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Key value for chemical safety assessment

Additional information

There are no studies available in which the toxicokinetic behaviour of glycerides, C16-18 and C18-unsaturated, mono-and di-citrates (CAS 91052-16-3) has been investigated. 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, 2014), assessment of the toxicokinetic behaviour of the substance 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 relevant Guidance (ECHA, 2014) and taking into account further available information from structural analogous substances.

The substance glycerides, C16-18 and C18-unsaturated, mono-and di-citrates (UVCB) is a complex mixed ester of glycerol, citric acid and linear, even-numbered fatty acids with chain lengths ranging from C16 (hexadecanoic acid) to C18 (octadecanoic acid), also including unsaturated C18:1 fatty acids.

Glycerides, C16-18 and C18-unsaturated, mono-and di-citrates has a molecular weight range of 330.51 – 1760.25 g/mol. The substance is a liquid at 20 °C with a melting point of -12.6 to 26.6 °C at 1013 hPa (Du Pont, 2016) and a water solubility of 1.86E-37 – 1.2721 mg/L at 25°C (Műller, 2016). A log Pow of > 5.63 – 36.44 (Műller, 2016) and a vapour pressure of 1.35E-50 - 1.37E-08 Pa Pa at 20 °C (Ehler, 2016) were predicted for the substance.

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, 2014).

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) which would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2014).

Log Pow of > 4 and poor water solubility suggest that the components of Glycerides, C16-18 and C18-unsaturated, mono-and di-citrates are favorable for absorption by micelullar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), poorly soluble in water (1 mg/L or less).

 

The potential of a substance to be absorbed in the GI tract may be influenced by 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 no longer apply (ECHA, 2014).

It is well-accepted knowledge that triglycerides (e.g. from dietary fat) undergo hydrolysis by lipases (a class of ubiquitous carboxylesterases) prior to absorption; and there is sufficient evidence to assume that all of the mono-, di- and triglycerides will 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., 1966; 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 structurally related substance Glycerides, castor-oil-mono, hydrogenated, acetates (CAS 736150-63-3), rapid ester hydrolysis in intestinal fluid simulant was confirmed (Jensen, 2002).

The substance glycerides, C16-18 and C18-unsaturated, mono-and di-citrates is therefore anticipated to be enzymatically hydrolysed to glycerol, citric acid and even-numbered fatty acids ranging from C16 (hexadecanoic acid) to C18 (octadecanoic acid) as well as the monounsaturated C18:1 fatty acids.

 

Following hydrolysis, the resulting products free glycerol, free fatty acids, citric acid and (in the case of di and triglycerides) 2-monoacylglycerols are absorbed by the intestinal mucosa. Within the epithelial cells, triglycerides are reassembled, primarily by re-esterification of absorbed 2-monoacylglycerols. Thus, free glycerol is readily absorbed independently of the fatty acids and little of it is re-esterified. As for hydrolysis, the absorption rate of free fatty acids is chain length-dependent. The absorption of short-chain carboxylic acids can therefore begin already in the stomach. In general, for intestinal absorption short-chain or unsaturated carboxylic acids are more readily absorbed than long-chain, saturated fatty acids. However, the absorption 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 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 showed 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, absorption was higher than 80%. A high rate of absorption was also demonstrated in a feeding study with soybean oil in rats, resulting in oral absorption of 95 -98% when administered at 17% of the diet (Nolen, 1972). Furthermore, for palmitic acid it was shown that absorption rate was depending on the form in which it was fed, i.e. absorption was greatest when palmitic acid was fed as β-palmitoyl diolein, and least when it was fed as the free acid (Mattson and Volpenhein, 1962).

In conclusion, based on the available information, the physicochemical properties and molecular weight of glycerides, C16-18 and C18-unsaturated, mono-and di-citrates suggest low oral absorption. However, the substance is anticipated 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 considered to be moderate/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, 2014).

The physicochemical properties (log Pow and water solubility) of the substance and the molecular weight are in a range suggestive of low absorption through the skin.

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, 2014).

No data is available on skin irritation or skin sensitisation for the substance itself. However, data are available for the structurally related substances glycerides, C14-18 and C16-22-unsatd, mono- and di- (CAS 91744-13-7) and glyceryl citrate/lactate/linoleate/oleate (CAS 91744-23-9), which caused slight, but fully reversible skin irritation reactions in rabbits. Furthermore, skin sensitisation studies in guinea pigs did not show any skin sensitisation reactions for the structurally related substances glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1) and glycerides, C16-18 mono-, di- and tri-, hydrogenated, citrates, potassium salts (CAS 91744-38-6). Based on the available studies on the structural analogue substances, glycerides, C16-18 and C18-unsaturated, mono-and di-citrates is not expected to cause any skin irritation and sensitisation reactions, which might enhanced penetration of the substance due to local skin damage and thus increase dermal absorption.

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

Inhalation

Glycerides, C16-18 and C18-unsaturated, mono-and di-citrates is a liquid with low vapour pressure (1.35E-50 to 1.37E-08 Pa), thus being of low volatility. 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 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 (ECHA, 2014).

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive that absorption across the respiratory tract epithelium by micellar solubilisation is possible.

Overall, systemic bioavailability 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, 2014).

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

Absorbed glycerol is readily distributed throughout the organism and can be re-esterified to form endogenous triglycerides, be metabolised and incorporated into physiological pathways or be excreted in 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 (Bergström, 1951). Fatty acids of carbon chain length ≤ 12 may be transported as the free acid bound to albumin directly to the liver via the portal vein, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon 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 for energy or they are released into the systemic circulation and returned to the liver (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1998; NTP, 1994; Stryer, 1996; WHO, 2001; Matulka, 2009).

Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.

In the study 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 736150-63-3)), systemic distribution of the radiolabelled material was confirmed 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 highest levels recovered in the gastrointestinal tract, liver and the remaining carcass. Due to excretion and absorption of the radiolabelled material, the radioactivity content in the gastrointestinal tract decreased rapidly over the course of the study (168 h). This was similar for the radioactivity recovered in liver, whereas the radioactivity found in the carcasses was nearly constant at the selected time points, indicating that the radiolabelled material may have been distributed to other tissues than the ones selected for analyses. Based on the results of this study, no bioaccumulation potential was observed for 12-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 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 thus reduced by 2 carbon atoms in 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). Thus 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 feeds naturally into 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; Adolph, 1999). Furthermore, a similar path as the acetate is expected for citric acid in the body. Citric acid, resulting from the hydrolysis glycerides, C16-18 and C18-unsaturated, mono-and di-citrates, will be readily absorbed and will feed naturally into physiological pathways of the body and will be utilized in the citric acid cycle (tricarboxylic acid cycle (TCA)).

Excretion

As far as glycerides are not hydrolysed in the gastrointestinal tract, they are excreted in the faeces.

In general, the hydrolysis products glycerol and fatty acids are catabolised entirely by oxidative physiologic pathways ultimately leading to the production of carbon dioxide and water. Glycerol, being a polar molecule can readily be excreted in 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%) was excreted by 24 h post dose (St-Pierre, 2004). The results thus confirm that Glycerides 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 the CSR.

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