Fatty acids, coco, iso-Bu esters

Endpoint summary

Description of key information

The target substance FATTY ACIDS, COCO, ISO-BU ESTERS (CAS 91697-43-7) and its analouge, the source substance FATTY ACIDS, C16-18, ISOBUTYL ESTERS (CAS 85865-69-6) are both Short Chain Alcohol Esters (SCAE C2-C8) composed by a fatty acid (C16-C18) and a C4 alcohol (isobutanol).

The source and the target substance show therefore the same reactive groups and a similar composition. A read-across to the source is therefore justified.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Both target and source substances are fatty acid esters produced by chemical reaction of an alcohol (isobutanol) with organic acids (e. g. stearic acid) in the presence of an acid catalyst. The esterification reaction is started by a transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. The carboxylic acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to a carbonyl carbon of acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester. Monoesters are the final product of esterification.  

3. ANALOGUE APPROACH JUSTIFICATION

Since both target and source substances are fatty acid esters produced by chemical reaction of an alcohol (isobutanol) with an organic acid and therefore share similar/overlapping structural features and functional groups, it is justified to use a read across approach. The source substance has been registered already and its basic toxicokinetics has been assessed on the basis of the available information.

Based on the similarity of the two substances, the same assessment is used for the target substance FATTY ACIDS, COCO, ISO-BU ESTERS (CAS 91697-43-7) .

BASIC TOXICOKINETICS ASSESSMENT of source substance FATTY ACIDS, C16-18, ISOBUTYL ESTERS (CAS 85865-69-6)

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C16-18, isobutyl esters (CAS No. 85865-69-6) 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, 2008), assessment of the toxicokinetic behaviour of the substance Fatty acids, C16-18, isobutyl 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, 2008) and taking into account further available information on the SCAE C2-8 category. The substance Fatty acids, C16-18, isobutyl esters consists of esters of isobutanol and fatty acids with a chain length of C16-18 and meets the definition of an UVCB substance. The substance Fatty acids, C16-18, isobutyl esters is liquid at room temperature. It has a molecular weight in the range of 312.54 to 340.60 g/mol and the log Pow is calculated to be in the range of 8.65 to 9.63 (Kampara, 2012). The vapour pressure for the single components is calculated to be 1.35E-5 to 1.68E-4 Pa at 20 °C (Nagel, 2011). The water solubility of Fatty acids, C16-18, isobutyl esters is estimated to be < 0.05 mg/L (Frischmann, 2012). 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, 2008). 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, 2008). As the molecular weight of Fatty acids, C16-18, isobutyl esters is 312.54 to 340.60 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, C16-18, isobutyl esters, as all rules are fulfilled except for the log Pow, which is above the given range of -0.4 to 5.6. The log Pow of 8.65 to 9.63 suggests that Fatty acids, C16-18, isobutyl esters are 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, 2008). 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 Fatty acids, C16-18, isobutyl 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, 2008). As the molecular weight of Fatty acids, C16-18, isobutyl esters is in the range of 312.54 to 340.60 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, 2008). As Fatty acids, C16-18, isobutyl esters 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 in the range of 1.26E-05 to 3.41-E05 mg/cm2/event (very low) was predicted for Fatty acids, C16-18, isobutyl esters (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, 2008). As the water solubility of Fatty acids, C16-18, isobutyl esters is estimated to be less than 0.05 g/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 Fatty acids, C16-18, isobutyl esters in humans is considered as very limited. Inhalation: Fatty acids, C16-18, isobutyl esters have a low vapour pressure in the range of 1.35E-5 to 1.68E-4 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, 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 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, 2008). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C16-18, isobutyl esters can be taken up by micellar solubilisation. Overall, a systemic bioavailability of Fatty acids, C16-18, isobutyl esters 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 high log Pow of > 5 implies that Fatty acids, C16-18, isobutyl esters may have the potential to accumulate in adipose tissue (ECHA, 2008). However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, leading to the cleavage products isobutanol and the respective C16-18 fatty acid. The log Pow of the first cleavage product isobutanol is 0.76, indicating a high solubility in water (HSDB). Consequently, there is no potential for isobutanol to accumulate in adipose tissue. 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, 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, 2008). Fatty acids, C16-18, isobutyl esters undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products isobutanol and the respective fatty acid. Isobutanol, a small, water-soluble substance, 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, isobutanol and the fatty acid will be distributed in the organism. Metabolism Esters of fatty acids are hydrolysed to the corresponding alcohol (isobutanol) 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 that 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 rate of hydrolysis of the similar substance Fatty acids, C16-18, butyl esters was determined to be 242 µmol/g*min by in vitro analysis. After 4 h 50% of the substance was hydrolysed in simulated intestinal fluid in the presence of pancreatin but no hydrolysis occurred in simulated saliva or simulated gastric fluid (Cognis, 1993a/b). The first cleavage product, isobutanol, is either oxidized by the non-specific alcohol dehydrogenase (ADH) to isobutyraldehyde, which is further oxidized to isovaleric acid via mitochondrial aldehyde dehydrogenase (HSDB). The second cleavage product, the fatty acid, is stepwise degraded byβ-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 The main route of excretion of Fatty acids, C16-18, isobutyl esters 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 route is renal excretion via the urine due to the low molecular weight and the high water solubility. Isobutanol is excreted via exhalation and urinary excretion of the glucuronidated alcohol. Experimental data of the structurally similar 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 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).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential