Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid

Endpoint summary

Description of key information

Oral absorption

Based on available data, absorption after oral ingestion is predicted to be limited. 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 indicate that dermal uptake in humans is likely to be low. Again, a low order of systemic toxicity is expected, if absorption via the dermal route of exposure occurs.

Inhalative absorption

A systemic bioavailability in humans after inhalation exposure cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm. The absorption rate is not expected to be higher than that following oral exposure. Applying a worst-case approach, the absorption potential via the inhalation route of exposure is assumed to be the same as via the oral route of exposure. After absorption of the parent compound or its predicted hydrolysis products, a low order of systemic toxicity is expected.

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 the beta-oxidation for energy generation. In contrast, pentaerythritol (PE) 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 feces. 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 feces but excreted via exhaled air as CO2. Pentaerythritol is not metabolized but excreted mainly unchanged via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No. 1907/2006 and with the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behavior 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.

Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid is a UVCB substance as it contains esters of pentaerythritol with a huge variety of fatty acids with unknown and/or variable composition: C10-29 branched, C14-18-hydroxyl, C16-18 branched hydroxyl, C18 unsaturated, and C10-28 straight chain. It is a dark brown paste like solid substance which is poorly water soluble (< 0.15 mg/L) with a molecular weight of 612.96 – 1306.14 g/mol, a log Pow > 10 and a vapour pressure of < 0.0001 Pa at 20 °C (QSAR, SPARC v4.6).

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 favorable for oral absorption (ECHA, 2017). As the molecular weight of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid ranges between 612.96 and 1306.14 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 the given range of ¬0.4 to 5.6 and the molecular weight is well above 500 g/mol.

The log Pow > 10 of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid 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 hydrolised 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 C5-9 to C16-18, with both saturated as well as unsaturated and 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, the structurally related substance Pentaerythritol ester of pentanoic acids , mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS No. 146289-36-3) showed no systemic effects up to the high-dose group (1000 mg/kg bw/day) in a 90-day repeated oral dose subchronic toxicity study (NOAEL ≥ 1000mg/kg bw/day). Therefore, if absorption of the intact parent compound or the respective metabolites occurred, it resulted in a low order of systemic toxicity. These findings are supported by investigations of the short-term repeated oral dose toxicity (28-day) performed with Fatty acids, C7, C8, C10 and 2-ethylhexanoic acid, tetraesters with pentaerythritol (CAS No. 68424-31-7) and Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8). 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 1 – 6 fatty acids will undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. Pentaerythritol (PE, parental polyol) as well as the fatty acids (C10-C28) 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 pentaerythritol), 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. Pentaerythritol, having a low molecular weight (136.15 g/mol) and being a highly water-soluble substance (25 g/L, OECD SIDS, 1998), 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 (DiCarlo et al., 1965).

In summary, the physical-chemical properties of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid and relevant data from available literature on fatty acid esters with more than three ester bonds do not indicate rapid hydrolysis before absorption of the parent substance.

Dermal absorption

Similar to oral absorption, dermal absorption is favored for small molecules. In general, a molecular weight below 100 g/mol favors dermal absorption, while a molecular weight above 500 g/mol may be considered too large (ECHA, 2017). As the molecular weight of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid ranges between 612.96 and 1306.14 g/mol, a dermal absorption of the substance is not likely.

If a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration through the skin. As Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid 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 cover C-chain distributions of C5-9 to C16-18, with saturated as well as unsaturated and linear as well as branched alkyl moieties. None of the source substances was identified as skin irritant or corrosive to skin. 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 Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid 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 the Kp and dermal flux were calculated for four main constituents of the target substance using the SMILES codes.

Constituents	Molecular weight	Kp [cm/h]	Dermal flux [mg/cm²h]	Estimated water concentration [mg/cm³)
Di-, C16	612.98	246	1.23e-008	1.06e-012
Tri-, C18:2	923.47	5.21e+006	8.25e-013	4.5e-022
Tetra-, C18:1	1193.97	2.37e+011	1.7e-014	2.24e-032
Tetra-, C20:1	1306.19	2.27e+013	5.1e-016	1.65e-036

The calculated dermal flux rates indicated very low dermal absorption potential.

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). As the water solubility of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid is less than 1 mg/L and the log Pow is estimated to be > 10, dermal uptake is likely to be very low.

The available data on dermal toxicity of the structurally related substances 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 No. 62125-22-8) and Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS No. 71010-76-9) are also considered for the assessment of dermal absorption. Two acute dermal toxicity studies are available for Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS No. 71010-76-9) and 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS No. 62125-22-8). At a dose of up to 2000 mg/kg bw in rats no signs of systemic toxicity were observed. Moreover, in a dermal subchronic (90-day) repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 2000 mg/kg bw/day in male and female rats.

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 or corrosive to skin indicates that dermal uptake of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid in humans will be very limited.

Inhalation absorption

Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid has 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 vapours, gases or mists is not expected to be significant. 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, 2017).

Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid 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 test substance to be hydrolysed enzymatically to the respective metabolites and their respective absorption is considered to be low as well.

The available data on inhalation toxicity of the structurally related substances Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS No. 85536-35-2) are also considered for assessment of inhalation absorption. An acute inhalation toxicity study conducted with Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS No. 85536-35-2) in rats revealed no effects of systemic toxicity. Moreover, in a subchronic (90-day) repeated dose toxicity study via inhalation performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2), no toxicologically relevant effects were observed up to and including the highest dose level of 0.5 mg/mL air in male and female rats. Therefore, respiratory absorption of the test substance is considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid in humans is considered likely after inhalation but not expected to be higher than following oral exposure. It is important to note that due to the low vapour pressure, exposure via the inhalation route is expected only if aerosols/droplets of an inhalable size (i.e. < 15 µm) are generated, e.g. in spray applications.

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 > 10 of Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid 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-catalyzed hydrolysis, leading to the hydrolysis products pentaerythritol and the fatty acids. The log Pow of the hydrolysis 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 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 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, 2012). 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 Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid 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 pentaerythritol and various fatty acids. Pentaerythritol is highly water-soluble (25 mg/L and log Pow < 0.3) with a low molecular weight. It will be distributed in aqueous fluids by diffusion through aqueous channels and pores. There is no protein binding 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

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).

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 hydrolised 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.

Thus, Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid is expected to be hydrolysed to pentaerythritol and the respective fatty acids by esterases, even though the hydrolysis rate is expected to be low.

Pentaerythritol (PE) is absorbed rapidly but excreted unchanged. DiCarlo et al. (1965) 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 PE in the urine and faeces after 4 hours already. Fatty acids are stepwise degraded by means of beta -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 four main constituents of the target substance:

		# Metabolites	# Metabolites	# Metabolites
Constituents	Molecular weight	Skin metabolism simulator	Rat liver S9 simulator	Microbial metabolism simulator
Di, C16	612.98	2	9	64
Tri, C18:2	923.47	2	10	131
Tetra, C18:1	1193.97	6	8	107
Tetra, C20:1	1306.19	6	8	118

Excretion

On the basis of its low absorption, one route of excretion for Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid is expected to be by biliary excretion via faeces. Hydrolysis of the parent compound yields fatty acids 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 CO2 or stored as described above. Pentaerythritol is not metabolized but excreted unchanged via urine. 10 mg/kg 14C-labled PE 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 PE in the urine and faeces after 4 hours (DiCarlo 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 PE in the urine of humans ingesting PE.

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

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