Dodecanoic acid, ester with 1,2,3-propanetriol

Endpoint summary

Description of key information

The target substance Dodecanoic acid, ester with 1,2,3-propanetriol (CAS 37318-95-9) is expected to be hydrolysed within the gastrointestinal tract and the hydrolysis products are predicted to be readily absorbed via the oral route. Potential for absorption via inhalation and dermal route is predicted to be low. 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 can be re-esterified to form endogenous triglycerides. The major metabolic pathway for linear and branched fatty acids is the β-oxidation pathway for energy generation, while alternatives are the ω-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.

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 target substance Dodecanoic acid, ester with 1,2,3-propanetriol (CAS 37318-95-9) 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 Dodecanoic acid, ester with 1,2,3-propanetriol was investigated.

Dodecanoic acid, ester with 1,2,3-propanetriol (CAS 37318-95-9) is a UVCB substance. The substance contains primarily monoester and diester of glycerol and dodecanoic acid, with some triester present. Dodecanoic acid, ester with 1,2,3-propanetriol has a molecular weight ranging from 274.4 to 639 g/mol. The substance is a solid with a paste-like consistency. It has a melting point of 45 °C at 1013 hPa, an estimated water solubility of > 1.63E-03 mg/L and < 6.0 mg/L at 20 °C and an estimated vapour pressure of 7.76E-7 at 20 °C. The log Pow was estimated to be 3.67.

 

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; 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, 2017).

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.No mortality occurred and no toxicologically relevant adverse effects were observed in the acute oral toxicity studies performed with the source substances 2,3-dihydroxypropyl laurate (CAS 142-18-7), Glycerol tristearate (CAS 555-43-1) and Glycerides, C12-18 di- and tri- (CAS 91744-28-4). The LD50 value was > 2000 mg/kg bw (Key, 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 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 (Key, 2010; Supp., 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 on the physico-chemical characteristics of the parent substance may in some cases no longer apply (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.

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 since main hydrolysis product FFA 180ac increased to 27.7% within 1 h (Key, 2002).

Dodecanoic acid, ester with 1,2,3-propanetriol is therefore predicted to be enzymatically hydrolysed to glycerol and dodecanoic 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). A study has been conducted with 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester, to investigate the pharmacokinetics, tissue distribution, excretion and mass balance of radioactivity in rats after a single oral dose of the test material (Key, 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 Dodecanoic acid, ester with 1,2,3-propanetriol 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. 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).

Dodecanoic acid, ester with 1,2,3-propanetriol is a solid, which limits dermal absorption. Additionally, the molecular weight indicates a low or limited absorption rate through the skin. The log Pow and the upper end of the water solubility range for the monoester falls within the range that is favourable for dermal 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 in the range of 0.000112 to 0.0124 cm/h for the mono-, di- and triester, using the log Pow of 3.67. Considering the water solubility (< 6.0 mg/L at 20 °C) the dermal flux is estimated to be approximately 0.0375 - 0.396 μg/cm²/h and the dermal absorption potential for the substance is predicted as 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 Glycerol triheptanoate (CAS 620-67-7) at doses of 2000 mg/kg bw (WoE, 2010; WoE, 1993). This indicates low dermal absorption rate and/or low acute toxicity.

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, 2017).

No adverse local or systemic effects were observed in skin irritation studies in rabbits performed with the source substances Glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1), Glycerol trilaurate (CAS 538-24-9) and Glycerides, mixed decanoyl and octanoyl (CAS 73398-61-5).The result of the skin sensitisation tests (Buehler and GMPT) performed with source substancesGlycerol tristearate (CAS 555-43-1), Glycerol triheptanoate (CAS 620-67-7) and Glycerides and C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1) was negative (WoE, 1998; WoE, 1993; WoE, 1985).Furthermore, the prediction for the main constituents of substance in the OECD QSAR Toolbox v3.4 using the profiler ‘Skin sensitisation (Danish EPA data base)’ was negative (WoE, 2017). Therefore, no enhanced penetration of the substance due to skin damage is expected.

Taking all the available information into account, the dermal absorption potential of Dodecanoic acid, ester with 1,2,3-propanetriol is considered to be low.

Inhalation

Dodecanoic acid, ester with 1,2,3-propanetriol is a paste -like solid with low vapour pressure (7.76E-7 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, 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).

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 source 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.

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, 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 or 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 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 (Key, 2004). 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.

The target substance is considered to also be extensively distributed to tissues and organs, as was shown for the source substance, 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 mitochondrialβ-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 eachβ-oxidation cycle Each two-carbon unit resulting fromβ-oxidation enters the citric acid cycle as acetyl-CoA, through which they are completely oxidized to CO2. 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 byω-oxidation. 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 Dodecanoic acid, ester with 1,2,3-propanetriol 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 and micronucleus test in vivo) using source substances were consistently negative, with and without metabolic activation. The result of the skin sensitisation studies performed in guinea pigs and mice using source substances were likewise negative.

 

Excretion

The non-absorbed fraction of Dodecanoic acid, ester with 1,2,3-propanetriol 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%; 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 hours post-dose sampling time point (Key, 2004). The results confirm that glycerides, including Dodecanoic acid, ester with 1,2,3-propanetriol , are mainly excreted as CO2 in the expired air as a result of metabolism.

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.

Barry, R.J.C. et al. (1967). Handling of glycerides of acetic acid by small rat intestine in vitro. J. Physiol., 185, 667-683

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 3.0, June 2017. 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. (1962). Rearrangement of glyceride fatty acids during digestion and absorption. J Biol Chem 237:53-5.

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.

US EPA (2004).  Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) Interim.http://www.epa.gov/oswer/riskassessment/ragse/index.htm

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.