Branched and linear octadecanoic acid, esters with glycerol oligomers

Endpoint summary

Description of key information

Based on the available information, limited oral absorption of the parent substance is expected. Following enzymatic hydrolysis in the gastrointestinal tract, absorption of the hydrolysis products is expected to be high. Following dermal contact or inhalation, only low absorption potential is predicted.

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.

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.

Non-metabolised parent substance is expected to be excreted via the faeces, while the hydrolysis products glycerol and fatty acids are catabolised entirely by oxidative physiologic pathways, ultimately leading to the formation of carbon dioxide and water.

Key value for chemical safety assessment

Bioaccumulation potential:

low 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, 2014), an assessment of the toxicokinetic behaviour of the target substance Polyaldo 2-1-IS(CAS 73296-86-3) 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, 2014) and taking into account further available information from source substances. There are no studies available in which the toxicokinetic behaviour of the target substance has been investigated.

 

The substance Polyaldo 2-1-ISrepresents a mixture of mono- and diesters of di- and triglycerol esterified with isooctadecanoic (C18, stearic) acid.

Polyaldo 2-1-IShas a molecular weight ranging from 432.6 – 699.12 g/mol. The substance is a viscous liquid at 20 °C with a water solubility of< 0.03mg/L at 20 °C (Erler, 2016), a log Pow > 6.5 (Simon, 2016) and a vapour pressure of 3E-8 Pa at 20 °C (Wagner Rivas, 2016).

 

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

The physicochemical characteristics, especially the high log Pow and low water solubility are in a range that indicates poor absorption from the gastrointestinal tract following oral ingestion although a moderate water solubility is estimated for the test substance. However, the molecular weight of the smaller molecules may favour absorption from the GI-tract.

The indications that the substance has low oral absorption are supported by the available data on acute oral toxicity. When mice were orally exposed to a single dose of 5000 mg Isooctadecanoic acid, ester with oxybis[propanediol] (CAS 73296-86-3)/kg bw/day, no mortality was observed. Moreover, despite decreased activity which was noted in one male during the first three days after administration, no clinical signs indicative for systemic toxicity were observed. Furthermore, no lesions were noted at necropsy except a small testis observed in one male (Mallory, 1990). In addition, the analogue substance Di(isoocta-decanoic) acid, diester with oxydi(propanediol) (CAS 67938-21-0) failed to induce adverse effects in rats at 5000 mg/kg bw/day. Despite hair-raising and crouching (observed 50 min after gavage), no systemic signs of toxicity were observed in any test animal (Mayer, 1980).

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 physicochemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2014).

It is well-accepted 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 the mono-, di- and triglycerides of the target and source substances 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 ones. Monoglycerides are hydrolysed by gastric and pancreatic lipases with high specificity for the sn1- and sn3-positions. For 2-monoacylglycerol (monoglyceride at the sn2-position), 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, monoesters of short-chain fatty acids are hydrolysed more rapidly and to a larger extent than monoesters of long-chain fatty acids. (Barry et al., 1967; Cohen et al.,1971; Dias, 1971; Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1964, 1966, 1968; WHO, 1967). Thus, the target substance, especially the monoester, is predicted to be enzymatically hydrolysed to glycerol and the respective fatty acid moiety, namely isooctadecanoic (C18) acid.

Following hydrolysis, the resulting products (free glycerol, free fatty acid and (in the case of di- and triglycerides) 2 -monoacylglycerols) are absorbed by the intestinal mucosa. Within the epithelial cells, triglycerides will be (re)assembled, 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).

In conclusion, based on the available information, the physicochemical properties and molecular weight of Polyaldo 2-1-ISsuggest limited oral absorption of the parent substance. However, the substance is predicted to undergo enzymatic hydrolysis in the gastrointestinal tract to some extent and absorption of the ester hydrolysis products 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. Moreover, in general, 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 100-1000 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).

Polyaldo 2-1-IS is a liquid with low vapour pressure. Regarding the broad range of the molecular weight, dermal absorption of the smaller components cannot be excluded whereas dermal absorption of the larger molecules is considered unlikely. Moreover, the other physicochemical properties (log Pow and water solubility) 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 for the smallest component is estimated to be 0.0318 cm/h which is correlated to a dermal flux rate of 1.08E-05 mg/cm²/h (QSAR analysis based on DermWin v2.02; SMILES code: OC(COCC(O)COC(=O)CCCCCCCCCCCCCCC(C)C)CO). Accordingly, a Kp (est) of 383 cm/h was estimated for the larger component (QSAR analysis based on DermWin v2.02; SMILES code: OC(COCC(O)COC(=O)CCCCCCCCCCCCCCC(C)C)COC(=O) CCCCCCCCCCCCCCC(C)C) resulting in a dermal flux rate of 9.27E-10 mg/cm²/h.

Based on these results, only low dermal absorption potential is predicted for Polyaldo 2-1-IS.

 

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 Isooctadecanoic acid, ester with oxybis[propanediol] (CAS 73296-86-3)in rabbits (N´itka, 2001). Furthermore, the skin sensitisation data from animal studies support a non-sensitising outcome (N´itka, 2002). Thus, the target substance is not considered to be skin irritating or skin sensitising, since the results of the available studies do not meet the criteria for the corresponding classification according to Regulation (EC) 1272/2008. 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

Polyaldo 2-1-ISis a liquid with low vapour pressure (3E-08 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, 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.

As discussed above, 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 parent substance may be absorbed across the respiratory tract epithelium by micellar solubilisation to a certain extent.

 

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 will 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 than of the parent compound(s).

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 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 for 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.

 

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

Unchanged parent substance is considered to be excreted via the faeces based on its physico-chemical characteristics.

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).

 

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 RAT SMALL 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.

 

Dias, F.F. and Alexander, M. (1971). Effect of chemical structure on the biodegradability of aliphatic acids and alcohols. Applied Microbiology 22(6): 1114-1118.

 

ECHA (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

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.