Fatty acids, C16-18, iso-Pr esters

Endpoint summary

Additional information

The Short Chain Alcohol Esters (SCAE C2-C8) category covers esters from a fatty acid (C8-C29) and a C2-C8 alcohol (ethanol, isopropanol, butanol, isobutanol, pentanol, iso-pentanol, hexanol, 2-ethylhexanol or octanol). This category includes both well-defined mono-constituent substances as well as related UVCB substances with varying fatty acid chain lengths.

Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. isopropanol) with an organic acid (e.g. stearic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by a transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. 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 (Liu et al, 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Esters are the final product of esterification.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met”. In particular, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

The rationale for grouping the substances in the SCAE C2-C8 category is based on similarities in physicochemical, ecotoxicological and toxicological properties.

In this particular case, the similarity of the SCAE C2-C8 category members is justified, in accordance with the specifications listed in Regulation (EC) No. 1907/2006 Annex XI, 1.5

Grouping of substances and read across, based on representative molecular structure, physico-chemical properties, tox-, ecotoxicological profiles, supported by a robust set of experimental data and QSAR calculations. There is no convincing evidence that any one of these chemicals might lie out of the overall profile of this category, respectively.

Grouping of substances into this category is based on:

• Similar/overlapping structural features or functional groups: All category members are monoesters of alcohols (C2-C8) and fatty acids (C8-C29), with 13 to 32 carbons in total.

• Common precursors and the likelihood of common breakdown products via biological processes: All category members are subject to enzymatic hydrolysis by pancreatic lipases (Mattson and Volpenhein, 1972; and references therein). The resulting free fatty acids and alcohols are absorbed from the intestine into the blood stream. Fatty acids are either metabolised via the beta-oxidation pathway in order to generate energy for the cell or reconstituted into glyceride esters and stored in the fat depots in the body. The alcohols are metabolised primarily in the liver through a series of oxidative steps, finally yielding carbon dioxide (Berg et al., 2002; HSDB).

• Similar physico-chemical properties: The log Kow and log Koc values of all category members are high (log Kow > 4, log Koc > 3), increasing with the size of the molecule. The substances are poorly soluble in water and have low vapour pressure. 

• Common properties for environmental fate & eco-toxicology: Based on experimental data, all substances (all substances to be registered and read-across substances used for environmental fate and ecotoxicology) are readily biodegradable and do not show toxic effects up to the limit of water solubility.

• Common levels and mode of human health related effects: All available experimental data indicate that the members of the SCAE C2-C18 category are not acutely toxic, are not irritating to the skin or to the eyes and do not have sensitizing properties. Repeated dose toxicity was shown to be low for all substances. None of the substances showed mutagenic effects, and toxicity to reproduction was low throughout the category.

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substances listed below are allocated to the category of SCAE C2-C8.

 

Members of the SCAE C2-C8 Category:

EC No.	CAS No.	Chemical name	Alcohol Carbon No.	Fatty acid Carbon No.	Total Carbon	MW
208-868-4	544-35-4 (b)	Ethyl linoleate	2	18	20	308.50
203-889-5	111-62-6	Ethyl oleate	2	18	20	310.52
293-054-1	91051-05-7	Fatty acids, essential, ethyl esters	2	14 - 22	16 - 24	252.39-368.64
233-560-1	10233-13-3	Isopropyl laurate	3	12	15	242.41
203-751-4	110-27-0	Isopropyl myristate	3	14	17	270.46
205-571-1	142-91-6	Isopropyl palmitate	3	16	19	298.51
269-023-3	68171-33-5 (a)	Isopropyl isostearate	3	18	21	326.56
203-935-4	112-11-8	Isopropyl oleate	3	18	21	324.55
292-962-5	91031-58-2	Fatty acids, C16-18, isopropyl esters	3	16 - 18	19 - 21	312.54-326.57
264-119-1	63393-93-1	Fatty acids, lanolin, isopropyl esters	3	10 - 29	13 - 32	214.34-480.85
204-666-5	123-95-5	butyl stearate	4	18	22	340.59
267-028-5	67762-63-4	Fatty acids, tall-oil, butyl esters	4	18	22	423.72
287-039-9	85408-76-0	Fatty acids, C16-18, Bu esters	4	16 - 18	20 - 22	312.53-340.58
284-863-0	84988-74-9	Fatty acids, C16-18 and C18-unsatd., Bu esters	4	16 - 18	20 - 22	312.53- 340.58
	163961-32-8	Fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters	4	16 - 18	20 - 22	312.54- 340.58
211-466-1	646-13-9	Isobutyl stearate	4	18	22	340.59
288-668-1	85865-69-6	Fatty acids, C16-18, iso-Bu esters	4	16 - 18	20 - 22	312.54- 340.60
84988-79-4	84988-79-4	Fatty acids, C16-18 and C18-unsatd., iso-Bu esters	4	16 - 18	20 - 22	312.54- 340.60
228-626-1	6309-51-9	Isopenthyl laurate Dodecanoic acid, 2-methyl butyl ester	5	12	17	270.46
694-886-1	1365095-43-7	Isopentyl decanoate and octanoate	5	8 - 10	13 - 15	214.344- 242.40
251-932-1	34316-64-8	Dodecanoic acid, hexyl ester	6	12	18	284.49
218-980-5	2306-88-9	octyl octanoate	8	8	16	256.42
	84713-06-4	Dodecanoic acid, isooctyl ester	8	12	20	312.53
243-697-9	20292-08-4	2-Ethylhexyl laurate	8	12	20	312.53
692-946-1	649747-80-8	Fatty acids, C8-10, 2-ethylhexyl esters	8	8 - 10	16 - 18	256.42-284.48
603-931-6	135800-37-2	Fatty acids, C8-16, 2-ethylhexyl esters	8	12 - 14	20 - 22	256.42-368.65
249-862-1	29806-73-3	2-ethylhexyl palmitate	8	16	24	368.64
	22047-49-0	2 -ethylhexyl stearate	8	18	26	396.69
295-366-3	92044-87-6	Fatty acids, coco, 2-ethylhexyl esters	8	12 - 18	20 - 26	312.53-340.60
292-951-5	91031-48-0	Fatty acids, C16-18, 2-ethylhexyl esters	8	16 - 18	24 - 26	368.65-396.70
285-207-6	85049-37-2	Fatty acids, C16-18 and C18-unsatd., 2-ethylhexyl esters	8	16 - 18	24 - 26	368.65-396.70
247-655-0	26399-02-0	2-Ethylhexyl oleate	8	18	26	394.67

 

(a) Category members subject to registration are indicated in bold font.

(b) Substances not subject to registration are indicated in normal font.

 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. For a detailed review of the data matrix please refer to the category justification attached in section 13 in IUCLID.

 

Terrestrial toxicity

Due to their low solubility and high adsorption potential, members of the SCAE C2-C8 category are expected to mostly sorb to soil natural organic matter, in terrestrial systems. Concentrations in soil pore water are expected to be low, also due to ready biodegradation. These substances will therefore be relevant for uptake mainly for soil dwelling organisms feeding on soil organic matter, such as earthworms.

The terrestrial toxicity of short chain fatty acid esters has been tested on the earthworm Eisenia fetida with the test substance isopropyl myristate (CAS No. 110-27-0). No mortality was observed during the 14-day exposure period at the test concentration of 20,000 mg/kg. Additionally, data is also available for tests with terrestrial plants for the substance Fatty acids, C16-18 and C18-unsaturated, 2-ethylhexyl esters (CAS No. 85049-37-2). The 21-day NOEC value is determined to be 100 mg/kg for all plants tested, and EC50 values between 390 and 600 mg/kg are reported.

Based on the available data, the terrestrial toxicity of the test substance isopropyl myristate is very low. The tested substances represent C20-22 and C24-26 fatty acid esters. Since all category members are poorly soluble in water (< 0.05 mg/L to < 0.15 mg/L), have high adsorption potential (Koc > 3) and a high log Kow (> 4), their behaviour in the terrestrial compartment is expected to be similar. Furthermore, all category members are expected to be metabolised by organisms after ingestion, which is conidered to be the main uptake route. Esters of primary alcohols, containing from 1 to 18 carbon atoms, with fatty acids, containing from 2 to 18 carbon atoms, have shown to be hydrolysed by pancreatic lipases in a study by Mattson and Volpenhein (Mattson and Volpenhein, 1972; and references therein). Measured rates of enzyme catalysed hydrolysis varied between 2 and 5 µeq/min/mg enzyme for the different chain lengths. The longer esters possibly present in the UVCB substance Fatty acids, lanolin, isopropyl esters (CAS 63393-93-1), are also expected to be hydrolysed. Only moderate differences in the rate of hydrolysis were observed for different long chain saturated and unsaturated fatty-acid esters, in studies investigating the fatty acid specificity of pancreatic lipases (Macrae and Hammond, 1985; and references therein). Exceptionally poor substrates were esters of fatty acids containing a double bond or a bulky substituent close to the carboxyl group, probably due to steric reasons. However, Fatty acids, lanolin, isopropyl esters (CAS 63393-93-1) only contains saturated fatty acids and branching may only occur on the penultimate or the ante-penultimate carbon atom, i.e. far from the carboxyl group. All esters of the SCAE C2-C8 category are thus expected to be hydrolysed by lipases. The resulting free fatty acids and alcohols are absorbed from the intestine into the blood stream. The alcohols are metabolised primarily in the liver through a series of oxidative steps, finally yielding carbon dioxide (Berg et al., 2001; HSDB). Fatty acids are either metabolised via the beta-oxidation pathway in order to generate energy for the cell or reconstituted into glyceride esters and stored in the fat depots in the body (Berg et al., 2001). For fatty acids up to C22, beta-oxidation generally takes place in the mitochondria, resulting in the final product acetyl-CoA, which directly enters the citric acids cycle (Berg, 2002). Beta-oxidation of longer fatty acids takes place in the peroxisomes and is incomplete (Reddy and Hashimoto, 2001; Singh et al., 1987; Le Borgne and Demarquoy, 2012; and references therein). It gives rise to medium chain acyl-CoA, which are then taken in charge by the carnitine octanoyl transferase and converted into acyl-carnitine that can leave the peroxisome and, at least for some of them, may be fully oxidized in the mitochondria (Le Borgne and Demarquoy, 2012; and references therein). Plants and most fungi harbour the beta-oxidation cycle only in the peroxisomes (Poirier, 2006).

The available earthworm study can therefore be used as part of a read-across approach for all other substances within the category. Based on the available information, toxicity to terrestrial organisms is not expected to be of concern, and consequently, no further testing is proposed.

 

References:

Berg, J.M., Tymoczko, J.L. and Stryer, L., 2002, Biochemistry, 5^thedition, W.H. Freeman and Company

Bilbao, E., Cajaraville, M.P., Cancio, I. (2009), Cloning and expression pattern of peroxisomal β-oxidation genes palmitoyl-CoA oxidase, multifunctional protein and 3-ketoacyl-CoA thiolase in mussel Mytilus galloprovincialis and thicklip grey mullet Chelon labrosus, Gene, 443(1-2): 132-42

Le Borgne, F., Demarquoy, J. (2012): Interaction between peroxisomes and mitochondria in fatty acid metabolism, Open Journal of Molecular and Integrative Physiology, 2012, 2, 27-33

Frøyland, Lie, Berge (2000), Mitochondrial and peroxisomalβ-oxidation capacities in various tissues from Atlantic salmon Salmo salar, Aquaculture Nutrition, 6 (2): 85-89

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196

Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12.

Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286.

Macrae, A.R., Hammond, R.C. (1985) Present and future applications of lipases, Biotechnology and Genetic Engineering Reviews, 3: 193-217

Mattson, F.H. and Volpenheim, R.A. (1972): Relative rates of hydrolysis by rat pancreatic lipase of esters of C2-C18 fatty acids with C1-C18 primary n-alcohols, Journal of Lipid Research, 10, 1969

Poirier, Y., Antonenkov, V.C., Glumoff, T, Hiltunen, K. (2006) Peroxisomal β-oxidation - A metabolic path- way with multiple functions Biochimica et Biophysica Acta 1763 (12), 1413-1426

Radzi, S.M. et al.(2005). High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica. Electronic Journal of Biotechnology 8: 292-298.

Reddy and Hashimoto (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: An adaptive metabolic System, Annual Review of Nutrition, 21, 193-230

Rocha, M.J., Rocha, E., Resende, A.D., Lobo-da-Cunha (2003) Measurement of peroxisomal enzyme activities in the liver of brown trout (Salmo trutta), using spectrophotometric methods, BMC Biochemistry, 4:2,doi:10.1186/1471-2091-4-2

Singh, H., Derwas, N. and Puolos, A. (1987) Beta-oxidation of very-long-chain fatty acids and their coenzyme A derivatives by human skin fibroblasts, Arch Biochem Biophys, 254(2): 526-33

Tocher, D.R. (2003): Metabolism and function of lipids and fatty acids in teleost fish, Reviews of Fisheries Science, 11 (2), 197

Winkler, U., Säftel, W., Stabenau, H. (1988), beta-Oxidation of fatty acids in algae: Localization of thiolase and acyl-CoA oxidizing enzymes in three different organisms, Planta, 175(1): 91-98

Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.