hydrolysis product, 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione, is potentially favourable for absorption cross the skin but the log K_ow value (-4.0) indicates it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the systemic circulation is likely to be minimal.Therefore absorption of substance-related material will slow down as hydrolysis progresses.

Some treatment-related effects were observed in the key acute dermal toxicity study, however the applied dose was very high and it exceeds the dose-range limit for classification (BRRC, 1990).

 

Inhalation

The uptake of substances into the lungs requires that the substance should be sufficiently water soluble to dissolve in the mucous of the respiratory tract lining. In addition, the substance needs to have a log K_ow which is favourable to absorption, i.e. between -1 and 4. 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 (K_{oct: air}) as independent variables.

Using these values for 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione predicts a blood: air partition coefficient of approximately 0.18:1 indicating that, if lung exposure occurred, uptake into the systemic circulation would be unlikely.

For the hydrolysis product 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione, the predicted blood: air partition coefficient is approximately 2.8E+12:1 meaning that significant uptake in to the systemic circulation is likely. However, the high water solubility may lead to some of it being retained in the mucus of the lungs so once hydrolysis has occurred, absorption is likely to slow down.

There were no systemic effects observed in the key acute inhalation toxicity study (BRRC 1990)

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 this value for 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione predicts that, should systemic exposure occur, potential distribution into the main body compartments would primarily be into fatty tissues with similar but much lower proportions into the other tissues.

For the hydrolysis product 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione, distribution into the main body compartments is predicted to be minimal.

Table: Tissue: blood partition coefficients

	log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione	2.4	2510	3.8	2.6	77.0	2.5	1.8
1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione	-4.0	0.001	0.6	0.7	0.0	0.7	0.8

 

 

Metabolism

There are no data on the metabolism of 1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione. However, once absorbed into the body, it will hydrolyse to form methanol and 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione. In vitro bacterial mutagenicity studies showed no observable differences 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 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 tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione in blood is approximately 36% indicating that, once absorbed, there is some potential for the substance to be eliminated via the kidneys in urine. The corresponding value for the hydrolysis product, 1,3,5-tris[3-(trihydroxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione, the figure is >>99% meaning that once absorbed the hydrolysis product is likely to be eliminated via the kidneys in urine and accumulation is therefore unlikely.

References:

De Jongh, 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.