Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters

Endpoint summary

Description of key information

The target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) is expected to be hydrolysed within the gastrointestinal tract. 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 C16-C18 fatty acid and C12-C15 fatty alcohol, which facilitates the absorption. The fatty acid will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; the absorbed alcohol is readily distributed throughout the organism and can be re-esterified to form endogenous triglycerides. The major metabolic pathway for linear fatty acids is the beta-oxidation pathway for energy generation. The excretion will mainly be as CO2 in expired air; with a smaller fraction excreted as conjugated molecules in the urine. Fatty alcohol 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

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, 2017), an assessment of the toxicokinetic behaviour of the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) 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, 2017) and taking into account further available information from a source substance. There are no studies available in which the toxicokinetic behaviour of Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) was investigated.

Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) is a UVCB substance with a linear and branched C12-15 alcohol moiety and linear C16-C18 acid moiety. The substance has a molecular weight range of 424.74 to 492.86 g/mol. It is a liquid with melting point of 3°C, and a water solubility of < 6.57 µg/L at 20 °C (pH 6.3). The log Pow was calculated to be >10 and the vapour pressure was calculated to be <0.0001 Pa at 20 °C.

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, 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. Solids must be dissolved before absorption; the degree depends on the water solubility (Aungst and Shen, 1986; ECHA, 2017). 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 physico-chemical characteristics of the substance and hence predictions based on the physico-chemical characteristics of the parent substance may in some cases no longer apply or should be adjusted (ECHA, 2017).

In general, alkyl esters are readily hydrolysed in the GI-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 speed of hydrolysis of esters of primary n-alcohols containing from 1 to 18 carbon atoms with fatty acids containing from 2 to 18 carbon atoms was found to depend on both, the chain length of either the alcohol or acid. With respect to fatty acid moiety, esters of C12 and C4 were hydrolysed at the most rapid rate. With respect to alcohol moiety C7 was hydrolysed most rapidly (Mattson and Volpenhein, 1969).

The target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) is expected to be enzymatically hydrolysed to the C16-C18 fatty acid and the C12 -C15 fatty alcohol.

The molecular weight of the target substance favours uptake, while the log Pow and water solubility is in a range that indicate poor absorption from the GI-tract following oral ingestion. Micellar solubilisation may have an effect on the overall absorption rate of the substance.

The indications that the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) has low oral absorption are supported by the available data on source substances covering acute and repeated dose oral toxicity:

In an acute oral toxicity study female mice were administered a single dose of 2000 mg/kg bw decyl oleate (CAS 3687-46-5). There was no mortality, no clinical signs of toxicity and no effect on the body weight noted (key study, 1994).

Rats were orally administered Tetradecyl oleate (CAS 22393-85-7) for 28 days (males) and 54 days (females) once daily by gavage in a combined repeated dose toxicity study with reproduction/developmental toxicity screening. No toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (WoE, 2014).

Male and female rats were orally administered decyl oleate (CAS 3687-46-5) once daily by gavage on 5 days per week in a repeated dose 28-day oral toxicity study. No toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (WoE, 1987).

In conclusion, the physico-chemical properties and molecular weight of Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) suggest that some oral absorption is likely to 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, 2017).

The molecular weight of Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) ranging from 424.74 to 492.86 g/mol favours dermal absorption. However, other physico-chemical properties (low water solubility, log Pow >10 ) indicate a limited dermal absorption, as the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis is considered to be slow as well (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2012), using the Epi Suite software:

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

Using a water solubility of 6.57 µg/L and a log Pow of 10 Dermwin v2.02 calculated Kp in the range of 11.9 to 28.7 cm/h and dermal flux rates in the range of 0.0017 to 0.00223 mg/cm²h, indicating a low dermal absorption potential.

SMILES code	Molecular weight	Kp (predicted):	Dermal flux
		[cm/h]	[mg/cm²h]
A	450.8	20.5	0.00223
B	492.8	11.9	0.0017
C	492.8	11.9	0.0017
D	424.7	28.7	0.00201

 

The indications that the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) has low dermal absorption are supported by the available data on source substances covering acute dermal toxicity:

An acute dermal toxicity study was performed with the source substance Decyl oleate (CAS 3687-46-5), in which rats were exposed to 2000 mg/kg bw for 24 hours under occlusive conditions (key study, 2010). No mortality occurred and no toxicologically relevant systemic effects were observed. Erythema (score 1) was noted during Day 3-7 in 4/10 animals, while scales or scabs were observed in 8/10 animals for up to 9 days during Day 7-15.

An acute dermal toxicity study was performed with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3), in which rats were exposed to 2000 mg/kg bw for 24 hours under occlusive conditions (supporting study, 1998). No mortality occurred and no toxicologically relevant systemic effects were observed.

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).

The available skin irritation data on the source substances Decyl oleate (CAS 3687-46-5), Fatty acids, C8-10, C12-18-alkyl esters (CAS 95912-86-0) and 2-octyldodecyl isooctadecanoate (CAS 93803-87-3), show only mild skin irritating effects in the rabbit (WoE, 1994, 1998, and 1991). In the acute dermal toxicity study with decyl oleate reversible skin irritation was observed (key study, 2010).

In a local lymph node assay in mice with the source substance Decyl oleate (CAS 3687-46-5) only slight erythema was seen, which was fully reversible within 3 days after the last application.

In a guinea pig maximisation test with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) no erythema or oedema was seen after topical challenge with the undiluted test substance for 24 hours under semi-occlusive conditions.

No relevant increase in the penetration rate of the substance due to skin damage is expected for the target substance.

Overall, based on the available information and using a worst-case approach, the dermal absorption potential of Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) is predicted to be low.

Inhalation

Substances that can be inhaled include gases, vapours, liquid aerosols (both liquid substances and solid substances in solution) and finely divided powders/dusts. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inspired. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed (ECHA, 2017).

Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) is a liquid with a low vapour pressure (<0.0001 Pa at 20 °C), and therefore inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases or mists is limited by the low volatility. A systemic bioavailability after inhalation exposure cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm. The absorption rate is not expected to be higher than that following oral exposure. Applying a worst-case approach, the absorption potential via the inhalation route of exposure is assumed to be the same as via the oral route of exposure.

Low systemic toxicity upon acute inhalation exposure was seen for the source substance 2-ethylhexyl oleate (CAS 26399-02-0); male and female rats were exposed for 4 hours to 2-ethylhexyl oleate aerosol at a limit dose of 5.7 mg/L air (key study, 2010). There was no mortality and no effects on body weight. The animals had a hunched posture on Day 2; no further clinical signs were observed during the 14-day observation period.

For the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) limited availability for inhalation exposure is expected with low toxicity following absorption.

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical 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, Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) may undergo enzymatic hydrolysis in the GI-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, 1993; 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 un-metabolised 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, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding C16-C18 fatty acid and C12-C15 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 C12-15 fatty alcohol of the target substance, as well as the fatty alcohols of the source substances, 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. Fatty acids having an odd number are oxidized in the same way as fatty acids having an even number, except that propionyl CoA and acetyl CoA, rather than two molecules of acetyl CoA, are produced in the final round of degradation. The activated three-carbon unit in propionyl CoA enters the citric acid cycle after it has been converted into succinyl CoA (Berg, 2002).

Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂ (Lehninger, 1993). 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, sulphates) to more polar products that are excreted in the urine.

The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox (OECD, 2018). The QSAR tool was used to predict metabolites result from enzymatic activity in (rat) liver and in the skin, and by intestinal bacteria in the GI-tract. The number of metabolites predicted four the four constituents of Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) are tabulated:

SMILES code	Number of skin metabolites	Number of rat liver S9 metabolites	Number of microbial metabolites
A	2	12	124
B	2	12	136
C	2	13	174
D	2	11	86

 

Primarily, the ester bond is broken both specifically in the liver and in general in vivo, and the hydrolysis products may be further metabolised. The resulting liver metabolites are 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 general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Two skin metabolites per constituent were predicted, which comprised a total of five different skin metabolites (C12 alcohol, linear C15 alcohol, branched C15 alcohol, C16 fatty acid, C18:1 fatty acid). The metabolites formed in the skin are expected to enter the blood circulation and eventually meet the same fate as the hepatic metabolites. Between 86 - 136 metabolites were predicted to result from all kinds of microbiological metabolism of the ester in the GI-tract, including hydrolysis of the ester bond, aldehyde formation and fatty acid chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature on metabolism.

There is no indication that Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) 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, and chromosome aberration assay in mammalian cells in vitro using source substances were negative, with and without metabolic activation.

Excretion

The C12-C15 fatty acid derived from the oxidation of the corresponding alcohol as well as the C16-C18 fatty acid 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 (Bookstaff et al., 2003). At sacrifice (72 hours 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 hours after dosing, 40-70% of the administered dose was excreted in expired air (consistent with beta-oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine.

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, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) that is not absorbed in the GI-tract will be excreted via the faeces.

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