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EC number: 306-232-1
CAS number: 96690-38-9
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
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:
Fatty alcohol chain length
Fatty acid chain length
CAS 20292-08-4 (b)
Fatty acids, C16 - 18, 2-ethylhexyl esters
CAS 59231-34-4 (a)
Fatty acids, C8 - 10, C12 - 18-alkyl esters
312.53 – 424.74
C20H40O2; C22H44O2; C26H52O2; C28H56O2
Fatty acids, C16 - 18, C12 - 18-alkyl esters
424.74 - 536.96
C28H56O2; C30H60O2; C34H68O2; C36H72O2
Fatty acids, coco, isotridecyl esters
382.66 - 410.72
Fatty acids, C14 - 18 and C16 - 18 unsaturated, isotridecyl esters
410.72 - 466.82
C27H54O2; C29H56O2; C31H60O2;
Fatty acids, C16 - 18, isotridecyl esters
438.78 - 466.83
Fatty acids, C16 - 18, 2-hexyldecyl esters
Fatty acids, C16 - 18, C16 - 18-alkyl esters
480.85 - 536.97
C32H64O2; C34H68O2; C36H72O2
Fatty acids, C16 - 18, 2-octyldodecyl esters
565.01 - 649.17
CAS 111937-03-2 (c)
Isononanoic acid, C16 - 18 alkyl esters
(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 (<
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
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).
There are no experimental studies available in which the toxicokinetic
behaviour of Fatty acids, C16 - 18, 2-octyldodecyl esters (CAS
96690-38-9) 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 Fatty acids, C16-18, 2-octyldodecyl esters is an UVCB with
a branched C20-alcohol moiety and a C16-18-acid moiety, and a molecular
weight ranging from 536.96-565.01 g/mol. It is liquid at 20 °C
(Frerichs, 2011), with an estimated water solubility of < 0.05 mg/L at
20 °C (Frischmann, 2011). Depending on the individual components of the
substance, the log Pow was estimated to be 16.51-17.49 (Müller, 2011)
and the vapour pressure was calculated to be ≤ 0.000145 Pa at 20 °C
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).
The molecular weight of Fatty acids, C16-18, 2-octyldodecyl esters is
above 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 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, performed with the source
substances Tetradecyl oleate (CAS 22393-85-7) and Docosyl docosanoate
(CAS 17671-27-1) no toxicologically relevant effects were noted up to
and including the highest dose level of 1000 mg/kg bw/day (Reig, 2014;
Rossiello, 2014). In a combined repeated dose toxicity and reproduction/
developmental toxicity screening study performed with the source
substance Isodecyl oleate (CAS 59231-34-4) adverse effects were noted in
parental females and F1-offspring at the highest dose level of 1000
mg/kg bw/day (Hansen, 2013). Reduced food intake and weight loss was
observed in the dams. These adverse systemic effects subsequently caused
impaired fertility in the dams, and reduced pup viability and body
weight. The effects observed in the pups at 1000 mg/kg bw/day were not
considered to be relevant due to the maternal toxicity at the highest
dose level. No effects were observed in parental animals and
F1-offspring at 300 mg/kg bw/day.
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).
The substance Fatty acids, C16-18, 2-octyldodecyl esters is therefore
anticipated to be enzymatically hydrolysed to the C16-18 fatty acids and
the branched C20 (2-octyldodecyl) 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 alcohols 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, 2-octyldodecyl
esters 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.
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 Fatty acids, C16-18, 2-octyldodecyl esters is almost
insoluble in water, indicating a low dermal absorption potential (ECHA,
2008). The molecular weight of 536.96-565.01 g/mol is exceeding the 500
g/mol limit above which dermal absorption is low. 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 1.42-4.43E+05 cm/h. Considering the water solubility
(0.00005 mg/cm³) and the individual components of the substance with log
Pows ranging from 16.51-17.49, the dermal flux is estimated to be ca.
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;
Overall, based on the available information, the dermal absorption
potential of Fatty acids, C16-18, 2-octyldodecyl esters is predicted to
be medium low.
As the vapour pressure of Fatty acids, C16-18, 2-octyldodecyl 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
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
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
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 Fatty acids, C16-18, 2-octyldodecyl 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, 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 Fatty acids, C16-18,
2-octyldodecyl 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.
The metabolism of Fatty acids, C16-18, 2-octyldodecyl esters initially
occurs via enzymatic hydrolysis of the ester resulting in the
corresponding C16-18 fatty acids and the branched C20 (2-octyldodecyl)
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 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 branched C20 (2-octyldodecyl) 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 two main
constituents 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. Twelve hepatic metabolites and
14 dermal metabolites were predicted for both the esters of C20 alcohol
with C16 fatty acid and C18 fatty acid, respectively. 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. Up to 146
metabolites were predicted to result from all kinds of microbiological
metabolism for the esters of C20 alcohol with C16 fatty acid 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, C8-10, C12-18-alkyl 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 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).
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 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).
The branched C20 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.
Bookstaff et al. (2003). The safety of the use of ethyl oleate in food
is supported by metabolism data in rats and clinical safety data in
humans. Regul Toxicol Pharm 37: 133-148.
Cosmetic Ingredient Review Expert Panel (CIR) (1985). Final report on
the Safety assessment of Stearyl Alcohol, Oleyl Alcohol, and Octyl
Dodecanol. J Am Coll Toxicol 4(5):1-29.
ECHA (2008). Guidance on information requirements and chemical safety
assessment, Chapter R.7c: Endpoint specific guidance.
Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases.
Drug Metabolism and Pharmacokinetics, Advance publication July 17th,
Greenberger et al. (1966). Absorption of medium and long chain
triglycerides: factors influencing their hydrolysis and transport. J
Clin Invest. 45(2):217-27.
Gubicza, L. et al. (2000). Large-scale enzymatic production of natural
flavour esters in organic solvent with continuous water removal. Journal
of Biotechnology 84(2): 193-196.
Institute of the National Academies (IOM) (2005). Dietary Reference
Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol,
Protein, and Amino Acids (Macronutrients). The National Academies Press.
Johnson W Jr; Cosmetic Ingredient Review Expert Panel. (2001). Final
report on the safety assessment of trilaurin, triarachidin, tribehenin,
tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin,
triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin,
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