Calcium di(octanoate)

Endpoint summary

Description of key information

The following assessment of the toxicokinetic profile of calcium dioctanoate, EC#228-067-8 is based on the physical chemical properties and toxicity data on the substance and its ionized forms. No experimentally derived ADME data are available for this substance.

Description of key information

IUPAC name                                     calcium dioctanoate

Chemical structure                        Please see general information

SMILES                                               CCCCCCCC(=O)[O-].CCCCCCCC(=O)[O-].[Ca+2]

Substance type                               monoconstituent

CAS-No.                                             6107-56-8

Molecular formula                        C₁₆H₃₀CaO₄

Molecular weight                          326.5 g/mol

Description, at 25°C                      solid

Since the test item is an organic salt which dissociates in an aqueous solute, only the carboxylate (i.e. octanoate) has been considered for its toxicokinetic properties. Indeed, in experimental tests for organic salts, the concentration of the counter-ion is usually not measured and only the organic ion (or its neutral form) is monitored. Moreover the medium used to conduct toxicological and ecotoxicological assays is buffered at a pH between 6 – 9, where there is an equilibrium between the non-ionized form (free acid) and the ionised form (carboxylate), and both are present in the test medium, no matter if the acid or a salt of it was introduced first. In fact, at this pH, most of the substance will be in its ionized form (carboxylate). Consequently, the toxicokinetic properties of the test item predicted in this study are based on those of octanoic acid, which is a C8 fatty acid. The toxicokinetic properties of fatty acids in general are therefore relevant to this substance.

Fatty acids are almost completely absorbed after oral intake, whereas only limited dermal uptake can 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. In addition, fatty acids are stored as lipids in adipose tissue, used as part of cellular membranes, as well as precursors for signalling molecules and long chain fatty acids.

Physical Chemical Properties

Molecular weight, water solubility, log Kow, and vapor pressure are key physical chemical properties for assessing the toxicokinetic properties of a substance. This substance is a solid and has a molecular weight of 326.5. The solubility in water is moderate (1.9 g/L at 20°C) and the partition coefficient (log Pow) is <1 at 20°C and the substance has surface active properties. The substance has a low vapour pressure (1 x 10^-4Pa at 25°C).

Additional information

Additional information

The available data show that 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.  

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), and an absorption of 99.9% was found for C8 fatty acid.

The dermal penetration of fatty acids 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.

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, logP_ow 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.

The dermal uptake of fatty acids 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 is 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, 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 such as octanoic acid 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 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.

 

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