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EC number: 240-367-6
CAS number: 16260-09-6
Toxicokinetics, metabolism and distribution
The substance (Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) is
a secondary fatty amide formed from long chain saturated fatty acids
(C16) with the primary amine oleylamine.
It is a bead-like solid at 20 °C (Croda, 2011) with a molecular weight
of 505.90 g/mol. The substance has a melting point of 65 °C at normal
pressure (Croda, 2011), water solubility of < 0.01 mg/L at 20 °C
(Henkel, 2013), log Pow > 5.7 at 23 °C (Henkel, 2013) and vapour
pressure of < 8.3E-05 Pa at 20 °C (Henkel, 2012).
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, 2017). The log
Pow value provides information on the relative solubility of the
substance in water and lipids (ECHA, 2017).
The molecular weight of (Z)-N-octadec-9-enylhexadecan-1-amide (CAS
16260-09-6) is higher than 500 g/mol, indicating that the substance is
poorly available for absorption (ECHA, 2017). Lipophilic compounds may
be taken up by micellar solubilisation by bile salts, but this mechanism
may be of particular importance for highly lipophilic compounds (log Pow
> 4), in particular for those that are hardly soluble in water (≤ 1
mg/L), which would otherwise be poorly absorbed (ECHA, 2017). The high
log Pow in combination with the very low water solubility suggests that
any absorption of the substance will likely happen via micellar
solubilisation by bile salts (ECHA, 2017).
The absorption potential of a substance may also be derived from oral
toxicity data, in which e.g. treatment-related systemic toxicity were
observed (ECHA, 2017).
The available acute oral toxicity data on the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) showed an oral
LD50 value > 2400 mg/kg bw based on the lack of mortality and systemic
effects in rats (Notox C.V., 1986). Moreover, data on the oral repeated
dose toxicity in rat is available for the substance, indicating that
continuous dietary application of the substance for 90 days did not
result in any treatment-related adverse effects up to and including the
highest dose level of 1000 mg/kg bw/day (IBR, 1988). Furthermore, no
adverse effects were observed in rats after receiving the substance via
oral gavage for 5 consecutive days at the relatively high dose level of
approx. 5000 mg/kg bw/day (Leberco Laboratories, 1962).
Overall, the available data indicate that substance has a low potential
for toxicity via the oral route, although no assumptions can be made
regarding the actual amount absorbed based on these 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
pH-dependent hydrolysis, metabolism by GI flora, or by enzymes released
into the GI tract. 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, 2017).
Possible metabolites following hydrolysis of the substance were
predicted using the OECD QSAR Toolbox version 3.0 (OECD, 2012). The
simulation of acidic and basic hydrolysis of the substance resulted in
the formation of two metabolites, identified to be the corresponding
saturated long-chain fatty acid stearic acid (C16) and the primary amine
oleylamine after hydrolysis of the parent compound.
However, having regard to the in vivo situation, acidic hydrolysis of
the substance in the stomach is not expected to occur, since it shows a
very low solubility in water. This assumption is further supported by
hydrolysis data on the structurally related water-insoluble long-chain
fatty acid amide oleamide, showing a negligible rate of hydrolysis after
incubation for 4 h at 37 °C in simulated gastric fluid containing the
hydrolase pepsin (Cooper et al., 1995). In contrast, simulated
intestinal fluid enriched with a mixture of several digestive enzymes
(pancreatin) and bile salts was found to significantly increase
the rate of hydrolysis of oleamide to about 95% after incubation for 4 h
at 37 °C, suggesting that the environmental conditions in the intestinal
fluid in vivo may likewise favour hydrolysis of water-insoluble fatty
acid amides. However, only in the presence of bile salts a complete
hydrolysis of the fatty acid amide oleamide in intestinal fluid was
achieved, indicating that spontaneous micelle formation by the
involvement of bile salts seems to be an important prerequisite for the
hydrolysis of long-chain fatty acid amides.
In contrast to the predicted acid- or base-catalysed chemical
hydrolysis, data from naturally occurring long-chain fatty acid amides
suggest that the substance may rather be cleaved via enzymatic action of
intestinal hydrolases after uptake into the body.
There is evidence provided from the physiologically occurring, bioactive
substances oleamide and anandamide (arachidonylethanolamide) to show
that primary and secondary amides derived from long-chain fatty acids
are substrates for fatty acid amide hydrolase (FAAH), a serine hydrolase
enzyme widely distributed in the body, including small intestine, liver,
kidney and brain (Bisogno et al., 2002; Boger et al., 2000; Wei, et al.
2006). In humans, the liver is one of the organs with the highest FAAH
expression and, in contrast to rat and mice, both forms of fatty acid
amide hydrolase (FAAH-1 and FAAH-2) are expressed here (Wei et al.,
2006). Therefore, the final and complete hydrolysis of those minor
amounts of fatty acid amides, which might have escaped hydrolysis in the
lumen and the cells of the small intestine so far, may be hydrolysed by
FAAH enzymes located in the liver.
Data on the in vitro hydrolysis of the substance in freshly prepared rat
liver homogenate, which is known to contain typical mammalian amidases
such as FAAH, is available (FDRL, 1960). In this study, 3.6 mg of the
substance were incubated for 4 h with rat liver homogenate. At the end
of the incubation time, total ammonia liberated from the hydrolysis of
the parent substance was determined using the aeration technique of Van
Slyke and Cullen and corrected for the amount of naturally occurring
ammonia in the liver using blank values from the untreated liver
homogenates. The results showed that 3.6 mg of the test substance was
hydrolysed by ca. 21% within 4 h in the rat liver homogenate, which is
considerably low compared to the degree of hydrolysis reported for other
secondary fatty amides (Bisogno et al., 2002; Boger et al., 2000).
In summary, for the in vivo situation, it cannot be directly ruled out
if the parent substance or a fraction of it may be absorbed unchanged by
micellar solubilisation and be hydrolysed within the body. Therefore, in
a worst case approach, the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) is anticipated to
be enzymatically hydrolysed to the long-chain saturated fatty acidstearic
acid (C16)as well as the primary amine oleyl amine.
In general, free fatty acids are readily absorbed by the intestinal
mucosa after hydrolysis from triglycerides. 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 (Greenberger et al.,
1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964).
The second hydrolysis product, oleyl amine, is anticipated to be
oxidatively deaminated by monoaminooxidases to yield the corresponding
aldehyde and ammonia (Hayes, 2001).
Ammonia, which is liberated from the hydrolysis product oleylamine, is
an endogenously occurring molecule resulting from various metabolic
processes, including the catabolism of amino acids, amines, nucleic
acids, glutamine and glutamate in peripheral tissues (especially in
muscle, liver and kidney). Most of the naturally occurring ammonia (ca.
0.23 mol/day) is formed in the gastrointestinal tract, especially in the
colon, by hydrolysis of dietary proteins. In the intestine, ammonia is
also produced from glutamine or by the rehydrolysation from urea to
ammonium (Kuntz and Kuntz, 2008). Ammonia is freely diffusible and toxic
to the mammalian organism. However, under physiological conditions, more
than 90% of ammonia resulting from metabolic degradation is available as
non-diffusible ammonium, resulting in cellular accumulation (Kuntz and
Kuntz, 2008; Lehninger, 1993). In the gastrointestinal system, ammonia
is readily absorbed in the portal circulation and to a great part
detoxified in liver via the urea cycle (Kuntz and Kuntz, 2008;
In conclusion, based on the available information, the physicochemical
properties and molecular weight of the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) suggest poor oral
absorption. However, the substance is anticipated to undergo enzymatic
hydrolysis in the gastrointestinal tract and absorption of the
hydrolysis products may also be relevant.
In general, the physical state may already be taken into consideration
for a crude estimation of the absorption potential of a substance, which
means that 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.
Furthermore, the dermal uptake of substances with a high water
solubility of > 10 g/L (and log Pow < 0) will be low, as the substance
may be too hydrophilic to cross the stratum corneum. Log Pow values
between 1 and 4 favour dermal absorption (values between 2 and 3 are
optimal), in particular if water solubility is high. In contrast, log
Pow values < –1 suggest that a substance is not likely to be
sufficiently lipophilic to cross the stratum corneum, therefore dermal
absorption is likely to be low (ECHA, 2017).
The (Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) is a solid
with very low water solubility, thus indicating a poor dermal absorption
potential (ECHA, 2017). The high log Pow suggests that the rate of skin
penetration by the substance may be limited by the rate of transfer
between the stratum corneum and the epidermis (ECHA, 2017).
Apart from the physico-chemical properties, further criteria may apply
to assume the dermal absorption potential of the substance.
In general, substances that show skin irritating or corrosive properties
may enhance penetration by causing damage to the surface of the skin.
Furthermore, if a substance has been identified as a skin sensitiser,
then some uptake must have occurred although it may only have been a
small fraction of the applied dose (ECHA, 2017).
The experimental animal data on the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) show that no
significant skin irritation and no signs of systemic intoxication
occurred, which excludes enhanced penetration of the substance due to
local skin damage (Notox C.V., 1986b). Furthermore, no skin reactions
attributable to a sensitisation reaction and no systemic effects were
observed in the skin sensitisation study with the substance (Notox C.V.,
Furthermore, data on dermal toxicity may indicate whether a substance
may be absorbed, if signs of systemic toxicity were clearly attributable
to treatment (ECHA, 2017).
Consistent with the data on skin irritation and sensitisation, there is
no indication for clinical signs of toxicity and any other
treatment-related adverse effects from the acute dermal toxicity study
with the substance (Z)-N-octadec-9-enylhexadecan-1-amide (CAS
16260-09-6), resulting in an dermal LD50 > 2000 mg/kg bw in rat (Harlan
Laboratories Ltd, 2012). Thus, consistent with the data from acute oral
toxicity, a low potential for acute dermal toxicity has been
demonstrated, although no information on the actual amount of absorbed
substance may be derived from these observations.
Overall, based on the available information on physicochemical
properties, the dermal absorption potential of the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) is predicted to
As the vapour pressure of the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) is very low
(8.3E-05 Pa at 20 °C), the volatility is also low. Therefore, the
potential for exposure to vapours and subsequent absorption via
inhalation during normal use and handling is considered to be negligible.
In general, particles with an aerodynamic diameter < 100 μm have the
potential to be inhaled, whereas only particles with an aerodynamic
diameter < 50 μm can reach the thoracic region and those < 15 μm may
enter the alveolar region of the respiratory tract (ECHA, 2017). Data on
the particle size distribution of the substance demonstrate that the
inhalable fraction of the substance is considerably low, as it contains
only 0.03% of particles with an aerodynamic diameter < 500 µm (Croda,
2011). Therefore, under normal conditions of handling, human exposure to
the substance via the inhalation route is negligible. Moreover, if any
inhalation exposure may occur, the molecular weight, log Pow and water
solubility of the substance are suggestive of very low absorption across
the respiratory tract epithelium, preferably by micellar solubilisation.
Hydrolases present in the lung lining fluid may also hydrolyse the
substance, hence making the hydrolysis products of the substance, the
primary fatty amine oleylamine and the corresponding long-chain fatty
acids (C16), available for inhalative absorption.
However, due to the information available (low volatility and no
inhalable particle size fraction), absorption via inhalation route is
assumed to be unlikely, but in case exposure via inhalation should
actually occur, absorption is expected to be identical compared to the
oral route which is considered to be sufficiently conservative for
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, 2017).
Considering the worst case situation, the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) will mainly be
absorbed in the form of the hydrolysis products. Therefore, the primary
fatty amine oleylamine and the long-chain fatty acid (C16) are the most
relevant components to assess for the substance.
After being absorbed, fatty acids are (re-)esterified along with other
fatty acids into triglycerides and released into chylomicrons, which 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 tissue and oxidised in order to
generate energy, or they are released into the systemic circulation and
transported in chylomicrons or lipoproteins and returned to the liver
(IOM, 2005; Johnson, 1990; Lehninger, 1993; Stryer, 1996).
There is strong evidence that the primary amine oleyl amine will be
readily distributed within the organism as experimental animal data on
several alkyl amines, e.g. octanamine, demonstrated that alkyl amines
are rapidly distributed to the lung, brain, heart, spleen, kidneys and
liver (Committee for Risk Assessment, 2011).
Taken together, the potential hydrolysis products of the substance are
anticipated to distribute systemically in the organism.
The potential metabolism of the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) initially occurs
via hydrolysis of the amide bond resulting in saturated and
mono-unsaturated long-chain fatty acids (C16 and C18:1) and ammonia.
Besides chemical hydrolysis, fatty acid amides may be cleaved via
enzymatic action of hydrolases, e.g. FAAH, present in the GI tract and
other compartments of the body, e.g. the liver. 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 is likely to take place (ECHA, 2017).
A major metabolic pathway for linear fatty acids is the beta-oxidation
which is one of the main mechanisms required 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. The complete oxidation of mono-unsaturated fatty acids such as
oleic acid, requires an additional isomerisation step. Further oxidation
via the citric acid cycle leads to the formation of H2O and CO2
(Lehninger, 1993). Alternative pathways for long-chain fatty acids
include the omega-oxidation at high concentrations (WHO, 1999). The
fatty acids can also be conjugated (by e.g. glucuronides, sulphates) to
form more polar products that are easily excreted in the urine.
The primary amine oleyl amine may be oxidatively deaminated by
monoaminooxidases to yield the corresponding aldehyde and ammonia
(Hayes, 2001). The aldehyde may be further oxidised via the enzymatic
action of aldehyde dehydrogenase to the corresponding carboxylic acid,
which may be fed into further metabolic pathways such as beta-oxidation
Ammonia, resulting from the deamination of the hydrolysis product
oleylamine, may be transported to the liver, where it will be converted
to urea via the urea cycle. About two-thirds of the ammonia transported
to the liver is detoxified via the urea cycle in the periportal
hepatocytes, whereas the remaining part is trapped by periportal
hepatocytes involved in the glutamine cycle (Kuntz and Kuntz, 2008;
Lehninger, 1993). The urea formed in periportal hepatocytes diffuses
into the blood and is then transported to the kidneys for re-absorption
or final excretion (Lehninger, 1993). However, urea transported in the
blood stream may also be taken up into the lumen of the
gastro-intestinal tract, in a process termed ‘urea nitrogen salvaging’,
where bacterial ureases can cleave urea to provide nitrogen for the
synthesis of amino acids and peptides, which may also be reabsorbed by
the host mammalian circulation (Stewart and Smith, 2005). Glutamine, the
non-toxic transport form of ammonia, is generated in periportal
hepatocytes via the action of the enzyme glutamine synthetase (Kuntz and
Kuntz, 2008). Hepatic glutamine may be released into blood, distributed
to other tissues and fed into the synthesis of amino acids (Lehninger,
The potential metabolites following enzymatic metabolism of the
substance were predicted using the OECD QSAR Toolbox version 3.0 (OECD,
2012). 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. Thirty-nine hepatic metabolites
and 8 dermal metabolites were predicted for the substance. The amide
bond is cleaved in both the liver and skin, and the hydrolysis products
(the long-chain saturated fatty acids (C16) as well as the primary fatty
amine oleylamine) may be further metabolised. Besides hydrolysis, liver
and skin metabolites of the substance are mainly the product of
beta-oxidation of the C16 fatty acid and C18:1 fatty acid, the latter
resulting from the oxidative deamination of oleyl amine and subsequent
aldehyde dehydrogenase-dependent oxidation of the corresponding
aldehyde. The metabolites formed in the skin are expected to enter the
blood circulation and have the same fate as the hepatic metabolites. Up
to 140 metabolites were predicted to result from all kinds of
microbiological metabolism after hydrolysis of the substance.
Furthermore, the available data from the substance
(Z)-N-octadec-9-enylhexadecan-1-amide (CAS 16260-09-6) provide evidence
that the substance is not activated to reactive metabolites in the
presence of an artificial metabolic system in vitro, since studies
performed on genotoxicity (Ames test, gene mutation in mammalian cells
in vitro, chromosome aberration assay in mammalian cells in vitro)
consistently showed negative results independent of metabolic activation
(Jones, 1990; Debets and Enninga, 1986; Linscombe, 1991a; Linscombe,
The saturated long-chain fatty acids resulting from hydrolysis of the
substance and the monounsaturated fatty acid resulting from the
metabolism of the hydrolysis product oleylamine will be further
metabolised in order to generate energy or stored as lipids 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 they are expected to be excreted via exhaled
air as CO2 or stored as described above.
Most of the urea resulting from the detoxification of ammonia in the
liver will be transported to the kidneys, where it will either be
re-absorbed or directly passed into the urine (Lehninger, 1993).
Taken together, the available data support the assumption that the major
portion of the substance may be cleaved after absorption, and the
resulting hydrolysis products may either be utilised in physiological
pathways or may be excreted from the organism.
A detailed reference list is provided within the CSR.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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