Fatty acids, C16-18, stearyl esters

Endpoint summary

Description of key information

Fatty acids, C16-18 (even numbered), stearyl esters (CAS 85536-04-5) is expected to be readily absorbed via the oral route, and partly absorbed via the dermal route. The ester will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective C18 fatty acid and C16-C18 fatty alcohol, which facilitates the absorption. The fraction of ester that is absorbed 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 alcohol is mainly oxidised to the corresponding fatty acid and then to a triglyceride. 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 is expected to 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

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, C16-18 (even numbered), stearyl esters (CAS 85536-04-5) 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 source substances. There are no studies available in which the toxicokinetic behaviour of Fatty acids, C16-18 (even numbered), stearyl esters (CAS 85536-04-5) was investigated.

Fatty acids, C16-18 (even numbered), stearyl esters (CAS 85536-04-5) is a UVCB substance with a linear C16-18 alcohol moiety and linear C16-20 acid moiety consisting of two main constituents, each of which consists of two compounds which could not be distinguished in the GC spectrum. Therefore, four SMILES codes were used for description of the substance. The substance has a molecular weight of 508.92 – 536.97 g/mol. It is a solid at 20°C with melting point 57.7°C at 1013 hPa, and a water solubility of < 0.507 mg/L at 20°C. The log Pow was estimated to be >15 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 molecular weight, log Pow and water solubility are in a range that indicate poor absorption from the GI-tract following oral ingestion. Micellar solubilisation is expected to have an effect on the overall absorption rate of the substance.

The indications that the target substance Fatty acids, C16-18 (even numbered), stearyl esters has low-moderate oral absorption and/or low acute toxicity are supported by the available acute and repeated oral toxicity data on source substances.

No adverse toxic effects were seen in rats and mice in acute oral toxicity studies conducted with the source substances Fatty acids, C16 and C18-22 - unsatd., C16-18 and C18 unsatd. alkyl ester (CAS 90990-29-7), Decyl oleate (CAS 3687-46-5), 2-octyldodecyl myristate (CAS 22766-83-2), and Hexadecanoic-acid,-isooctadecyl-ester (CAS 72576-80-8) at concentrations of ≥2000 mg/kg bw.

In two combined repeated dose toxicity and reproduction/developmental toxicity studies performed using the source substances Tetradecyl oleate (CAS 22393-85-7) and docosyl docosanoate (CAS 17671-27-1), no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (key study, 2014 and supporting study 2014). In a short term repeated dose toxicity study conducted with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (supporting study 1998).

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). 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, C16-18, stearyl esters is expected to be enzymatically hydrolysed to the C16-20 fatty acid and the C16-18 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 physico-chemical properties and molecular weight of Fatty acids, C16-18, stearyl esters suggest that some oral absorption is likely to occur. The substance is anticipated to undergo enzymatic hydrolysis in the GI-tract and therefore absorption of the ester hydrolysis products is also relevant. The results of in vivo studies indicate that the target substance and the source substance will be systemically available. Therefore the absorption rate of the ester and 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. 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, C16-18 (even numbered), stearyl esters of 242 - 565 g/mol indicates low-moderate dermal absorption. Also physico-chemical properties (low water solubility, log Pow) 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 DermWin v2.02 four SMILES codes representing Fatty acids, C16-18 (even numbered), stearyl esters were used to calculate the Kp. The Kp values for the four SMILES codes (A-D) were calculated.

SMILES code	Kp (predicted):	Log Kow (estimated)	Water solubility (estimated)	Dermal flux
	[cm/h]		[mg/cm³]	[mg/cm²/h]
A	1.58e+005	16.58	2.87e-015	1.32e-008
B	1.58e+005	16.58	2.87e-015	1.32e-008
C	5.07e+004	15.60	3e-014	3.68e-008
D	5.07e+004	15.60	3e-014	3.68e-008

 

The DermWin calculations indicate a very low dermal absorption potential.

An acute dermal toxicity study was performed with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) rats were exposed to 2000 mg/kg bw for 24 hours under occlusive conditions (key study, 1998). No treatment related clinical signs were observed. Another 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 (supporting 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. No mortality occurred and no toxicologically relevant systemic effects were observed. Based on the results from the source substances, the target substance is not expected to be acutely toxic via the dermal route.

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 Fatty acids, C16 and C18-22 - unsatd., C16-18 and C18 unsatd. alkyl ester (CAS 90990-29-7), 2-octyldodecyl isooctadecanoate (CAS 93803-87-3), and 2-octyldodecyl myristate (CAS 22766-83-2) showed no skin irritating effects in the rabbit (WoE, 1982, 1986, and 1998). In the acute dermal toxicity studies with the source substance Decyl oleate (CAS 3687-46-5) reversible skin irritation was observed (supporting study, 2010) and no skin irritation was seen in the acute dermal toxicity study with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) (key study, 1998).

Slight erythema was observed at the test site on both ears in 5/5 mice exposed to 100% the source substance Decyl oleate (CAS 3687-46-5) in a Local Lymph Node Assay. In a guinea pig maximisation test with the undiluted source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) slight to well-defined erythema was observed at the intradermal induction injection site in 3/10 treated animals; following the topical induction, severe erythema and scabs were observed at the test site in 3/10 treated animals.

Overall, based on the available information and using a worst-case approach, the dermal absorption potential of Fatty acids, C16-18, stearyl esters is predicted to be low.

 

Inhalation

Fatty acids, C16-18, stearyl esters is a solid in form of bead shape with low vapour pressure (< 0.0001 Pa at 20°C ). In general, particles with aerodynamic diameters below 100 μm have the potential to be inspired (ECHA, 2017). Particle size analysis of Fatty acids, C16-18, stearyl esters revealed that particle size was at least 228 µm, therefore no particles smaller than 100 µm were formed. Based on the physico-chemical properties, availability for respiratory absorption of the substance in the form of inhalable/respirable particles, vapours, gases or liquid aerosols (both liquid substances and solid substances in solution) is considered to be limited. The potential for exposure via the inhalation route is considered as negligible.

Nevertheless, data on acute inhalation toxicity was available for a structural similar source substance: In an acute inhalation toxicity study with the source substance 2-ethylhexyl oleate (CAS 26399-02-0) performed according to OECD guideline 436 no mortality occurred, no toxicologically relevant adverse effects were observed and the inhalation LC50 value was > 5.7 mg/L.

 

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, C16-18 (even numbered), stearyl esters 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 is also relevant to the C16-20 fatty acid hydrolysis product of the target substance. 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 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. The C16-18 fatty alcohol hydrolysis product of the target substance is likewise assumed to be oxidised to the corresponding fatty acid.

Metabolism

The metabolism of Fatty acids, C16-18, stearyl esters initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C16-20 fatty acid and the linear C16-18 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 C16-18 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. 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 substance were predicted using the QSAR OECD toolbox (OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in vivo (rat), in (rat) liver and in the skin, and by intestinal bacteria in the GI-tract. The following number of metabolites were predicted:

 

		Skin metabolism	Rat liver S9 metabolism	Microbial metabolism
Chemical name	Molecular weight	# predicted metabolites	# predicted metabolites	# predicted metabolites
stearyl stearate	536.93	5	11	106
palmityl stearate	508.88	5	11	102

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. Five skin metabolites were predicted: linear C16-alcohol, C18-alcohol, C16-fatty acid, C18-fatty acid, and C20-fatty acid respectively. The metabolites formed in the skin are expected to enter the blood circulation and eventually meet the same fate as the hepatic metabolites. Metabolites predicted to result from all kinds of microbiological metabolism of the ester in the GI-tract included 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, C16-18, stearyl 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 (Ames, 1998; Ames, 2007; HPRT 1994, CA 1994, CA 1998). The result of the skin sensitisation studies performed with source substance was likewise negative (WoE studies 2010 and 1998, QSAR 2017).

Excretion

The linear C16-18 fatty acid derived from the oxidation of the corresponding alcohol as well as the C16-20 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, C16-18, stearyl esters that is not absorbed in the GI-tract will be excreted via the faeces.

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