Hexadecyl (R)-12-hydroxyoleate

Endpoint summary

Description of key information

The target substance Hexadecyl (R)-12-hydroxyoleate (CAS 10401-55-5) is expected to be  absorbed via the oral and inhalation route (following hydrolysis of the ester bond to a free fatty acid and alcohol), and absorbed at a moderate rate via the dermal route. The ester will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and fatty alcohol moities, which facilitates the absorption. The fraction of absorbed ester will be hydrolysed mainly in the liver. The respective fatty acid moiety 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 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, 2014), an assessment of the toxicokinetic behaviour of the target substance Hexadecyl (R)-12-hydroxyoleate (CAS 10401-55-5) 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 physicochemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2014) and taking into account further available information from source substances. There are no studies available in which the toxicokinetic behaviour of Hexadecyl (R)-12-hydroxyoleate was investigated.

The target substance Hexadecyl (R)-12-hydroxyoleate (CAS 10401-55-5) is a UVCB substance (substance of Unknown or Variable composition, Complex reaction products or Biological materials). The main constituent, by which the substance is named, has a linear unsaturated C18-acid moiety with a double bond at C9 and a hydroxyl group at C12, and a linear C16-alcohol moiety.

Hexadecyl (R)-12-hydroxyoleate has a molecular weight range of 504.87 - 522.89 g/mol. The substance is a pasty solid at 20 °C and 1013 hPa, with an estimated water solubility of < 0.7 mg/L at 24 °C. The log Pow was estimated 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, 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. 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 Chen, 1986; ECHA, 2014).

The log Pow, molecular weight and water solubility of the substance are in a range that indicate poor absorption from the gastrointestinal tract following oral ingestion. Although it is unclear how much micellar solubilisation will increase the absorption rate of the substance, it is likely to affect the absorption based on the lipophilic character of the substance.

The indications that the target substance Hexadecyl (R)-12-hydroxyoleate has low acute oral toxicity potential are supported by the available data on source substances. In two acute oral toxicity studies performed with the source substances Hexadecanoic-acid,-isooctadecyl-ester (CAS 72576-80-8) and Tetradecanoic acid, tetradecyl ester (CAS 3234-85-3), there was no mortality at dose levels of ≥ 2000 mg/kg bw (Bouffechoux, 1999; Cade, 1976). There were no treatment-related clinical signs, no effects on body weight, and no lesions were noted at necropsy. In a combined repeated dose toxicity and reproduction/developmental toxicity study performed in rats 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, administered via gavage (Rossiello, 2014). Likewise, the 28-days repeated dose oral toxicity study conducted with Decyl oleate (CAS 3687-46-5) showed no toxicologically relevant effects up to and including the highest dose level of 1000 mg/kg bw/day in rats (Potokar, 1987). This indicates that Hexadecyl (R)-12-hydroxyoleate also has a low potential for oral toxicity following repeated exposure. 

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 physicochemical characteristics of the substance and hence predictions based upon the physicochemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2014).

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 hydrolysis rate of linear esters increases with increasing chain length of either the alcohol or acid. Branching in the C-chain reduces the ester hydrolysis rate, compared with linear esters (Mattson and Volpenhein, 1969, 1972; Mukherji, 2003; WHO, 1999).

Based on the generic information on hydrolysis of alkyl esters, the target substance Hexadecyl (R)-12-hydroxyoleate is expected to be enzymatically hydrolysed to the linear unsaturated C18 fatty acid and the linear C16 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 of Hexadecyl (R)-12-hydroxyoleate suggest that limited oral absorption may occur. However, the substance is expected 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 higher, as they will be more water soluble with a smaller molecular weight, compared with the parent substance. Applying a conservative approach, it is assumed that the hydrolysis products of the parent ester will be absorbed at a high rate.

Dermal

The dermal absorption 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 absorption 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. 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 Hexadecyl (R)-12-hydroxyoleate is of low water solubility, indicating a low dermal absorption potential (ECHA, 2014). The molecular weight range of 504.87 - 522.89 g/mol indicates limited dermal absorption. The log Pow is > 10, which means that the uptake into the stratum corneum is limited 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 (2004):

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

The Kp was calculated for Hexadecyl (R)-12-hydroxyoleate, using the conservative log Pow value of 10 and a molecular weight of 522.89. The calculation gave a Kp of 8.06 cm/h. Considering the water solubility (0.7 µg/cm³), the dermal flux is estimated to be 5.64 µg/cm²/h, indicating a moderate 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 for Hexadecyl (R)-12-hydroxyoleate show that only mild skin irritating effects were observed in the rabbit (Dufour, 1994). In the acute dermal toxicity study at the limit dose of 2000 mg/kg bw, performed with a source substance, focal erythema was observed for 1 -4 days in 4/5 females, while 5/5 females and 2/5 males has scales, and 1/5 females and 2/5 males had scabs in the treated skin area (Beerens-Heijnen, 2010). However, the exposure was performed using an occlusive dressing, which is a worst-case approach. The result of the skin sensitisation test performed in guinea pigs with a source substance was negative (Pitterman, 1995) and the target substance was not predicted to have a skin sensitising potential in the OECD QSAR Toolbox, specifically in the ‘skin sensitisation (Danish EPA database)’ tool (Nordheim, 2015). Therefore, no facilitated penetration of the substance due to skin damage is expected.

As carboxylesterases have been shown to be present in the skin, hydrolysis of the ester may take place in the skin, although at a lower rate than via the oral route due to the lower amount of enzymes in the skin. For the fraction of ester that penetrate the upper skin layer, the ester bond will be hydrolysed and the hydrolysis products may enter the blood circulation.

Overall, based on the available information, the dermal absorption potential of Hexadecyl (R)-12-hydroxyoleate is predicted to be low to moderate.

Inhalation

Hexadecyl (R)-12-hydroxyoleate is a pasty solid 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 potentially be absorbed across the respiratory tract epithelium by micellar solubilisation. However, relatively low water solubility (<0.7 mg/L) does restrict the diffusion/dissolving into the mucus lining fluid 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 source substance 2-Ethylhexyl oleate (CAS 26399-02-0), in which rats were exposed nose-only to 5.7 mg/L (analytical concentration) of an aerosol for 4 hours (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. Accordingly, the target substance is not expected to be acutely toxic by the inhalation route, but no firm conclusion can be drawn regarding the respiratory absorption rate of the target substance.

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 for Hexadecyl (R)-12-hydroxyoleate and its hydrolysis products.

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, Hexadecyl (R)-12-hydroxyoleate 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, 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. The hydroxyl group on the fatty acid chain will make the molecule more water soluble and therefore more likely to be absorbed.

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 carbon chain lengths 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 Hexadecyl (R)-12-hydroxyoleate initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C18:1(OH) fatty acid and the linear C16 fatty alcohol moities. 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 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 acid 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). The complete oxidation of unsaturated fatty acids requires an additional isomerisation step, while the removal of the hydroxyl group requires several additional steps. 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). 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, particularly via the hydroxyl group.

The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox (OECD, 2014). This QSAR toolbox predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Sixteen hepatic metabolites and 10 dermal metabolites were predicted for Hexadecyl (R)-12-hydroxyoleate. Primarily, the ester bond is broken both in the liver and in the skin and the hydrolysis products may be further metabolised. The resulting liver and skin metabolites are the product of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, the substance 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. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Up to 164 metabolites were predicted to result from all kinds of microbiological metabolism 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 Hexadecyl (R)-12-hydroxyoleate is activated to reactive intermediates under the relevant test conditions. The genotoxicity studies performed with source substances (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) were consistently negative, with and without metabolic activation (Bertens, 1998; Marquardt, 1994; Poth, 1994; Verspeek-Rip, 1998; Völkner, 1994). The result of the skin sensitisation study performed with a source substance was likewise negative (Pitterman, 1995), while the target substance was not predicted to have a skin sensitising potential in the OECD QSAR Toolbox, specifically in the ‘skin sensitisation (Danish EPA database)’tool (Nordheim, 2015).

Excretion

The linear, unsaturated 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). The fatty acid metabolites are likely to primarily 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 beta-oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine (Bookstaff et al., 2003). A fraction of the fatty acid may be conjugated directly and excreted, due to the hydroxyl group.

The linear alcohol component may be oxidised to the corresponding acid as described above. A fraction may also be conjugated with e.g. glutathione to form a more water-soluble molecule followed byexcretion via the urine, bypassing further metabolism steps (WHO, 1999). The fraction of Hexadecyl (R)-12-hydroxyoleate that is not absorbed in the GI-tract will be excreted via the faeces.

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