Glycerol monomyristate

Endpoint summary

Description of key information

Glycerol monomyristate (CAS 27214-38-6) is expected to be readily absorbed via the oral route after enzymatic hydrolysis in the gastrointestinal tract into glycerol and myristic acid, as hydrolysis facilitates the absorption. The fatty acid will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; 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. Absorption via the dermal and inhalation route of exposure is expected to be negligible. The excretion will mainly occur as carbon dioxide in expired air. Non-metabolised glycerol is a polar molecule and can readily be excreted via the urine. No bioaccumulation is expected to take place, as excess triglycerides are stored and used as the energy need rises.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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, 2017), an assessment of the toxicokinetic behaviour of the registration substance glycerol monomyristate (CAS 27214 -38 -6) 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, 2017) and taking into account further available information from source substances. There are no studies available in which the toxicokinetic behaviour of glycerol monomyristate was investigated.

Glycerol monomyristate is a UVCB substance containing aliphatic mono, di and triesters of glycerol with myristic acid as majoritarian. It has a molecular weight of 302.45 - 512.81 g/mol. Glycerol monomyristate is a solid at 20 °C with a melting point of 53.5 °C at 101 325 Pa, measured water solubility of < 12.1 µg/L at 20 °C and estimated vapour pressure of 6.7E-06 Pa at 25 °C. The log Pow was estimated to be 4.66 and >10 (refer to IUCLID section 4.7).

 

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, 2017).

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. Solids must be dissolved before absorption; the degree depends on the water solubility (Aungst and Shen, 1986; ECHA, 2017).

The molecular weight of glycerol monomyristate being less than and around 500 g/moL favours uptake, while the negligible water solubility (< 12.1 µg/L) and high log Pow of > 4 suggests poor absorption from the GI-tract following oral ingestion. Micellar solubilisation may have an effect on the overall absorption rate of the substance.

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 and by enzymes released into the GI-tract. These changes will alter the physico-chemical characteristics of the substance and therefore predictions based on the physico-chemical characteristics of the parent substance may in some cases no longer apply or should be adjusted (ECHA, 2017).

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 of importance. 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. (Cohen, 1971; Greenberger, 1966; IOM, 2005; Mattson and Volpenhein, 1964, 1968). The speed of hydrolysis of esters of primary n-alcohols containing from 1 to 18 carbon atoms with fatty acids containing from 2 to 18 carbon atoms was found to depend on both, the chain length of either the alcohol or acid. With respect to fatty acid moiety, esters of C12 and C4 were hydrolysed at the most rapid rate. With respect to alcohol moiety C7 was hydrolysed most rapidly (Mattson and Volpenhein, 1969).

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).

The available data on acute and repeated dose oral toxicity of either the registration substance and/or structural analogues support a conclusion of no/low toxicity. When mice were administered a single dose of 2000 mg/kg bw glycerol monomyristate, there was no mortality, no adverse clinical signs and no adverse effects on body weight (please refer to IUCLID section 7.2.1). 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, please refer to IUCLID section 7.5.1) 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.

Glycerol monomyristate is predicted to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products, glycerol and myristic acid, rather than the parent substance. The absorption rate of the hydrolysis products is expected to be high. In conclusion, the available information indicates a high oral absorption rate of the hydrolysis products of glycerol monomyristate.

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, 2017).

Glycerol monomyristate is a solid, which does not necessarily favour dermal absorption. Furthermore, the negligible water solubility, high log Pow and molecular weight are in ranges that indicate a negligible to low absorption rate through the skin.

No local or systemic effects were observed in the acute dermal toxicity study performed with two 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 a dose of 2000 mg/kg bw, respectively, (please refer to IUCLID section 7.2.3). 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 glycerol monomyristate in rabbits. No skin effects were noted in the acute dermal toxicity study at the limit dose of 2000 mg/kg bw, performed with two 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), respectively (please refer to IUCLID section 7.2.3). Also, the available skin sensitisation studies with two source substances, Glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1) and C12: Glycerides, C8-21 and C8-21-unsatd., mono- and di-, acetates (CAS 97593-30-1), were negative. Therefore, no enhanced penetration of the substance due to skin damage is expected. Overall, the dermal absorption potential is considered to be low/negligible.

 

Inhalation

Glycerol monomyristate is a solid with negligible low vapour pressure (6.97E-06 Pa at 25 °C), and therefore is of negligible fugacity. 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, 2017). 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. Based on the uses information, the potential for exposure via the inhalation route is considered to be low/negligible.

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical 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, 2017).

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 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 within the body. 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 hrs). 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 >95% 72 hrs 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. This conclusion is considered to be applicable to the target substance, as well due to structural similarities and common functional groups.

 

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. 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).

There is no indication that glycerol monomyristate is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) using source substances were all negative, with and without metabolic activation. The result of the skin sensitisation studies performed in guinea pigs and humans using source substances were likewise negative.

 

Excretion

The non-absorbed fraction of glycerol monomyristate 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 very high (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 hrs post-dose sampling time point. The results confirm that glycerides, including glycerol monomyristate, 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 6, section 13) and within the CSR.

 

References

Aungst B. and Shen D.D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

Cohen, M. et al. (1971). Lipolytic activity of human gastric and duodenal juice against medium and long chain triglycerides. Gastroenterology 60(1):1-15.

Cosmetic Ingredient Review Expert Panel (CIR) (1983). Final report on the safety assessment of Isostearic acid.J. of the Am. Coll. of Toxicol.2(7):61-74

Cosmetic Ingredient Review Expert Panel (CIR) (1987) Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid.J. of the Am. Coll. of Toxicol.6(3):321-401.

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 2.0, November 2014. European Chemicals Agency, Finland.

Greenberger, N.J. et al. (1966). Absorption of medium and long chain triglycerides: factors influencing their hydrolysis and transport. J Clin Invest 45(2):217-27.

Institute of the National Academies (IOM) (2005). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). The National Academies Press. http://www.nap.edu/openbook.php?record_id=10490&page=R1

Johnson, R.C. et al. (1990). Medium-chain-triglyceride lipid emulsion: metabolism and tissue distribution. Am J Clin Nutr 52(3):502-8.

Johnson W Jr; Cosmetic Ingredient Review Expert Panel. (2001). Final report on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate. Int J Toxicol. 2001;20 Suppl 4:61-94.

Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1998).Prinzipien der Biochemie. 2. Auflage. Heidelberg Berlin Oxford: Spektrum Akademischer Verlag.

Lippel, K. (1973). Activation of branched and other long-chain fatty acids by rat liver microsomes. Journal of Lipid Research 14:102-109.

Mattson, F.H. and Volpenhein, R.A. (1964). The digestion and absorption of triglycerides. J Biol Chem 239:2772-7.

Mattson, F.H. and Volpenhein, R.A. (1966). Carboxylic ester hydrolases of rat pancreatic juice. J Lipid Res 7(4):536-43.

Mattson, F.H. and Volpenhein, R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lipid Res 9(1):79-84.

National Toxicology Program (NTP) (1994) Comparative toxicology studies of Corn Oil, Safflower Oil, and Tricaprylin (CAS Nos. 8001-30-7, 8001-23-8, and 538-23-8) in Male F344/N Rats as vehicles for gavage. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr426.pdf (2011-12-19). Report No.: C62215. Owner company: U.S. Department of Health and Human Services, Public Health Services, National Institutes of Health.

Stryer, L. (1996). Biochemie. 4. Auflage. Heidelberg Berlin Oxford: Spektrum Akademischer Verlag.

WHO (1967). Toxicological Evaluation of Some Antimicrobials, Antioxidants, Emulsifiers, Stabilizers, Flour-Treatment Agents, Acids and Bases: Acetic Acid and Fatty Acid Esters of Glycerol. FAO Nutrition Meetings Report Series No. 40A, B, C.

WHO (1974). Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents: Acetic Acid and Its Potassium and Sodium Salts. WHO Food Additives Series No. 5.

WHO (1975). Toxicological evaluation of some food colours, thickening agents, and certain other substances: Triacetin. WHO Food Additives Series No. 8.

WHO (2001). Safety Evaluation of Certain Food Additives and Contaminants: Aliphatic Acyclic Diols, Triols, and Related Substances. WHO Food Additives Series No. 48.