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EC number: 306-084-8 | CAS number: 95912-88-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
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 in a total of 6 studies and up to and including 300 mg/kg bw/day in one study, 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 Fatty acids, C16-18, isotridecyl esters (CAS 95912-88-2) 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, 2012), 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, 2012) and taking into account available information on the analogue substances from which data was used for read-across to cover data gaps.
The substance Fatty acids, C16-18, isotridecyl esters is an UVCB with a branched C13-alcohol moiety and saturated C16-18-acid moieties. The molecular weight ranges from 438.78-466.83 g/mol. It is a liquid at 20 °C, with a water solubility of < 0.05 mg/L at 20 °C (Frischmann, 2010). Depending on the individual components of the substance, the log Pow was estimated to be >10 (Müller, 2013) and the vapour pressure was calculated to be < 0.0001 at 20 °C (Knoell, 2009).
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, 2012). The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).
Oral
The molecular weight of Fatty acids, C16-18, isotridecyl esters is lower than 500 g/mol, indicating that the substance is available for absorption (ECHA, 2012). The high log Pow in combination with the low water solubility suggests that any absorption will happen via micellar solubilisation (ECHA, 2012).
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 and 90-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; Leuschner, 2006; Pitterman, 1993; Potokar, 1987). In combined repeated dose toxicity and reproduction/ developmental toxicity screening studies, no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (Reig, 2014; Rossiello, 2014), and up to and including 300 mg/kg bw/day (Hansen, 2013).
This indicates that Fatty acids, C14-18 and C16-18 unsaturated, isotridecyl esters, 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, 2012).
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).
The substance Fatty acids, C16-18, isotridecyl esters is therefore anticipated to be enzymatically hydrolysed to C16-18 fatty acids and isotridecyl (isoC13) fatty alcohol.
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 Fatty acids, C16-18, isotridecyl esters suggest 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, 2012).
The substance Fatty acids, C16-18, isotridecyl esters is poorly soluble in water, indicating a low dermal absorption potential (ECHA, 2012). The molecular weight (438.78-466.83 g/mol) is relatively close to the 500 g/mol limit above which dermal absorption is low. The log Pow is > 10, 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, 2012).
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 15.3 – 22.0 cm/h. Considering the water solubility (<0.05 mg/L) the dermal flux is estimated to be <18 mg/cm²/h.
If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012).
The experimental data on the target substance and other category members show that no skin irritation occurred, which excludes enhanced penetration of the substance due to local skin damage (Kästner, 1987; Bouffechoux, 1999; Guillot, 1977; Planchette, 1985).
Overall, based on the available information, the dermal absorption potential of Fatty acids, C16-18, isotridecyl esters is predicted to be low.
Inhalation
As the vapour pressure of Fatty acids, C16-18, isotridecyl esters 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, 2012).
As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of absorption across the respiratory tract epithelium by micellar solubilisation.
Absorption after oral administration of the substance is mainly driven by enzymatic hydrolysis of the ester bond to the respective metabolites and subsequent absorption of the breakdown products. Therefore, for effective absorption in the respiratory tract enzymatic hydrolysis in the airways would be required first. The presence of esterases and lipases in the mucus lining fluid of the respiratory tract is therefore essential. Due to the physiological function of enzymes in the GI-tract for nutrient absorption, esterase and lipase activity in the lung is expected to be lower in comparison to the gastrointestinal tract. Therefore, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to be less effective. A fraction of the ester may also be absorbed directly through the mucous membrane of the respiratory tract, without hydrolysis. The low water solubility and size of the ester molecule will affect the absorption rate, and it is not clear which percentage of the inhaled aerosol could be absorbed as the ester.
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, 2012).
The substance Fatty acids, C16-18, isotridecyl esters 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, 1994).
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 Fatty acids, C16-18, isotridecyl esters 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 Fatty acids, C16-18, isotridecyl esters initially occurs via a stepwise enzymatic hydrolysis of the ester resulting in the corresponding saturated C16-18 fatty acids and the branched isotridecyl fatty alcohol. 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 gastro-intestinal tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will generally take place.
The isotridecyl 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 increasing chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, in a reaction catalysed by aldehyde dehydrogenase. Both the alcohol and the aldehyde may also be conjugated with e.g. glutathione and excreted directly, bypassing 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. glucoronides, sulfates) to more polar products that are excreted in the urine.
The potential metabolites following enzymatic metabolism of the four main constituents of the substance were predicted using the QSAR OECD toolbox (OECD, 2013). This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Eighteen hepatic metabolites and 12 dermal metabolites were predicted for the esters of isotridecyl alcohol with saturated C16- and C18 fatty acid, respectively. Primarily, the ester bond is broken both in the liver and in the skin and the resulting molecules 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. Up to 104 metabolites were predicted to result from all kinds of microbiological metabolism for the esters with saturated C16- and C18 fatty acid, respectively. 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 Fatty acids, C16-18, isotridecyl esters 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 the target substance and read-across substances were negative, with and without metabolic activation (Bertens, 1998; Poth, 1994; Verspeek-Rip, 1998). The results of the skin sensitisation studies performed with read-across substances were likewise negative (Beerens-Heijnen, 2010; Busschers, 1998).
Excretion
The fatty acids 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 acids 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 contrast, the branched C13 fatty acid resulting from the oxidation of the corresponding alcohol is unlikely to be used for energy generation and storage, since saturated aliphatic, branched-chain acids are described to be subjected to omega-oxidation due to steric hindrance by the methyl groups at uneven position, which results in the formation of various diols, hydroxyl acids, ketoacids or dicarbonic acids. In contrast to the products of beta-oxidation, these metabolites may be conjugated to glucuronides or sulphates, which subsequently can be excreted via urine or bile or cleaved in the gut with the possibility of reabsorption (entero-hepatic circulation) (WHO, 1998).
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 the CSR.
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