Decanoic acid, mixed esters with octanoic acid and pentaerythritol

Endpoint summary

Description of key information

Oral absorption:

Based on available data, absorption of Tetraesters of 2,2-bis(hydroxymethyl)propane-1,3-diol and decanoic and octanoic acid 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 fact that the source substances are not considered to be irritating to skin indicate that dermal uptake of Tetraesters of 2,2-bis(hydroxymethyl)propane-1,3-diol and decanoic and octanoic acid in humans is considered to be low.

Inhalative absorption:

A systemic bioavailability of Tetraesters of 2,2-bis(hydroxymethyl)propane-1,3-diol and decanoic and octanoic acid in humans after inhalation exposure cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm, but 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.

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 in adipose tissue of the parent substance and its anticipated hydrolysis products is expected.

Metabolism:

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by esterases. It is assumed, however, that the hydrolysis rate of Tetraesters of 2,2-bis(hydroxymethyl)propane-1,3-diol and decanoic and octanoic acid is low 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 for Tetraesters of 2,2-bis(hydroxymethyl)propane-1,3-diol and decanoic and octanoic acid via the gastrointestinal tract, thus the biggest part of the ingested substances is assumed to be excreted in the feces. Following the potential hydrolysis of the parent molecule, the fatty acid component is 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

METABOLIC PATHWAYS

There are no studies available in which the toxicokinetic behaviour of the target substance Decanoic acid, mixed esters with octanoic acid and pentaerythritol has been investigated. The toxicokinetic statement was thus based on available information from theoretically possible hydrolysis products and the structurally similar members of this analogue approach, i.e. the source substances. The assessment is additionally based on the physico-chemical information of the target substance.

The analogue substances are organic liquids with a molecular weight in the range 473 – 1193.93 g/mol. All analogue substances show predicted or measured log Pow values > 6 with the exception of the source substance no. 1 (CAS 11138-60-6, Fatty acids, C8-10 (even numbered), di- and triesters with propylidynetrimethanol) with a measured log Pow > 2.7. Furthermore, all source substances are poorly water soluble with measured water solubility values < 1 mg/L (20 - 22 °C).

Absorption

Absorption is a function of the potential of 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) and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2016).

Oral absorption

The smaller a molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2016). As the molecular weight of Decanoic acid, mixed esters with octanoic acid and pentaerythritol is in the range from 641 to 753 g/mol, absorption of the molecule in the gastrointestinal tract (GIT) is considered to be limited. Moreover, absorption after oral administration can also be assessed applying the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)). The target substance fails to satisfy two rules for good bioavailability: the molecular weight is > 500 g/mol and the log Pow is > 5. Thus, oral absorption is not expected to be high according to this set of rules.

If absorption occurs, the favourable mechanism will be absorption by micellar solubilisation, as this mechanism is of importance for the absorption of highly lipophilic substances (i.e. substances with log Pow > 4), that are poorly soluble in water (< 1 mg/L), via the oral exposure route (Aungst and Shen, 1986). This is relevant to the absorption potential of Decanoic acid, mixed esters with octanoic acid and pentaerythritol via the oral route of exposure.

In the gastrointestinal tract (GIT), metabolism prior to absorption may occur. Following oral ingestion, fatty acid esters of pentaerythritol may be hydrolysed by ubiquitously expressed esterases followed by absorption of the hydrolysis products (Mattsson and Volpenhein 1972a). However, lower rates of enzymatic hydrolysis in the GIT were shown for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a, b). The in vitro hydrolysis rate of a pentaerythritol ester was about 2000 times slower in comparison to that of glycerol esters (Mattson and Volpenhein, 1972a, b).

Furthermore, in vivo studies in rats demonstrated the incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased (Mattson and Volpenhein, 1972c). Based on the general information on absorption via the oral route and hydrolysis in the GIT, it can be assumed that the tetraesters of pentaerythritol will not be rapidly hydrolysed in the GIT by esterases and that absorption of the whole parent substance is likely to be very low. For example, pentaerythritol tetraoleate ester had an absorption rate of 64% and 90%, when ingested at 25% and 10% of dietary fat, respectively, while the absorption rate of 100% was observed for glycerol trioleate when ingested at 100% of dietary fat (Mattson and Nolen, 1972).

Even though the hydrolysis is assumed to be slow, the potential effects should be addressed. The physico-chemical characteristics of the theoretical hydrolysis products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based on the physico-chemical characteristics of the parent substance will no longer apply (ECHA, 2016).

Pentaerythritol (PE), a highly water-soluble substance (25 g/L, OECD SIDS, 1998), will readily dissolve into the gastrointestinal fluids. DiCarlo et al. (1965) showed that 10 mg/kg C14-labled PE orally administered to mice was absorbed rapidly. Almost half of the administered dose left the GIT within 15 minutes. The highly lipophilic fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

The remaining fatty acid components will be absorbed and metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological processes, e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994).

Acute oral toxicity studies were performed with 5 of the source substances: Fatty acids, C8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6, source substance no. 1), Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9, source substance no. 3), Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3, source substance no. 4), Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7, source substance no. 5), and Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, source substance no. 9). All available studies result in acute oral LD50 > 2000 mg/kg bw with no indication of systemic toxicity. Moreover, sub-acute (28-day) and sub-chronic (90-day) repeated dose toxicity studies conducted with the source substances Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7, source no. 5), Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8, source no. 8), and Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3, source no. 4) did not induce overt toxicity; resulting in NOAELs ≥1000 mg/kg bw/day.

The available data indicate low systemic toxicity, due to low toxicity potency and/or low absorption potential. In conclusion, based on the available data, absorption of Decanoic acid, mixed esters with octanoic acid and pentaerythritol 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 smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favours dermal absorption, while molecules with molecular weights > 500 g/mol will most likely be too large (ECHA, 2016). As the molecular weights of the target substance Decanoic acid, mixed esters with octanoic acid and pentaerythritol are in a range 473 – 1193.93 g/mol and those of the analogue substances range from 641 to 753 g/mol, dermal absorption of the molecules is considered to be negligible.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2016). The skin irritation properties of the source substances Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, source no. 9), Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8, source no. 8), Pentaerythritol tetraesters of n decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7, source no. 5), and Fatty acids, C8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6, source no. 1) have been investigated in in vivo studies which indicated no skin irritation for the listed substances.

Acute dermal toxicity studies were performed with the source substances Fatty acids, C8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6, source no. 1) and Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9, source no. 3) demonstrating no signs of systemic toxicity and resulting in acute dermal LD50 > 2000 mg/kg bw. Moreover, a sub-chronic (90-day) repeated dose toxicity study with dermal exposure was performed with the analogue substance no. 9 (Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2)) no signs of systemic toxicity were observed up to the highest dose tested. Thus, the 90-day dermal NOAEL was considered to be 2000 mg/kg bw/day in male and female rats.

Overall, the low water solubility, the high molecular weight (> 500 g/mol), the high log Pow value of the target substance and the fact that the source substances are not considered to be irritating to skin indicates that dermal uptake of the source substances and of Decanoic acid, mixed esters with octanoic acid and pentaerythritol in humans is considered to be low.

Inhalation absorption

All analogue substances as well as the target substance have a predicted low vapour pressure of < 0.001 Pa at 20 °C and have low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the target substance in the form of vapours, gases, or mists is not expected.

However, the target 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, 2016).

Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like the source and target substances may be taken up by micellar solubilisation. Additionally, as described above, the source substances and the target substance may be hydrolysed enzymatically to the respective metabolites, for which absorption can be expected to be higher. However, enzymatic hydrolysis of the source substances is considered to be slow and hence only limited respiratory absorption of the respective hydrolysis products is considered likely.

Acute inhalation toxicity studies were performed with the structurally similar source substances Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, source no. 9) and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS 85536-35-2, source no. 6), and Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7, source no. 5), all indicating no hazard for systemic toxicity resulting in acute inhalation LC50 values ≥5 mg/L air. Moreover, a second acute inhalation study with Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, source no. 9) yielded an LC50 >4.06 mg/L which was the highest practical concentration that could be achieved with a nebulizer operated at high pressure and with the air flow through the chamber reduced to maximize the aerosol concentration. With respect to repeated dose toxicity, a sub-chronic (90-day) study is available with the analogue substance Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, source no. 9). Briefly, no substance-related adverse effects were observed at any dose level. The lungs of the high dose animals revealed a slight increase in organ weight which correlated with slightly increased numbers of macrophages in the pulmonary alveoli. Based on the results of the study and the absence of any toxicologically relevant finding the sub-chronic NOAEC is considered to be 0.5 mg/L air for male and female rats.

Overall, a systemic bioavailability of the analogue substances in humans cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm, but is not expected to be higher than that following oral exposure. Following 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.

Accumulation

Highly lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow >6 implies that the source substances may have the potential to accumulate in adipose tissue (ECHA, 2016).

Absorption is a prerequisite for accumulation within the body. As absorption of the source substances is considered to be low, the potential for bioaccumulation is low as well. Nevertheless, as further described in the section metabolism below, esters of pentaerythritol and fatty acids may undergo slow esterase-catalysed hydrolysis, leading to the hydrolysis products pentaerythritol and the fatty acids (e.g. decanoic and octanoic acid).

The log Pow of the first 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 other hydrolysis products, (e.g. decanoic and octanoic acid moieties) may be stored in adipose tissue. However, stored fatty acids are subject to a continuous turnover as they are permanently metabolised for energy generation. Thus, bioaccumulation of fatty acids will only take 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 anticipated hydrolysis products can be expected.

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 extracellular concentration particularly in fatty tissues (ECHA, 2016). Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption.

As discussed above, only limited absorption of the target and source substances is considered based on their physico-chemical characteristics thereby limiting their distribution. Esters of pentaerythritol and fatty acids can undergo chemical changes as a result of enzymatic hydrolysis, leading to the hydrolysis products pentaerythritol and the corresponding fatty acids which might be distributed within the body.

With regard to its physico-chemical properties, pentaerythritol will be able to distribute in aqueous fluids by diffusion through aqueous channels and pores. No protein binding or distribution in adipose tissue is expected (OECD SIDS, 1998). The remaining hydrolysis products, decanoic and octanoic acid, are considered to distribute in the organism via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994).

Overall, the available information indicates that the intact parent compounds are 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.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: after oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. However, as discussed previously, only slow enzymatic hydrolysis of the parent substance is considered to occur in the GIT due to the high number of ester bonds and the complex structure of the molecule.

The source substances will slowly be hydrolysed to the corresponding alcohol (pentaerythritol) and fatty acid moieties (e.g. decanoic and octanoic acid) by esterases. It was shown in in vitro experiments that the hydrolysis rate for another polyol ester (pentaerythritol tetraoleate) was lower when compared with the hydrolysis rate of the triglyceride glycerol trioleate (Mattson and Volpenhein, 1972). Therefore, it is assumed that the hydrolysis rate of the target substance Decanoic acid, mixed esters with octanoic acid and pentaerythritol is low as well. Therefore, ester bond hydrolysis is expected to occur to a minor extent in the GIT and after systemic uptake. The metabolism of the hydrolysis products is discussed below.

Following hydrolysis of the ester bond, the hydrolysis products, fatty acids and polyol, will be absorbed and metabolised. A major metabolic pathway for linear and simple 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 by sequential removal of two 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).

The second hydrolysis product pentaerythritol (PE) is absorbed rapidly and mainly excreted unchanged. DiCarlo et al. (1965) reported that 10 mg/kg C14-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 feces after 4 hours already.

Overall, the fraction of the source substances that is systemically available, may be hydrolysed and the hydrolysis products can be further metabolized.

Excretion

A low absorption rate is expected for the target and source substances via the gastrointestinal tract, thus the biggest part of the ingested substances is assumed to be excreted in the feces. The remaining fatty acid component, (e.g. decanoic and octanoic acid), will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological processes, e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or feces but excreted via exhaled air as CO2 or stored as described above.

The pentaerythritol (PE) is not metabolized and excreted mainly unchanged via urine as described previously. Additionally, Kutscher (1948) found 85 - 87% of unaltered PE in the urine of humans ingesting pentaerythritol.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.