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Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) has been investigated.

Therefore, 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, 2014), assessment of the toxicokinetic behavior of the substance Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

The substance Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is an UVBC substance based on the analytical characterization. The organic liquid is poorly water soluble (< 5 µg/L) with a molecular weight range of 374.56 - 1193.93 g/mol, a predicted log Pow of 6.11 - >10 and a vapour pressure <0.0001 Pa at 20 °C based on QSAR predictions (KOWWIN v1.68 (log Pow) and SPARC v4.6 (vapour pressure)).

 

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, 2014).

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2014). As the molecular weight of the substance Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) ranges from 374.56 - 1193.93 g/mol absorption of the molecule in the gastrointestinal tract is considered to be very limited.

Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) as the substance fails two rules for good bioavailability (the molecular weight is >500 and the log Pow is >5). Thus, oral absorption is not expected to be high either.

The log Pow of 6.11 - >10 of the substance Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) suggests that the absorption of such a highly lipophilic substance may be limited by the inability to dissolve into gastrointestinal (GI) fluids. It might be enhanced by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), which are poorly soluble in water (1 mg/L or less). However, for large molecules the gastrointestinal absorption is not likely to occur.

In the gastrointestinal tract (GIT), metabolism prior to absorption may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) have been shown to be rapidly hydrolised by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpenhein, 1972a). However, lower rates of enzymatic hydrolysis in the GIT were showed for compounds with more than 3 ester groups. In vitro hydrolysis rate of a pentaerythritol ester was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a, b).

Moreover, in vivo studies in rats demonstrated the incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased (Mattson and Volpenhein, 1972c). In vivo studies in rats showed that the hexaester of sorbitol is not absorbed (Mattson and Nolen, 1972). Based on this, it can be assumed that, on the one hand, the tri- and tetraesters of pentaerythritol is not considered to be rapidly hydrolysed in the GIT by esterases and, on the other hand, absorption of the whole substance can be considered to be very low.

Even though hydrolysis is assumed to be slow, it needs to be addressed that the physico-chemical characteristics of the theoretical 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, 2014).

Pentaerythritol, being a highly water-soluble substance (25 g/L, OECD SIDS, 1998), will readily dissolve into the gastrointestinal fluids. DiCarlo et al. (1965) showed that 10 mg/kg C14-labled PE orally administered to mice was absorbed rapidly. Almost half of the administered dose left the gastrointestinal tract within 15 minutes.

 

Acute oral toxicity studies are available for the structurally related substances pentaerythritol tetraoleate (CAS 19321-40-5) and 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8) indicating no signs of systemic toxicity resulting in acute oral LD50 values >5000 mg/kg bw (Croda, 1984a, Croda, 1997).

A repeated dietary administration (28-day) of the structurally related substance Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) to rats, up to and including a dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/day for female rats, did not produce any evidence of overt toxicity (Croda, 1993). These results suggest that Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) are of low systemic toxicity, either due to low toxicity potency or by a low absorption in combination with a low systemic toxicity.

In summary, the above discussed physico-chemical properties of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) and relevant data from available literature on fatty acid esters with more than 4 ester bonds do not indicate rapid hydrolysis before absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) to the respective fatty acids and the polyol pentaerythritol. On the basis of the above mentioned data, a low absorption of the test material is predicted.

 

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2014). As the molecular weight of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) ranges from 374.56 - 1193.93 g/mol, a dermal absorption of the molecule is considered to be very limited.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). A skin irritation study with Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) showed that the substance was not considered as skin irritating in humans (Oleon, 2016a). Therefore, an enhanced penetration of the substance due to local skin damage is not expected.

An acute dermal toxicity study is available for the structurally related substance 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8) indicating no signs of systemic toxicity resulting in an acute dermal LD50 value >2000 mg/kg bw (Croda, 1984b).

In support of this, QSAR calculations revealed a dermal absorption value for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) of 1.0E-05 - 6.8E-04 µg/cm²/h (Episuite 4.1, DERMWIN 2.02, 2012). Based on this value, the substance has a very low (1%) potential for dermal absorption.

For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2014). As the water solubility of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is less than 1 mg/L and log Pow is estimated to be 6.11 - >10, dermal uptake is likely to be very low.

Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (>100 g/mol), the high log Pow values and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) in humans is considered as very low.

 

Inhalation

Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) have a low vapour pressure of less than <0.0001 Pa at 20 °C, thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapors, gases, or mists is not expected.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2014).

Lipophilic compounds with a log Pow >4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) can be taken up by micellar solubilisation.

Additionally, as described above, theoretically, Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) will be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher. However, hydrolysis of fatty acid esters with more than 3 ester bounds is considered to be slow (Mattson and Volpenhein, 1972a). Therefore, Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) will be slowly hydrolysed enzymatically to the respective metabolites and thus, their respiratory absorption is considered to be low.

Overall, a systemic bioavailability of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) in humans cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm, but is not expected to be higher than following oral exposure.

Accumulation

Highly lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of 6.11 - >10 implies that Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) may have the potential to accumulate in adipose tissue (ECHA, 2014).

Absorption is a prerequisite for accumulation within the body. As absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is considered to be very low the potential of bioaccumulation is very low as well.

Nevertheless, as further described in the section metabolism below, esters of pentaerythritol and fatty acids may undergo slow esterase-catalyzed hydrolysis, leading to the cleavage products pentaerythritol and the fatty acids.

The log Pow of the first cleavage product pentaerythritol is <0.3 and it is highly soluble in water (25 g/L) (OECD SIDS, 1998). Consequently, there is no potential for pentaerythritol to accumulate in adipose tissue. The other cleavage products, the corresponding fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear are not likely to accumulate in adipose tissue, as fatty acids are subject to a constant turn-over depending on the bodies energy needs.

Overall, the available information indicates that no significant bioaccumulation in adipose tissue of the parent substance can cleavage products can be anticipated.

 

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, 2014). Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption.

As discussed above, absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is considered very low based on its physicochemical characterization as poor water solubility and high molecular weight.

As data from acute and repeated dose toxicity studies from source substances show no signs of systemic toxicity the distribution of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is considered very low.

Esters of pentaerythritol and fatty acids can undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products pentaerythritol and the different fatty acids. Only the potential cleavage products of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) after chemical changes as a result of enzymatic hydrolysis, namely pentaerythritol and the fatty acids (C16-18 (even numbered) and C18-unsatd., branched and linear), might be distributed within the body.

Pentaerythritol on the basis of its physicochemical properties will be distributed in aqueous fluids by diffusion through aqueous channels and pores. There is no protein binding and it is distributed poorly in fatty tissues (OECD SIDS, 2009). The fatty acids are also distributed in the organism and can be taken up by different tissues.

Overall, the available information indicates that the cleavage products, pentaerythritol and fatty acids can be distributed in the organism.

 

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: after oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. However, as discussed previously, it is not anticipated that enzymatic hydrolysis of the parent substance is taking place in the gastrointestinal tract due to the high molecular weight and the complex structure of the molecule. Additionally, the hydrolysis of esterified alcohol with more than 3 ester groups is assumed to be slow as discussed above. In in vivo studies in rats, a decrease in absorption was observed with increasing esterification. For example, pentaerythritol tetraoleate ester had an absorption rate of 64% and 90% (25% and 10% of dietary fat), whereas the hexaester of sorbitol was not absorbed (Mattson and Nolen, 1972). As Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) reflects tri- and tetraesters the absorption rate is expected to be low.

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.

Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is expected to be slowly hydrolysed to the corresponding alcohol (pentaerythritol) and fatty acids (C16-18 (even numbered) and C18-unsatd., branched and linear) by esterases. It was shown in-vitro that the hydrolysis rate for another polyol ester (pentaerythritol tetraoleate) was lower when compared with the hydrolysis rate of the triglyceride glycerol trioleate (Mattson and Volpenhein, 1972). Thus, it is assumed that the hydrolysis rate for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is comparable low. Therefore, ester bond hydrolysis is expected to occur to a minor extent in the gastrointestinal tract. Nevertheless possible cleavage products should be discussed here.

The other cleavage product, Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear are metabolised by stepwise beta-oxidation before entering the citric acid cycle as acetyl CoA (Stryer 1996). Branched fatty acids may also be metabolized via omega-oxidation. In this case, the resulting metabolites (diols, hydroxyl acids, ketoacids, dicarbonic acids) will be conjugated to glucuronides or sulfates, which are excreted via the urine or bile (WHO, 1998).

Overall, the part of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) that have become systemically available, might be hydrolysed and the cleavage products can be further metabolized. However, due to its high molecular weight, absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) is not likely and thus, no extensive metabolism is expected but rather direct elimination.

Excretion

Low absorption is expected for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol (CAS 85186-72-7) via the gastrointestinal tract, thus much of the ingested substance is assumed to be excreted in the feces.

However, based on the anticipated enzymatic hydrolysis, pentaerythritol and fatty acids as breakdown products will be present in the body. The fatty acid components will be metabolized for energy generation and afterwards mainly excreted by expired air as CO2, or stored as lipids in adipose tissue or used for further physiological properties e.g., incorporation into cell membranes (Stryer, 1996). Therefore, the branched and linear C16 – C18 unsaturated and saturated fatty acid components are not expected to be excreted to a significant degree via the urine or feces but excreted via exhaled air as CO2 or stored as described above. The main route for elimination of the alcohol is renal excretion via the urine (Gessner, 1960).

References

DiCarlo F.J., Hartigan J.M. Jr., Couthino, C.B. and Phillips, G.E. (1965): Absorption, distribution and excretion of Pentaerythritol and Pentaerythritol Tetranitrate by mice. Proceedings of the Society for Experimental Biology and Medicine. 118: 311-314.

ECHA (2014): Guidance on specific guidance. information requirements and chemical safety assessment, Chapter R.7c: Endpoint

EPA (2012): Dermwin v2.02, Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA. Downloaded from http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.

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

Gessner PK, Parke DV, Williams RT (1960): Studies in detoxification. 80. The metabolism of glycols Biochem J 74: 1-5.

Ghose et al. (1999): A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Lipinski et al. (2001): Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.

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

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

Mattson F.H. and Volpenhein R.A., (1972b): Digestion in vitro of erythritol esters by rat pancreatic juice enzymes. J Lip Res 13, 777-782

Mattson F.H. and Volpenhein R.A., (1972c): Rate and extent of absorption of the fatty acids of fully esterified glycerol, erythritol, xylitol, and sucrose as measured in thoracic duct cannulated rats. J Nutr 102, 1177-1180

OECD SIDS (1998): www.inchem.org/documents/sids/sids/115775.pdf

Stryer, L. (1996): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

WHO (1998): Safety evaluation of certain food additives and contaminants. Saturated Aliphatic Acyclic Branched-Chain Primary Alcohols, Aldehydes, and Acids. WHO food additives series 40.

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