Fatty acids, C8-10, octyl esters

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C8-10, octyl esters (CAS 91031-98-0) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of Fatty acids, C8-10, octyl esters is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014) and taking into account further available information on structural analogue substances.

The substance Fatty acids, C8-10, octyl esters (CAS 91031-98-0) is liquid at room temperature and has a molecular weight of 256.42 – 284.48 g/mol. Based on available physio-chemical properties of octyl octanoate (CAS 2306-88-9), representing a main component of Fatty acids, C8-10, octyl esters, a water solubility < 0.05 mg/L, a log Pow ≥ 6.51 and a vapour pressure of 0.0152 Pa are considered for Fatty acids, C8-10, octyl esters (CAS 91031-98-0)

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, 2012).

Oral:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). As the molecular weight of of Fatty acids, C8-10, octyl esters is 256.42 – 284.48 g/mol, absorption of the molecule in the gastrointestinal tract is in general anticipated.

Absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) is applied to the substance Fatty acids, C8-10, octyl esters, as all rules are fulfilled except for the log Pow, which is above the given range -0.4 to 5.6.

The log Pow of >6 suggests that Fatty acids, C8-10, octyl esters is favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow > 4), which are poorly soluble in water (1 mg/L or less).

After oral ingestion, esters of short-chain (C2-8) alcohols and fatty acids undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. The respective alcohol as well as the fatty acid is formed, even though it was shown in vitro that the hydrolysis rate of methyl oleate was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972). The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) are likely to be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for both cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract. The highly lipophilic fatty acid is absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the alcohol is readily dissolved into the gastrointestinal fluids and absorbed from the gastrointestinal tract.

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

Overall, a systemic bioavailability of Fatty acids, C8-10, octyl esters and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

Dermal:

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). As the molecular weight of fatty acids, C8-10, octyl esters is 256.42 – 284.48 g/mol, dermal absorption of the molecule cannot be excluded.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2013). As Fatty acids, C8-10, octyl esters is not skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculation dermal absorption was predicted to be 0.00032 mg/cm²/event (very low) for octyl octanoate (CAS 2306-88-9), which is the smallest component of Fatty acids, C8-10, octyl esters. Based on this value it could be concluded, that the substance also has a low potential for dermal absorption.

For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of Fatty acids, C8-10, octyl esters is less than 1 mg/L, and the log Pow is > 6 dermal uptake is likely to be (very) low.

Overall, the low dermal absorption potential , the low water solubility, the molecular weight (>100), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, C8-10, octyl esters in humans is considered as very limited.

Inhalation:

Fatty acids, C8 -10, octyl esters has a low vapour pressure of 0.0152 Pa at 20 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited.

However, Fatty acids, C8 -10, octyl esters may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C8-10, octyl esters can be taken up by micellar solubilisation. Overall, systemic bioavailability of Fatty acids, C8 -10, octyl esters is considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm.

Accumulation

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow > 5 implies that Fatty acids, C8 -10, octyl esters may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, leading to the cleavage products ethanol and the fatty acid moiety.

The log Pow of the first cleavage product ethanol is -0.3 which indicats a high solubility in water (HSDB) and hence, accumulation in adipose tissue is not considered relevant. The second cleavage product, the fatty acid, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

Overall, based on the physico-chemical properties, accumulation of the parent substance in adipose tissue may occur whereas no significant bioaccumulation in adipose tissue is anticipated for the cleavage products.

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012).

Fatty acids, C8 -10, octyl esters undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products ethanol and the respective fatty acid moiety.

Ethanol, a small (MW = 46.07 g/mol), polar water-soluble substance (log Pow = -0.3), will be distributed in aqueous compartments of the organism. Fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro, 1977).

Overall, the available information indicates that the cleavage products, ethanol and the fatty acid will be distributed in the organism.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol (ethanol) and fatty acids by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

The first cleavage product of atty acids, C8 -10, octyl esters, ethanol, is oxidized by the non-specific alcohol dehydrogenase (ADH) to acetone, which is either excreted directly or further metabolized, depending on the substance level in the organism. Acetone can be oxidized to hydroxyl-acetone, which is then further metabolized. A minor metabolic pathway was found leading to β-isopropyl-glucuronide, which is excreted in the urine (glucuronidation) (EFSA, 2010; IARC, 1987; Wiley online library, 2012).

The second cleavage product, C8 and C10 fatty acids, are stepwise degraded by β-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

Excretion

Excretion of 14C labelled ethyl oleate(CAS 111-62-6, ethyl ester of oleic acid) was studied in Sprague-Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw. At sacrifice (72 h post-dose), mesenteric fat was the tissue with the highest concentration of radioactivity. The other organs and tissues had very low concentrations of test material-derived radioactivity. The main route of excretion of radioactivity in the groups was via expired air as CO₂. Excretion of¹⁴CO₂was rapid in the groups, thus 12 h after dosing 40-70% of the administered dose was excreted in expired air (consistent with β-oxidation of fatty acids). The females had a higher percentage of radioactivity expired as CO₂than the corresponding males. A second route of elimination of radioactivity was via the faeces. Faecal elimination of ethyl oleate appeared to be dose-dependent. At the dose of 1.7 g/kg bw, 7–8% of the administered dose was eliminated in the faeces. At the dose of 3.4 g/kg bw, approximately 20% of the administered dose was excreted in the faeces. Renal elimination was minimal, with approximately 2% of the radioactivity recovered in urine over 72 h post-dose for the groups (Bookstaff et al., 2003).

Based on these data, the main route of excretion for Fatty acids, C8-10, octyl esters, is expected to be expiration as CO₂after metabolic degradation. The second route of excretion is expected to be by biliary excretion with the faeces. For the cleavage products, the main route is renal excretion via the urine due to the low molecular weight and the high water solubility. A large proportion of ethanol is excreted unchanged via exhalation and urinary excretion.