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Please refer to expert statement regarding toxicokinetic behaviour given under "Toxicokinetics, metabolism and distribution".

Key value for chemical safety assessment

Additional information

Toxicokinetic assessment of Amides, C16-C18 (even numbered):

Possible ways for the uptake of Amides, C16-C18 (even numbered), stearamide and oleamide are the oral and the dermal route due to their use as slipping agents in the production of plastic articles and films, which might also be used as beverage containers.

Therefore, Amides, C16-C18 (even numbered) might enter the body as a result of foodstuff contamination, although it represents only small proportion of the plastic; oleamide, for example, usually represents a proportion of less than 1% (Hiley and Hoi, 2007). However, more than 95% of oleamide were demonstrated to be degraded in simulated gastrointestinal fluids after 4 hours at 37°C in the presence of bile salts; the product formed to a great extent was oleic acid (Cooper and Tice, 1995; Cooper, 1995). Due to the structural similarity between oleamide and Amides, C16-C18 (even numbered) it is reasonable to assume a similar degradation for Amides, C16-C18 (even numbered) into stearic and palmitic acid. Actually it was shown that a certain amount of dietary stearic acid is even oxidized to oleic acid in humans (Emken, 1994).

Both molecules will be able to penetrate biomembranes like their fatty acid derivatives stearic acid and oleic acid due to their similar characteristics. Free fatty acids can penetrate the plasma membranes due to their poor water solubility and their high fat solubility.


Stearamide, the main constituent of Amides, C16-C18 (even numbered), is, like oleamide, one of the elements of the human meibomian gland secretions, which is a complex mixture of triglycerides, free fatty acids, diesters, cholesterol and wax esters, free cholesterol, hydrocarbons and polar lipids that prevents evaporation and assists in the maintenance of a stable tear film, which protects the surface of the eye (Nichols, 2007).


Stearamide (and palmitamide, the constituents of Amides, C16-C18 (even numbered)) is also a substrate of the fatty acid amide hydrolase (FAAH), originally named oleamide hydrolase (Patterson, 1996), which is able to hydrolyse a wide range of fatty acid amides (Boger, 2000, Cravatt, 1996), which are a large and diverse class of lipid transmitters (Cravatt, 1995). The magnitude and duration of fatty acid amide signalling are controlled in vivo by enzymatic hydrolysis (Wei, 2006). Endogenous substrates of this enzyme were demonstrated to be, amongst others, the endogenous cannabinoid anandamide (a fatty acid amide identified as the endogenous ligand for the cannabinoid receptor), and the sleep-inducing substance oleamide (Lerner, 1994; Patterson, 1996; Cravatt, 1995; Day, 2001); both have messenger functions in the human CNS (Fedorova, 2001; Bisogno, 2002). A significant hydrolase activity by FAAH of 69% and 72%, in relation to that for oleamide, was also demonstrated for stearamide and palmitamide, respectively (Boger, 2000). FAAH is an integral membrane protein (Day, 2001) widely distributed in mammalian tissues and belongs to a large family of enzymes that share a highly conserved ~130 amino acid motif designated the “amidase signature” (AS) sequence. Blockade of FAAH activity leads to highly elevated endogenous levels of fatty acid amides in the nervous system and peripheral tissues (Wei, 2006).


Lately, a second enzyme with FAAH activity has been discovered which has been termed FAAH-2, referring to the original AS enzyme as FAAH-1 (Wei, 2006). These enzymes exhibit overlapping but distinct tissue distribution, substrate selectivity, and inhibitor sensitivity profiles. Interestingly, the FAAH-2 gene is present in primates, as well as in a variety of distantly related vertebrates, but not in murids (mice and rats), suggesting even more possibilities for the metabolisation of fatty acid amides in humans. Whereas only FAAH-1 is expressed in brain, small intestine and testis, only FAAH-2 is expressed in the heart. Both enzymes are expressed in kidney, liver, lung and prostate (Wei, 2006).


The expression of both enzymes in tissues known to be closely associated with absorption, metabolism and excretion of chemicals in the body, like small intestine, liver and kidney, makes it reasonable to assume their contribution also in the metabolism of fatty acid amides to their respective metabolites, which, in case of Amides, C16-C18 (even numbered), are palmitic acid and stearic acid.


Another possibility for the desamidation of fatty acid amides is the degradation by gastrointestinal fluid, as demonstrated for oleamide. Oleamide, which is the mono-unsaturated form of stearamide, was shown to be degraded to oleic acid in simulated gastrointestinal fluids; about 95% of oleamide was destroyed within 4 hours at 37°C in the presence of bile salts leading to the formation of 86% oleic acid (Cooper and Tice, 1995; Cooper, 1995). Due to the high structural similarity it is reasonable to assume a comparable degradation by gastric fluids for stearamide and palmitamide, which are the main constituents of Amides, C16-C18 (even numbered), as well.


Due to the presence of adequate and effective metabolic pathways in the mammalian and especially the human organism, and the characteristics of the substance itself, a rapid and effective absorption, distribution and metabolism of the metabolites of Amides, C16-C18 (even numbered) is very likely. The most abundant metabolite stearic acid is one of the most common saturated fatty acids (only exceeded by palmitic acid) and is present in nearly all naturally occurring animal and vegetable oils and fats, including cashew (6.0-12.0%), corn (<3.3%), hazelnut (2.0%), olive (0.5-5%), pecan (1.6%), peanut (1.9-4.4%), rape seed (0.5-3.1%), sesame (4.8-6.1%), sunflower (3.5-4.5%) and tomato seed oil (4.0-6.5%), cocoa butter (33.2%), shea butter (28-45%), illipe fat (40-45%, used for production of chocolate), palm oil (3.5-6.0%), lard (5.0-24.0%), bacon fat (~12%), beef fat (14.7%), cream (13.3%), poultry meat (7.7-13.7%), sausages and salami (6.1-16.3%), tallow (~19%), eggs (5.5-9.3%), heart (13.6-17.9%), kidney (15.3-23.6%), liver (19.4-33.4%), meat (6.0-24.4%) and milk (11.2-15.1%), to name only a few, which are common elements of our daily food uptake. Stearic acid is included to a considerable extent (7.0%) even in human milk (Beare-Rogers, 2001). Additionally, a considerable amount of dietary stearic acid was demonstrated to be oxidised to oleic acid in humans (Emken, 1994), which is the most abundant fatty acid in humans and also one of the most abundant ones in their daily diets (Beare-Rogers, 2001).

Fats are absorbed in the gastrointestinal tract and are transported in form of lipoproteins and chylomicrons via blood and lymph, respectively. Most of the absorbed triglycerides are used by muscle and fat tissue. Fatty acids are separated from triglycerides by lipases. Free fatty acids can penetrate the plasma membranes due to their poor water solubility and their high fat solubility. They are activated in the cytoplasm by coupling to coenzyme A and are transported into the mitochondria by a transporter system after coupling to L-carnitine. Inside the mitochondria they are again coupled to coenzyme A before they enter the cycle of beta-oxidation.

Subsequently to the desamidation of Amides, C16-C18 (even numbered), the metabolites stearic and palmitic acid can enter the catabolic pathway of beta-oxidation which breaks down the fatty acid chain to acetyl-CoA in subsequent passages of the cycle. Acetyl-CoA enters the citric acid cycle and is used for the chemical reduction of NAD+and FAD, which in turn are used for the production of ATP in the process of oxidative phosphorylation. In case of the C18-compound 146 molecules of net ATP are produced, for example, which serve as energy source for the cells of the organism.


On the contrary, acetyl-CoA can also be used for the endogenous synthesis of fats which can be stored in fat cells and serve as energy reservoirs that can be mobilised in times of low carbohydrate availability. Here, palmitic acid is the first fatty acid produced during synthesis, which serves as precursor for longer fatty acids. Stearic acid was shown to be abundant in human adipose tissue; it is present in quantities of 3.7 to 8.2%, depending on the anatomical site, age and race of the individual (Kokatnur, 1979).


However, the available literature demonstrates that stearic acid might rather be used for anabolic processes than for catabolic ones, as 98% of labelled compound can be found in endogenous products like liver, bile and plasma lecithins (sphingolipids) as early as 1 hour after intravenous application; the highest activity was found in hepatic lecithins, followed by bile lecithin. Less than 2% of 14C-activity was present in fatty acids other than stearic acid (Balint, 1967). In conclusion, the intravenously applied stearic acid does not seem to be broken down by beta-oxidation; it rather seems to enter anabolic pathways.

Stearic acid is also known to be a common element of intracellular messenger molecules of the phosphoinositide cascade, which is relevant for the conversion of extracellular signals into intracellular ones. After phosphorylation of phosphatidylinositol (PI) to PI 4,5-bisphosphate (PIP2) this molecule is cleaved into the second messengers diacylglycerol, which activates protein kinase C, and inositol 1,4,5-triphosphate (IP3), which opens Ca-channels and releases Ca2+from the endoplasmatic reticulum. Here, stearic acid represents one of the acylchains of diacylglycerol.

Considering the presence of effective metabolic pathways and the fact that the metabolites of Amides, C16-C18 (even numbered) are educts for the most effective processes of energy production and storage, and their abundant endogenous availability even in the human body, adverse effects after application of the substance are not to be expected.



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