10-Undecenoic acid, monoester with 1,2,3-propanetriol

Endpoint summary

Description of key information

The target glyceryl undecylenate (CAS 123759-97-7) is expected to be hydrolysed and the hydrolysis products readily absorbed via the oral and inhalation route, and partly absorbed via the dermal route. The ester bonds will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and glycerol, which facilitates the absorption. The absorbed ester fraction will be hydrolysed mainly in the liver. The fatty acid will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; the absorbed glycerol is readily distributed throughout the organism and it can be re-esterified to form endogenous triglycerides. The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-pathway or direct conjugation to more polar products. The excretion will mainly be as CO₂ in expired air; with a smaller fraction excreted as conjugated molecules in the urine. Glycerol can likewise be metabolised and incorporated into physiological pathways. No bioaccumulation will take place, as excess triglycerides are stored and used as the energy need rises.

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, 2014), an assessment of the toxicokinetic behaviour of the target substance glyceryl undecylenate (CAS 123759-97-7) 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 and taking into account further available information from source substances. There are no studies available in which the toxicokinetic behaviour of glyceryl undecylenate was investigated.

Glyceryl undecylenate (CAS 123759-97-7) is a UVCB substance. The substance contains primarily monoester and diester of glycerol and undecylenic acid, with some triester present. Glyceryl undecylenate has a molecular weight range of 258.36 – 590.87 g/mol. The substance is a liquid at 20 °C with a melting point of ≤ 16 °C at normal pressure, water solubility of 8.5 - 182.5 µg/L at 20 °C (pH = 6.3) and estimated vapour pressure of < 0.0001 Pa at 20 °C. The log Pow was estimated to be 3.04, 7.92 and > 10 for the mono-, di, and triester respectively.

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; this mechanism is important 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, 2014).

The partition coefficient (log Pow) and the molecular weight range of the monoglyceride are in a range that indicate absorption from the gastrointestinal tract following oral ingestion is possible. It is unclear to what degree micellar solubilisation will affect the absorption rate of the substance, as it has low water solubility.

The available data on acute and repeated dose oral toxicity support a conclusion of no/low toxicity. When rats were administered a single dose of 5000 mg/kg bw glyceryl undecylenate, there was no mortality, no clinical signs and no effects on body weight (Catroux, 1988). 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 guideline 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).

The potential of a substance to be absorbed from the gastrointestinal tract may be influenced by several parameters, like chemical changes taking place in gastrointestinal fluids, as a result of metabolism by gastrointestinal flora, by enzymes released into the gastrointestinal 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, 2014).

In general, 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 gastrointestinal tract as the first step in their absorption, distribution, metabolism and excretion (ADME) pathways.

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 736150-63-3), rapid ester hydrolysis in intestinal fluid simulant was confirmed (Jensen, 2002).

Glyceryl undecylenate is therefore predicted to be enzymatically hydrolysed to glycerol and undecylenic 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 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. 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 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%.

The target substance glyceryl undecylenate 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. The double bond on the undecylenic acid moiety is not expected to affect the absorption rate.

In conclusion, the available information indicates that the hydrolysis products of glyceryl undecylenate will have a moderate-high oral absorption.

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. 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).

Glyceryl undecylenate is a liquid, which favours dermal absorption. However, the water solubility and molecular weight are in ranges that indicate a low or limited absorption rate through the skin. The log Pow for the monoester indicates that dermal absorption is likely, while the higher values for the di- and triester fall outside the range favourable for absorption.

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 calculated to be 0.00583 cm/h, using the lowest log Pow of 3.04. Considering the water solubility (≤ 0.183 μg/cm³), the dermal flux is estimated to be approximately 1.06⁻³ μg/cm²/h and the dermal absorption potential is predicted as very low.

No local or systemic effects were observed in acute dermal toxicity studies performed with the source substances Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) and Glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1) at doses of 2000 mg/kg bw (Mürmann, 1993; Potokar, 1985). 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).

The available data provide no indications for skin irritating effects of glyceryl undecylenate in rabbits (Catruox, 1988). No skin effects were noted in the acute dermal toxicity studies at the limit dose of 2000 mg/kg bw, performed with source substances glycerol tristearate (CAS 620-67-7) and Glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1) (Mürmann, 1993; Potokar, 1995). The result of the skin sensitisation tests (LLNA and GMPT) performed with source substances C12: Glycerides, C8-21 and C8-21-unsatd., mono- and di-, acetates (CAS 97593-30-1) and Glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 97593-30-1) was negative (Kästner, 1985; Vohr, 2008). Furthermore, no alerts for the mono- and diester of the target substance were predicted in the OECD QSAR Toolbox using the ‘Protein binding alerts for skin sensitisation’ in the OASIS v1.3 database (Nordheim, 2015, 2016). Therefore, no enhanced 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 low.

Inhalation

Glyceryl undecylenate is a liquid with low vapour pressure (< 0.0001 Pa at 20 °C), and therefore low volatility. 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, 2014). 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 increased 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 gastrointestinal tract for nutrient absorption, esterase and lipase activity/expression in the lung is expected to be lower in comparison to the gastrointestinal tract. Therefore, hydrolysis within the respiratory tract 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 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 target substance is not expected to be acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption based on these data.

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, 2014).

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, like the glycolysis pathway (Lehninger, 1998). 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 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 gastrointestinal 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 hours). 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 most animal tissues and uses an enzyme complex for a series of oxidation- and hydration reactions, resulting in the cleavage of acetate groups in the 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 undecylenic 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 non-absorbed fraction of glyceryl undecylenate 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. Non-metabolised 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 may be excreted via the urine, however, the major part of the fatty acids will enter an oxidative pathway as described above under ‘Metabolism’ (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 hour period post-dose was 108.5% of the dose (urine, 6.5%; faeces, 24.5%; CO_₂

77%; and cage wash, 0.5%). Most of the recovered radioactivity (97.5%, of which 71% CO_₂, 21% faeces, 5.5% urine) was excreted up to and including the 24 hours post-dose sampling time point (St-Pierre, 2004). The results confirm that glycerides, including glyceryl undecylenate, 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.