Sorbitan monolaurate, ethoxylated

Endpoint summary

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behavior of the substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics as well as on available data fort the test substance.

The test substance is a liquid, which is slightly soluble in water (< 0.2 mg/L at 20 °C, pH=6.3 - 7.9). The log Pow is 1.23 -3.86 and the vapour pressure <0.0001 at 20°C. Depending on the degree of ethoxylation, CAS No 9005 -64 -5 can be differentiated into Polysorbate 21 (4 -5 EO indicated by the figure "1", molecular weight of 434.56 g/mol) and Polysorbate 20 (20 EO indicated by the figure "0", molecular weight of 1227.46 g/mol). Both are mono-esterified with lauric acid, which is indicated by the first figure ("2").

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008).

Oral

The physicochemical characteristics of the test substance (log Pow 1.23 -3.86), the molecular mass and the poor water solubility for Sorbitan monolaurate, ethoxylated are suggestive of low absorption from the gastro-intestinal tract subsequent to oral ingestion.From the acute oral toxicity studies, LD50 values exceeding 30000 mg/kg bw were found for Polysorbate 20 and 21. The only clinical sign observed in these studies was diarrhea. In the subchronic and chronic studies, diarrhea was also observed going along with an enlargement of the caecum that was observed at gross pathology. However, since effects on intestinal organs were observed at histopathology, an indication for systemic availability of the test substance or metabolites after a oral ingestion is given.

After oral ingestion, Sorbitan fatty acid esters will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. The hydrolysis of Sorbitan fatty acid esters occurs within a maximum of 48h for mono-, di- and tri-ester but decreases with the number of esterified fatty acid so that no hydrolysis of hexa-ester occurs (Krantz 1951, Mattson and Nolen 1972, Treon 1967, Wick and Joseph 1953).The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2008). However, for all cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract.The highly lipophilic fatty acid will be absorbed by micelullar solubilisation (Ramirez et al., 2001), whereas the D-glucitol, being a highly water-soluble substance, will dissolve into the gastrointestinal fluids and slowly be absorbed with a subsequent metabolism in the liver (Senti 1986, Touster 1975).For the ethoxylated residues it was previously shown that small proportions can be recovered as 14CO2 in the exhaled air but also in the faeces. With regard to the latter, the proportions increased with longer ethoxylate length (HERA 2009).

Overall, a systemic bioavailability of Sorbitan monolaurate, ethoxylated and/or its metabolites is considered likely after oral ingestion.

Dermal

Molecular weight and N-octanol/water partition coefficient in combination with the low water solubility of the compound argue for not favouring dermal absorption. According to Dermwin v2.0 QSAR prediction dermal absorption of the test substance was also predicted to be low (see section 7.1.2.). One dermal acute toxicity study (with a reliability of 4) revealed a LD50 of >3000 mg/kg bw in guinea pigs without any clinical signs or effects seen at gross pathology and histopathology. Neither the substance is irritating to the rabbit skin/eye nor causes sensitisation. Because no signs of systemic toxicity were seen in the skin/eye irritation studies, it is unclear if the lack of general toxicity is due to low or no dermal absorption or due to the low toxicity of the test substance. It can however be conjectured that the dermal absorption is propably not high.

Overall, the calculated very low dermal absorption potential, water insolubility, the high molecular weight and the fact that the substance is not irritating to skin and eyes implies that dermal uptake of Sorbitan monolaurate, ethoxylated is considered as very limited in humans.

Inhalation

No data on acute inhalative toxicity is available. The log Po/w and the low water solubility of the test substance would suggest absorption via the respiratory tract. However, taking the low vapour pressure of < 0.0001 Pa at 20 °C into consideration, it can be overall concluded that the availabilty for inhalation in general might be low.

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. 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, 2008).

Sorbitan fatty acid esters acids will undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products D-glucitol and fatty acids.

D-glucitol, a small (MW 182.2 g/mol), polar water-soluble substance (log Pow -2.2), will be distributed in aqueous fluids by diffusion through aqueous channels and pores and oxidized by L-iditol dehydrogenase to fructose which is subsequently metabolized by the fructose metabolic pathway (Touster 1975).

The fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro 1977). At the same time, fatty acids are also required as a source of energy and undergo beta-oxidisation. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism. An ethoxylated residue might also occur which most likely remains intact and might be excreted via bile into the small intestine as such (HERA 2009).

Experimental data obtained in the repeated dose toxicity studies showed abnormalities in kidney, spleen, testes and ovaries at gross pathology as well as microscopic observations of alterations in kidney, testes, lymphoid tissue, liver, and coronary tissues.Assumably, the test substance and/or their metabolites may at least reach the intestinal organs but probably not crosses the placental barrier, since there were no effects on litters observed in the available prenatal study.

Metabolism

The test substance is a Sorbitan fatty acid ester.Esters are known to hydrolyse into carboxylic acids and alcohols by esterases (Fukami and Yokoi, 2012).Therefore it is expected that the test substance hydrolyses to D-glucitol and the respective fatty acids under physiological conditions. Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, Sorbitan fatty acid esters will undergo chemical changes already in the gastro-intestinal fluids as a result of enzymatic hydrolysis.In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

The first cleavage product, the fatty acid, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues.The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The alpha- and omega-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

For the second cleavage product D-glucitol it was found, that it is relatively slowly absorbed from the gastro-intestinal tract compared with glucose and that it can be metabolized by the intestinal microflora (Senti 1986). Once absorbed, D-glucitol is primarily metabolized in the liver.The first step involves oxidation by L-iditol dehydrogenase to fructose which is metabolized by the fructose metabolic pathway (Touster 1975).D-glucitol does not enter tissues other than the liver and does not directly influence the metabolism of endogenous D-glucitol in other tissues.

However, using the OECD toolbox Vs. 2.3, the liver metabolism simulator provided 42 and the GI metabolism simulator provided 260 potential metabolites. As diverse genotoxicity studies did not reveal any evidence of mutational properties, intracellular occuring metabolites seem not to exhibit reactive properties.

Excretion

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. In the rat, molecules that are excreted in the bile are amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have a high molecular weight.In general, in rats for organic cations with a molecular weight below 300 it is unlikely that more than 5-10% will be excreted in the bile, for organic anions this cut off may be lower.Substances excreted in bile may potentially undergo enterohepatic circulation. Little is known about the determinants of biliary excretion in humans. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells (ECHA, 2008).

Due to the high molecular weight and the poor solubility in water, excretion of the test substance via urine or bile is unlikely after oral administration.

After oral ingestion, Sorbitan fatty acid esters will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis.As the physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2008). However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract. The highly lipophilic fatty acids will be readily absorbed by micelullar solubilisation und undergo beta-Oxidation or will be stored in fat tissue (Ramirez et al., 2001).The D-glucitol, being a highly water-soluble substance, will dissolve into the gastrointestinal fluids and slowly be absorbed with a subsequent metabolization to fructose in the liver by L-iditol dehydrogenase (Senti 1986, Touster 1975). Non-metabolized D-glucitol will most probably mainly be excreted via urine, due to the low molecular weight and the high water solubilty of the substance whereas non-absorbed cleavage products including fatty acids will be excreted via faeces. High amounts of D-glucitol in the intestine trigger diarrhea (Peters 1958) and de facto, diarrhea was observed in nearly all acute oral toxicity and repeated dose toxicity studies with high amounts of ethoxylated Sorbitan monolaurate, ethoxylated exceeding concentrations of 30000 mg/kg bw.

 

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