Fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol

Endpoint summary

Description of key information

Fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol is expected to have a high absorption potential via the oral route, but low absorption potential via the dermal and the inhalation route. Fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol will be probably hydrolysed to di- or triesters, followed by a complete hydrolysis to the alcohol pentaerythritol and the corresponding fatty acids C18-C22 in the gastrointestinal tract and mucus membranes, which facilitates the absorption. The fatty acids will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons. The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-pathway or direct conjugation to more polar products. The excretion will mainly be as CO₂ in expired air; with a smaller fraction excreted as conjugated molecules in the urine. No bioaccumulation will take place, as excess triglycerides are stored and used as the energy need rises.

Additional information

There are no toxicokinetic studies available for fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol. In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the substance fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol (CAS 61682-73-3) 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 physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017).

Fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol is a solid at 20 °C with a molecular weight ranging from 1370.31 to 1426.42 g/mol and a water solubility of < 0.518 mg/L. The calculated log Pow value is > 10 and the calculated vapour pressure is < 0.0001 Pa at 20 °C.

 

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, 2017).

 

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2017).

When assessing the potential of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol to be absorbed in the gastrointestinal (GI) tract, it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972; National technical information service, 1973). The possibility to hydrolyse is also based on QSAR analysis using the OECD QSAR Toolbox(v4.2, OECD, 2018), which is further described in the metabolism section below. Thus, due to the hydrolysis the predictions based upon the physico-chemical characteristics of the intact parent substance alone may no longer apply but also the physico-chemical characteristics of the breakdown products of the UVCB; di- or triesters, followed by a complete hydrolysis the alcohol pentaerythritol and the corresponding fatty acids C18-C22.

The low water solubility (< 0.518 mg/L) and the high log Pow value > 10 of the parent compound indicate that absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986).

Moreover, acute oral toxicity studies with appropriate analogue substances 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8), pentaerytritol tetraoleate (CAS 19321-40-5), fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), pentanoic acid, mixed esters with PE, isopentanoic acid and isononanoic acid (CAS 146289-36-3), decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9) and fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) showed no signs of systemic toxicity resulting in a LD50 value greater than 2000 mg/kg bw. Furthermore, available data on subacute and subchronic oral toxicity with fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) and fatty acids, C8-10 mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) and pentanoic acid, mixed esters with PE, isopentanoic acid and isononanoic acid (CAS 146289-36-3), respectively, showed no adverse systemic effects resulting in a NOAEL ≥ 1000 mg/kg bw/day.

In conclusion, taking into account the physico-chemical and toxicological properties of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol, the oral absorption potential by micellular solubilisation is expected to be high for the hydrolysis products.

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. Log Pow values in the range of 1 to 4 are favourable for dermal absorption (values between 2 and 3 are optimal), in particular if the 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).

Fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol has a molecular weight ranging from 1370.31 to 1426.42 g/mol and a water solubility of < 0.518 mg/L; therefore a low dermal absorption potential might be assumed (ECHA, 2017). The log Pow is > 10, which means that the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2017).

Damage to the skin surface may enhance penetration of the test substance (ECHA, 2017). However, available in vivo skin irritation studies with the appropriate analogue substances 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8), fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), fatty acids, C8-10 mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) and fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) revealed neither skin corrosive nor skin irritant properties of the test substance. Moreover, a local lymph node assay performed with fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol did not show a potential for skin sensitisation.

Overall, taking into account the physico-chemical properties and toxicological properties of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol, the dermal absorption potential of the substance is anticipated to be low.

Inhalation

Inhalation of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol is considered negligible as the test substance has a very low calculated vapour pressure > 0.0001 Pa and a very high boiling point > 300 °C, thus being of low volatility. Moreover, based on the results of the granulometric analysis, the substance has particle sizes: D10: 2611.2 µm, D50: 391 µm and D90: 552.5 µm. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant.

Based on the physico-chemical properties of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol, absorption via the lung is expected to be negligible.

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical 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. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. 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, 2017).

As the parent compound fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol will be probably hydrolysed prior to absorption (as discussed above); the distribution of the intact substance is not relevant but rather the distribution of the breakdown products of hydrolysis.

Like all medium and long chain fatty acids, the fatty acids may be re-esterified with glycerol into triacylglycerides (TAGs) and transported via chylomicrons or absorbed from the small intestine directly into the bloodstream and transported to the liver. Via chylomicrons, fatty acids are transported via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994). The alcohol pentaerythritol is expected to have a high water solubility and a low log Pow value due to the small molecular weight and the four hydroxyl groups, which are polar and therefore hydrophilic.

Therefore, the intact parent compound is not assumed to accumulate as hydrolysis takes place before absorption and distribution. Accumulation of the fatty acids in triglycerides in adipose tissue or the incorporation into cell membranes is possible as further described in the metabolism section below. However, at the same time, fatty acids may also be used for energy generation. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolised and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism. Accumulation of water soluble compounds such as the alcohol pentaerythritol is not expected.

In summary, the available information on fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol and its breakdown products indicate that no significant bioaccumulation of the parent substance and its hydrolysis products in adipose tissue is expected.

Metabolism

As previously described, when assessing the potential of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol to be absorbed in the gastrointestinal (GI) tract it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972; National technical information service, 1973).

In addition, the potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.2, OECD, 2018). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 33 hepatic and 2 dermal metabolites were predicted for the test substance, respectively. In the skin, hydroxylation of the aliphatic side chain may occur. In the liver, several hydrolysis products were predicted which were further hydrolysed or oxidised.These predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic.Phase II metabolism by e.g. uridine 5′-diphospho(UDP)-glucuronosyltransferases (UGT) and sulfotransferases typically generate excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrates, respectively (Aktories, 2005). Besides the skin and liver metabolites, up to 92 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule.

However, an important metabolic pathway for fatty acids is also the beta-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 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂ (Lehninger, 1970; Stryer, 1994).

Available genotoxicity data from the target substance fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol do not reveal mutagenic properties in bacterial cells. Moreover, an in vitro chromosomal aberration test and an in vitro and in vivo mammalian gene mutation assay with appropriate source substances were consistently negative and therefore no indication of genotoxic reactivity is indicated.

Excretion

Based on the metabolism described above, fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol and its breakdown products are expected to be metabolised in the body to a high extent. The fatty acid components may be further metabolised by phase II enzymes and excreted via urine or further metabolized for energy generation or stored as lipid in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO₂ or stored as described above.

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005): Allgemeine und spezielle Pharmakologie und Toxikologie. 9. Auflage, Urban & Fischer Verlag.

Aungst B. and Shen D.D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 2.0, June, 2017.

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Long, C.L. et al.(1958). Studies on absorption and metabolism of propylene glycol distearate.Arch Biochem Biophys, 77(2):428-439.

Mattson F.H. and Volpenhein R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lip Res 9, 79-84.

Mattson, F.H. and Volpenheim, R.A. (1972).Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171 -1176.

National technical information service (1973). Evaluation of the Health Aspects of Propylene Glycol and Propylene Glycole Monostearate as Food Ingredient. Fed of America Societies for Experimental Biology, Bethesda, MD. Contract No. FDA 72 – 85.

OECD, 2018: OECD QSAR Toolbox v4.2, February, 2018, Laboratory of Mathematical Chemistry Oasis. Downloaded from https://qsartoolbox.org/ Prediction performed on 06 April 2018.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad.Verlag.