Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters

Endpoint summary

Additional information

Basic toxicokinetics

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies evaluating the toxicokinetic properties of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) available.

The substance Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) is a diester of Triethylene glycol and fatty acids with a chain length from C16 to C18 saturated.

Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) is a solid at 20 °C and has a molecular weight range of 388.58-683.1 g/mol and a water solubility of <0.05 mg/L at 25°C (Frischmann, 2012). The log Pow is calculated to be in the range of 5.73 to 15.57 (Müller, 2011) and the vapour pressure is calculated to be < 0.0001 Pa (Nagel, 2012).

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, 2008).

Oral

When assessing the potential of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) to be absorbed in the gastrointestinal (GI) tract, it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). Thus, due to the hydrolysis the predictions based upon the physico-chemical characteristics of the intact parent substance alone may no longer apply but also the physico-chemical characteristics of the breakdown products of the ester (ECHA, 2008). The cleavage products of ester hydrolysis are the alcohol component Triethylene glycol and the fatty acids Palmitic acid (C16) and Stearic acid (C18).

The molecular weight of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (388.58 – 683.1 g/mol) does suggest absorption for the smaller molecular weight fraction but does not favour absorption for the fraction with a molecular weight above 500 g/mol. Furthermore, the low water solubility and the high log Pow value of the parent compound indicate that the absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986).

When considering the hydrolysis products, it is anticipated that they are absorbed in the GI tract. The respective molecular weight of Triethylene glycol (150.17 g/mol) and the Fatty acids (256.42 and 284.48 g/mol) does favour absorption. This is supported by the results of an in-vivo study in rats administering 1.2 g/kg bw Triethylene glycol or 3.5 g/kg bw Triethylene glycol diacetate. The study showed that 59% and 64.4% of the administered dose of Triethylene glycol and Triethylene glycol diacetate were excreted as Triethylene glycol via the urine after 1 day. The unchanged ester Triethylene glycol diacetate was not found in urine or feces and the authors concluded that large doses of Triethylene glycol diacete were completely absorbed, metabolised to the parent glycol and rapidly excreted in the urine. However, the fate of the remainder was not described (NTIS, 1984).

Furthermore, highly lipophilic long chain fatty acids like Stearic acid will be absorbed into the walls of the intestine villi due to their role as nutritional energy source (Lehninger, 1970). The alcohol component is highly water-soluble and has a low molecular weight and can therefore dissolve into GI fluids. Thus, the alcohol component Triethylene glycol will be readily absorbed through the GI tract.

No studies investigating the acute oral toxicity of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) are available however studies on the structurally related analogue substances Ethylene distearate (CAS No. 627-83-8) and Glycol monostearate (CAS No. 111-60-4) are available. The studies from Ethylene distearate and Glycol monostearate after oral administration to rats, consistently showed no signs of systemic toxicity in acute oral toxicity tests, resulting in LD50 values greater than 2000 mg/kg bw (Wnorowski, 1991; Gloxhuber, 1982). Furthermore, available data on the subchronic oral toxicity of three structurally related analogue substances (Stearic acid, monoester with propane-1,2-diol, Fatty acids, C18 and C18 unsatd. epoxidized, ester with Ethylene glycol and Decanoic acid, mixed diesters with Octanoic acid and Propylene glycol, consistently showed no adverse systemic effects in animals resulting in NOAELs of 1000 mg/kg bw/day (Pittermann, 1991, 1993; Saatman, 1967). The lack of short- and long-term systemic toxicity of the surrogate substances 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.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO). On the basis of the following considerations, the dermal absorption of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) is considered to be low. Regarding the molecular weight range of 388.58 - 683.1 g/mol and a calculated octanol/water partition coefficient of 5.73-15.57 (Müller, 2011) in combination with the low water solubility, a low dermal absorption rate is anticipated. Log Pow values above 6, will slow the rate of transfer between the stratum corneum and the epidermis and therefore absorption across the skin will be limited and uptake into the stratum corneum itself is slow.

Furthermore, QSAR calculation using EPIwebv4.1 confirmed this assumption, resulting in a low Dermal Flux of 1.1E-4 to 8.73E-10 mg/cm2 per h. In addition, available data on acute dermal toxicity of three analogue substances (Fatty acids, C18 and C18 unsatd. epoxidized, ester with Ethylene glycol (CAS 151661-88-0); Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) and Octanoic acid ester with 1,2-propanediol, mono- and di- (CAS 31565-12-5, Potokar, 1989; Mürmann, 1992a,b) showed no systemic toxicity. Moreover, different studies with the test substance showed no sensitizing effects or signs of systemic toxicity (Steiling, 1991a,b; Pittermann, 1994).

Overall, taking into account the physico-chemical properties Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO), the QSAR calculation and available toxicological data on several structurally related substances and the test material, the dermal absorption potential of the substance is anticipated to be low.

Inhalation

Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) has a very low vapour pressure of < 0.001 Pa at 20 °C thus being of low volatility (Nagel, 2012). 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 significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated substance is sprayed. In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2008). For the solid test material a D50 value of 500 µm was determined, thus being too large to be inhaled. In addition, the acute inhalation studies with the category member Decanoic acid, mixed esters with octanoic acid and Propylene glycol (CAS No. 68583-51-7) in rats and guinea pigs did not show any mortality or systemic toxicity after inhalative exposure (Re, 1978a,b).

The lack of short-term systemic toxicity of the surrogate substance 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. Based on the physicochemical properties of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) and data on acute inhalation toxicity of the category member Decanoic acid, mixed esters with octanoic acid and Propylene glycol the absorption via the lung is expected to be not higher than after oral absorption.

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, 2008).

As the parent compound Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) will be hydrolysed to a substantial amount before absorption as discussed above, the distribution of intact substance Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) is not solely relevant but the distribution of the breakdown products of hydrolysis, as well. As the parent compound has a high logPow it is likely to be distributed into cells. The fraction of ester absorbed unchanged will probably undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). Thus, the absorbed products of hydrolysis, the free fatty acids and Triethylene glycol are the most important components to assess. The alcohol component has a low molecular weight (150.17 g/mol) and high water solubility (log Pow = -1.24/-1.9; IPCS, 1996). Based on its physico-chemical properties Triethylene glycol will be distributed within the body. Substances with high water solubility like triethylene glycol do not have the potential to accumulate in adipose tissue due to their low log Pow. Like all medium and long chain fatty acids, Palmitic and Stearic acid may be re-esterified with Glycerol into triacylglycerides (TAGs) and transported via chylomicrons. Via these transport vehicles, fatty acids are transported via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994).

Therefore, the intact parent compound Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) is not assumed to be accumulated to a high amount as hydrolysis takes place before absorption or during liver metababolism. However, accumulation of the fatty acids in triglycerides in adipose tissue or the incorporation into cell membranes is possible as further described in the metabolism section below. At the same time, the free fatty acids may also be used for energy generation. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolised and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism. In summary, the available information on Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) indicate that no significant bioaccumulation of the parent substance in adipose tissue is expected. The breakdown products of hydrolysis, Triethylene glycol and Palmitic and Stearic acid will be distributed in the organism.

Metabolism

Metabolism of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) occurs initially via enzymatic hydrolysis of the ester resulting in the corresponding free fatty acids Pamitic and Stearic acid and Triethylene glycol.

In-vivo studies in rats with fatty acid esters containing one, two (like Ethylene glycol esters) or three ester groups showed that they are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson und Volpenheim, 1968; 1972). Furthermore, the in-vivo hydrolysis of Propylene glycol distearate (PGDS), a structurally related Glycol ester, was studied using isotopically labeled PGDS (Long et al., 1958). Oral administration of PGDS showed intestinal hydrolysis into Propylene glycol monostearate, Propylene glycol and Stearic acid. In addition, the conversion of the structurally related ester Triethylene glycol diacetate into the parent glycol Triethylene glycol has been shown in vivo in rats (NTIS, 1984).

In addition, simulation of intestinal metabolism of the different esters of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO), using the OECD QSAR ToolBox v.2.3.0, resulted in 99-142 intestinal metabolites including the free fatty acids Palmitic and Stearic acid supporting the metabolism pathway of intestinal hydrolysis, as well. Following hydrolysis, absorption and distribution of the alcohol component, triethylene glycol has been shown to be excreted via the urine to a high extent without further metabolisation (NTIS, 1984). Another metabolism and excretion study performed in rats with Triethylene glycol showed that both the unmetabolized and the oxidized form (a monocarboxylic acid) were excreted (McKennis, 1962). Following absorption into the intestinal lumen, fatty acids like Palmitic and Stearic acid are re-esterified with Glycerol to triacylglycerides (TAGs) and included into chylomicrons for transportation via the lymphatic system and the blood stream to the liver. An important metabolic pathway for fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into Acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic Acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1970; Stryer, 1994). Using the OECD QSAR ToolBox 2.3.0, liver metabolism simulation resulted in 31-38 metabolites including different metabolites of beta oxidation.

Excretion

Based on the metabolism described above the fatty acids will be metabolised in the body to a high extent. In-vivo studies with Triethylene glycol diacetate showed, that no unchanged ester was found in urine or feces whereas a large dose was convereted to the parent glycol Triethylene glycol, and was excretd via the urine (NTIS, 1984). In a further study with radiolabeled Triethylene glycol in rats and rabbits a high degree of urinary exretion of the unchanged Triethylene glycol is described. The total elimination via urine, feces and expired air during a 5-day period following a single oral dose of 22.5 mg was 91-98% (McKennis, 1962).

The fatty acid components will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994). Therefore, the fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above.

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