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Description of key information

Fatty acids are almost completely absorbed after oral intake, whereas only limited dermal uptake has to be expected.

The 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.

Key value for chemical safety assessment

Additional information

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 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, 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 acid chains.

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 studies.  

Toxicokinetics, metabolism and distribution

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).

Absorption

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 application.

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.

 

Distribution and Metabolism

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 and muscle 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).

 

Excretion

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.

 

References

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. 2(2-3):123-34. Review.

Tanojo, H. et al., 1998. In vivo human skin barrier modulation by topical application of fatty acids. Skin Pharmacol Appl Skin Physiol.11(2):87-97.

 

Wanders, R.J. et al., 2010. Peroxisoms, lipid metaboism and lipotoxicity. Biochim Biophys Acta 1801(3):272-80.