Fatty acids, C10-12, esters with polylactic acid, sodium salts

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1) has been assessed. However, the substance is structurally closely related to the two approved food additives esterification product of C16-C18 even numbered, saturated fatty acids and lactic acid, sodium salt (sodium stearoyl lactylate, SSL, E 481, CAS No. 25383-99-7, EC No. 246-929-7) and calcium stearoyl-2-lactylate (CSL, E 482). Whilst Dermosoft decalact contains C10 (caproyl) and C12 (lauroyl) moieties, the alkyl chains in SSL and CSL are derived from C16 (palmitoyl) and C18 (stearyl). There are no differences with respect to the lactyl lactate (lactylate) moiety. With regard to the differences between sodium and calcium, the latest EFSA evaluation report on SSL and CSL states: ‘both, sodium and calcium are endogenous cations without toxicological relevance for the evaluation of SSL and CSL as food additives’ (EFSA, 2013). Therefore, it is considered appropriate to base the toxicokinetics assessment of Dermosoft decalact also on the EFSA evaluation and on the toxicokinetic data given for SSL and CSL.

In accordance with Annex VIII, Column 1, Item 8.8.1, of the REACH Regulation (EC) No. 1907/2006 and with the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of the Dermosoft decalact is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant guidance (ECHA, 2017) and taking into account available information provided in the latest EFSA evaluation report on SSL and CSL (EFSA, 2013).

Fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1) is an UVCB substance containing a C10 (caproyl) or C12 (lauroyl) fatty acid moiety esterified with the hydroxyl group of lactyl lactate. The molecular weight of the reaction product is 316.40 g/mol for the caproyl-derived ester and 344.45 g/mol for lauroyl lactylate. The substance is a yellowish to brownish (amber), highly viscous liquid for which the water solubility was determined to be 0.12 g/L at 20 °C. The octanol/water partition coefficient (log Pow) was calculated to be in the range 1.6 - 3.7 for pH values varying from 5 to 9. The vapour pressure was assessed to be 2.85E-03 Pa at 25 °C.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters to provide information on this potential are the molecular weight, octanol/water partition coefficient (log Pow) value and water solubility (ECHA, 2017). The log Pow value provides information on the relative solubility of the substance in water and lipids.

Oral

The molecular weight range of Dermosoft decalact is 316.40 - 344.45 g/mol, indicating that the substance is favourable for absorption (ECHA, 2017). The moderate log Pow in combination with the moderate water solubility suggests that absorption via micellar solubilisation is not the favoured mechanism of absorption (ECHA, 2017).

No acute oral toxicity study is available for Dermosoft decalact. However, data from a short-term (28-day) oral repeated dose toxicity study indicate a low systemic toxicity. Effects observed in the study were attributed to local irritation in the forestomach of test animals. The No-Observed-Adverse-Effect-Level (NOAEL) determined in the study was 750 mg/kg bw/day (highest dose tested). The finding with Dermosoft decalact is supported by repeated dose toxicity studies with SSL, including a long-term (1-year) feeding study in rats, cited in the EFSA report. The NOAEL determined in the latter study for SSL was 5% in the diet, corresponding to the highest dose tested of app. 2200 mg/kg bw/day (EFSA, 2013). Therefore, all available studies indicate the lack of systemic toxicity of alkyl lactylates, incl. Dermosoft decalact.

The potential of a substance to be absorbed in the gastro-intestinal (GI) tract may be influenced by chemical changes taking place in GI fluids due to metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance and hence predictions based upon the physicochemical characteristics of the parent substance may no longer apply (ECHA, 2017).

In general, alkyl esters are expected to be hydrolysed in the GI tract, blood and liver to the corresponding alcohol and fatty acid by the enzymatic activity of ubiquitous carboxylesterases. There are indications that the hydrolysis rate in the intestine by action of pancreatic lipase is lower for alkyl esters than for triglycerides, the natural substrate of this enzyme (Mattson and Volpenhein, 1969, 1972; WHO, 1999). Several in vitro and in vivo investigations of the hydrolysis of CSL are referred to in the EFSA report and the results of these studies are summarised as follows: ‘The in vitro and in vivo studies […] show that CSL is nearly completely hydrolysed to lactic acid and stearic acid after oral application’. Dermosoft decalact is, therefore, also predicted to be enzymatically hydrolysed to the linear capric (C10) and lauric (12) acids, respectively, and lactic acid.

Free fatty acids and alcohols are readily absorbed by the intestinal mucosa. Within the epithelial cells, fatty acids are (re-)esterified with glycerol to triglycerides. In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964; OECD, 2006; Sieber, 1974). In addition, the lactate moiety is rapidly and completely absorbed (EFSA, 2013).

In conclusion, the available information, the physicochemical properties and molecular weight of Dermosoft decalact suggest oral absorption. However, the substance is anticipated to undergo enzymatic hydrolysis in the GI tract and absorption of the hydrolysis products is also relevant. The absorption rate of the hydrolysis products is predicted to be high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1 - 100 mg/L; and moderate to high if it is between 100 - 10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

Dermosoft decalact is moderately soluble in water (0.12 g/L) , indicating a moderate to high dermal absorption potential based on the banding scheme mentioned in the previous paragraph and given in ECHA, 2017. The molecular weight of 316.40 - 344.45 g/mol g/mol is within the 500 g/mol limit above which dermal absorption is low. The log Pow is 1.6 - 3.7, which means that the rate of transfer between the stratum corneum and the epidermis will be fast and uptake into the stratum corneum is likely to occur (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = - 2.80 + 0.66 log Pow - 0.0056 MW

The Kp is thus 0.01 - 0.03 cm/h. Considering the water solubility (0.12 g/L), the dermal flux is estimated to be approx. 1.3 - 3.9 mg/cm²/h  , indicating a very low absorption potential. The calculations have been performed using caproyl and lauroyl lactylate, i.e. the non-ionised compounds, because the QSAR model is not applicable to ionic species.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). The experimental data on Dermosoft decalact show that no skin irritation occurred in appropriate in vitro assays. An enhanced penetration of the substance due to local skin damage can therefore be excluded. If a substance is a skin sensitiser, absorption through the skin must have been occurred, though it might be in very small quantities. Dermosoft decalact was found to be a weak sensitiser (warranting classification as Skin Sens. 1B).

Overall, based on the available information, the dermal absorption potential of Dermosoft decalact is predicted to be very low. However, some absorption did occur as observed in an in vivo skin sensitisation study.

Inhalation  

As the vapour pressure of Dermosoft decalact is very low (2.85E-03 Pa at 25 °C), the volatility is also low. Therefore, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible. If the substance is available as an aerosol, the potential for absorption via the inhalation route is increased. While droplets with an aerodynamic diameter < 100 μm can be inhaled, in principle, only droplets with an aerodynamic diameter < 50 μm can reach the bronchi and droplets < 15 μm may enter the alveolar region of the respiratory tract (ECHA, 2017).

Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst-case approach.

Distribution, accumulation and excretion

Distribution of a compound within the body depends on the physicochemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. 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 its extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Dermosoft decalact will mainly be absorbed in the form of its hydrolysis products. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). Consequently, the hydrolysis products are the most relevant components to assess. All hydrolysis products are expected to be distributed widely in the body.

The EFSA report summarises an investigation of the absorption, distribution, metabolisms and excretion (ADME) of CSL after a single oral dose (gavage) in mice and guinea pigs (EFSA, 2013). CSL was radio-labelled in the lactylate moiety (i.e. calcium stearoyl-2-[14C-lactylate]). The results indicate rapid absorption of radioactivity from the GI tract as more than 50% of the applied radioactivity was exhaled as CO2 within 7 h. In both species, approx. 80% of the applied dose was exhaled within 48 h. This finding also indicates a fast metabolism. Most of the remaining radioactivity was excreted in the urine (within 24 h) and only minor amounts were detected in the faeces. Only about 2% (mice) or 6% (guinea pig) of the administered dose remained in the tissues: mainly in the liver and GI tract. Only traces of radioactivity were found in kidneys, lungs, testes, spleen and heart. These results are supported by similar investigations with sodium and calcium lactates (EFSA, 2013).

Taken together, the hydrolysis products of Dermosoft decalact are anticipated to distribute systemically. The fatty acids are distributed in the form of triglycerides, which can be used as energy source or stored in adipose tissue. Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and exhaled as CO2. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

Metabolism

As indicated in the EFSA report (EFSA, 2013), it is reasonable to assume that the metabolism of Dermosoft decalact initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C10 (capric) and 12 (lauric) fatty acids and lactic acid. The carboxylesterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI tract and the liver (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the body. After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the GI tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin, may enter the systemic circulation directly before entering the liver where hydrolysis will generally take place (ECHA, 2017).

A major metabolic pathway for linear and branched fatty acids is the β-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of C2 units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1993). Alternative pathways for long-chain fatty acids include the ω-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (e.g. with glucuronides or sulphates) to more polar products that are excreted in the urine. This theoretical consideration is fully supported by the findings of the studies cited in the EFSA report (EFSA, 2013).

The potential metabolites following enzymatic metabolism of Dermosoft decalacte were predicted using the OECD QSAR Toolbox v4.4 (OECD, 2020). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the GI tract. 30 hepatic metabolites and four dermal metabolites were predicted for both the C10 and the C12 fatty acid-based constituents of Dermosoft decalact. Primarily, the ester group is hydrolysed both in the liver and in the skin and the hydrolysis products may be further metabolised by oxidative processes, i.e. addition of a hydroxyl group and its subsequent oxidation. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Up to 50 metabolites were predicted to result from all kinds of microbiological metabolism. Most of the metabolites were found to be a consequence of fatty acid oxidation and associated chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature.

There is no indication that Dermosoft decalact is activated to reactive intermediates under the relevant test conditions. The experimental studies on genotoxicity (Ames test, chromosome aberration and gene mutation in mammalian cells in vitro) were negative, with and without metabolic activation.

References  

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, version 3, June 2017

EFSA (2013). Scientific Opinion on the re-evaluation of sodium stearoyl-2-lactylate (E 481) and calcium stearoyl-2-lactylate (E 482) as food additives, EFSA Journal 2013;11(5):3144

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

Greenberger et al. (1966). Absorption of medium and long chain triglycerides: factors influencing their hydrolysis and transport. J Clin Invest. 45(2):217-27.

Institute of the National Academies (IOM) (2005). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). The National Academies Press. http://www.nap.edu/openbook.php?record_id=10490&page=R1

Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1993). Principles of Biochemistry. Second Edition. Worth Publishers, Inc., New York, USA. ISBN 0-87901-500-4.

Mattson, F.H. and Volpenhein, R.A. (1962). Rearrangement of glyceride fatty acids during digestion and absorption. J Biol Chem. 237:53-5.

Mattson, F.H. and Volpenhein, R.A. (1964). The digestion and absorption of triglycerides. J Biol Chem. 239:2772-7.

Mattson, F.H. and Volpenhein, R.A. (1969). Relative rates of hydrolysis by rat pancreatic lipase of esters of C2 - C18 fatty acids with C1 – C18 primary n-alcohols. J Lipid Res Vol(10): 271-276.

Mattson, F.H. and Volpenhein, R.A. (1972). Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of the rat pancreatic juice. Journal of Lipid Research 13: 325-328.

OECD (2006). Long Chain Alcohols. SIDS Initial Assessment Report For SIAM 22. Paris, France, 18-21 April 2006. TOME 1: SIAR. http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=7A14361C-4676-4339-A915-2CFD51F12483

OECD (2020). (Q)SAR Toolbox v4.4. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 10 August 2020. http://toolbox.oasis-lmc.org/?section=overview

Sieber, S.M., Cohn, V.H., and Wynn, W.T. (1974). The entry of foreign compounds into the thoracic duct lymph of the rat. Xenobiotica 4(5), 265.

US EPA (2004). Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) Interim. http://www.epa.gov/oswer/riskassessment/ragse/index.htm

WHO (1999). Evaluation of certain food additives and contaminants. Forty-ninth report of the joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series 884. ISBN 92 4 120884 8.