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EC number: 500-204-4
CAS number: 68334-05-4
There are no studies available in which the toxicokinetic
behaviour of Fatty acids, C18-unsaturated dimers, 2-ethylhexyl esters
(CAS 68334-05-4) has been investigated.
Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of
Regulation (EC) No 1907/2006 and with Guidance on information
requirements and chemical safety assessment Chapter R.7c: Endpoint
specific guidance (ECHA, 2012c), assessment of the toxicokinetic
behaviour of the substance Fatty acids, C18 -unsaturated dimers,
2-ethylhexyl esters 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 physico-chemical
and toxicological properties according to Guidance on information
requirements and chemical safety assessment Chapter R.7c: Endpoint
specific guidance (ECHA, 2012c) and taking into account further
available information on structurally similar substances and hydrolysis
The substance Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl
esters is a liquid at room temperature and has a molecular weight of
673.10 g/mol, and a water solubility < 1 mg/L at 21 °C. The log Pow and
the vapour pressure is estimated to be >10 and < 0.0001 Pa at 20 °C
Absorption is a function of the potential for a substance to
diffuse across biological membranes. The most useful parameters
providing information on this potential are the molecular weight, the
octanol/water partition coefficient (log Pow) value and the water
solubility. The log Pow value provides information on the relative
solubility of the substance in water and lipids (ECHA, 2012c).
The smaller the molecule, the more easily it will be taken up. In
general, molecular weights below 500 are favourable for oral absorption
(ECHA, 2012c). As the molecular weight of Fatty acids, C18 -unsaturated
dimers, 2-ethylhexyl esters is 673.10 g/mol, absorption of the molecule
in the gastrointestinal tract is considered to be low.
If absorption occurs, the favourable mechanism will be absorption
by micellar solubilisation, as this mechanism is of importance for
highly lipophilic substances (log Pow > 4), which are poorly soluble in
water (1 mg/L or less) like Fatty acids, C18 -unsaturated dimers,
2-ethylhexyl esters with a log Pow > 10 and a water solubility < 1 mg/L.
No studies by the oral route are available for Fatty acids, C18
-unsaturated dimers, 2-ethylhexyl esters, thus no additional information
from animal studies is available.
After oral ingestion, an ester undergoes stepwise hydrolysis of
the ester bond by gastrointestinal enzymes (Lehninger, 1970; Mattson and
Volpenhein, 1972). The respective alcohol as well as the corresponding
acid is formed. In general, the physico-chemical characteristics of the
cleavage products (e.g. physical form, water solubility, molecular
weight, log Pow, vapour pressure, etc.) are likely to be different from
those of the parent substance before absorption into the blood takes
place, and hence the predictions based upon the physico-chemical
characteristics of the parent substance do no longer apply (ECHA,
2012c). For the expected cleavage product 2-ethylhexanol, it is known
that it will be absorbed in the gastro-intestinal tract by dissolution
into the gastrointestinal fluids quite rapidly (Deisinger, 1994). The
second cleavage product, Fatty acids, C18 unsatd., dimers, seems to be
less absorbed than monomeric fatty acids, as indicated by studies
carried out to investigate the absorption, distribution and excretion of
dimeric fatty acids (Hsieh and Perkins, 1975). Upon oral administration
only ca. 0.4% of the 14C-labeled dimeric fatty acid methyl esters given
by gastric intubation were absorbed within 12 h. Ca. 1% of the labeled
material was excreted via urine and ca. 2% as CO2. Ca. 80% of the
radioactivity was recovered in the gastrointestinal tract and the
faeces. About 0.115% of the administered test material was incorporated
in the liver and metabolized to different lipid classes.
Overall, a systemic bioavailability of Fatty acids, C18
-unsaturated dimers, 2-ethylhexyl esters and/or the respective cleavage
products in humans is considered possible but limited after oral uptake
of the substance due to its high molecular weight.
The smaller the molecule, the more easily it may be taken up. In
general, a molecular weight below 100 favours dermal absorption, above
500 the molecule may be too large (ECHA, 2012c). As the molecular weight
of Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl esters is 673.10
g/mol, dermal absorption of the molecule is not likely.
If the substance is a skin irritant or corrosive, damage to the
skin surface may enhance penetration (ECHA, 2012). As Fatty acids, C18
-unsaturated dimers, 2-ethylhexyl esters is not skin irritating in
humans, enhanced penetration of the substance due to local skin damage
can be excluded.
For substances with a log Pow above 4, the rate of dermal
penetration is limited by the rate of transfer between the stratum
corneum and the epidermis, but uptake into the stratum corneum will be
high. For substances with a log Pow above 6, the rate of transfer
between the stratum corneum and the epidermis will be slow and will
limit absorption across the skin, and the uptake into the stratum
corneum itself is also slow. The substance must be sufficiently soluble
in water to partition from the stratum corneum into the epidermis (ECHA,
2012). With a log Pow > 10 and a water solubility < 1 mg/L, dermal
uptake of Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl esters is
likely to be low.
In support of this, data available for several fatty acids
indicate that the skin penetration both in vivo (rat) and in vitro (rats
and human) decreases with increasing chain length. Thus, after 24 h
exposure about 0.14% and 0.04% of C16 and C18 soap solutions are
absorbed through human epidermis applied in vitro at 217.95 µg C16/cm²
and 230.77 µg C18/cm². At 22.27 µg C16/cm² and 24.53 µg C18/cm², about
0.3% of both C16 and C18 soap solutions is absorbed through rat skin
after 6 h exposure in vivo (Howes, 1975).
Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl esters has a
low vapour pressure below 0.0001 Pa thus being of low volatility.
Therefore, under normal use and handling conditions, inhalation exposure
and thus availability for respiratory absorption of the substance in the
form of vapours, gases, or mists is considered negligible.
However, the substance may be available for respiratory absorption
in the lung after inhalation of aerosols, if the substance is sprayed.
In humans, particles with aerodynamic diameters below 100 μm have the
potential to be inhaled. Particles with aerodynamic diameters below 50
μm may reach the thoracic region and those below 15 μm the alveolar
region of the respiratory tract (ECHA, 2012c). Lipophilic compounds with
a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like
Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl esters can be taken
up by micellar solubilisation.
In an acute aerosol inhalation study with Fatty acids, C18
-unsaturated dimers, 2-ethylhexyl esters performed according to OECD
guideline 436 (acute toxic class method, limit test), an LC50 value of
greater than 5.3 mg/L was found for rats. No effects were observed
indicating absorption after inhalation.
Overall, a systemic bioavailability of Fatty acids, C18
-unsaturated dimers, 2-ethylhexyl esters in humans is considered to be
Highly lipophilic substances tend in general to concentrate in
adipose tissue, and depending on the conditions of exposure may
accumulate. Although there is no direct correlation between the
lipophilicity of a substance and its biological half-life, it is
generally the case that substances with high log Pow values have long
biological half-lives. The high log Pow of > 10 implies that with Fatty
acids, C18 -unsaturated dimers, 2-ethylhexyl esters may have the
potential to accumulate in adipose tissue (ECHA, 2012c).
Absorption is a prerequisite for accumulation within the body. Due
to its MW and high log Pow, absorption is expected to be minimal for
with Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl esters,
therefore accumulation is not favoured as well. In case of
esterase-catalysed hydrolysis, the cleavage products with Fatty acids,
C18-unsaturated dimers and 2–ethylhexanol are produced. 2-ethylhexanol
is known to be metabolized and excreted well, thus no accumulation is
expected (Deisinger, 1994). The second cleavage product, the fatty acid,
can be stored as triglycerides in adipose tissue depots or be
incorporated into cell membranes. At the same time, fatty acids are also
required as a source of energy. Thus, stored fatty acids underlie a
continuous turnover as they are permanently metabolized and excreted.
Bioaccumulation of fatty acids only takes place, if their intake exceeds
the caloric requirements of the organism. The available information
indicates that dimeric fatty acids are poorly absorbed and that the
absorbed fraction follows the same pattern of metabolism and excretion
as the monomeric acids. Thus, no significant bioaccumulation in adipose
tissue is expected.
Overall, the available information indicates that no significant
bioaccumulation of the parent substance in adipose tissue is anticipated.
Distribution within the body through the circulatory system
depends on the molecular weight, the lipophilic character and water
solubility of a substance. 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
Distribution of the parent substance is not expected as only very
limited absorption will occur. Only the potential cleavage products of
Fatty acids, C18 -unsaturated dimers, 2 -ethylhexyl esters might be
distributed within the body.
Esters of fatty acids are hydrolysed to the corresponding alcohol
and fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the
route of exposure, esterase-catalysed hydrolysis takes place at
different places in the organism: After oral ingestion, esters of
alcohols and fatty acids undergo enzymatic hydrolysis already in the
gastro-intestinal fluids. In contrast, substances that are absorbed
through the pulmonary alveolar membrane or through the skin enter the
systemic circulation directly before entering the liver where hydrolysis
will basically take place. Dimeric acids are of more complex structure
than the simple fatty acid esters, therefore, ester bond hydrolysis is
expected to occur to a minor extent. Nevertheless possible cleavage
products should be discussed here. The first possible cleavage product,
2-ethylhexanol, is metabolized by oxidation and/or glucuronidation. The
metabolism of 2 -ethylhexanol (CAS 104 -76 -7) was studied in rats
(Deisinger, 1994). Upon oral application, 2 -ethylhexanol was absorbed
effectively by the gastrointestinal tract. The major portion of the dose
was excreted within 24 h, primarily in the urine. Smaller amounts of the
dose were excreted in the faeces primarily within 24 h. A mean of 11% of
the dose was recovered as 14CO2, but only a fraction of a percent of the
dose was recovered from the breath as [14C] volatile organics. Upon
dermal application, only a small portion of the dose was absorbed, which
was eliminated primarily in the urine, with smaller amounts eliminated
in the faeces, and as 14CO2, in the breath.
The second cleavage product, the fatty acid, is stepwise degraded
by beta-oxidation based on enzymatic removal of C2 units in the matrix
of the mitochondria in most vertebrate tissues. The C2 units are cleaved
as acyl-CoA, the entry molecule for the citric acid cycle. The omega-
and alpha-oxidation, alternative pathways for oxidation, can be found in
the liver and the brain, respectively (CIR, 1987). The cyclic portion of
dimers cannot be degraded by β- or ω-oxidation and is probably
hydroxylated or conjugated, which are common detoxification mechanisms
of cyclic compounds, leading to polar metabolites readily excreted via
urine (Iwaoka and Perkins, 1976). Likewise, after oxidative degradation
of aromatic fatty acids, the remaining structure can be excreted in the
urine after conjugation with glycine or glutamine in a similar way as in
the case of benzoic and phenylacetic acid, respectively (WHO, 2000;
Caldwell et al., 1980).
Overall, the part of Fatty acids, C18 -unsaturated dimers, 2
-ethylhexyl esters that has become systemically available, may be
hydrolysed and the cleavage products are metabolized by beta oxidation
and/or glucuronidation. However, due to its high molecular weight,
absorption of the parent substance is not likely and thus, no extensive
metabolism is expected but rather direct elimination.
The main route of excretion of Fatty acids, C18 -unsaturated
dimers, 2 -ethylhexyl esters is expected to be excretion of unabsorbed
substance with the faeces. The second route of excretion is expected to
be by expired air as CO2 after metabolic degradation (beta-oxidation).
The potential cleavage products might also be excreted via the urine,
unchanged or metabolised and exhaled (Deisinger, 1994; Hsieh and
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