2-ethylhexyl nonanoate

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 2-ethylhexyl nonanoate has been investigated. The substance 2-ethylhexyl nonanoate is an ester of 2-ethylhexanol and nonanoic acid and meets the definition of a mono-constituent substance based on the analytical characterization.

The substance 2-ethylhexyl nonanoate is liquid at room temperature and has a molecular weight of 270.45 g/mol. The water solubility of this substance is < 0.05 mg/L. The log Pow is 7.17 (Dr. Knoell Consult GmbH, 2014) and the vapour pressure is estimated to be 0.00837 Pa at 20 °C (Dr. Knoell Consult GmbH, 2013).

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, 2013).

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, 2013). As the molecular weight of 2-ethylhexyl nonanoate is 270.45 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 2-ethylhexyl nonanoate, 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 7.17 suggests that 2-ethylhexyl nonanoate 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, 2013). 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 similar Ethyl oleate (CAS No. 111-62-6) confirmed this assumption: 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. It was shown that the test material was well (approximately 70–90%) absorbed (Bookstaff et al., 2003).

Overall, a systemic bioavailability of 2-ethylhexyl nonanoate 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, 2013). As the molecular weight of 2-ethylhexyl nonanoate is 270.45 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 2-ethylhexyl nonanoate is not skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculated dermal absorption a value of 0.0002 mg/cm²/event (very low) was predicted for 2-ethylhexyl nonanoate (Dermwin v.2.01, EPI Suite). Based on this value the substance 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, 2013). As the water solubility of 2-ethylhexyl nonanoate is less than 1 mg/L, dermal uptake is likely to be (very) low.

Overall, the calculated 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 2-ethylhexyl nonanoate in humans is considered as very limited.

Inhalation:

2-ethylhexyl nonanoate has a low vapour pressure in the range of 0.00837 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 not significant.

However, 2-ethylhexyl nonanoate 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 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2013). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like 2-ethylhexyl nonanoate can be taken up by micellar solubilisation.

Overall, a systemic bioavailability 2-ethylhexyl nonanoate in humans 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 of > 5 implies that 2-ethylhexyl nonanoate may have the potential to accumulate in adipose tissue (ECHA, 2013).

However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, leading to the cleavage products 2-ethylhexanol and the fatty acid.

The first cleavage product, 2-ethylhexanol, is moderately soluble in water (HSDB). 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, the fatty acid is 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, the available information indicates that no significant bioaccumulation in adipose tissue is anticipated.

 

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, 2013).

2-ethylhexyl nonanoate undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products 2-ethylhexanol and the corresponding fatty acid.

Overall, the available information indicates that the cleavage products, 2-ethylhexanol and the fatty acid will be distributed in the organism.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol (2-ethylhexanol) 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 thatare 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, 2-ethylhexanol, is mainly oxidized to 2-ethylhexanoic acid which is either glucuronidated or to a small extend further oxidized leading to various products (HSDB, 2011).

The second cleavage product, the fatty acid, is 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). The metabolism of the uneven fatty acids results in carbon dioxide and an activated C3-unit, which undergoes a conversion into succinyl-CoA before entering the citric acid cycle (Stryer, 1996).

Excretion

For 2-ethylhexyl nonanoate, the main route of excretion is expected to be by expired air as CO2 after metabolic degradation. The second route of excretion is expected to be by biliary excretion with the faeces. For the cleavage products, the main routes are renal excretion via the urine and exhalation as CO2. Up to 10% of 2-ethylhexanol is excreted via faeces in rats (HSDB, 2011).

Experimental data of the structurally similar substance ethyl oleate (CAS No. 111-62-6, ethyl ester of oleic acid) are regarded exemplarily. 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 expired air as CO2. Excretion of 14CO2 was 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 CO2 than 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).

Potential cleavage products, the fatty acid component (C9) will be metabolized for energy generation or stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above.

The other cleavage product 2-ethylhexanol may either further be metabolized or conjugated to polar products (e.g. glucuronides, sulfates, etc.) or excreted unchanged via urine (OECD SIDS, 2013).