1,2,3-propanetriyl triisooctadecanoate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), an assessment of the toxicokinetic behaviour of the target substance 1,2,3-propanetriyl triisooctadecanoate (CAS No. 26942-95-0) is 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 physicochemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2012) and taking into account further available information from a source substance. There are no studies available in which the toxicokinetic behaviour of 1,2,3-propanetriyl triisooctadecanoate was investigated.

The substance 1,2,3-propanetriyl triisooctadecanoate is a triester of glycerol and isooctadecanoic (C18, stearic) acid.

1,2,3-propanetriyl triisooctadecanoate has a molecular weight of 891.5 g/mol. The substance is a liquid (viscous) at 20 °C with a melting point of -36 °C at normal pressure (Mir, 2014), water solubility of 3.1 μg/L at 20 °C (Frischmann, 2014), log Pow > 10 at 25 °C (Birkhofer, 2014) and vapour pressure of < 0.0001 Pa at 20 °C (Nagel, 2014).

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

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2012).

The physicochemical characteristics (log Pow and water solubility) of the substance and the molecular weight are in a range that indicate poor absorption from the gastrointestinal tract following oral ingestion. It is unclear to what degree micellar solubilisation will affect the absorption rate of the substance.

The indications that the substance has low oral absorption and/or low acute toxicity are supported by the available data on acute and repeated dose oral toxicity. When rats or mice were administered a single dose of 2000 mg/kg bw/day 1,2,3-propanetriyl triisooctadecanoate , there was no mortality, no effects on body weight, and no lesions were noted at necropsy (Bouffechoux, 1996; Jones, 1987; Saboureau, 1989). No adverse effects were observed in two subacute repeated dose toxicity studies (Combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, according to OECD TG 422) performed with the source substances Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) and 2,3-dihydroxypropyl oleate (CAS 111-03-5) at dose levels up to and including 1000 mg/kg bw/day (Otterdijk, 2010; Yamaguchi, 2005). In a subchronic (90-day) repeated dose toxicity study performed with the source substance Castor oil (CAS 8001-79-4) in rats and mice, no effects were noted at the highest dose levels of more than 5500 mg/kg bw/day for rats and more than 15.000 mg/kg bw/day in mice, respectively (NTP, 1992).

The potential of a substance to be absorbed in the GI-tract may be influenced by several parameters, like: chemical changes taking place in GI-fluids, as a result of metabolism by GI-flora, by enzymes released into the GI-tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2012).

It is well-accepted knowledge that mono-, di- and triglycerides (e.g. from dietary fat) undergo hydrolysis by lipases (a class of ubiquitous carboxylesterases) prior to absorption (Lehninger et al., 1998). There is sufficient evidence to assume that mono-, di- and triglycerides in general will likewise undergo enzymatic hydrolysis in the GI-tract as the first step in their absorption, distribution, metabolism and excretion (ADME) pathways as summarised below.

In the gastrointestinal tract, gastric and intestinal (pancreatic) lipase activities are the most important. Triglycerides are hydrolysed by gastric and pancreatic lipases with high specificity for the sn1- and sn3-positions. For the remaining monoester at the sn2-position (2-monoacylglycerol), there is evidence that it can either be absorbed as such by the intestinal mucosa or isomerize to 1-monoacylglycerol, which can then be hydrolysed. The rate of hydrolysis by gastric and intestinal lipases depends on the carbon chain length of the fatty acid moiety. Thus, triesters of short-chain fatty acids are hydrolysed more rapidly and to a larger extent than triesters of long-chain fatty acids (Barry et al., 1967; Cohen et al., 1971; Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1964, 1966, 1968; WHO, 1967, 1975). In a recent study conducted with the substance Glycerides, castor-oil-mono, hydrogenated, acetates (CAS No. 736150-63-3), rapid ester hydrolysis in intestinal fluid simulant was confirmed (Jensen, 2002).

1,2,3-propanetriyl triisooctadecanoate is therefore predicted to be enzymatically hydrolysed to glycerol and isooctadecanoic (stearic, C18) acid.

Following hydrolysis, the resulting products (free glycerol, free fatty acids and (in the case of di- and triglycerides) 2-monoacylglycerols) are absorbed by the intestinal mucosa. Within the epithelial cells, triglycerides will be reassembled, primarily by re-esterification of absorbed 2-monoacylglycerols. The free glycerol is readily absorbed independently of the fatty acids and little of it is re-esterified. The absorption of short-chain fatty acids can begin already in the stomach. This is because, in general, for intestinal absorption short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. However, the absorption rate of saturated long-chain fatty acids is increased if they are esterified at the sn2-position of glycerol (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964). Recently a study was conducted with 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester, serving as surrogate for the substance Glycerides, castor-oil-mono, hydrogenated, acetates (CAS No. 736150-63-3) to investigate the pharmacokinetics, tissue distribution, excretion and mass balance of radioactivity in rats after a single oral dose of the test material (St-Pierre, 2004). The results of the study show that the test material, specifically the fatty acid moiety, was readily absorbed from the gastrointestinal tract, systemically distributed and metabolised. Based on the reported data on mass balance of radioactivity, the absorption degree was higher than 80%.

In conclusion, based on the available information, the physicochemical properties and molecular weight of 1,2,3-propanetriyl triisooctadecanoate suggest poor oral absorption. However, the substance is predicted to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products rather than the parent substance is likely. The absorption rate of the hydrolysis products is expected to be high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. 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. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2012).

1,2,3-propanetriyl triisooctadecanoate is a liquid, which favours dermal absorption. However, other physicochemical properties (log Pow and water solubility) and the molecular weight are in a range that indicate a low absorption rate through the skin.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) by applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp is thus 0.0688 cm/h. Considering the water solubility (3.1 μg/cm³), the dermal flux is estimated to be ca. 0.0061 μg/cm²/h.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2012).

The available data provide no indications for skin irritating effects of 1,2,3-propanetriyl triisooctadecanoate in rabbits (Bouffechoux, 1996; Jones, 1987; Saboureau, 1989) and no indications for skin sensitisation in guinea pigs or humans (Jones, 1987; Tanabe, 1999). Furthermore, none of the target substances are considered to be skin irritating or skin sensitising either, since the results of the available studies do not meet the criteria for the corresponding classification according to Regulation (EC) 1272/2008. Therefore, no penetration of the substance due to skin damage is expected.

Taking all the available information into account, the dermal absorption potential is considered to be very low.

Inhalation

1,2,3-propanetriyl triisooctadecanoate is a viscous liquid with low vapour pressure (< 0.0001 Pa at 20 °C), and therefore low volatility. Therefore, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited (ECHA, 2012). However, the substance may be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed.

Absorption after oral administration of the substance is mainly driven by enzymatic hydrolysis of the ester bond to the respective metabolites and subsequent absorption of the breakdown products. Therefore, for effective absorption in the respiratory tract enzymatic hydrolysis in the airways would be required, and the presence of esterases and lipases in the mucus lining fluid of the respiratory tract would be important. Due to the physiological function of enzymes in the GI-tract for nutrient absorption, esterase and lipase activity in the lung is expected to be lower in comparison to the gastrointestinal tract. Therefore, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to happen at a lower rate. The molecular weight, log Pow and water solubility indicate that the substance may be absorbed across the respiratory tract epithelium by micellar solubilisation to a certain extent. However, low water solubility (3.1 μg/L) does restrict the diffusion/dissolving into the mucus lining before reaching the epithelium, and it is not clear which percentage of the inhaled aerosol could be absorbed as the ester. 

An acute inhalation toxicity study was performed with the read-across substance Glycerides, mixed decanoyl and octanoyl (CAS 73398-61-5), in which rats were exposed nose-only to > 1.86 mg/L of an aerosol for 4 hours (Reminghaus, 1976). No mortality occurred and no toxicologically relevant effects were observed. Thus, the test substance is not acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption.

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, also taking into consideration the potentially increased absorption as a consequence of hydrolysis of the ester.

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).

As discussed under oral absorption, mono-, di- and triesters of glycerol undergo enzymatic hydrolysis in the gastrointestinal tract prior to absorption. Therefore, an assessment of distribution and accumulation of the hydrolysis products is considered more relevant.

Absorbed glycerol is readily distributed throughout the organism and it can be re-esterified to form endogenous triglycerides, be metabolised and incorporated into physiological pathways, or be excreted via the urine. After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Fatty acids of carbon chain length ≤ 12 may be transported directly to the liver via the portal vein as the free acid bound to albumin, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are likewise taken up by muscle and oxidized to derive energy or they are released into the systemic circulation and returned to the liver, where they are metabolised, stored or re-enter the circulation (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1998; NTP, 1994; Stryer, 1996; WHO, 2001).

There is a continuous turnover of stored fatty acids, as they are constantly metabolised to generate energy and then excreted as CO2. Accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism.

In a study performed by St-Pierre (2004) with 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester (surrogate of Glycerides, castor-oil-mono, hydrogenated, acetates (CAS No. 736150-63-3)), the systemic distribution of the radiolabelled material was assessed in rats. Radioactivity was detected in all tissues and organs sampled (adipose tissue, gastrointestinal tract and content, kidneys and adrenals, liver, thymus and the remaining carcass) with the highest levels recovered in the gastrointestinal tract, liver and the remaining carcass. This shows that the substance was extensively absorbed from the GI-tract and distributed. Due to excretion and absorption of the radiolabelled material, the radioactivity content in the gastrointestinal tract decreased rapidly from the 1-hr time point over the course of the study (168 h). This was similar for the radioactivity recovered in liver, which peaked at the 24-hr time point before decreasing gradually. The radioactivity found in the carcasses was nearly constant at the selected time points (app. 7%), indicating that the radiolabelled material may have been distributed to other tissues than the ones selected for analyses. The recovery of the radioactivity in excreta was 109% 72 hours after administration, with the greatest amount of radioactivity eliminated via CO2 (app. 77%). Based on the results of this study, no bioaccumulation potential was observed for 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester.

Metabolism

Glycerol can be metabolised to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which can then be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Fatty acids are degraded by mitochondrial β-oxidation which takes place in the most animal tissues and uses an enzyme complex for a series of oxidation and hydration reactions resulting in the cleavage of acetate groups in form of acetyl CoA. The alkyl chain length is reduced by 2 carbon atoms during each β-oxidation cycle. The complete oxidation of unsaturated fatty acids such as oleic acid requires an additional isomerisation step. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates and to be metabolised to a large extent by ω-oxidation. Each two-carbon unit resulting from β-oxidation enters the citric acid cycle as acetyl CoA, through which they are completely oxidized to CO2. Acetate, resulting from hydrolysis of acetylated glycerides, is readily absorbed and will enter into the physiological pathways of the body and can be utilized in oxidative metabolism or in anabolic syntheses (CIR, 1983, 1987; IOM, 2005; Lehninger, 1998; Lippel, 1973; Stryer, 1996; WHO, 1967, 1974, 1975, 2001).

Excretion

The fraction of 1,2,3-propanetriyl triisooctadecanoate that is not hydrolysed in the gastrointestinal tract, will be excreted via the faeces.

In general, the hydrolysis products glycerol and fatty acids are catabolised entirely by oxidative physiologic pathways, ultimately leading to the formation of carbon dioxide and water. Glycerol is a polar molecule and can readily be excreted via the urine. Small amounts of ketone bodies resulting from the oxidation of fatty acids are excreted via the urine (Lehninger, 1998; IOM, 2005; Stryer, 1996).

In rats given a single dose of 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester at 5000 mg/kg bw, the mean total recovery of radioactivity in the excreta of the 72 h period post-dose was 108.5% of the dose (urine, 6.5%; faeces, 24.5%; CO₂, 77%; and cage wash, 0.5%). Most of the recovered radioactivity (97.5%, of which 71% CO₂, 21% faeces, 5.5% urine) was excreted up to and including the 24 h post-dose sampling time point (St-Pierre, 2004). The results confirm that glycerides, including 1,2,3-propanetriyl triisooctadecanoate, are mainly excreted as CO2 in the expired air as a result of metabolism.

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

 

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