Tetraesters of pentaerythritol with 2-ethylhexanoic acid and heptanoic acid and nonanoic acid

Endpoint summary

Description of key information

The target substance Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid (EC 806-879-4) may be hydrolysed at a slow rate and the hydrolysis products absorbed via the oral and inhalation route, and poorly absorbed via the dermal route. The ester bonds will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and polyol, which facilitates the absorption. The absorbed ester fraction will be hydrolysed mainly in the liver. The fatty acid will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; the absorbed glycerol is readily distributed throughout the organism and it can be re-esterified to form endogenous triglycerides. The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-pathway or direct conjugation to more polar products. The excretion will mainly be as CO2 in expired air; with a smaller fraction excreted as conjugated molecules in the urine. Pentaerythritol is expected to be metabolised to a more polar molecule that is subsequently excreted.

Additional information

There are no studies available in which the toxicokinetic behaviour of Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid (EC 806-879-4) has been investigated. In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), an assessment of the toxicokinetic behaviour of the target substance Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2014) and taking into account further available information from source substances.

The substance Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid (EC 806-879-4) is a UVCB containing mainly tetraesters with C7, C9 and 2-ethylhexyl fatty acids. It has a molecular weight range of 584.82 - 697 g/mol. It is a liquid at 20 °C with melting point -57 °C, and water solubility estimated to be < 0.15 mg/L at 20 °C. The log Pow was estimated to be > 10 and the vapour pressure was calculated to be < 0.001 Pa at 20 °C.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2014).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed. Solids must be dissolved before absorption; the degree depends on the water solubility (Aungst and Shen, 1986; ECHA, 2014).

The physico-chemical characteristics molecular weight, water solubility and log Pow of the target substance Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid indicate poor absorption from the gastrointestinal tract following oral ingestion. However, the liquid state is favourable for oral absorption. The lipophilicity indicates that micellar solubilisation may increase the relative overall absorption rate of the tetraester.

The potential of a substance to be absorbed from the GI-tract may be influenced by several parameters, like: chemical changes taking place in GI-fluids, as a result of metabolism by GI-flora, by enzymes released into the GI-tract or by hydrolysis. These changes will alter the physico-chemical characteristics of the substance and hence predictions based on the physico-chemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2014).

In general, fatty acid esters with glycerol (glycerides) may be rapidly hydrolysed by ubiquitously expressed esterases into fatty acids and glycerol, and almost completely absorbed from the GI-tract (Mattsson and Volpenhein, 1972a). A lower rate of enzymatic hydrolysis in the GI-tract was shown for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b). The in vitro hydrolysis rate of 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 compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased (Mattson and Volpenhein, 1972c), and it was shown that a hexaester of sorbitol is not absorbed (Mattson and Nolen, 1972). It is likely that Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid will be hydrolysed in the GI-tract by esterases to fatty acids and pentaerythritol at a slow rate. These hydrolysis products have a lower MW and are most likely more water soluble than the parent compound, leading to a relatively higher absorption rate.

The available data on source substances, covering acute and repeated dose oral toxicity, also indicate that the target substance Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid has low oral absorption and/or low toxicity. In the acute oral toxicity studies, the LD50 in rats was > 2000 mg/kg bw (Mallory, 2006; Reijnders, 1987; Robinson, 1991; Zolyniene, 1999). No toxicologically relevant effects were observed in the rat in studies performed with 4 source substances (Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2), Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9), 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 78-16-0), and fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7)).

In a 28-day repeated dose toxicity study performed with the source substance Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7) and in a 90-day repeated dose toxicity study performed with the source substance Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3), the NOAEL was considered to be ≥ 1000 mg/kg bw/day, the highest dose level tested (Brammer, 1993; Müller, 1998). Furthermore, no adverse systemic effects were observed in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test performed with the source substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester (CAS 7299-99-2), up to and including the highest dose level of 1000 mg/kg bw/day (Ohta, 2005).

The 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 C14-labled PE to mice, almost half of the administered dose was absorbed from the gastrointestinal tract within 15 minutes (DiCarlo et al., 1965).

In conclusion, the log Pow, water solubility and molecular weight of Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid suggest that oral absorption is likely to be very low. The substance is expected to undergo enzymatic hydrolysis in the GI-tract to a certain degree and therefore absorption of the ester hydrolysis products is also relevant. The absorption rate of the hydrolysis products is expected to be high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2014).

The substance Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid has a weight range of 584.82 - 697 g/mol and < 0.15 mg/L water solubility, which indicates a very low potential for dermal absorption (ECHA, 2014). The log Pow is > 10, which means that the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis is considered to be slow as well (ECHA, 2014).

Three acute dermal toxicity study were available with the source substances Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9), 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 78-16-0) and Fatty acids, C8-10 (even numbered), di-and triesters with propylidynetrimethanol (CAS 11138-60-6), in which rats were exposed to 2000 mg/kg bw for 24 hours under occlusive conditions (Blanset, 1997; Mallory, 2006; Morgareidge, 1974). No mortality occurred and no toxicologically relevant local or systemic effects were observed. No adverse systemic effects were observed in a 90-day dermal repeated dose toxicity study performed with the source substance Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2), up to and including the highest dose level of 2000 mg/kg bw/day (Cruzan, 1988). The skin penetration in rats was shown to be 2 – 6% (measured as recovery of radioactivity from urine, faeces and tissue samples). Based on these results, the target substance is not expected to be toxic via the dermal route.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2014).

The available data on 4 source substances (Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2), 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 78-16-0), Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), and Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester (CAS 7299-99-2 )), showed no or low indications of skin irritating effects in the rabbit (Bouffechoux, 1998; Robinson, 1991; Weterings, 1987; Zolyniene, 1999). Therefore, no increased penetration of the substance in the presence of skin damage is expected. No indications of skin sensitisation were noted in studies performed in the guinea pig using the source substances Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2), Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) and fatty acids, C8-10 (even numbered), di-and triesters with propylidynetrimethanol (CAS 11138-60-6) (Blanset, 1997; Lees, 1991; Zolyniene, 1999). Likewise, no skin sensitisation reactions were observed in an RIPT study with human volunteers, performed with the source substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester (CAS 7299-99-2 ) (Tolman and Harrison, 1997).

Overall, based on the available information, the dermal absorption potential of Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid is predicted to be low.

Inhalation

Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid is a liquid with low vapour pressure (< 0.001 Pa at 20 °C), and therefore very low volatility. Under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases or mists is considered to be limited (ECHA, 2014). However, the substance may be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed. Limited absorption after oral administration of the target substance may occur directly. However, due to the high molecular weight of the substance, the enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption is likely to play an important role in absorption via the inhalation route. This would require enzymatic hydrolysis in the airways, and the presence of esterases and lipases in the mucus lining fluid of the respiratory tract would be important. Due to the physiological function of enzymes in the GI-tract for nutrient absorption, esterase and lipase activity in the lung is expected to be lower in comparison to the gastrointestinal tract. Therefore, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to happen at a lower rate. Furthermore, hydrolysis of fatty acid esters with more than three ester bonds is considered to be slow (Mattson and Volpenhein, 1968, 1972a) and the possibility of the test substance being hydrolysed enzymatically to the respective hydrolysis products and their subsequent absorption is considered to be low.

In the acute inhalation toxicity studies performed with source substances (Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) and Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), the LC50 in rats was ≥ 5.10 mg/L, analytical concentration (Hoffman, 1999; Parr-Dobrzanski, 1994). No adverse systemic effects were observed in a 90-day inhalation repeated dose toxicity study performed with the source substance Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2), up to and including the highest dose level of 0.5 mg/L, analytical concentration (Dulbey, 1992).

Due to the limited information available on the absorption potential, a worst case approach is applied, and absorption via inhalation of Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid is assumed to be as high as via the oral route.

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. 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).

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, estimated to be > 10, suggests that Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid may have the potential to accumulate in adipose tissue. However, no adverse systemic effects were noted in the repeated dose toxicity studies via the oral, dermal and inhalation route performed with source substances, indicating that if there is a build-up in adipose tissue it will not cause adverse effect. Furthermore, the absorbed tetraester is expected to partly be metabolised in the liver, limiting the total amount distributed to the adipose tissues. The absorption potential of the hydrolysis products of Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid is expected to be relatively high. The accumulation potential of the hydrolysis products is considered to be low, due to the lower molecular weight and expected higher water solubility. 

Following absorption, the fatty acids will be esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. This route of absorption and metabolism of a fatty acid was shown in an in vivo study performed by Sieber (1974). Twenty-four hours after intraduodenal administration of a single dose of [¹⁻¹⁴C]-radiolabelled octadecanoic acid to rats, 52.5 ± 26% of the radiolabelled carbon was recovered in the lymph. A large majority (68 - 80%) of the recovered radioactive label was incorporated in triglycerides, 13 - 24% in phospholipids and 0.7 - 1% in cholesterol esters. No octadecanoic acid was recovered. Almost all the radioactivity recovered in the lymph was localized in the chylomicron fraction. Fatty acids of carbon chain length ≤ 12 may be transported directly to the liver via the portal vein as the free acid bound to albumin, instead of being re-esterified. This is supported by the Sieber study (1974), in which, following the same protocol as described above, administration of hexanoic acid lead to only 3.3% recovery from lymphatic fluid. Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are also taken up by muscle and oxidized to derive energy or they are released into the systemic circulation and returned to the liver, where they are metabolised, stored or re-enter the circulation (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1993; NTP, 1994; Stryer, 1996; WHO, 2001). There is a continuous turnover of stored fatty acids, as they are constantly metabolised to generate energy and then excreted as CO₂. Accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism. Pentaerythritol is expected to be readily absorbed.

 

Metabolism

The metabolism of Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C7, C9 fatty acids, 2-ethylhexanoic acid and pentaerythritol. The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI tract and in the liver (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the body. After oral ingestion, esters of alcohols and fatty acids can undergo enzymatic hydrolysis in the GI-tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin may enter the systemic circulation directly before entering the liver where hydrolysis will generally take place.

The fatty acids can be further metabolised directly following absorption, following oxidation from an alcohol or following de-esterification of triglycerides. A major metabolic pathway for linear and branched fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂ (Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (by e.g. glucuronides, sulfates) to more polar products that are excreted in the urine. Pentaeryhtritol will mainly remain unchanged (DiCarlo et al., 1965).

The potential metabolites following enzymatic metabolism of the substance were predicted using the OECD QSAR Toolbox v3.3 (OECD, 2014). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Eight hepatic metabolites and 2 dermal metabolites were predicted for the tetraester with C7 fatty acid. Eight hepatic metabolites and 2 dermal metabolites were predicted for the tetraester with C9 fatty acid. Nine hepatic metabolites and 4 dermal metabolites were predicted for the tetraester with 2-ethylhexanoic acid. In the liver, primarily the ester bond is broken and the hydrolysis products may be further metabolised. The resulting liver metabolites are the product of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. For a branched fatty acid, the alpha- and omega pathways are particularly relevant. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. In the skin, the resulting skin metabolites have hydroxyl groups added in various positions. The metabolites formed in the skin are expected to enter the blood circulation and to have the same fate as the hepatic metabolites. Up to 42 metabolites were predicted to result from all kinds of microbiological metabolism in the GI-tract, including hydrolysis of the ester bond, aldehyde formation and fatty acid chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature on metabolism.

There is no indication that Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) using source substances were negative, with and without metabolic activation (Bailey, 1996; Griffiths and Mackay, 1992; Gudi, 1996; Masumori, 2005a,b; Mecchi, 1999; Verspeek-Rip, 2010; Wagner and Burnett, 1997). The results of the skin sensitisation studies performed with source substances were likewise negative (Blanset, 1997; Lees, 1991; Tolman and Harrison, 1997; Zolyniene, 1999).

Excretion

A low absorption percentage is expected for Tetraesters of pentaerythritol with 2-ethylhexanoic acid, heptanoic acid and nonanoic acid via the gastrointestinal tract, therefore much of the ingested substance is expected to be excreted in the faeces.

For the absorbed hydrolysis products, the linear C7 and C9 fatty acids, and 2-ethylhexyanoic acid resulting from hydrolysis of the ester will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological functions, like incorporation into cell membranes (Lehninger, 1993). Therefore, the fatty acid metabolites are not expected to be excreted to a significant degree via the urine or faeces but to be excreted via exhaled air as CO₂ or stored as described above. Experimental data with ethyl oleate (CAS 111-62-6, ethyl ester of oleic acid) support this principle. The absorption, distribution, and excretion of ¹⁴C-labelled ethyl oleate was studied in Sprague Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw (Bookstaff et al., 2003). At sacrifice (72 hours post-dose), mesenteric fat was the tissue with the highest concentration of radioactivity. The other organs and tissues had very low concentrations of test material-derived radioactivity. The main route of excretion of radioactivity in the groups was via the expired air as CO₂. 12 hours after dosing, 40-70% of the administered dose was excreted in expired air (consistent with beta-oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine.

DiCarlo et al. (1965) reported that C14-labeled PE, orally administered at 10 mg/kg to mice, was absorbed to 50% from the gastrointestinal tract within 15 minutes. 68% of the dose appeared as unchanged PE in the urine and faeces after 4 hours.

              

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