Fatty acids, C8-12, isopentyl esters

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic-Assessment

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C8-12, isopentyl ester has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of Fatty acids, C8-12, isopentyl ester 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 of Fatty acids, C8-12, isopentyl ester is a multi-constituent substance specified by C8, C10 and C12 linear saturated fatty acids esterified with isopentanol resulting in monoesters which meets the definition of an UVCB substance.

Fatty acids, C8-12, isopentyl ester is a liquid at 20°C which has a molecular weight ranging from 214.39 – 270.45 g/mol and a water solubility of 2-50 µg/L. The calculated log Pow value is between 5.21 and 7.17 (KOWWIN v1.68) (Birkhofer, 2016) and the vapour pressure is calculated to be ≤ 0.66 Pa at 20°C (SPARC v4.6) (Erler, 2015).

 

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) and in particular for those that are poorly soluble in water (≤ 1 mg/L), as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2014).

When assessing the potential of Fatty acids, C8-12, isopentyl ester to be absorbed in the GI tract, it has to be considered that fatty acid esters will to a high extent undergo hydrolysis by ubiquitous gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). Thus, due to the likely hydrolysis, the predictions based on the physico-chemical characteristics of the intact parent substance alone may not apply exclusively, and the physico-chemical characteristics of the breakdown products of the ester may also be relevant (the alcohol isopentanol and the corresponding fatty acids, C8, C10 and C12).

The low water solubility (2-50 µg/L) and the high log Pow values between 5.21 and 7.17 of the parent compound indicate that absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986). Regarding molecular weight, the breakdown products isopentanol (88.15 g/mol) and octanoic, decanoic or dodecanoic acid (144.21, 172.27 or 200.32 g/mol, respectively) are generally favourable for absorption. The alcohol component isopentanol is highly water-soluble and has a low molecular weight and can therefore dissolve into GI fluids. Thus, isopentanol will be readily absorbed through the GI tract. The highly lipophilic fatty acids are absorbed by micellar solubilisation (Ramirez et al., 2001). Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

Experimental data of the structurally similar Ethyl Oleate (CAS 111-62-6) confirmed this prediction: 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).

Moreover, studies on the acute oral toxicity of the structural analogue substances Isopropyl Myristate (CAS 110-27-0), Octyl Octanoate (CAS 2306-88-9) and Isopropyl Laurate (CAS 10233-13-3) showed no signs of systemic toxicity, resulting in a LD50 values greater than 2000 mg/kg bw (Dufour, 1991; Potokar, 1981; Reijnders, 1988). Furthermore, available data on subacute or subchronic oral toxicity of the analogue substances Isopropyl Myristate (CAS 110-27-0), Fatty Acids, C8-16, 2-Ethylhexyl Esters (CAS 135800-37-2), Hexyl Laurate (CAS 34316-64-8), Fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl Esters (CAS 163961-32-8) and Ethyl Oleate (CAS 111-62-6) showed no adverse systemic effects, resulting in NOAELs of 800 mg/kg bw/day or greater (Bookstaff, 2004; Fitzgerald, 1991; Gloxhuber, 1982; Potokar, 1973; McRae, 2004). The lack of systemic toxicity of the structurally related analogue substances is not due to a lack of absorption but rather due to a low toxic potential of Fatty acids, C8-12, isopentyl ester and the breakdown products themselves.

Overall, a high systemic bioavailability of Fatty acids, C8-12, isopentyl ester and/or the respective breakdown products in humans is considered likely after oral uptake of the substance.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Fatty acids, C8-12, isopentyl ester. On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Therefore, with a water solubility of 2-50 µg/L, the dermal uptake of the substance is likely to be low. In addition, for substances with an octanol/water partition coefficient above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and limit absorption across the skin. Furthermore, uptake into the stratum corneum itself may be slow.

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

The Kp was calculated for the 3 constituents of the substance (please refer to Table 1). QSAR calculations confirmed this assumption, as low dermal flux rates ranging from 1.05E-3 – 3.9E-9 mg/cm2 per h were calculated indicating only low dermal absorption potential for the components of Fatty acids, C8-12, isopentyl ester (please refer to Table 1, Dermwin v2.02, EpiSuite 4.1).

Table 1: Dermal absorption values for the components of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) (calculated with Dermwin v 2.02, Epiweb 4.1)

Component	Structural formula	Flux (mg/cm2/h)
Isopentyl octanoate	C13 H26 O2	1.0E-3
Isopentyl decanoate	C15 H30 O2	3.9E-4
Isopentyl laurate	C17 H34 O2	1.5E-4

 

In addition, available data on acute dermal toxicity of the analogue substances Ethyl Linoleate (CAS 544-35-4) and Fatty acids, C16-18 and C18-unsatd., branched and linear, Bu esters (CAS 163961-32-8) showed no systemic toxicity, resulting in LD50 values greater than 2000 mg/kg bw (Otterdijk, 2010; Sanders, 2004).

Moreover, skin irritation studies with the structurally related substances Isopropyl Myristate (CAS 110-27-0) and Isopropyl Laurate (CAS 10233-13-3) showed no or only mild skin irritating effects (Dufour, 1991; Mulder, 1986).

Overall, taking into account the physico-chemical properties of Fatty acids, C8-12, isopentyl ester, the QSAR calculations and available toxicological data on structural analogue substances, the dermal absorption potential of the target substance is anticipated to be low.

Inhalation

Fatty acids, C8-12, isopentyl ester has a low vapour pressure of ≤ 0.66 Pa at 20°C and therefore low volatility. Therefore, under normal use and handling conditions, exposure via inhalation and the availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

However, the substance 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, 2014). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C8-12, isopentyl ester can be taken up by micellar solubilisation.

Available data on acute toxicity of the analogue substance Isopropyl Laurate (CAS 10233-13-3) showed no systemic toxicity, and a LC50 value greater than 5.3 mg/L (van Huygevoort, 2010).

Based on the physical state and the physico-chemical properties of Fatty acids, C8-12, isopentyl ester, systemic bioavailability in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm.

As a worst-case approach, the absorption potential via the inhalative route is considered to be as high as via the oral route of exposure.

 

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, 2014).

As the parent compound Fatty acids, C8-12, isopentyl ester will be hydrolysed prior to absorption (as discussed above), the distribution of the intact substance is less relevant than the distribution of the breakdown products of hydrolysis. The absorbed hydrolysis products 3-methyl-1-butanol (isopentanol) and the respective fatty acid moieties can be distributed within the body.

The alcohol isopentanol is a small water soluble substance with a log Pow of 1.16 that will be distributed in aqueous compartments of the organism. After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Thus, the fatty acids (C8, C10 or C12) 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). Substances with high water solubility like isopentanol do not have the potential to accumulate in adipose tissue due to its low log Pow.

Overall, the available information indicates that the cleavage products, isopentanol and C8, C10 or C12 fatty acids will be distributed in the organism.

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 Fatty acids, C8-12, isopentyl ester 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 isopentanol and C8, C10 or C12 fatty acids. Therefore, the intact parent compound is not assumed to accumulate as hydrolysis takes place before absorption and distribution.

The first cleavage product, isopentanol, has a log Pow of 1.16 and is thus soluble in water (HSDB). Consequently, there is no potential for isopentanol to accumulate in adipose tissue. The second cleavage product, C8, C10 or C12 fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, C8, C10 or C12 fatty acids are also required as a source of energy. Thus, there is a continuous turnover of stored fatty acids as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

In summary, the available information on Fatty acids, C8-12, isopentyl ester indicates that no significant bioaccumulation of the parent substance in adipose tissue is expected. The breakdown products of hydrolysis, isopentanol and the respective fatty acids will be distributed within the organism.

 

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol (isopentanol) and fatty acid 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 generally take place.

The first cleavage product, isopentanol, is mainly oxidized to the respective acid and/or glucuronidated (HSDB). 

The second cleavage product, the C8, C10 or C12 fatty acid, is stepwise degraded by β-oxidation. In this multi-step process, the fatty acids are at first esterificated 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, 1970; Stryer, 1994). The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

Following absorption into the intestinal lumen, fatty acids are re-esterified with glycerol to triacylglycerides (TAGs) and included into chylomicrons for transportation via the lymphatic system and the blood stream to the liver. In the liver, fatty acids can be metabolised in phase I and II metabolism.

There is no indication that the target and source substances will be activated to reactive intermediates under the relevant test conditions. In particular, Ames tests with Isopropyl Myristate (CAS 110-27-0; Oleon, 2014) and Hexyl Laurate (CAS 34316-64-8); in-vitro chromosomal aberration tests with Isopropyl Laurate (CAS 10233-13-3; Buskens, 2010), Fatty acids, C16-18 and C18-unsaturated, branched and linear, Butyl Esters (CAS 163961-32-8; Durward, 2004) and 2-Ethylhexyl oleate (CAS 26399-02-0; Buskens, 2010) and in-vitro mammalian gene mutation assays with Isopropyl Laurate (CAS 10233-13-3; Verspeek-Rip, 2010), Fatty acids, C16-18 and C18-unsaturated, branched and linear, Butyl Esters (CAS 163961-32-8; Flanders, 2007) and 2-Ethylhexyl oleate (CAS 26399-02-0; Verspeek-Rip, 2010) were consistently negative.

Excretion

Based on the metabolism described above, Fatty acids, C8-12, isopentyl ester and its breakdown products will be metabolised in the body to a high extent. For Fatty acids, C8-10, 3-methylbutyl esters, 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.

Experimental data of the structurally similar Ethyl Oleate (CAS 111-62-6) demonstrate 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 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).

 

References

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.