Decyl 2-ethylhexanoate

Endpoint summary

Description of key information

The target substance Decyl 2-Ethylhexanoate (CAS 93777-46-9) is expected to be systemically available after oral exposure or inhalation of aerosols with aerodynamic diameters below 15μm. In contrast, dermal absorption is considered to be limited. After oral ingestion, Decyl 2-Ethylhexanoate will be hydrolysed in the gastrointestinal tract to the respective fatty acids’ moiety (2-Ethylhexanoic acid) and the corresponding alcohol (decanol) which facilitates the absorption and distribution within the organism. In general, metabolism of alcohols primary occurs in the liver by alcohol dehydrogenase to the respective aldehyde, which might then be further oxidised to different end products. The second cleavage product 2-Ethylhexanoic acid can either be glucuronidated or further be oxidized via cytochrome P-450-dependent pathways leading to various products. In addition, 2-Ethylhexanoic acid is, similarly to fatty acids, likely to be broken down by ß-oxidation, finally leading to acetyl-CoA. The main route of excretion for Decyl 2-ethylhexanoate is expected to be by expired air as CO2 after metabolic degradation. The second route of excretion is expected to be by biliary excretion within the faeces. Bioaccumulation in adipose tissue might be possible for Decyl 2-Ethylhexanoate and the breakdown product decanol. In contrast, the hydrolysis product 2-Ethylhexanoic acid is not expected to accumulate in adipose tissue.

 

 

 

 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Decyl 2-Ethylhexanoate (CAS 93777-46-9) has been investigated. 

Therefore, in accordance with Annex VIII, Column 1, Item 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 the substance Decyl 2-Ethylhexanoate 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 Decyl 2-Ethylhexanoate represents an ester of 2-Ethylhexanoic acid and decanol. Decyl 2-Ethylhexanoate is a monosubstance containing > 80% Decyl 2-Ethylhexanoate. Free 2-Ethylhexanoic acid is contained to < 2%.

The substance Decyl 2-Ethylhexanoate is liquid at room temperature with low vapour pressure (≤ 0.17 Pa at 20 °C (Kintrup, 2014)) and has a molecular weight of 284.48 g/mol, a water solubility of 1.8 – 2.4 µg/mL (Schwarzkopf, 2014) and a calculated log Pow of 7.67 (Mayer, 2016).

 

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:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2014). Based on the low molecular weight, absorption of the Decyl 2-Ethylhexanoate in the gastrointestinal tract following oral ingestion is considered likely.

Absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance Decyl 2-Ethylhexanoate, as all rules are fulfilled except for the log Pow, which is above the given range of -0.4 to 5.6.

The high log Pow > 4 suggests that Decyl 2-Ethylhexanoate 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 alcohols (including short and long chain fatty acids in the range of C2 – C18) and fatty acids undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. As results, the respective alcohol and the fatty acid moieties will be released. 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, 2014). However, also for both cleavage products, it is anticipated that absorption in the gastro-intestinal tract takes place. 2-Ethylhexanoic acid is known to be absorbed via the gastrointestinal tract (BG Chemie, 2000), whereas thealcohol decanol is assumed to be absorbed by micellar solubilisation based on its physico-chemical properties (low water solubility and log Pow > 4) (Wikipedia).

Exemplarily, experimental data of the structurally similar 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, systemic bioavailability of Decyl 2-Ethylhexanoate 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, 2014). As the molecular weight of Decyl 2-Ethylhexanoate is 285 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, 2014). As Decyl 2-Ethylhexanoate did not exhibit skin irritating properties in the conducted in vitro study, enhanced penetration of the substance due to local skin damage can be excluded.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

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

QSAR calculations estimated a low dermal flux of 9.1E-5 mg/cm2 per h indicating only low dermal absorption potential for Decyl 2-Ethylhexanoate (Dermwin v2.02, EpiSuite 4.1; Mayer, 2016).

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, 2014). As the water solubility of Decyl 2-Ethylhexanoate 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 Decyl 2-Ethylhexanoate in humans is considered as very limited.

 

Inhalation:

Decyl 2-Ethylhexanoate has a low vapour pressure of ≤ 0.17 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, Decyl 2-Ethylhexanoate 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, 2014). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Decyl 2-Ethylhexanoate can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of Decyl 2-Ethylhexanoate in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15μm.

 

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 log Pow of > 4 implies that Decyl 2-Ethylhexanoate may have the potential to accumulate in adipose tissue (ECHA, 2014).

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

The first cleavage product, 2-Ethylhexanoic acid, has a low to moderate water solubility (EPA, 1986). As described below, 2-Ethylhexanoic acid will be distributed in aqueous compartments of the organism and may also be taken up by different tissues. However, no accumulative potential is expected. In contrast, accumulation within adipose tissue of the second cleavage product, the alcohol moiety decanol cannot be excluded due to its rather moderate logPow (log Pow: 4.57 (Wikipedia).

Overall, the available information indicates that bioaccumulation in adipose tissue might be possible for Decyl 2-Ethylhexanoate and the breakdown product decanol. In contrast, the hydrolysis product 2-Ethylhexanoic acid is not expected to have the potential to accumulate in adipose tissue.

 

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, 2014).

Decyl 2-Ethylhexanoate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products 2-Ethylhexanoic acid and the alcohol Decanol.

2-Ethylhexanoic acid, a rather small (MW = 144.21 g/mol) molecule of low to moderate water solubility (2 g/L), will be distributed in aqueous compartments of the organism and may also be taken up by different tissues. In the mouse and the rat, 2-Ethylhexanoic acid is preferentially distributed in the kidneys, liver and blood. It is also able to cross the placenta and can be detected in smaller concentrations in embryos (BG Chemie, 2000). The alcohol moiety decanol is also assumed to be distributed in the organism considering the low molecular weight. As discussed previously, uptake in different adipose tissues is considered likely.

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

 

Metabolism

Esters of fatty acids are hydrolysed to the corresponding fatty acid (in that case 2-Ethylhexanoic acid) and the respective alcohol moiety (decanol) 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 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. In general, metabolism of alcohols primary occurs in the liver by alcohol dehydrogenase to the respective aldehyde, which might then be further oxidised to different end products. The second cleavage product 2-Ethylhexanoic acid can either be glucuronidated or further be oxidized via cytochrome P-450-dependent pathways (BG Chemie, 2000) leading to various products (HSDB). In addition, 2-Ethylhexanoic acid is, similarly to fatty acids, likely to be broken down by ß-oxidation, finally leading to acetyl-CoA (BG Chemie, 2000). The major metabolites found in the urine include glucuronide conjugate of 2-Ethylhexanoic acid and 2-Ethyl-1,6-hexanedioic acid and 6-hydroxy-2-Ethylhexanoic acid and their glucuronide conjugates (BG Chemie, 2000).

 

 

Excretion

For Decyl 2-Ethylhexanoate, 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 within the faeces. For the cleavage products including their metabolites, the main routes are renal excretion via the urine and exhalation as CO2.

Experimental data of the structurally similar Ethyl oleate (CAS 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 withβ-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).

 

References:

*BG Chemie (2000) Toxicological evaluation No. 275, 2-Ethylhexanoic acid 06/00.

* Bookstaff et al. (2003). The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans. Regul Toxicol Pharm 37: 133-148.

* ECHA (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

* Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

* Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.

* HSDB – Hazardous Substances Data Bank, Toxnet Home, National Library of Medicinehttp://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

* Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.

* Wikipedia. https://en.wikipedia.org/wiki/1-Decanol