Fatty acids, C12-18 (even-numbered), 3-methylbutyl esters

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2) has been investigated. 

Therefore, in accordance with Annex VIII, Column 1, Section 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, 2014), assessment of the toxicokinetic behaviour of Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2) 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, 2014) and taking into account further available information on structural analogue substances.

The substance Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2) consists of esters of 3-methylbutanol and fatty acids with a chain length C12-18 (even numbered) and meets the definition of an UVCB substance.

Fatty acids, C12-18, even numbered, 3-methylbutyl esters is a liquid at room temperature and has a molecular weight of 270.45 – 354.61 g/mol. The water solubility of the substance is < 0.05 mg/L (Frischmann, 2012; Evonik 2015). The log Pow is estimated to be 7.18 - 10.12 (Birkhofer, 2015) and the vapour pressure is estimated to be 3.57E-06 – 3.36E-03 Pa at 20 °C (Szymoszek, 2015).

Absorption

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, 2014). As the molecular weight of Fatty acids, C12-18, even numbered, 3-methylbutyl esters, is 270.45-354.61 g/mol, absorption of the molecule in the gastrointestinal tract is in general anticipated.

The log Pow of 7.18 - 10.12 suggests that Fatty acids, C12-18, even numbered, 3-methylbutyl esters is favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow > 4), which are poorly soluble in water (1 mg/L or less).

After oral ingestion, esters of short-chain alcohol and fatty acids (C2-8) undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. The respective alcohol as well as the fatty acid is formed, although it was shown in-vitro that the hydrolysis rate of methyl oleate was lower compared with the hydrolysis rate of the triglyceride glycerol trioleate (Mattson and Volpenhein, 1972). The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure) are likely to be different from those of the parent substance, and hence the predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2014). However, also for both cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract. The highly lipophilic fatty acid is absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the alcohol is readily dissolved into the gastrointestinal fluids and absorbed from the gastrointestinal tract.

Exemplarily, experimental data of the structurally similar ethyl oleate (CAS 111-62-6) confirmed this assumption: the absorption, distribution, and excretion of 14C-labelled ethyl oleate was studied in Sprague Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw. It was shown that the test material was well (approximately 70–90%) absorbed into blood (Bookstaff et al., 2003).

Overall, based on data from a read-across substance, a systemic bioavailability of Fatty acids, C12-18, even numbered, 3-methylbutyl esters and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

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, 2014). As the molecular weight of Fatty acids, C12-18, even numbered, 3-methylbutyl esters, is 270.45-354.61 g/mol, dermal absorption of the molecule cannot be excluded.

Based on a QSAR calculated dermal absorption a value of 0.00027-0.00997 mg/cm²/event (low to very low) was predicted for Fatty acids, C12-18, even numbered, 3-methylbutyl esters (Dermwin v.2.01, EPI Suite). Based on this value the substance is expected to have a 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, 2014). As the water solubility of Fatty acids, C12-18, even numbered, 3-methylbutyl esters is less than 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), the high log Pow value and the fact that the substance is not expected to be irritating to skin based on read-across data means that dermal uptake of Fatty acids, C12-18, even numbered, 3-methylbutyl esters in humans is considered as very limited.

Inhalation:

Fatty acids, C12-18, even numbered, 3-methylbutyl esters has a low vapour pressure in the range of 3.57E-06 – 3.36E-03 Pa at 20 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and the availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

However, Fatty acids, C12-18, even numbered, 3-methylbutyl esters 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, 2014). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C12-18, even numbered, 3-methylbutyl esters can be taken up by micellar solubilisation.

Overall, systemic bioavailability of Fatty acids, C12-18, even numbered, 3-methylbutyl esters in humans is considered likely 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 Fhat fatty acids, C12-18, even numbered, 3-methylbutyl esters may have the potential to accumulate in adipose tissue (ECHA, 2014).

However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, leading to the cleavage products 3-methylbutanol and C12-18 fatty acids.

The first cleavage product, 3-methylbutanol, has a log Pow of 1.16 and is moderately soluble in water (HSDB, 2015). Consequently, there is no potential for 3-methylbutanol to accumulate in adipose tissue. The second cleavage product, the C12-18 fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes (Masoro, 1977). At the same time, C12-18 fatty acids are also required as a source of energy. Thus, stored fatty acids are subject to 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.

Overall, the available information indicates that no significant bioaccumulation 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, 2014).

Fatty acids, C12-18, even numbered, 3-methylbutyl esters undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products 3-methylbutanol and the corresponding fatty acid.

3-methylbutanol, a small water soluble substance with a log Pow of 1.16 substance, will be distributed in aqueous compartments of the organism. The fatty acids (C12-18) will be 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 the cleavage products, 3-methylbutanol and the fatty acids will be distributed in the organism.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol (3-methylbutanol) and fatty acids 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 fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. 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 generally take place.

The first cleavage product, 3-methylbutanol, is mainly oxidized to the respective acid and/or glucuronidated (HSDB, 2015).

The second cleavage product, the C12-18 fatty acid, is stepwise degraded by β-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).

Excretion

For Fatty acids, C12 -18, even numbered, 3-methylbutyl esters, the main route of excretion is expected to be by expired air as CO2 after metabolic degradation. The second route of excretion is expected to be by biliary excretion with the faeces. For the cleavage products, the main routes are renal excretion via the urine and exhalation as CO2.

Experimental data of the structurally similar substance ethyl oleate (CAS 111-62-6, ethyl ester of oleic acid) are regarded exemplarily. The absorption, distribution, and excretion of 14C labelled ethyl oleate was studied in Sprague Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw. At sacrifice (72 h post-dose), mesenteric fat was the tissue with the highest concentration of radioactivity. The other organs and tissues had very low concentrations of test material-derived radioactivity. The main route of excretion of radioactivity in the groups was via expired air as CO2. Excretion of 14CO2 was rapid in the groups, thus 12 h after dosing 40-70% of the administered dose was excreted in expired air (consistent with β-oxidation of fatty acids). The females had a higher percentage of radioactivity expired as CO2 than the corresponding males. A second route of elimination of radioactivity was via the faeces. Faecal elimination of ethyl oleate appeared to be dose-dependent. At the dose of 1.7 g/kg bw, 7–8% of the administered dose was eliminated in the faeces. At the dose of 3.4 g/kg bw, approximately 20% of the administered dose was excreted in the faeces. Renal elimination was minimal, with approximately 2% of the radioactivity recovered in urine over 72 h post-dose for the groups (Bookstaff et al., 2003).

References:

* Birkhofer, K. (2015). EPIsuite 4.11 calculation with Fatty acids, C12-18, even numbered, 3-methylbutyl esters. Testing laboratory: Dr. Knoell Consult GmbH, 68165 Mannheim, Germany. Report no.: 2580–bir-20150518. Owner company: Evonik Industries AG, Essen, Germany. Report date: 2015-05-18.

* Bookstaff et al. (2003). The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans. Regul Toxicol Pharm 37: 133-148.

* 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 (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance (version 2.0).

* Evonik Industries AG (2015). Evonik [trade name] Report. Testing laboratory: Evonik Industries AG, Essen, Germany.Owner company: Evonik Industries AG, Essen, Germany. Report date: 2015 -01-12.

* Frischmann, M. (2012). Determination of water solubility (EEC A.6) of test item isopentyl laurate. Testing laboratory: Oleon NV, Oelegem, Belgium. Report no.: 12-07853/1-1. Owner company: Oleon NV, Oelegem, Belgium. Report date: 2012-06-05.

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

* HSDB (2015) – Hazardous Substances Data Bank, Toxnet Home, National Library of Medicinehttp://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

* 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

* Ramirez et al. (2001). Absorption and distribution of dietary fatty acids from different sources. Early Human Development 65 Suppl.: S95–S101.

* Szymoszek, A. (2015). SPARC v4.6 calculation with Fatty acids, C12-18, even numbered, 3-methylbutyl esters. Testing laboratory: Dr. Knoell Consult GmbH, 68165 Mannheim, Germany. Report no.: 2580-szy-20151015. Owner company: Evonik Industries AG, Essen, Germany. Report date: 2015-10-15.