Fatty acids, C8-C18 (even numbered), decyl esters

Endpoint summary

Description of key information

The target substance Fatty acids, coco, decyl esters (CAS 93455-79-9) is expected to be readily absorbed via the oral and inhalation route, and partly absorbed via the dermal route. The esters will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and fatty alcohols, which facilitates the absorption. Absorbed esters will be hydrolysed mainly in the liver. The fatty acids will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; while the absorbed alcohols are mainly oxidised to the corresponding fatty acid and then to a triglyceride, as described above. The fatty alcohol is generally metabolised to the corresponding fatty acid. The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-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. 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

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, coco, decyl esters (CAS 93455 -79 -9) was investigated.

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 Fatty acids, coco, decyl esters (CAS 93455-79-9) was 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 the Chapter R.7c Guidance document (ECHA, 2014) and taking into account further available information from a source substance.

The substance Fatty acids, coco, decyl esters (CAS 93455-79-9) is a UVCB with an aliphatic and linear C10-alcohol moiety and linear C8-18 acid moieties, of which the main components are C12- and C14-linear acid moieties.

Fatty acids, coco, decyl esters has a molecular weight ranging from 340.58 – 368.64 g/mol. It is a liquid at 20 °C (Keune, 2014), with an estimated water solubility of 0.05 mg/L at 25 °C (Evonik Industries AG, 2014). Depending on the individual components of the substance, the log Pow was estimated to be > 9.70 (Müller, 2014) and the vapour pressure was calculated to be < 0.0001 Pa at 20 °C (Nagel, 2014).

 

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 Shen, 1986; ECHA, 2014).

The physicochemical characteristics (log Pow and water solubility) of the substance are in a range that indicate poor absorption from the gastrointestinal tract following oral ingestion, while the molecular weight favours uptake. It is unclear to what degree micellar solubilisation will affect the absorption rate of the substance.

The indications that the target substance Fatty acids, coco, decyl esters has low-medium oral absorption and/or low acute toxicity are supported by the available data on acute oral toxicity. When mice were administered a single dose of 2000 or 5000 mg/kg bw of a source substance, there was no mortality, no effects on body weight, and no lesions were noted at necropsy (Bouffechoux, 1996; Dufour, 1991). In a combined repeated dose toxicity and reproduction/developmental toxicity study performed using the source substance tetradecyl oleate (CAS 22393-85-7), no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (Rosiello, 2014). This indicates that Fatty acids, coco, decyl esters also has a low potential for oral toxicity.

The potential of a substance to be absorbed in the gastrointestinal (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 physico-chemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2014).

In general, alkyl esters are readily hydrolysed in the gastrointestinal tract, blood and liver to the corresponding alcohol and fatty acid by the ubiquitous carboxylesterases. There are indications that the hydrolysis rate in the intestine catalysed by pancreatic lipase is lower for alkyl esters than for triglycerides, which are the natural substrates of this enzyme. The hydrolysis rate of linear esters increases with increasing chain length of either the alcohol or acid. Branching reduces the ester hydrolysis rate, compared with linear esters (Mattson and Volpenhein, 1969, 1972; WHO, 1999).

Based on the generic information on hydrolysis of alkyl esters, the target substance Fatty acids, coco, decyl esters is expected to be enzymatically hydrolysed to the C8-18 fatty acids and the linear C10 fatty alcohol.

Free fatty acids and alcohols are readily absorbed by the intestinal mucosa. Within the epithelial cells, fatty acids are (re-)esterified with glycerol to triglycerides. In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. As for fatty acids, the rate of absorption of alcohols is likely to decrease with increasing chain length (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964; OECD, 2006; Sieber, 1974).

In conclusion, the physicochemical properties and molecular weight of Fatty acids, coco, decyl esters suggest some oral absorption may occur. However, the substance is anticipated to undergo enzymatic hydrolysis in the GI-tract and therefore absorption of the ester hydrolysis products is also relevant. 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; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 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).

The substance Fatty acids, coco, decyl esters has a very low water solubility, indicating a low dermal absorption potential (ECHA, 2014). The molecular weight of 340.58 – 368.64 g/mol is in a range indicating a potential for dermal absorption. The log Pow is > 6, which means that the uptake into the stratum corneum is likely to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2014).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp was calculated for the two main constituents of the substance; a C10 alcohol- and C12 fatty acid or C14 fatty acid component. This gave a Kp of 53.7 cm/h and 37.4 cm/h for the C12- and C14 component, respectively. Considering the water solubility (0.00005 mg/cm³), the dermal flux is estimated to be ca. 0.00219 mg/cm²/h and 0.00182 mg/cm²/h for the C12- and C14-component, respectively. The most conservative value is then 0.00219 mg/cm²/h, indicating a medium dermal absorption potential.

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 on two source substances provide no indications for skin irritating effects in the rabbit (Dufour, 1991, 1994). Therefore, no penetration of the substance due to skin damage is expected. No indications were noted in skin sensitisation studies performed in the mouse and the guinea pig, using two source substances (Beerens-Heijnen, 2010; Steiling, 1991).

Overall, based on the available information, the dermal absorption potential of Fatty acids, coco, decyl esters is predicted to be moderate.

 

Inhalation

Fatty acids, coco, decyl esters is a liquid with low vapour pressure (< 0.0001 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.

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 substance may be absorbed across the respiratory tract epithelium by micellar solubilisation to a certain extent. However, low water solubility (< 0.05 mg/L) 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 read-across (source) substance 2-ethylhexyl oleate (CAS 26399-02-0), in which rats were exposed nose-only to 5.7 mg/L of an aerosol for 4 hours (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. The target substance is not expected to be acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption.

Due to the limited information available a worst case approach is made, and absorption via inhalation is assumed to be as high as via the oral route.

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, Fatty acids, coco, decyl esters will mainly undergo enzymatic hydrolysis in the gastrointestinal tract prior to absorption. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). The distribution and accumulation of the hydrolysis products is considered the most relevant.

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. This route of absorption and metabolism of a fatty acid was shown in an in vivo study performed by Sieber (1974). Twenty-four hours after intraduodenal administration of a single dose of [1-¹⁴C]-radiolabelled octadecanoic acid to rats, 52.5 ± 26% of the radiolabelled carbon was recovered in the lymph. A large majority (68 - 80%) of the recovered radioactive label was incorporated in triglycerides, 13 - 24% in phospholipids and 0.7 - 1% in cholesterol esters. No octadecanoic acid was recovered. Almost all the radioactivity recovered in the lymph was localized in the chylomicron fraction. 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. This is supported by the Sieber study (1974), in which, following the same protocol as described above, administration of hexanoic acid lead to only 3.3% recovery from lymphatic fluid. 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 also 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.

Absorbed alcohols are mainly oxidised to the corresponding fatty acid and then follow the same metabolism as described above for fatty acids, to form triglycerides. The absorption and metabolism of a fatty alcohol was assessed in an in vivo study performed by Sieber (1974). Twenty-four hours after intraduodenal administration of a single dose of [1-¹⁴C]-radiolabelled octadecanol to rats, 56.6 ± 14% of the radiolabelled carbon was recovered in the lymph. More than half (52-73%) of the recovered radioactive label was incorporated in triglycerides, 6-13% in phospholipids, 2-3% in cholesterol esters and 4-10% in unmetabolised octadecanol. Almost all the radioactivity recovered in the lymph was localized in the chylomicron fraction. The results of administration of hexanol resulted in a recovery of 8.5% in the lymph (Sieber, 1974), indicating that alcohols with shorter-length carbon chains are hydrolysed to the corresponding fatty acid and transported directly to the liver via the portal vein as the free acid bound to albumin. The conversion into the corresponding fatty acids by oxidation and distribution in the form of triglycerides, means that the metabolites of fatty alcohols are also used as an energy source or stored in adipose tissue.

Metabolism

The metabolism of Fatty acids, coco, decyl esters initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C8-18 fatty acids and the linear C10 fatty alcohol. The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI tract and in the liver (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the body. After oral ingestion, esters of alcohols and fatty acids can undergo enzymatic hydrolysis in the GI-tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin may enter the systemic circulation directly before entering the liver where hydrolysis will generally take place.

The C10 fatty alcohol will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). The stepwise process starts with the oxidation of the alcohol by alcohol dehydrogenase to the corresponding aldehyde, where the rate of oxidation increases with increased chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, catalysed by aldehyde dehydrogenase. Both the alcohol and the aldehyde may also be conjugated with e.g. glutathione and excreted directly, bypassing additional metabolism steps (WHO, 1999).

The fatty acids can be further metabolised directly following absorption, following oxidation from an alcohol or following de-esterification of triglycerides. A major metabolic pathway for linear and branched fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂ (Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (by e.g. glucuronides, sulfates) to more polar products that are excreted in the urine.

The potential metabolites following enzymatic metabolism of the two main constituents of the substance were predicted using the QSAR OECD toolbox (OECD, 2013). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Eleven hepatic metabolites and 10 dermal metabolites were predicted for the esters of C10 alcohol with C12 or C14 fatty acid, respectively. Primarily, the ester bond is broken both in the liver and in the skin and the hydrolysis products may be further metabolised. Besides hydrolysis, the resulting liver and skin metabolites are all the product of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. In a few cases the ester bond remains intact, and only fatty acid oxidation products are found, which result in the addition of one hydroxyl group to the molecule. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Up to 74 metabolites were predicted to result from all kinds of microbiological metabolism for the esters of C10 alcohol with C12 and C14 fatty acid, respectively. Most of the metabolites were found to be a consequence of fatty acid oxidation and associated chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature.

There is no indication Fatty acids, coco, decyl esters 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 negative, with and without metabolic activation (Banduhn, 1989, 1990; Buskens, 2010; Verspeek-Rip, 2010; Wollny, 2000). The results of the skin sensitisation studies performed with source substances were likewise negative (Beerens-Heijnen, 2010; Steiling, 1991).

Excretion

The linear C10 fatty acid from the oxidation of the corresponding alcohol as well as the fatty acids resulting from hydrolysis of the ester will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological functions, like incorporation into cell membranes (Lehninger, 1993). Therefore, the fatty acid metabolites are not expected to be excreted to a significant degree via the urine or faeces but to be excreted via exhaled air as CO₂ or stored as described above. Experimental data with ethyl oleate (CAS 111-62-6, ethyl ester of oleic acid) support this principle. 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 the expired air as CO₂. 12 h after dosing, 40-70% of the administered dose was excreted in expired air (consistent with β -oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine (Bookstaff et al., 2003).

The alcohol component may be conjugated with e.g. glutathione to form a more water-soluble molecule and excreted via the urine, bypassing further metabolism steps (WHO, 1999). The fraction of Fatty acids, coco, decyl esters that is not absorbed in the GI-tract, will be excreted via the faeces.

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