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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters 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 physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012).

The substance Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters mainly consists of di- or triester of 2-ethylhexanol with a trimer of C18 unsaturated fatty acid and meets the definition of an UVCB substance based on the analytical characterization.

The substance Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is liquid at room temperature and has a molecular weight in the range of 973.62 to 1184.02 g/mol and a water solubility of < 1 mg/L at 20 °C (Lobbes, 2009). The log Pow is calculated to be > 10 (Hopp, 2012) and the vapour pressure is estimated to be < 0.0001 Pa at 20 °C (Nagel, 2012).

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, 2012).

Oral:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). As the molecular weight of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is between 973.62 and 1184.02 g/mol, absorption of the molecule in the gastrointestinal tract is considered limited.

By applying the “Lipinski Rule of Five” (Lipinski et al., 2001; refined by Ghose et al., 1999), the potential for absorption after oral administration can be assessed. When Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is considered, three of the rules are not fulfilled; the molecular weight, the log Pow as well as the total number of atoms are above the given ranges. Thus, based on this method, oral absorption is not expected to be high either.

Consistently, no mortality and no clinical signs of toxicity were observed in an acute oral toxicity study (limit test) (Pels Rijcken, 1997); thus, absorption after oral ingestion is not likely and/or the acute toxicity of the substance is low.

If absorption occurs, the favourable mechanism will be absorption by micellar solubilisation. This mechanism is of importance for highly lipophilic substances (log Pow > 4), which are poorly soluble in water (1 mg/L or less) like Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters with a log Pow > 10 and a presumably low water solubility.

After oral ingestion, an ester undergoes stepwise hydrolysis of the ester bond by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the corresponding acid is formed. In this case, it is not anticipated that enzymatic hydrolysis of the parent substance is taking place due to the high molecular weight and the complex structure of the molecule. Hence, the potential theoretical cleavage products probably do not play a prominent role in the toxicokinetic behaviour of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters, nevertheless they will be discussed briefly here. In general, the physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) are likely to be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). For the expected cleavage product 2-ethylhexanol, it is anticipated that it can theoretically be absorbed in the gastro-intestinal tract by dissolution into the gastrointestinal fluids (ECHA, 2012).The second cleavage product, Fatty acids, C18 unsatd., trimers, seems to be less absorbed than monomeric fatty acids, as indicated by studies carried out to investigate the absorption, distribution and excretion of the polymeric fraction of heated cooking oils of vegetable origin (Combe et al., 1981; Perkins et al., 1970; Márquez-Ruiz et al., 1992 Hsieh and Perkins, 1976).

Overall, a systemic bioavailability of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters and/or the respective cleavage products in humans is considered very limited after oral uptake of the substance due to its high molecular weight.

Dermal:

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). As the molecular weight of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is between 973.62 and 1184.02 g/mol, dermal absorption of the molecule is not likely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is not skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculated dermal absorption a value in the range of 1.08E-11 to 7.28E-15 mg/cm2/event (very low) was predicted for Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (Dermwin v.2.01, EPI Suite). Based on this value the substance has a very low potential for dermal absorption.

For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is <1 mg/L, dermal uptake is likely to be very low.

Overall, the calculated low dermal absorption potential, the low water solubility, the molecular weight (>100), and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters in humans is considered as very limited.

Inhalation:

Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters has a low vapour pressure below 0.0001 Pa thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered negligible.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters in humans cannot be excluded after inhalation of aerosols with aerodynamic diameters below 15 μm.

Accumulation

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of > 5 implies that Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters may have the potential to accumulate in adipose tissue (ECHA, 2012).

Absorption is a prerequisite for accumulation within the body. Due to its molecular weight and high log Pow, absorption is expected to be minimal for the registered substance, therefore accumulation is not favoured as well. In the exceptional case of esterase-catalysed hydrolysis in the gastrointestinal tract, the cleavage products 2-ethylhexanol and trimers of fatty acids, C18 unsatd. are produced. The log Pow of the first cleavage product 2-ehtylhexanol is 2.9, indicating a moderate solubility in water (HSDB, 2011). Consequently, there is no potential for 2-ethylhexanol to accumulate in adipose tissue. Fatty acids can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism. The available information indicates that dimeric (and consequently higher oligomerised) fatty acids are poorly absorbed and that the absorbed fraction follows the same pattern of metabolism and excretion as the monomeric acids. Thus, no significant bioaccumulation in adipose tissue is expected.

Overall, the available information indicates that no significant bioaccumulation of the parent substance in adipose tissue is anticipated.

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. 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, 2012).

Distribution of the parent substance is not expected as only very limited absorption will occur. Only the potential cleavage products of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters after chemical changes as a result of enzymatic hydrolysis, namely 2-ethylhexanol and the fatty acid trimer, might be distributed within the body.

2-ethylhexanol, a rather small (MW = 130.22 g/mol) substance of moderate water solubility will mainly be distributed in aqueous compartments of the organism and may also be taken up by different tissues (HSDB, 2011). Fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro, 1977).

Overall, the available information indicates that only the cleavage products and not the parent substance might be distributed in the organism.

Metabolism

Esters of fatty acid trimers are hydrolysed to the corresponding alcohol and trimerized fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and trimerized fatty acids might theoretically undergo enzymatic hydrolysis in the gastro-intestinal fluids. However, as discussed previously, it is not anticipated that enzymatic hydrolysis of the parent substance is taking place in the gastrointestinal tract due to the high molecular weight and the complex structure of the molecule.

In contrast, substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place. Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters are of much more complex structure than a simple fatty acid ester. Therefore, it is not known if at all or to what extent ester bond hydrolysis occurs.

Nevertheless, possible theoretical cleavage products should be discussed here. The first possible cleavage product, 2-ethylhexanol, is mainly oxidised step by step into the corresponding acid which is either glucuronidated or to a small extend further oxidised leading to various products (HSDB, 2011)

The second cleavage product, the fatty acid trimer, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987). The cyclic portion of mono- and dimers cannot be degraded by β- or ω-oxidation and is probably hydroxylated or conjugated, which are common detoxification mechanisms of cyclic compounds, leading to polar metabolites readily excreted via urine (Iwaoka and Perkins, 1976). Likewise, after oxidative degradation of aromatic fatty acids, the remaining structure can be excreted in the urine after conjugation with glycine or glutamine in a similar way as in the case of benzoic and phenylacetic acid, respectively (WHO, 2000; Caldwell et al., 1980).

Overall, the part of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters that have become systemically available, might be hydrolyzed and the cleavage products can be further metabolized. However, due to its high molecular weight, absorption of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters is not likely and thus, no extensive metabolism is expected but rather direct elimination.

Excretion

Very low absorption is expected for dimeric and trimeric fatty acid esters via the gastrointestinal tract, thus much of the ingested substance is excreted in the faeces. Absorbed fatty acid esters undergo rapid metabolisation and excretion either in the expired CO2 or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic and aromatic fatty acids.

 

References (not in Iuclid):

Caldwell et al. (1980) in Extrahepatic metabolism of drugs and other foreign compounds, GRAM T.E. Ed., MTD Press, Lancaster UK, 453-492.

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.

Combe, N. et al. (1981). Lymphatic absorption of Nonvolatile Oxidation Products of Heated Oils in the Rat. Lipids, 16(1):8-14.

ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.

Hsieh, A. and Perkins, E. G. (1976). Nutrition and Metabolic Studies of Methyl Ester of Dimer Fatty Acids in the Rat. Lipids, 11(10):763-768.

Iwaoka, W. T. and Perkins, E. G. (1978). Metabolism and Lipogenic Effects of the Cyclic Monomers of Methyl Linolenate in the Rat. The Journal of the American Oil Chemists' Society, 55(10):734-738.

HSDB – Hazardous Substances Data Bank, Toxnet Home, National Library of Medicinehttp://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.

Márquez-Ruiz, G. et al. (1992). Digestibility of Fatty Acid Monomers, Dimers and Polymers in the Rat. The journal of the American Oil Chemists' Society, 69(9):930-934.

Masoro (1977). Lipids and lipid metabolism. Ann. Rev. Physiol.39: 301-321.

Mattson, F.H. and Volpenhein, R.A. (1972). Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of the rat pancreatic juice. Journal of lipid research 13: 325-328.

Perkins, E. G. et al. (1970). Absorption by the Rat of Nonvolatile Oxidation Products of Labeled Randomized Corn Oil. J. Nutrition, 100:725-731.

WHO (2000). Benzoic Acid and Sodium Benzoate. Concise International Chemical Assessment Document 26. World Health Organization.