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EC number: 204-677-5
CAS number: 124-07-2
acids are almost completely absorbed after oral intake, whereas only
limited dermal uptake has to be expected.
major metabolic pathway for linear fatty acids is the β-oxidation
pathway for energy generation, while alternatives are the α- and
ω-oxidation. Besides this, fatty acids are stored as lipids in adipose
tissue, used as part of cellular membranes, as well as precursors for
signalling molecules and even long chain fatty acids.
Justification for grouping of substances and read-across
The fatty acids category covers aliphatic (fatty) acids, which all
contain the carboxylic acid group attached to an aliphatic acid chain.
The category contains mono-constituent substances and UVCB substances
being compositions of these substances.
Mono-constituent substances are predominantly saturated,
even-numbered acids, in the carbon range C6 to C22. Other
mono-constituent fatty acids include:
- odd-numbered acids: heptanoic acid C7 and nonanoic acid C9;
- unsaturated acids: elaidic acid C18:1, oleic acid C18:1,
linoleic acid C18:2, conjugated linoleic acid C18:2, linolenic acid
C18:3 and erucic acid C22:1;
- dicarboxylic acids: azelaic acid C9d and sebacic acid C10d.
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, 40 substances are allocated to the
category of fatty acids.
Grouping of substances into this category is based on:
(1) common functional groups: all members of the Fatty acids
category are carboxylic acids with a linear aliphatic tail (chain),
which is either saturated or unsaturated. The carbon chain lengths
varies between C6 and C22 (uneven/even-numbered); and
(2) common precursors and the likelihood of common breakdown
products via biological processes, which result in structurally similar
chemicals: the members of the Fatty Acids category result from the
hydrolysis of the ester linkages in a fat or biological oil (both of
which are triglycerides), with the removal of glycerol. Fatty acids are
almost completely absorbed after oral intake by the intestinal mucosa
and distributed throughout the body. Fatty acids are an energy source.
They are either re-esterified into triacylglycerides and stored in
adipose tissues, or oxidized to yield energy primarily via the
β-oxidation pathway. The excretion products are carbon dioxide and water
after metabolisation; and
(3) constant pattern in the changing of the potency of the
properties across the category: the available data show similarities and
trends within the category in regard to physicochemical, environmental
fate, ecotoxicological and toxicological properties. For those
individual endpoints showing a trend, the pattern in the changing of
potency is clearly and expectedly related to the length of the fatty
A detailed justification for the grouping of chemicals and
read-across is provided in the technical dossier (see IUCLID Section 13).
The available data show that the category of fatty acids possess a
chain length- and saturation dependent trend concerning
irritation/corrosion potential. Fatty acids with a chain length of C6-C8
are corrosive to skin and eye; C9 and C10 is considered as skin and eye
irritating and C12 at concentrations > 73% causes corrosive effects to
the eye. Members of the category with a saturated chain length > C12 are
only causing negligible effects when applied to the skin or eyes.
Unsaturated C22 fatty acid is irritating to the skin. No further human
health hazards are identified. All available studies show that fatty
acids are not acutely toxic via the oral and dermal routes, all LD50
values are greater than 2000 mg/kg bw. The available animal studies
indicate that fatty acids are not skin sensitising. No mutagenic
potential was identified in in vitro genotoxicity studies including gene
mutations tests in bacteria and mammalian cells and chromosome
aberration assays in mammalian cells. No adverse effects were observed
up to, including and even above the limit dose of 1000 mg/kg bw/day in
the available short- and long-term toxicity studies via the oral route.
No reproductive toxicity effects were noted in any of the available
Fatty acids are typically unbranched, long chain organic acids
with different chain length. They are found in all living organism
fulfilling three fundamental roles. Besides their function as part of
molecules like phospholipids and glycolipids important for the
cell-structure, they are often precursors of signalling molecules such
as prostanoids in animals or phytohormones in plants. The third and best
understood role of fatty acid is their role as an energy source,
particularly in higher animals and plants. Thus, the absorption,
distribution, metabolism and elimination of fatty acids have been well
investigated for years (Lehninger, 1970; Nelson and Cox, 2008).
Due to the role as nutritional energy source, fatty acids are
absorbed from the lumen of the intestine by different uptake mechanisms
depending on the chain length. Short- and medium chain fatty acids (C1 -
C12) are rapidly absorbed via intestine capillaries into the
blood stream. For butyrate (C4) for example, an absorption rate of 1.9
µmol/cm²/h (= 167 µg/cm²/h) was found in the human intestine (McNeil et
al., 1978). In contrast, long chain fatty acids (>C12) are absorbed into
the walls of the intestine villi
and assembled into triglycerides,
which then are transported in the blood stream via lipoprotein
particles (chylomicrons). This difference in the uptake mechanism of
fatty acids is reflected by the percentage of absorption found when
human infants were fed a diet containing different fat sources (Jensen
et al., 1986). While an absorption of 99.9% was found for C8 fatty acid,
the long chain C18 fatty acid showed only 64.4% absorption.
The dermal penetration of fatty acid is very variable based on the
heterogeneous physico-chemical properties such as melting temperature,
solubility and polarity. The polarity, for example, decreases with
increasing chain lengths and/or the abolition of ionisable charged
groups, so that they are less-water soluble but more permeable through
lipophilic membranes like the skin. As an example, unsaturated long
chain fatty acids like oleic acid (C18:1) have been shown to increase
the transepithelial water loss significantly compared to shorter
unsaturated fatty acids (Tanojo et al., 1998). Unsaturated long chain
fatty acids are therefore used in pharmaceutical transdermal drugs as a
flux enhancer for drugs that do not readily cross the skin-barrier on
their own. However, the fatty acid itself remains within the lipophilic
dermal layer due its polarity.
In contrast to the rapid uptake of fatty acids via the oral
exposure route, fatty acids are in general poorly absorbed through skin,
with a measured rate of less than 1% after 24-hours exposure (Schaefer
and Redelmeier, 1996). The dermal absorption of fatty acids ranged from
moderate to very low according to QSAR calculations which are based on
molecular weight, logPow and water solubility. The resulting
calculated absorption rates are 0.047 mg/cm²/h for C6 octanoic acid,
0.005 mg/cm²/h for lauric acid (C12), 0.26 µg/cm²/h for stearic acid
(C18) and 0.33 µg/cm²/h for oleic acid (C18:1), respectively (Danish EPA
Database, 2004). Thus, the dermal absorption is definitely lower than
the absorption after oral uptake.
This was demonstrated in a study where excretion of azelaic acid
was analyzed in urine after dermal application of six healthy male
volunteers with a single treatment with 5 g of an anti-acne cream
containing 20% azelaic acid and after oral application (Taeuber et al.,
1992). While 61% of orally administered azelaic acid was detected in the
urine, only 2.2% azelaic acid was found in the urine after dermal
The dermal uptake of fatty acid is further influenced by the fact
that significant skin irritation/corrosion is observed for fatty acids
with a chain length less than C10. In these cases local
irritation/corrosion is considered as the primary effect.
Taken together the experimental and calculated data show that
fatty acids are almost completely absorbed after oral intake, whereas
only limited dermal uptake has to be expected.
Fatty acids are absorbed through the intestine and transported
throughout the body. Short chain fatty acids are taken up and
transported complexed to albumin via the portal vein into the
blood vessels supplying the liver. Medium and long chain fatty acids are
esterified with glycerol to triacylglycerides (TAGs) and packaged in
chylomicrons (Spector, 1984). These are transported via the
lymphatic system and the blood stream to hepatocytes
in the liver as well as to adipocytes
fibers, where they are either stored (i.e. adipose tissue
storage depots) or oxidized to yield energy. In addition, some cell
types are known to synthesize medium and long chain fatty acids via elongation
of shorter fatty acids (Hellerstein, 1999).
The quantitatively most significant oxidation pathway (β-oxidation
pathway) is predominantly located in the cardiac and skeletal muscle. In
a first step, the fatty acids are converted to acyl-CoA derivatives
(aliphaticacyl-CoA) and transported into cells and mitochondria by
specific transport systems. Then, the acyl-CoA derivatives are
completely metabolized to acetyl-CoA or other key metabolites by the
efficient enzymatic removal of the 2-carbon units from the aliphatic
acyl-CoA molecule (Coppack et al., 1994). The complete oxidation of
fatty acids via the citric acid cycle leads to H2O and
CO2 (Coppack, 1994; MacFarlane, 2008). Other pathways for
fatty acid catabolism also exist and include α- and ω-oxidation. The
resulting main metabolites are acyl-carnitine, acetyl CoA, fatty
acyl-CoA, propionyl-CoA and succinyl-CoA (Wanders et al., 2010).
Fatty acids are metabolised by various routes in the body to
provide energy. Besides this, fatty acids are stored as lipids in
adipose tissue, used as part of cellular membranes, as well
as precursors for signalling molecules and even long chain fatty acids.
Thus, fatty acids are not expected to be excreted to any significant
amount in the urine or faeces under normal physiological conditions.
Coppack, S.W. et al., 1994. In vivo regulation of lipolysis in
humans. Journal of Lipid Research 35 177–193.
Dermwin v 1.43, US EPA, 2009. Estimation Programs Interface Suite™
for Microsoft® Windows, v 4.1.43], DC.
Hellerstein, M.K., 1999. De novo lipogenesis in humans: metabolic
and regulatory aspects. European Journal of Clinical Nutrition 53:53–65.
Lehninger, A.L., 1970. Biochemistry. Worth Publishers, Inc.
Jensen, C. et al., 1986. Absorption of individual fatty acids from
long chain or medium chain triglycerides in very small infants. The
American Journal of Clinical Nutrition 43:745-751.
MacFarlane, D.P., 2008. Glucocorticoids and fatty acid metabolism
in humans: fuelling fat redistribution in the metabolic syndrome.
Journal of Endocrinology 197:189–204.
McNeil, N.I. et al., 1978. Short chain fatty acid absorption by
the human large intestine. Gut 19:819-822.
Nelson, D.L. and Cox, M.M., 2008. Lehninger Principles of
Biochemistry, Fifth Edition. W. H. Freeman.
Schaefer, H. and Redelmeier, T.E., 1996. Skin barrier: principles
of percutaneous absorption. S. Karger Publishers, New York.
Spector A.A., 1984. Plasma lipid transport.Clin Physiol Biochem.
Tanojo, H. et al., 1998. In vivo human skin barrier modulation by
topical application of fatty acids. Skin Pharmacol Appl Skin
Wanders, R.J. et al., 2010. Peroxisoms, lipid metaboism and
lipotoxicity. Biochim Biophys Acta 1801(3):272-80.
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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