Fatty acids, C8-10, C12-18-alkyl esters

Endpoint summary

Additional information

The long-chain aliphatic ester (LCAE) category covers mono-esters of a fatty acid and a fatty alcohol. The category contains both mono-constituent and UVCB substances. The fatty acid carbon chain lengths range is C8 - C22 (even- and un-even numbered, including saturated, unsaturated, branched and linear chains) esterified with fatty alcohols with chain lengths from C8 - C22 (even-numbered, including saturated, unsaturated, branched and linear) in varying proportions to mono-esters.

Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. myristyl alcohol, stearyl alcohol) with an organic acid (e.g. myristic acid, stearic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by the transfer of a proton from the acid catalyst to the alcohol 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 the carbonyl carbon of the 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). Mono-esters are the final products of the 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).

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 LCAE.

 

CAS	EC Name	Molecular weight	Fatty alcohol chain length	Fatty acid chain length	Molecular formula
CAS 20292-08-4 (b)	2-ethylhexyl laurate	312.53	C8	C12	C20H40O2
CAS 91031-48-0	Fatty acids, C16 - 18, 2-ethylhexyl esters	368.65; 396.7	C8	C16 - 18	C24H48O2; C26H52O2
CAS 26399-02-0	2-ethylhexyl oleate	394.67	C8	C18	C26H50O2
CAS 868839-23-0	propylheptyl octanoate	284.48	C10	C8	C18H36O2
CAS 3687-46-5	decyl oleate	422.73	C10	C18	C28H54O2
CAS 59231-34-4 (a)	isodecyl oleate	422.73	C10	C18	C28H54O2
CAS 36078-10-1	dodecyl oleate	450.78	C12	C18	C30H58O2
CAS 95912-86-0	Fatty acids, C8 - 10, C12 - 18-alkyl esters	312.53 - 424.74	C12 - 18	C8 - 10	C20H40O2; C22H44O2; C26H52O2; C28H56O2
CAS 95912-87-1	Fatty acids, C16 - 18, C12 - 18-alkyl esters	424.74 - 536.96	C12 - 18	C16 - 18	C28H56O2; C30H60O2; C34H68O2; C36H72O2
CAS 91031-91-3	Fatty acids, coco, isotridecyl esters	382.66 - 410.72	C13	C12 - 18	C25H50O2; C27H54O2
CAS 85116-88-7	Fatty acids, C14 - 18 and C16 - 18 unsaturated, isotridecyl esters	410.72 - 466.82	C13	C14 - 18	C27H54O2; C29H56O2; C31H60O2; C31H62O2
CAS 95912-88-2	Fatty acids, C16 - 18, isotridecyl esters	438.78 - 466.83	C13	C16 - 18	C29H58O2; C31H62O2
CAS 3234-85-3	tetradecyl myristate	424.74	C14	C14	C28H56O2
CAS 22393-85-7	tetradecyl oleate	478.84	C14	C18	C32H62O2
CAS 101227-09-2	Fatty acids, C16 - 18, 2-hexyldecyl esters	480.85; 508.90	C16	C16 - 18	C32H64O2; C34H68O2
CAS 94278-07-6	2-hexyldecyl oleate	506.89	C16	C18	C34
CAS 97404-33-6	Fatty acids, C16 - 18, C16 - 18-alkyl esters	480.85 - 536.97	C16 - 18	C16 - 18	C32H64O2; C34H68O2; C36H72O2
Former CAS 97404-33-6	Fatty acids, C12-18 (even numbered); C16-20 (even numbered) alkyl esters	424.74 - 565.01	C16 - 20	C12 - 18	C28H56O2; C38H76O2
CAS 72576-80-8	isooctadecyl palmitate	508.90	C18	C16	C34H68O2
CAS 3687-45-4	(Z)-octadec-9-enyl oleate	532.92	C18	C18	C36H68O2
CAS 17673-56-2	(Z)-octadec-9-enyl (Z)-docos-13-enoate	589.03	C18	C22	C40H76O2
CAS 96690-38-9	Fatty acids, C16 - 18, 2-octyldodecyl esters	536.96; 565.01	C20	C16 - 18	C36H72O2; C38H76O2
CAS 93803-87-3	2-octyldodecyl isooctadecanoate	565.01	C20	C18	C38H70O2
CAS 17671-27-1	docosyl docosanoate	649.17	C22	C22	C44H88O2
CAS 111937-03-2 (c)	isononanoic acid, C16 - 18 alkyl esters	382.66; 410.72	C16 - 18	C9	C25H50O2; C27H54O2

(a) Category members subjected to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font.

(c) Surrogate substances are chemicals of structurally similar fatty acid esters. Available data on these substances are used for assessment of (eco-)toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

 

Grouping of substances into this category is based on:

(1) common functional groups: all the members of the category are esters of a mono-functional alcohol with one carboxylic (fatty) acid chain. The fatty alcohol moiety has chain lengths from C8 - C22 (uneven/even-numbered, including saturated and unsaturated, and branched and linear chains) in varying proportions. The fatty acid moiety consists of carbon chain lengths from C8 - C22 (uneven/even-numbered) and includes saturated and unsaturated, and branched and linear chains bonded to the alcohol, resulting in mono-esters; and

 

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: the members of the category result from esterification of the alcohol with the respective fatty acid(s). Esterification is, in principle, a reversible reaction (hydrolysis). Thus, the alcohol and fatty acid moieties are simultaneously precursors and breakdown products of the category members. Monoesters are hydrolysed by enzymes in the gastrointestinal tract. The rate varies depending on the acid and alcohol chain length, but is relatively slow compared with the ester bonds of triglycerides (Mattson and Volpenhein, 1969; Savary and Constantin, 1970). The hydrolysis products are absorbed via the lymphatic system and subsequently enter the bloodstream. Fatty acids can be oxidised or re-esterified and stored, depending on the need for metabolic energy. The oxidation occurs primarily via beta-oxidation, which involves the sequential cleavage of two-carbon units, released as acetyl-CoA through a cyclic series of reactions catalysed by several specific enzymes. This happens in the mitochondria and, to a lesser degree, the peroxisomes (Lehninger et al., 1993). Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids. Unsaturated fatty acids require additional isomerization prior to entering the β-oxidation cycle. The alcohol is, in general, enzymatically oxidized to the corresponding carboxylic acid, which can then be degraded via β-oxidation (Lehninger et al., 1993). (Refer to IUCLID Section 5.3 “Bioaccumulation” and 7.3 “Toxicokinetics, metabolism and distribution” for details); and

 

(3) constant pattern in the changing of the potency of the properties across the category: the available data show similarities within the category in regard to physicochemical, environmental fate, ecotoxicological and toxicological properties.

 

a) Physicochemical properties:

The molecular weight of the category members ranges from 284.48 to 649.17 g/mol. The physical appearance is related to the chain length of the fatty acid moiety, the degree of saturation and the branching. Monoesters of short-chain and/or unsaturated and/or branched fatty acids are mainly liquid, while the long-chain fatty acids are generally solids. All the category members are non-volatile (vapour pressure: <0.0001 Pa (minimum) - 0.11 Pa (maximum)). The octanol/water partition coefficient increases with increasing fatty acid chain length, ranging from 7.67 (C8 (FA)/C12iso (FAlc.) ester)) to 20.51 (C22-monoester). The water solubility is low for all category members (< 1 mg/L or even < 0.05 mg/L).

 

b) Environmental fate and ecotoxicological properties:

Considering the low water solubility (< 1 mg/L or even < 0.05 mg/L) and the potential for adsorption to organic soil and sediment particles (log Koc > 5), the main compartments for environmental distribution are expected to be the soil and sediment. Nevertheless, persistency in these compartments is not expected since all members of the LCAE Category are readily biodegradable and are thus expected to be eliminated in sewage treatment plants to a high extent. Release to surface waters, and thereby exposure of sediment, is very unlikely. Thus, the soil is expected to be the major compartment of concern. Nevertheless, the category members are expected to be metabolised by soil microorganisms. Evaporation into air and the transport through the atmosphere to other environmental compartments is not expected since the category members are not volatile based on the low vapour pressure (vapour pressure: <0.0001 Pa (minimum) - 0.11 Pa (maximum)). All members of the category did not show any effects on aquatic organisms in the available acute and chronic tests representing the category members up to the limit of water solubility. Moreover, bioaccumulation is assumed to be low since the category members undergo common metabolic pathways and will be excreted or used as energy source for catabolism.

 

c) Toxicological properties:

The available data indicate that all the category members show similar toxicological properties. Thus, none of the category members caused acute oral, dermal or inhalation toxicity, or skin or eye irritation, or skin sensitisation. No treatment-related effects were noted up to and including the limit dose of 1000 mg/kg bw/day after repeated oral exposure in a total of 6 studies. In one study the NOAEL was set at 300 mg/kg bw/day, due to reduced food intake and weight loss observed in dams at the highest dose level. These adverse systemic effects subsequently caused impaired fertility in the dams, and reduced pup viability and body weight. However, considering all the available data the category members have a very limited potential for toxicity. The substances did not show a potential for toxicity to reproduction, fertility and development unless systemic toxicity was also evident at the same dose level. No mutagenic or clastogenic potential was observed.

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 for 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.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

The terrestrial toxicity data of the LCAE category members are presented in the following table.

 

Terrestrial toxicity data of the LCAE category members

CAS	Toxicity to soil macroorganisms except arthropods	Toxicity to terrestrial arthropods	Toxicity to terrestrial plants	Toxicity to soil microorganisms
3687-46-5 (b)	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
59231-34-4 (a)	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
36078-10-1	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
95912-86-0	NOEC (56 d): 500 mg/kg soil dw	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
95912-87-1	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
91031-91-3	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
85116-88-7	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
95912-88-2	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
3234-85-3	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
22393-85-7	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
101227-09-2	RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
97404-33-6	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
Former CAS 97404-33-6	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
72576-80-8	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
3687-45-4	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
17673-56-2	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
96690-38-9	RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
93803-87-3	NOEC (56 d): ≥ 1000 mg/kg soil dw	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)
17671-27-1	RA: CAS 95912-86-0 RA: CAS 93803-87-3	Waiving based on CSA	Waiving based on CSA	Weight of Evidence (WoE)

(a) Category members subjected to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

Exposure of the soil compartment is generally considered to be low. Even if exposed to the soil the LCAE category members are readily biodegradable indicating that they will not be persistent in the environment. Indirect exposure via irrigation or atmospheric transport is considered to be negligible based on the physico-chemical properties of the LCAE category members (water solubility:< 1 mg/L or even < 0.05 mg/L;vapour pressure: <0.0001 Pa (minimum) - 0.11 Pa (maximum)).

Experimental data investigating the toxicity of the LCAE category members to earthworms are available for the two representative category members fatty acids, C8-10, C12-18-alkyl esters (CAS 95912-86-0) and 2-octyldodecyl isooctadecanoate (CAS 93803-7-3) covering the variability of the category with different alcohol and representative fatty acid chain lengths. Testing of the toxicity on earthworm evaluates the exposure to the test substance via soil pore water, surface contact as well as by ingestion of soil particles. Due to the high adsorption potential (log Koc > 5), long-term testing was considered to be relevant to investigate further the effects of the substance on terrestrial organisms. The available studies according to OECD 222 were performed for the category members fatty acids, C8-10, C12-18-alkyl esters (CAS 95912-86-0) and 2-octyldodecyl isooctadecanoate (CAS 93803-7-3). Fatty acids, C8-10, C12-18-alkyl esters is characterized by a short-chain fatty acid (C8-10) and fatty alcohol (C12-14) covering the lower end of the category. 2-octyldodecyl isooctadecanoate was selected to cover the upper end of the category since it is structurally characterized by a long-chain fatty acid (C18iso) and a branched fatty alcohol component with a chain length of C20. Therefore, most of the data gaps can be covered by interpolation. Both substances are also covering different routes for possible uptake of the substance. Dermal uptake via pore water is not considered to be a relevant exposure pathway based on the very low water solubility. However, the smallest substance of the category (Fatty acids, C8-10, C12-18-alkyl esters) represents a worst case for the uptake via dermal absorption since the substance is expected to be the most water soluble of all the category members. The water solubility is negatively correlated with the C-chain lengths of the fatty acid and fatty alcohol (Lide, 2005). Whereas, 2-octyldodecyl isooctadecanoate is representative as one of the category members with the highest potential for adsorption to soil particles which can be taken up via ingestion (log Koc: 10.49; Müller, 2011). Thus, the two main routes of exposure for terrestrial organisms are covered by studies with the two representative category members. The study with the read-across substance fatty acids, C8-10, C12-18-alkyl esters resulted on a NOEC (56 d) of 500 mg/kg dw whereas the available study with 2-octyldodecyl isooctadecanoate resulted in no effects on reproduction with a NOEC (56 d) ≥ 1000 mg/kg soil dw. After absorption, the LCAE category members are expected to be enzymatically hydrolyzed by carboxylesterases yielding to the corresponding alcohol and fatty acid. QSAR estimations using BCFBAF v3.0 support the expected rapid biotransformation of this substance with BCF/BAF values of 0.89 - 14.07 and 0.89 - 314 L/kg were obtained, respectively. The metabolism of the hydrolysis products is well established and not of concern in terms of bioaccumulation (for further information see chapter 5.3 of the technical dossier). Summarizing, the LCAE category members are expected to be rapidly hydrolyzed to the respective fatty acid and fatty alcohol. Both hydrolysis products are supposed to be satisfactory metabolized in terrestrial organisms. Therefore, the potential for bioaccumulation is low. Available acute and chronic aquatic toxicity tests to fish, invertebrates, algae and microorganisms showed no adverse effects occurred in the range of the water solubility of the LCAE category members (< 1 mg/L or even < 0.05 mg/L). These results support the assumption that the LCAE category members are of low toxicity to terrestrial organisms.

The available data for toxicity to aquatic microorganisms for the LCAE category members supports the determination of a lack of toxicity to soil microorganisms. No inhibition of respiration rate of aquatic microorganisms was observed in any of the available studies for the LCAE category members. The Guidance Document (ECHA, 2012, page 122) states that a test on soil microbial activity will only be additionally necessary for a valid PNEC derivation if inhibition of sewage sludge microbial activity has occurred and this is clearly not the case. This is supported by further evidence from literature data. This data showed that soil microorganism communities are well capable of degrading fatty acid esters (Hita et al., 1996 and Cecutti et al., 2002) and use them as energy source (Banchio & Gramajo, 1997). Based on the available information, effects on soil microorganisms are not expected to be of concern, and consequently, no further testing is required.

In conclusion the LCAE category members are of low toxicity to terrestrial organisms based on all available data.

 

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