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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Justification for grouping of substances and read-across

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 uneven numbered, including saturated, unsaturated, branched and linear chains) esterified with fatty alcohols with chain lengths from C8 - C22 (even and uneven 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 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 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.

LCAE category members include:

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

C8iso

C12

C20H40O2

CAS 91031-48-0

Fatty acids, C16 - 18, 2-ethylhexyl esters

368.65; 396.7

C8iso

C16-18 (even)

C24H48O2; C26H52O2

CAS 26399-02-0

2-ethylhexyl oleate

394.67

C8iso

C18:1

C26H50O2

CAS 868839-23-0

Propylheptyl octanoate

284.48

C10iso

C8

C18H36O2

CAS 3687-46-5

Decyl oleate

422.73

C10

C18:1

C28H54O2

CAS 59231-34-4 (a)

Isodecyl oleate

422.73

C10iso

C18:1

C28H54O2

CAS 36078-10-1

Dodecyl oleate

450.78

C12

C18:1

C30H58O2

CAS 95912-86-0

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

312.53 – 424.74

C12-18 (even)

C8-10 (even)

C20H40O2; C22H44O2; C26H52O2; C28H56O2

CAS 95912-87-1

Fatty acids, C16 - 18, C12 - 18-alkyl esters

424.74 - 536.96

C12-18 (even)

C16-18 (even)

C28H56O2; C30H60O2; C34H68O2; C36H72O2

CAS 91031-91-3

Fatty acids, coco, isotridecyl esters

382.66 - 410.72

C13iso

C12-18 (even)

C25H50O2; C27H54O2

CAS 85116-88-7

Fatty acids, C14 - 18 and C16 - 18 unsaturated, isotridecyl esters

410.72 - 466.82

C13iso

C14-18

C27H54O2; C29H56O2; C31H60O2;

C31H62O2

CAS 95912-88-2

Fatty acids, C16 - 18, isotridecyl esters

438.78 - 466.83

C13iso

C16-18 (even)

C29H58O2; C31H62O2

CAS 3234-85-3

Tetradecyl myristate

424.74

C14

C14

C28H56O2

CAS 22393-85-7

Tetradecyl oleate

478.84

C14

C18:1

C32H62O2

CAS 101227-09-2

Fatty acids, C16 - 18, 2-hexyldecyl esters

480.85; 508.90

C16iso

C16-18 (even)

C32H64O2; C34H68O2

CAS 94278-07-6

2-hexyldecyl oleate

506.89

C16iso

C18:1

C34

CAS 97404-33-6

Fatty acids, C16 - 18, C16 - 18-alkyl esters

480.85 - 536.97

C16-18 (even)

C16-18 (even)

C32H64O2; C34H68O2; C36H72O2

CAS 72576-80-8

Isooctadecyl palmitate

508.90

C18iso

C16

C34H68O2

CAS 3687-45-4

(Z)-octadec-9-enyl oleate

532.92

C18:1

C18:1

C36H68O2

CAS 17673-56-2

(Z)-octadec-9-enyl (Z)-docos-13-enoate

589.03

C18:1

C22:1

C40H76O2

CAS 96690-38-9

Fatty acids, C16 - 18, 2-octyldodecyl esters

536.96; 565.01

C20iso

C16-18 (even)

C36H72O2; C38H76O2

CAS 93803-87-3

2-octyldodecyl isooctadecanoate

565.01

C20iso

C18iso

C38H70O2

CAS 17671-27-1

Docosyl docosanoate

565.01 - 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 (even)

C9iso

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 and/or the liver. The hydrolysis 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 Chapter 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 lengths of the fatty acid and fatty alcohol moieties, 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 - 0.000217 Pa). The octanol/water partition coefficient increases with increasing fatty acid and fatty alcohol chain length, ranging from 8.65 (C12 (FA)/C8iso (FAlc.) ester) to 20.51 (C22 (FA) / C22 (FAl.) ester). The water solubility is low for all category members (< 0.05 mg/L).

b) Environmental fate and ecotoxicological properties:

Considering the low water solubility (< 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 andare 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 (< 0.0001 Pa).

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, indicating that the category members have a very limited potential for toxicity. The substances did not show a potential for toxicity to reproduction, fertility and development. 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).

 

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of (Z)-octadec-9-enyl (Z)-docos-13-enoate (CAS 17673-56-2) has been assessed.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 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 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 physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2008) and taking into account available information on the analogue substances from which data was used for read-across to cover data gaps.

The substance (Z)-octadec-9-enyl (Z)-docos-13-enoate is a monoconstituent with an unsaturated C18-alcohol moiety and an unsaturated C22-acid moiety, and a molecular weight of 589.03 g/mol. It is a yellowish liquid at 20 °C (Pittermann, 1995), with an estimated water solubility of < 0.05 mg/L at 20 °C (Frischmann, 2012). The log Pow was estimated to be 18.11 (Müller, 2011) and the vapour pressure was calculated to be < 0.0001 Pa at 20 °C (Pankewitz, 2012).

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters to provide information on this potential are the molecular weight, octanol/water coefficient (log Pow) value and water solubility (ECHA, 2008). The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008). 

Oral

The molecular weight of (Z)-octadec-9-enyl (Z)-docos-13-enoate is greater than 500 g/mol, indicating that the substance is less available for absorption (ECHA, 2008). The high log Pow in combination with the low water solubility suggests that any absorption will happen via micellar solubilisation (ECHA, 2008).

The available acute oral toxicity data on several category members consistently showed LD50 > 2000 mg/kg bw and no systemic effects (Bouffechoux, 1999; Cade, 1976; Dufour, 1994). In 28-day repeated dose toxicity studies on category members, no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (De Hoog, 1998; Pitterman, 1993; Potokar, 1987). This indicates that (Z)-octadec-9-enyl (Z)-docos-13-enoate, as part of the LCAE category, also has a low potential for toxicity, although no assumptions can be made regarding the absorption potential based on the experimental data.

The potential of a substance to be absorbed in the (GI) tract may be influenced by chemical changes taking place in GI fluids as a result of metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2008).

In general, alkyl esters are readily hydrolysed in the gastrointestinal tract, blood and liver to the corresponding alcohol and fatty acid by the enzymatic activity of ubiquitous carboxylesterases. There are indications that the hydrolysis rate in the intestine by action of pancreatic lipase is lower for alkyl esters than for triglycerides, the natural substrate of this enzyme. The hydrolysis rate of linear esters increases with increasing chain length of either the alcohol or acid. Branching reduces the ester hydrolysis rate, compared with linear esters. (Mattson and Volpenhein, 1969, 1972; WHO, 1999). (Z)-octadec-9-enyl (Z)-docos-13-enoate

The substance (Z)-octadec-9-enyl (Z)-docos-13-enoate is therefore anticipated to be enzymatically hydrolysed to the unsaturated C18 fatty alcohol ((Z)-octadec-9-enyl alcohol)and an unsaturated C22 fatty acid ((Z)-docos-13-enoic acid).

Free fatty acids and alcohols are readily absorbed by the intestinal mucosa. Within the epithelial cells, fatty acids are (re-)esterified with glycerol to triglycerides. In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. As for fatty acids, the rate of absorption of alcohol is likely to increase with decreasing chain length (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964; OECD, 2006; Sieber, 1974)

In conclusion, based on the available information, the physicochemical properties and molecular weight of (Z)-octadec-9-enyl (Z)-docos-13-enoate suggest limited oral absorption. However, the substance is anticipated to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products is also relevant. The absorption rate of the hydrolysis products is considered to be high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 favour dermal uptake, while for those above 500 the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2008).

The substance (Z)-octadec-9-enyl (Z)-docos-13-enoate is almost insoluble in water, indicating a low dermal absorption potential (ECHA, 2008). The molecular weight of 589.03 g/mol is exceeding the limit above which dermal absorption is low (MW > 500 g/mol). The log Pow is > 6, which means that the uptake into the stratum corneum is likely to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2008).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp is thus 8.46E+05 cm/h. Considering the water solubility (0.00005 mg/cm³), the dermal flux is estimated to be ca. 42.3 mg/cm²/hr.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2008).

The experimental data on read-across substances show that no skin irritation occurred, which excludes enhanced penetration of the substance due to local skin damage (Bouffechoux, 1999; Guillot, 1977; Planchette, 1985).

Overall, based on the available information, the dermal absorption potential of (Z)-octadec-9-enyl (Z)-docos-13-enoate is predicted to be medium low.

Inhalation

As the vapour pressure of (Z)-octadec-9-enyl (Z)-docos-13-enoate is very low (< 0.0001 Pa at 20 °C), the volatility is also low. Therefore, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible.

If the substance is available as an aerosol, the potential for absorption via the inhalation route is increased. While droplets with an aerodynamic diameter < 100 μm can be inhaled, in principle, only droplets with an aerodynamic diameter < 50 μm can reach the bronchi and droplets < 15 μm may enter the alveolar region of the respiratory tract (ECHA, 2008).

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of limited absorption across the respiratory tract epithelium by micellar solubilisation.

Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and acid available for inhalative absorption.

An acute inhalation toxicity study was performed with the read-across substance 2-ethylhexyl oleate (CAS 26399-02-0), in which rats were exposed nose-only to > 5.7 mg/L of an aerosol for 4 hours (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. Thus, the test substance is not acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption.

Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst case approach.

 

Distribution and Accumulation

Distribution of a compound within the body depends on the physicochemical 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, 2008).

The substance (Z)-octadec-9-enyl (Z)-docos-13-enoate will mainly be absorbed in the form of the hydrolysis products. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). Consequently, the hydrolysis products are the most relevant components to assess. Both hydrolysis products are expected to be distributed widely in the body.

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons. Fatty acids of carbon chain length ≤ 12 may be transported as the free acid bound to albumin directly to the liver via the portal vein, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are likewise taken up by muscle and oxidised for energy or they are released into the systemic circulation and returned to the liver (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1993; Stryer, 1996).

Absorbed alcohols are likewise transported via the lymphatic system. Twenty-four hours after intraduodenal administration of a single dose of radiolabelled octadecanol to rats, the percent absorbed radioactivity in the lymph was 56.6 ± 14. Thereof, more than half (52-73%) was found in the triglyceride fraction, 6-13% as phospholipids, 2-3% as cholesterol esters and 4-10% as unchanged octadecanol. Almost all of the radioactivity recovered in the lymph was localized in the chylomicron fraction. Thus, the alcohol is oxidised to the corresponding fatty acid and esterified in the intestine as described above (Sieber, 1974).

Taken together, the hydrolysis products of (Z)-octadec-9-enyl (Z)-docos-13-enoate are anticipated to distribute systemically. The fatty alcohols are rapidly converted into the corresponding fatty acids by oxidation and distributed in form of triglycerides, which can be used as energy source or stored in adipose tissue. Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.

 

Metabolism

The metabolism of (Z)-octadec-9-enyl (Z)-docos-13-enoate initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding the unsaturated C18 fatty alcohol ((Z)-octadec-9-enyl alcohol)and an unsaturated C22 fatty acid ((Z)-docos-13-enoic acid). The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI tract and the liver (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the body. After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastrointestinal tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin may enter the systemic circulation directly before entering the liver where hydrolysis will generally take place.

The unsaturated C18 ((Z)-octadec-9-enyl) fatty alcohol will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). The stepwise process starts with the oxidation of the alcohol by alcohol dehydrogenase to the corresponding aldehyde, where the rate of oxidation increases with increased chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, catalysed by aldehyde dehydrogenase. Both the alcohol and the aldehyde may also be conjugated with e.g. glutathione and excreted directly, by passing further metabolism steps (WHO, 1999).

A major metabolic pathway for linear and branched fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified 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, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (by e.g. glucuronides, sulfates) to more polar products that are excreted in the urine.

The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox (OECD, 2011). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Eleven hepatic metabolites and 10 dermal metabolites were predicted the substance. Primarily, the ester bond is broken both in the liver and in the skin and the hydrolysis products may be further metabolised. Besides hydrolysis, the resulting liver and skin metabolites are all the product of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. In a few cases the ester bond remains intact, and only fatty acid oxidation products are found, which result in the addition of one hydroxyl group to the molecule. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. One hundred sixty-one metabolites were predicted to result from all kinds of microbiological metabolism. Most of the metabolites were found to be a consequence of fatty acid oxidation and associated chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature.

There is no indication that (Z)-octadec-9-enyl (Z)-docos-13-enoate is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) using (Z)-octadec-9-enyl (Z)-docos-13-enoate and read-across substances were negative, with and without metabolic activation (Wallat, 1982; Bertens, 1998; Poth, 1994; Verspeek-Rip, 1998). The result of the skin sensitisation studies performed with (Z)-octadec-9-enyl (Z)-docos-13-enoate and read-across substances was likewise negative (Pittermann, 1995; Beerens-Heijnen, 2010; Busschers, 1998).

 

Excretion

The unsaturated C18 fatty acid from the oxidation of the corresponding alcohol as well as the fatty acid resulting from hydrolysis of the ester will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological functions e.g. incorporation into cell membranes (Lehninger, 1993). Therefore, the fatty acid metabolites are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above. Experimental data with ethyl oleate (CAS 111-62-6, ethyl ester of oleic acid) support 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. 12 h after dosing, 40-70% of the administered dose was excreted in expired air (consistent with β -oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine (Bookstaff et al., 2003).

In addition, the alcohol component may also be conjugated to form a more water-soluble molecule and excreted via the urine (WHO, 1999). In an alternative pathway, the alcohol may be conjugated with e.g. glutathione and excreted directly, bypassing further metabolism steps.

 

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