2-({3-(octadecanoyloxy)-2,2-bis[[](octadecanoyloxy)methyl]propoxy}methyl)-2-[[](octadecanoyloxy)methyl]propane-1,3-diyl dioctadecanoate

Endpoint summary

Description of key information

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the polyol esters category.

 

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 GIT is expected to occur, resulting in hydrolysis products that may be readily absorbed. If absorption of the intact parental compound or the respective metabolites occurs, it is predicted to cause a low order of systemic toxicity.

 

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. Again, a low order of systemic toxicity is expected, if absorption via the dermal route of exposure occurs.

 

Absorption by inhalation

During particle size analysis no particles were found to be smaller than 50 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 dipentaerythritol 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 the β-oxidation for energy generation. In contrast, dipentaerythritol 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 CO2. Dipentaerythritol is not metabolized but excreted mainly unchanged via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the polyol esters category.

 

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No. 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.

Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester is a mono-constituent substance containing esters of dipentaerythritol with saturated linear fatty (stearic) acids. It is a solid which is poorly soluble with a water solubility < 1.7E-4 mg/L at 20 °C, a molecular weight of 1853 g/mol, a log Pow of > 10 and a vapour pressure of < 0.0001 Pa at 20 °C (QSAR).

 

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 Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester is 1853 g/mol, absorption of the molecule in the gastrointestinal tract is not likely. Absorption after oral administration is also unexpected 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 Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester 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 (Mattsson and Volpenhein, 1972a). On the contrary, lower rates of enzymatic hydrolysis in the GIT 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 the oral absorption. Acute oral toxicity studies conducted with a variety of analogue source substances covering C-chain distributions of C5 - C9, C8 - 18, with saturated and unsaturated, linear as well as branched alkyl moieties, did not show any signs of systemic toxicity at concentrations of up to 2000 mg/kg bw in rats. In addition, in sub-acute oral repeated dose toxicity studies in rats with the source substances Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS No. 68424-31-7), Dipentaerythritol with fatty acids, C5 and C9 iso (CAS 647028-25-9), and Fatty acids, C8-10 mixed esters with dipenaterythritol, 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 by a low absorption in combination with a low systemic toxicity.

In general, after oral ingestion, aliphatic esters of polyhydroxy alcohols (Polyol) and fatty acids will undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. Dipentaerythritol (i.e. the parental polyol) as well as octadecanoic 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 physical-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 physical-chemical characteristics of the parent substance do no longer apply. However, also for both hydrolysis products (fatty acids and dipentaerythritol), it is anticipated that they will be readily absorbed in the gastro-intestinal 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. Dipentaerythritol, having a low molecular weight (254.28 g/mol) and being a highly water-soluble substance (2.8 g/L, Danish QSAR Database, 2017), will readily dissolve into the gastrointestinal fluids. After oral administration of 10 mg/kg 14C-labled PE to mice, almost half of the administered dose was absorbed from the gastrointestinal tract within 15 minutes (Di Carlo et al., 1965). As similar behaviour can be expected for dipentaerythritol.

In summary, the physical-chemical properties of Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester and relevant data from available literature on fatty acid esters with more than three ester bonds do not indicate relevant 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 Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] is 1853 g/mol.

If a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration through the skin. As Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester 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 Fatty acids, C16-18 (even numbered), esters with pentaerythritol (85116-93-4), Fatty acids, C5-9 tetraesters with pentaerythritol (CAS No. 67762-53-2), 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS 62125-22-8), Fatty acids, C8-10 mixed esters with dipenaterythritol, and isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8). 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).

None of the source substances was identified as skin irritant or corrosive to skin. Therefore, also Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester 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 in 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 log Pow of 10 as edge value, the Kp of CAS 70969-57-2 was calculated to be 2.76E-007 cm/h and the dermal flux was calculated was calculated to be 4.26E-020 mg/cm²h. This indicates that the target substance has virtually no 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 Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester was < 1.7E 4 mg/L at 20 °C, and log the Pow was estimated to be > 10. Based on the available physical data, virtually no dermal uptake is expected.

The available data on acute dermal toxicity of the structurally related substances Dipentaerythritol with fatty acids, C5 and C9 iso (CAS 647028-25-9) and 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 in rats no signs of systemic toxicity were observed.

Overall, the calculated low dermal absorption potential, the low-moderate water solubility, the high molecular weight, the high log Pow values and the fact that the structurally analogue source substances are not irritating or corrosive to skin indicates that dermal uptake of Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester 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 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. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed (ECHA, 2017c).

Particle size analysis of the target substance Octadecanoic acid, 1,1'-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester was performed according to DIN 66165. No particles of sizes below 50 µm and only 0.7% of the bulk solid was found to in the range of 50 to 100 µm in this sieve analysis. 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 No. 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 as no systemic effects have been observed in any inhalation study. However, the lack of systemic toxicity might also be attributed to no or a low toxicity. It can therefore be taken only as indication but not as proof of a low absorption after inhalation exposure.

Overall, a systemic bioavailability of Octadecanoic acid, 1,1'-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester in humans is not considered likely after inhalation. The absorption rate is not expected to be higher than that following oral exposure as no systemic toxicity was observed with structural analogue substances after inhalation exposure. The lack of inhalation toxicity hints that respiratory absorption is limited.

 

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 Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester 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 dipentaerythritol and fatty acids will undergo slow esterase-catalysed hydrolysis, leading to the hydrolysis products dipentaerythritol and the fatty acids. The log Pow of the hydrolysis product dipentaerythritol is -2.61 and it is highly soluble in water (2.8 g/L) (Danish QSAR Database, 2017). Consequently, there is no potential for dipentaerythritol 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 significant 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 Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester is considered very low based on its physical-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 dipentaerythritol and stearic acid. Dipentaerythritol is highly water-soluble (2.8 g/L and log Pow -2.61) with a low molecular weight (254.28 g/mol). It will be distributed in aqueous fluids by diffusion through aqueous channels and pores. By analogy to pentaerythritol, for dipentaerythritol 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 gastro-intestinal 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). Nonspecific lipase completely hydrolysed erythritol tetraoleate to free erythritol (Mattson and Volpenhein, 1972b).

Thus, Octadecanoic acid, 1,1’-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester is expected to be hydrolysed to dipentaerythritol and stearic acid by esterases, even though the hydrolysis rate is expected to be low.

Dipentaerythritol with a molecular weight of 254.28 g/mol is expected to be absorbed rapidly but excreted unchanged. Di Carlo et al. (1965) investigated the metabolism of pentaerythritol and reported that 10 mg/kg 14C-labled PE 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. A similar metabolic behaviour is expected for dipentaerythritol. 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 isomerization 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 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 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. A total of 101 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 GIT. 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 Octadecanoic acid, 1,1'-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester is expected to be by biliary excretion via faeces. Hydrolysis of the parent compound yields stearic acid and dipentaerythritol. 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 CO2 or stored as described above. Dipentaerythritol is not expected to be metabolised but excreted unchanged via urine. 10 mg/kg 14C-labled 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. Since dipentaerythritol is even more water soluble, a similar excretion scheme is expected to be applicable.

 

References

Di Carlo 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

 

Danish QSAR Database (2017). http://qsardb.food.dtu.dk/db/index.html; last accessed 2018-01-30

 

ECHA (2017). Guidance on information requirements and chemical safety assessment - Chapter 7c: Endpoint specific guidance; Version 3; June 2017; European Chemicals Agency, Helsinki, Finland

 

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metab Pharmacokinet 27(5): 466-477.

 

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.

 

Kutscher, W. (1948). Über das Verhalten des Pentaerythrits im Stoffwechsel. Hoppe-Seyler´s Zeitschrift für physiologische Chemie , Volume 283 (5-6)

 

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.

 

Masoro (1977). Lipids and lipid metabolism. Ann. Rev. Physiol.39: 301-321.

 

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). Pentaerythritol, CAS 115-77-5, SIDS Initial Assessment Report for 8th SIAM, http://www.inchem.org/documents/sids/sids/115775.pdf, (last accessed 2017-09-08)

 

OECD (2017). (Q)SAR Toolbox v4.1 Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 24 Jan 2018.

 

Ramirez et al. (2001). Absorption and distribution of dietary fatty acids from different sources. Early Human Development 65 Suppl.: S95–S101.

 

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