Pentaerythritol tetrastearate

Endpoint summary

Description of key information

Oral absorption

Based on available data, absorption after oral ingestion is predicted to be very low. Due to the rather high number of ester bonds, only slow hydrolysis in the gastrointestinal tract is expected to occur, resulting in hydrolysis products that may be readily absorbed.

Dermal absorption

The low water solubility, the high molecular weight, the high log Pow value and the lack of potential for skin irritation / corrosion indicates dermal uptake in humans is likely to be negligible.

Absorption by inhalation

During particle size analysis >94% of the particles were found to be > 150 µm. Therefore, under normal use and handling conditions, the potential for exposure via the inhalation route and thus availability for respiratory absorption is considered to be negligible.

Distribution and accumulation

The available information indicates that the intact parent compound is not assumed to distribute throughout the body due to limited absorption. In contrast, wide distribution within the body is expected for the hydrolysis products pentaerythritol and the fatty acids. However, no significant bioaccumulation of both the parent substance and its anticipated hydrolysis products in adipose tissue is expected.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by ubiquitously expressed esterases. It is assumed, however, that the hydrolysis rate is low as a result of steric hindrance due to the number of ester bonds and the complexity of the parent molecule. If hydrolysis occurs, a major metabolic pathway for linear and simple branched fatty acids is β-oxidation for energy generation. Pentaerythritol is absorbed rapidly and mainly excreted unchanged without metabolic conversion.

Excretion

A low absorption rate is expected via the gastrointestinal tract. Thus the biggest part of the ingested substance is assumed to be excreted in the faeces. Following the potential hydrolysis of the parent molecule, the fatty acids are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as carbon dioxide. Pentaerythritol is not metabolized but excreted mainly unchanged via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of Pentaerythritol tetrastearate has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 (REACH) and with the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour was conducted based on relevant available information. This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties and taking into account further available information on the polyol esters category from which data was used for read-across to cover data gaps.

Pentaerythritol tetrastearate is a mono-constituent substance consisting of esters of pentaerythritol with saturated linear fatty (stearic) acids. It is a solid which is poorly soluble in water (< 0.513 mg/L at 20 °C and pH 6); with a molecular weight of 1202 g/mol, a calculated log Pow of > 10 and a very low calculated vapour pressure of 6.36E-38 Pa at 20 °C.

 

General considerations on 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 absorption

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2017). As the molecular weight of Pentaerythritol tetrastearate is 1202 g/mol, absorption of the parent molecule in the gastrointestinal tract is not likely. This assumption is supported when the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) is applied. The log Pow value is well above 10 and the molecular weight is well above 500 g/mol.

The log Pow > 10 of Pentaerythritol tetrastearate is favourable for absorption 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 (GI) tract, metabolism prior to absorption via enzymes of gut microflora or in the GI mucosa may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson and Volpenhein, 1972a). On the contrary, lower rates of enzymatic hydrolysis in the GI tract were demonstrated for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a, b). The in vitro hydrolysis rate of Pentaerythritol esters 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, probably the results of different rates of hydrolysis in the intestinal lumen (Mattson and Volpenhein, 1972c).

The available data on oral toxicity of structurally related analogue substances are also considered for assessment of oral absorption. Acute oral toxicity studies conducted with a variety of analogue source substances did not show any signs of systemic toxicity at concentrations of up to 2000 mg/kg bw in rats. In addition, in sub-chronic and sub-acute oral repeated dose toxicity studies in rats with the source substances Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3), Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7), and Fatty acids, C8-10 mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) NOAELs were found to be ≥ 1000 mg/kg bw/day.

All results available suggest that the test substance is of low systemic toxicity, either due to low toxicity potency or due to low absorption in combination with a low systemic toxicity.

In general, after oral ingestion, aliphatic esters of polyhydroxy alcohols (Polyols) and fatty acids will undergo chemical changes in the gastrointestinal fluids as a result of enzymatic hydrolysis. Pentaerythritol (i.e. the parental polyol) as well as C18:0 stearic acid will be formed, even though it was shown in-vitro that the hydrolysis rate of Pentaerythritol tetraoleate when compared with the hydrolysis rate of the triglyceride Glycerol trioleate was very slow (Mattson and Volpenhein, 1972). The physico-chemical characteristics of the hydrolysis products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure) will be different from those of the parent substance before absorption into the blood stream takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply. However, also for both possible hydrolysis products (fatty acids and pentaerythritol), it is anticipated that they will be readily absorbed in the gastrointestinal tract.

The highly lipophilic fatty acids will be absorbed by micellar solubilisation (Ramirez et al., 2001). A study by Mattson and Nolen (1972) investigated the potential for absorption of the fatty acid moiety of the complete oleate esters of alcohols containing one to six hydroxyl groups. The fatty acids of the compounds containing less than four ester groups were almost completely absorbed. As the number of ester groups was increased (erythritol and pentaerythritol tetraoleate and xylitol pentaoleate) the potential for absorption of the fatty acids decreased but was still present. Pentaerythritol, having a low molecular weight of 136 g/mol and a high water solubility of 1E+06 mg/L (OECD QSAR toolbox v4.1, 2018), will readily dissolve into the gastrointestinal fluids. After oral administration of 10 mg/kg 14C-labeled pentaerythritol to mice, almost half of the administered dose was absorbed from the gastrointestinal tract within 15 minutes (Di Carlo et al., 1965).

In summary, the physico-chemical properties of Pentaerythritol tetrastearate and relevant data from available literature on fatty acid esters with more than three ester bonds indicate only slow hydrolysis before absorption of the parent substance.

 

Dermal absorption

Similar to oral absorption, dermal absorption is favoured for small molecules. In general, a molecular weight below 100 g/mol favours dermal absorption, while a molecular weight above 500 g/mol may be considered too large (ECHA, 2017). The molecular weight of pentaerythritol tetrastearate is 1202 g/mol.

If a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration through the skin. As Pentaerythritol tetrastearate was not tested for skin irritation or corrosion, read-across from a variety of structural analogue substances was applied. The structurally related source substances chosen comprise 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, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2), and Fatty acids, C8-10 mixed esters with dipentaerythritol, and isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8). None of the source substances was identified as irritant or corrosive to the skin of rabbits. No irritating or skin sensitising potential in human skin was found in a human repeated insult patch test with the source substance 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8).

Therefore, also Pentaerythritol tetrastearate is not considered to be irritating or corrosive to skin in humans and an enhanced penetration of the substance due to local skin damage can be excluded.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described by US EPA (2012), using the Epi Suite software:

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

Using DermWin v2.02 and entering a water solubility of 0.513 mg/L and a log Pow of 10 as edge values, the Kp for CAS 115-83-3 was calculated to be 0.00125 cm/h and the dermal flux was calculated to be 0.00136 mg/cm²h. This indicates that the target substance has a very low 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, 2017). The water solubility of Pentaerythritol tetrastearate was < 0.513 mg/L at 20 °C, and the log Pow was estimated to be > 10. Based on the available physico-chemical properties, virtually no dermal uptake is expected.

The available data on acute dermal toxicity of the structurally related substance 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8) is also considered for the assessment of dermal absorption. At a limit dose of 2000 mg/kg bw no signs of systemic toxicity were observed in rats.

Overall, the calculated low dermal absorption potential, the poor water solubility, the high molecular weight, the high log Pow value and the fact that the analogue source substances are not irritating or corrosive to skin indicate that dermal uptake of Pentaerythritol tetrastearate in humans will be negligible.

 

Inhalation absorption

Substances that can be inhaled include gases, vapours, liquid aerosols (both liquid substances and solid substances in solution) and finely divided powders/dusts. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inspired. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed (ECHA, 2017).

Particle size analysis of the target substance pentaerythritol tetrastearate was performed according to JIS K0069. In this sieve analysis more than 90% of the particles were distributed over ranges from 150 µm to 710 µm. The percentage of particles being smaller than 150 µm was only 5.8%. Moreover, the target substance has a low vapour pressure of < 0.0001 Pa at 20 °C thus being of low volatility.

Therefore, under normal use and handling conditions, the potential for exposure via the inhalation route and thus availability for respiratory absorption of the substance in the form of gases, vapours, liquid aerosols, or powders/dusts is considered to be negligible.

Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) can be taken up by micellar solubilisation. Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and fatty acids available for respiratory absorption. Due to the high molecular weight of the parent substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption. However, as discussed above, hydrolysis of fatty acid esters with more than 3 ester bounds is considered to be slow (Mattson und Volpenhein, 1972a) and the possibility of the target substance to be hydrolysed enzymatically to the respective metabolites and their respective absorption is considered to be low as well.

In addition, available in vivo data on acute inhalation toxicity with the source substances Fatty acids, C5-10 (linear and branched), tetraesters with pentaerythritol (CAS 68424-31-7) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) indicated no systemic toxicity. The acute inhalation LC50 values ranged from > 4.06 mg/L air to > 5 mg/L air for male and female rats and correspond to the highest concentrations tested in each study. Moreover, in a sub-chronic (90-day) repeated inhalation dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, additional data not used for read across), no toxicologically relevant effects were observed up to and including the highest dose level of 0.56 mg/mL air in male and female rats. The data indicate that respiratory absorption of the test substances is not higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of pentaerythritol tetrastearate in humans is not considered likely after inhalation. The absorption rate 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 accepted that substances with high log Pow values have long biological half-lives. The high log Pow of >10 of Pentaerythritol tetrastearate is therefore indicative of the potential to accumulate in adipose tissue (ECHA, 2017). However as the absorption of the substance is considered to be very low, the potential of its bioaccumulation is very low as well.

As will be discussed in the section metabolism below, esters of pentaerythritol and fatty acids will undergo slow esterase-catalysed hydrolysis, leading to the hydrolysis products pentaerythritol and respective fatty acids. The log Pow of the hydrolysis product pentaerythritol is -1.77 and it is highly soluble in water (1E+06 mg/L) (OECD QSAR toolbox v4.1, 2018). Consequently, there is no potential for pentaerythritol to accumulate in adipose tissue. The second hydrolysis product (fatty acids) can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. Fatty acids are also required as a source of energy. 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.

Overall, the available information indicates that no bioaccumulation in adipose tissue of the parent substance and its potential hydrolysis products is 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 it will be distributed. 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). Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution depends on the rates of absorption. As has been discussed above, absorption of Pentaerythritol tetrastearate is considered very low based on its physico-chemical characteristics (low water solubility and high molecular weight).

However, it can be anticipated that a small amount of the substance will be subject to slow enzymatic hydrolysis, leading to the hydrolysis products pentaerythritol and stearic acid. Pentaerythritol will be distributed in aqueous fluids by diffusion through aqueous channels and pores. No protein-binding is assumed and it is distributed poorly in fatty tissues (OECD SIDS, 1998). 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).

 

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid 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 are hydrolysed already in the gastrointestinal fluids. In contrast, esters which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before they are transported to the liver where hydrolysis will basically take place.

The hydrolysis of fatty acid esters containing more than 3 ester groups is assumed to be slow as already discussed above. In in- vivo studies in rats, a decrease in absorption was observed with increasing esterification grade. For example, for Pentaerythritol tetraoleate ester an absorption rate of 64% and 90% (25% and 10% of dietary fat) was observed, respectively, while an absorption rate of 100% was observed for Glycerol trioleate when ingested at 100% of dietary fat (Mattson and Nolen, 1972). In addition it has been shown in-vitro that the hydrolysis rate of pentaerythritol tetraoleate was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a). Non-specific lipase completely hydrolysed erythritol tetraoleate to free erythritol (Mattson and Volpenhein, 1972b).

Thus, Pentaerythritol tetrastearate is expected to be hydrolysed to pentaerythritol and stearic acid by esterases, even though the hydrolysis rate is expected to be low.

Di Carlo et al. (1965) investigated the metabolism of pentaerythritol and reported that 10 mg/kg 14C-labeled pentaerythritol orally administered to mice was absorbed and excreted rapidly from the gastrointestinal tract. Almost half of the administered dose left the gastrointestinal tract within 15 minutes and 68% of the dose appeared as unchanged pentaerythritol in the urine and faeces after 4 hours already. Fatty acids are stepwise degraded by means of β-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 isomerisation reaction step is required.

Using the OECD QSAR toolbox v4.1 metabolites were predicted for the target substance. Two skin metabolites were predicted, identified by addition of a hydroxyl group to the alkyl chain of the esters. Eight metabolites were predicted for rat liver S9 metabolism. As expected, the typical metabolic transformation of the parent compound is the cleavage of the various ester bonds that takes place mainly in the liver. Following the first reaction step, hydrolysis products may be metabolised further. The resulting liver metabolites are the products of α-, β- or ω-oxidation (i.e. addition of a hydroxyl group). In the case of ω-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. The ester bond may also remain intact, in which case a hydroxyl group is added to an alkyl chain. In general, the hydroxyl groups make the substance 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. A total of 76 metabolites were predicted to result from all kinds of microbiological metabolism for the low molecular weight and high molecular weight constituents, respectively. This rather high number includes many minor variations in the carbon-chain length and number of carbonyl and hydroxyl groups, reflecting the diversity of many microbial enzymes identified. Not all of these reactions are expected to take place in the human GI tract. The results of the OECD toolbox simulation support the information on metabolism routes retrieved in the literature.

Excretion

On the basis of its very low absorption, the main route of excretion for unchanged pentaerythritol tetrastearate is expected to be by biliary excretion via faeces. Hydrolysis of the parent compound yields stearic acid and pentaerythritol. The fatty acids will be metabolised for energy generation or stored as lipids in adipose tissue or used for further physiological processes, e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 2002). Therefore, the fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as carbon dioxide or stored as described above. Pentaerythritol is excreted unchanged via urine. 10 mg/kg 14C-labeled pentaerythritol orally administered to mice was absorbed from the gastrointestinal tract rapidly and excreted via urine. Almost half of the administered dose left the gastrointestinal tract within 15 minutes and 68% of the dose appeared as unchanged pentaerythritol in the urine and faeces after 4 hours (Di Carlo et al., 1965). The amount found in faeces was assumed to be contamination from urine due to the setup of the metabolic cages. Additionally, Kutscher (1948) found 85 - 87% of unaltered pentaerythritol in the urine of humans ingesting pentaerythritol.

 

References

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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

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OECD (2017). (Q)SAR Toolbox v4.1 Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculations performed on 15 Mar 2018.

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Stryer, L. (2002). Biochemistry. 5th Edition. W.H. Freeman, New York, USA. ISBN 0‐7167‐3051‐0.

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