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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

656.01 - 649.17

C18-C22 (even)

C20-C22 (even)

C38H76O2;

C40H80O2;

C44H88O2

CAS 111937-03-2 (c)

isononanoic acid, C16 - 18 alkyl esters

382.66; 410.72

C16 - 18

C9

C25H50O2; C27H54O2

(a) Category members subject 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 environmental fate parameters of the LCAE category members are presented in the following table.

 

Environmental fate parameters of the LCAE category members

CAS

Phototransformation in air [DT50, 24 h day]

Hydrolysis [DT50, pH 7]

Biodegradation: screening tests

BCF/BAF [L/kg]

Adsorption [log Koc]

3687-46-5

4.40 h (cis isomer); 4.05 h (trans isomer)

 

> 1 yr

RA: CAS 17671-27-1

 

0.93/55.56 (Arnot-Gobas)

> 5 (MCI)

59231-34-4 (a)

4.40 h (cis isomer); 4.05 h (trans isomer)

 

> 1 yr

RA: CAS 17671-27-1

RA: CAS 93803-87-3

RA: CAS 94278-07-6

0.93/51.10 (Arnot-Gobas)

> 5 (MCI)

36078-10-1

4.26 h (cis isomer); 3.93 h (trans isomer)

 

> 1 yr

RA: CAS 17671-27-1

0.89/16.80(Arnot-Gobas)

> 5 (MCI)

95912-86-0

11.16 - 16.60 h

> 1 yr

RA: CAS 3234-85-3

RA: 17671-27-1

0.99 - 14.07/58.01 - 314 (Arnot-Gobas)

> 5 (MCI)

95912-87-1

8.41 - 11.16 h

> 1 yr

readily biodegradable

0.89 - 0.91/0.95 - 23.72(Arnot-Gobas)

> 5 (MCI)

91031-91-3

11.64 - 12.72 h

 

> 1 yr

RA: CAS 3234-85-3

RA: 17671-27-1

0.94 - 1.13/35.1 - 75.03(Arnot-Gobas)

> 5 (MCI)

85116-88-7

3.88 - 11.64 h

> 1 yr

RA: CAS 17671-27-1

0.90 - 0.94/8.90 - 39.41(Arnot-Gobas)

> 5 (MCI)

95912-88-2

9.78 - 10.72 h

> 1 yr

RA: CAS 17671-27-1

0.90/5.03 - 13.61 (Arnot-Gobas)

> 5 (MCI)

3234-85-3

11.16 h

> 1 yr

readily biodegradable

0.91/23.70 (Arnot-Gobas)

> 5 (MCI)

22393-85-7

4.13 h (cis isomer); 3.82 h (trans isomer)

 

> 1 yr

RA: CAS 17671-27-1

0.89/4.55(Arnot-Gobas)

> 5 (MCI)

101227-09-2

8.82 - 9.43 h

> 1 yr

readily biodegradable

0.89/1.32 - 3.09(Arnot-Gobas)

> 5 (MCI)

94278-07-6 (b)

--

--

readily biodegradable

--

--

97404-33-6

8.41 - 9.59 h

> 1 yr

RA: CAS 17671-27-1

0.89/0.95 - 2.67(Arnot-Gobas)

> 5 (MCI)

Former CAS 97404-33-6

7.92 - 11.16 h

> 1 yr

RA: CAS 17671-27-1

0.89 - 0.91/0.90 - 23.72 (Arnot-Gobas)

> 5 (MCI)

72576-80-8

8.96 h

> 1 yr

RA: CAS 17671-27-1

0.89/1.27(Arnot-Gobas)

> 5 (MCI)

3687-45-4

2.54 h (cis isomer); 2.30 h (trans isomer)

 

> 1 yr

RA: CAS 17671-27-1

0.89/1.08(Arnot-Gobas)

> 5 (MCI)

17673-56-2

2.44 h (cis isomer); 2.23 h (trans isomer)

 

> 1 yr

RA: CAS 17671-27-1

0.89/0.89(Arnot-Gobas)

> 5 (MCI)

96690-38-9

7.81 - 8.28 h

> 1 yr

RA: CAS 93803-87-3

0.89/0.90 - 0.96(Arnot-Gobas)

> 5 (MCI)

93803-87-3

7.81 h

> 1 yr

readily biodegradable

0.89/0.90(Arnot-Gobas)

> 5 (MCI)

17671-27-1

6.74 h

 

> 1 yr

readily biodegradable

0.89/0.89(Arnot-Gobas)

> 5 (MCI)

(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 “--“.

(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. 

 

Environmental fate of the LCAE Category members

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, MCI method, KOCWIN v2.00), the main compartments for environmental distribution are expected to be soil and sediment. Nevertheless, persistency in these compartments is not expected since the members of the LCAE Category are readily biodegradable according to the OECD criteria in several experimental studies representing the category members (67 - 94.6% biodegradation after 28 d). Due to their ready biodegradability and high adsorption potential, it is assumed that the category members are eliminated in sewage treatment plants to a high extent. Release to surface waters, and thereby exposure of sediments, is very unlikely. Thus, the soil is expected to be the major compartment of concern. However, if exposure does occur the category members are expected to be metabolised rapidly by soil microorganisms. Degradation via abiotic hydrolysis is not considered to be a relevant degradation pathway in the environment, since QSAR results using HYDROWIN v2.00 resulted in DT50 > 1 yr at pH 7. Evaporation into air and the transport through the atmospheric compartment 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)). Accumulation in air and the subsequent transport to other environmental compartments is not anticipated. However, if released into air, all category members are susceptible to indirect photodegradation by OH-radicals with a half-life (DT50) < 24 h (AOPWIN v1.92). Due to the low exposure in the water phase (low water solubility), rapid environmental biodegradation and metabolisation via enzymatic hydrolysis of the LCAE category members, a relevant uptake and bioaccumulation in aquatic organisms is not expected. Enzymatic breakdown will initially lead to the free fatty acid (e.g. oleic acid) and the free alcohol (e.g. octan-1-ol). From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (Heymann, 1980; Lech & Bend, 1980; Lech & Melancon, 1980; Murphy & Lutenske, 1990). This is supported by low calculated BCF values of 0.89 - 14.07 L/kg ww (BCFBAF v3.01, Arnot-Gobas, including biotransformation, upper trophic; Müller, 2011 and 2013). Please refer to IUCLID Section 5.3 for a detailed overview on bioaccumulation of the LCAE category members.

Metabolism of LCAE Category members

Should the category members be taken up by fish during the process of digestion and absorption in the intestinal tissue, aliphatic esters like LCAE are expected to be initially metabolized via enzymatic hydrolysis to the corresponding free fatty acids and the free fatty alcohols such as oleic acid and tetradecan-1-ol, for example. The hydrolysis is catalyzed by classes of enzymes known as carboxylesterases or esterases (Heymann, 1980). The most important of which are the B-esterases in the hepatocytes of mammals (Heymann, 1980; Anders, 1989). Carboxylesterase activity has been noted in a wide variety of tissues in invertebrates as well as in fish (Leinweber, 1987; Soldano et al, 1992; Barron et al., 1999, Wheelock et al., 2008). The catalytic activity of this enzyme family leads to a rapid biotransformation/metabolism of xenobiotics which reduces the bioaccumulation or bioconcentration potential (Lech & Bend, 1980). It is known for esters that they are readily susceptible to metabolism in fish (Barron et al., 1999) and literature data have clearly shown that esters do not readily bioaccumulate in fish (Rodger & Stalling, 1972; Murphy & Lutenske, 1990; Barron et al., 1990). In fish species, this might be caused by the wide distribution of carboxylesterase, high tissue content, rapid substrate turnover and limited substrate specificity (Lech & Melancon, 1980; Heymann, 1980). The metabolism of the enzymatic hydrolysis products is presented in the following chapter.

Metabolism of enzymatic hydrolysis products 

Fatty alcohols

Fatty alcohols ranging from C8 (octan-1-ol) to C22 (docosan-1-ol) as well as unsaturated and branched alcohols are the expected corresponding alcohol hydrolysis products from the enzymatic reaction of the LCAE catalyzed by carboxylesterases. The metabolism of alcohols is well known. The free alcohols can either be esterified to form wax esters which are similar to triglycerides or they can be metabolized to fatty acids in a two-step enzymatic process by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) using NAD+ as coenzyme as shown in the gourami (Trichogaster cosby) (Sand et al., 1973). The responsible enzymes ADH and ALDH are present in a large number of animals, plants and microorganisms (Sund & Theorell, 1963; Yoshida et al., 1997). They were found among others in the zebrafish (Reimers et al., 2004; Lassen et al., 2005), carp and rainbow trout (Nilsson, 1988; Nilsson, 1990). The alcohol metabolism was investigated in the zebrafish Danio rerio, which is a standard organisms in aquatic ecotoxicology. Two cDNAs encoding zebrafish ADHs were isolated and characterized. A specific metabolic activity was shown in in-vitro assays with various alcohol components ranging from C4 to C8. The corresponding aldehyde can be further oxidized to the fatty acid catalyzed by an ALDH. Among the ALDHs the ALDH2, located in the mitochondria is the most efficient. The ALDH2 cDNA of the zebrafish was cloned and a similarity of 75% to mammalian ALDH2 enzymes was found. Moreover, it exhibits a similar catalytic activity for the oxidation of acetaldehyde to acetic acid compared to the human ALDH2 protein (Reimers at al., 2004). The same metabolic pathway was shown for longer chain alcohols like stearyl- and oleyl alcohol which were enzymatically converted to its corresponding acid, in the intestines (Calbert et al., 1951; Sand et al., 1973; Sieber, et al., 1974). Branched alcohols like 2-hexyldecanol or 2-octyldodecanol show a high degree of similarity in biotransformation compared to the linear alcohols. They will be oxidized to the corresponding carboxylic acid followed by the ß-oxidation as well. A presence of a side chain does not terminate the ß-oxidation process (OECD, 2006). The influence of biotransformation on bioaccumulation of alcohols was confirmed in GLP studies with the rainbow trout (according to OECD 305) with commercial branched alcohols with chain lengths of C10, C12 and C13 as reported in de Wolf & Parkerton, 1999. This study resulted in an experimental BCF of 16, 29 and 30, respectively for the three alcohols tested. The 2-fold increase of BCF for C12 and C13 alcohol was explained with a possible saturation of the enzyme system and thus leading to a decreased elimination.

Fatty acids

The metabolism of fatty acids in mammals is well known and has been investigated intensively in the past (Stryer, 1994). The free fatty acids can either be stored as triglycerides or oxidized via mitochondrial ß-oxidation removing C2-units to provide energy in the form of ATP (Masoro, 1977). Acetyl-CoA, the product of the ß-oxidation, can further be oxidized in the tricarboxylic acid cycle to produce energy in the form of ATP. As fatty acids are naturally stored as trigylcerides in fat tissue and re-mobilized for energy production is can be concluded that even if they bioaccumulate, bioaccumulation will not pose a risk to living organisms. Fatty acids (typically C14 to C24 chain lengths) are also a major component of biological membranes as part of the phospholipid bilayer and therefore part of an essential biological component for the integrity of cells in every living organism (Stryer, 1994). Saturated fatty acids (SFA; C12 - C24) as well as mono-unsaturated (MUFA; C14 - C24) and poly-unsaturated fatty acids (PUFA; C18 - C22) were naturally found in muscle tissue of the rainbow trout (Danabas, 2011) and in the liver (SFA: C14 - C20; MUFA: C16 - C20; PUFA: C18 - C22) of the rainbow trout (Dernekbasi, 2012).

In conclusion, the LCAE Category members are expected to be metabolized in aquatic organisms to a high extent.

 

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