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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Triacetin (CAS 102-76-1) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance Triacetin (CAS 102-76-1) has been conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012) and taking into account further available information on the breakdown products of ester hydrolysis.

The monoconstituent substance Triacetin (purity of > 80%) is a triester of acidic acid with glycerol. It is a colourless clear fluid (organic liquid) at 20°C (Aliti, 2009) with a molecular weight of 218.20 g/mol and a water solubility of 58 g/L at 25 °C (HSDB, 2009). The log Pow was determined to be 0.25 (HSDB, 2009), which is support by QSAR calculation of the partition coefficient of the substance, resulting in a log Pow value of 0.36 (Erler, 2013). A vapour pressure of 0.3306 Pa at 25°C was measured for Triacetin (HSDB, 2009).

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). As the molecular weight of Triacetin is 218.20 g/mol, absorption of the intact molecules in the gastrointestinal (GI) tract can be anticipated. Absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski, 2001), refined by Ghose et al., 1999) is applied to the substance.

However, when assessing the potential of Triacetin to be absorbed in the GI tract, it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long et al., 1958; Lehninger, 1998; Mattson and Nolen, 1972). Thus, due to the hydrolysis the predictions based upon the physico-chemical characteristics of the intact parent substance alone but also the physico-chemical characteristics of the breakdown products of the ester have to be considered (ECHA, 2012).

After oral ingestion, Triacetin will undergo stepwise chemical changes in the GI fluids as a result of enzymatic hydrolysis. The cleavage products of ester hydrolysis are glycerol and acetic acid which are anticipated to be easily absorbed in the GI tract based on their low molecular weight.

The anticipation of hydrolysis of the ester Triacetin is supported by experiments with the substance itself as well as the structurally related substances Monoacetin and Diacetin, which were incubated in sacs of everted intestine from rats. It was shown that the glyceride esters entered the epithelial cells and were completely hydrolysed to free glycerol and acetic acid. The released acetate appeared in higher concentrations on the serosal side of intestine and the acetate release increased with the number of acetic acid residues in the glyceride (Barry et al., 1966).

The available acute oral toxicity study on Triacetin in rats showed no signs of systemic toxicity, resulting in a LD50 value greater than 2000 mg/kg bw (Reijnders, 1988). Consistently, no adverse effects were observed in an acute oral toxicity study in mice, for which a LD50 value of 9288 mg/kg bw was determined. Furthermore, available data on the subacute oral toxicity of Triacetin showed no adverse systemic effects in rats, resulting in a NOAEL of 1000 mg/kg bw/day (MHLW, 1998). Based on the weight of evidence from various subchronic oral toxicity studies with the substance, no potential for long-term systemic toxicity was observed, as the substance was showing no or only very low toxicity at dose levels which significantly exceeded the currently applied limit dose of 1000 mg/kg bw (Shapira, 1969; Shapira, 1975). However, the lack of short- and long-term systemic toxicity of Triacetin cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of the test substance and the breakdown products themselves.

Overall, systemic bioavailability of Triacetin and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). As Triacetin has a molecular weight of 218.20 g/mol and high water solubility (> 58 g/L), dermal absorption of the substance may be favourable. However, dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum (ECHA, 2012). The log Pow value of Triacetin was experimentally determined to be 0.25 and is thus in the range of zero, which in combination with the very high water solubility is anticipated to result in a low dermal absorption potential for the substance.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration (ECHA, 2012). Triacetin showed no skin irritating properties in rabbits (Kästner, 1988), and thus no enhanced penetration of the substance due to local skin damage is expected.

Furthermore, QSAR dermal absorption values of 0.005 mg/cm²/event (low) for Triacetin support the assumption that the substance has a low potential for dermal absorption.

Overall, the calculated low dermal absorption potential, the high water solubility, the moderate molecular weight (< 500) and the low log Pow values imply that dermal uptake of Triacetin in humans is considered to be low.

Inhalation

The substance Triacetin has a low vapour pressure of 0.3306 Pa at 20 °C, thus being of low volatility (HSDB, 2009). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant. However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed.

If the substance is available as an aerosol, the potential for absorption via the inhalation route is increased. While droplets with an aerodynamic diameter < 100 μm can be inhaled, in principle, only droplets with an aerodynamic diameter < 50 μm can reach the bronchi and droplets < 15 μm may enter the alveolar region of the respiratory tract (ECHA, 2012).

Substances with a moderate log Pow values (between -1 and 4) and molecular weights below 500 g/mol are favourable for absorption directly across the respiratory tract epithelium by passive diffusion (ECHA, 2012). As Triacetin has a log Pow value of 0.25, absorption via passive diffusion is feasible.

The acute inhalation study with Triacetin in rats did not show any mortality or systemic toxicity after inhalative exposure (Pauluhn, 1985). The lack of acute systemic toxicity of substance cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of the test substance itself.

Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst case approach.

Overall, a systemic bioavailability of Triacetin in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15 µm.

Distribution and Accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2012).

Depending on the route of exposure, Triacetin will mainly be absorbed in the form of the hydrolysis products and/or the parent substance. The fraction of substance absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Barry et al., 1966). Consequently, glycerol and acetic acid are the most relevant components to assess. These hydrolysis products are, due to their size and water solubility (glycerol: 1000000 mg/L, 92.09 g/mol; acetic acid: 602.9 g/L, 60.05 g/mol) expected to be distributed widely in the body (Riddick, 1986; Yalkowsky, 2003). This is supported by experimental data on Triacetin intravenously administered to mongrel dogs, demonstrating that the majority of infused Triacetin undergoes intravascular hydrolysis and systemic acetate turnover, which accounted for approximately 70% of Triacetin-derived acetate, assuming complete hydrolysis of the triglyceride (Bleiberg et al., 1993). Therefore, the intact parent substance Triacetin is not assumed to be accumulated to a significant amount as hydrolysis is anticipated to take place either before absorption or thereafter.

In summary, the available information Triacetin indicates that no significant bioaccumulation of the parent substance is expected. The breakdown products of hydrolysis, glycerol and acetic acid, will feed into metabolic and physiological pathways and are therefore widely distributed in the organism.

Metabolism and Excretion

The substance Triacetin is expected to be hydrolysed to glycerol and acetic acid by ubiquitous esterases (Barry, 1966). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism. After oral ingestion, Triacetin will undergo chemical changes already in the GI fluids as a result of enzymatic hydrolysis. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place. Bleiberg et al. (1993) showed that during intravenous administration in dogs, the majority of infused Triacetin undergoes intravascular hydrolysis, and the majority of the resulting acetate will be oxidised. Systemic acetate turnover accounted for approximately 70% of Triacetin-derived acetate, assuming complete hydrolysis of the triglyceride. It is apparent that the majority (85%) of acetate entering the system is directly oxidised. This is consistent with the generally accepted view that short- and medium-chain fatty acids undergo near quantitative oxidation rather than being re-esterified or elongated to longer fatty acid chain (Groot and Hülsmann, 1973). The second cleavage product, Glycerol, is considered a primordial biomolecule found in all species of living organisms. It is a building block for lipid synthesis and one of the end products of lipid metabolism. It can be re-esterified to form endogenous glycerides or be metabolised to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which can be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Glycerol is phosphorylated to alpha-glycerolphosphate by glycerol kinase predominantly in the liver (80-90%) and kidneys (10-20%) and incorporated in the standard metabolic pathways to form glucose and glycogen (Tao et al., 1983; Lin, 1977). Glycerol kinase is also found in intestinal mucosa, brown adipose tissue, lymphatic tissue, lung and pancreas. Glycerol may also be combined with free fatty acids in the liver to form triglycerides (lipogenesis) which are distributed to the adipose tissues. The turnover rate is directly proportional to plasma glycerol levels (Bortz et al., 1972). Being a polar molecule, glycerol can also be readily excreted in the urine.

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

 

References

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Bleiberg, B. et al., (1993), Metabolism of triacetin-derived acetate in dogs, Am. J. Clin. Nutr. 58 (6): 908-911.

Bortz, W.M. et al. (1972). Glycerol turnover and oxidation in man. J Clin Invest. 51(6): 1537-46.

ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Ghose, A.K. et al. (1999). A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1 (1): 55-68.

Groot, P.H. and Hülsmann, W.C. (1973). The activation and oxidation of octanoate and palmitate by rat skeletal muscle mitochondria. Biochim. Biophys. Acta 316 (6): 124-35.

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Long, C.L. et al. (1958). Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys, 77(2): 428-439.

Mattson F.H. and Nolen G.A. (1972). Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition 102 (9): 1171-1175.

Riddick, J.A., Organic Solvents: Physical Properties and Methods of Purification, Techniques of Chemistry. 4th ed., Wiley-Interscience, New York, 1986.

Tao, R.C. et al. (1983). Glycerol: Its Metabolism and Use as an Intravenous Energy Source. JPEN J Parenter Enteral Nutr. 7(5): 479-88.

Yalkowsky, S.H and He, Y. Handbook of aqueous solubility data. CRC Press, 2003.