2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS # 25811-35-2) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate was conducted based on the relevant available information. This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to ‚Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance‘ (ECHA, 2012) and taking into account further available information on the structural analogue substances from which data was used for read-across to cover data gaps.

The monoconstituent substance 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is an organic liquid. It is poorly water soluble (< 1 mg/L, Affolter, 2004) with a molecular weight of 584.82g/mol, a log Pow > 10 (Birkhofer, 2014) and a vapour pressure of < 0.001 Pa at 20 °C (Nagel, 2013).

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, 2012).

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2012). The molecular weight 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is 584.82 g/mol and thus above 500 g/mol. Therefore, absorption of the molecule in the gastrointestinal tract is unlikely.

Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate as the log Pow value is > 10 and thus above the given range of ‑0.4 to 5.6 and the molecular weight is above 500 g/mol.

The log Pow > 10 of the substance 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate 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).

In the gastrointestinal (GI) tract, metabolism prior to absorption via enzymes of the microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolysed by ubiquitously expressed esterases and the cleavage products are almost completely absorbed (Mattson and Volpenhein, 1972a). On the contrary, lower rate of enzymatic hydrolysis in the GI tract was observed for compounds with more than three ester groups (Mattson and Volpenhein, 1972a,b). 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 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 the structurally related substances Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7), Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9), and Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-5) are also considered for assessment of oral absorption. In acute oral toxicity studies conducted at concentrations of 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Robinson, 1991; Malloey, 2006; Zolyniene, 1999 and D’Aleo, 1984). The structurally related substance Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) showed no systemic effects up the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL ≥1000mg/kg bw/day; Müller, 1998). Therefore, if absorption of the intact parental compound or the respective metabolites occurred, this will result in a low order of systemic toxicity. These results suggest that 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate 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 alcohol (Polyol) and 1 – 6 fatty acids will undergo chemical changes in the gastro-intestinal fluids as a result of slow enzymatic hydrolysis. Pentaerythritol (PE, parental polyol) as well as the fatty acids will be formed, even if according to the available literature hydrolysis is not assumed to be rapid for pentaerythriol- and dipentaerythritol-ester and in general for polyol esters with more than three ester groups (multiple linked polyol esters) probably due to steric hindrance. The in-vitro hydrolysis rate of Pentaerythritol tetraoleate when compared with the hydrolysis rate of the triglyceride Glycerol trioleate was very slow (Mattson and Volpenhein, 1972). The physico-chemical characteristics of the cleavage 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 upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for both cleavage products, it is anticipated that they will be 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) determined the absorbability of the fatty acid moiety of the complete oleate esters of alcohols containing from 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 absorbability of the fatty acids decreased but was still present.

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 summary, the above discussed physical-chemical properties of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate and relevant data from available literature on fatty acid esters with more than three ester bonds do not indicate rapid hydrolysis before absorption of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate to the respective fatty acids and the polyol pentaerythritol.

On the basis of the above mentioned data, a low absorption of the parent substance is anticipated.

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is 584.82 g/mol, a dermal absorption of the molecule is not likely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate was not tested for skin irritation, read-across from Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7) and Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) (Robinson, 1991 and Zolyniene, 1999) was applied. As the read –across substances are not considered skin irritating in humans an enhanced penetration of the substance due to local skin damage can be excluded.

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, 2012). As the water solubility of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is less than 1 mg/L and log Pow is > 10, dermal uptake is likely to be very low.

The available data on dermal toxicity of the structurally related substances Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are also considered for assessment of dermal absorption.

An acute dermal toxicity study was available for Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9). At a concentration of 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Mallory, 2006).

In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 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 (Cruzan, 1988).

Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (>100), the high log Pow values and the fact that the substance is not irritating to skin implies that dermal uptake of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate in humans is considered to be very low.

Inhalation

2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate 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, 2012).

Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Pentaerythritol tetraoleate 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 acid available for respiratory absorption. Due to the high molecular weight of the 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 three ester bonds is considered to be slow (Mattson und Volpenhein, 1968, 1972a) and the possibility the test substance to be hydrolysed enzymatically to the respective metabolites and its relative absorption is considered to be low as well.

The available data on inhalation toxicity of structurally related substances Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) and Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7) are also considered for assessment of inhalation absorption. Two acute inhalation toxicity read-across studies conducted with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, Mekitarin, 1990; Hoffman, 1999) and Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7, Parr-Dobrzansk, 1994) in rats show no effects of systemic toxicity.

In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 0.5 mg/L in male and female rats (Dulbey, 1992).

Therefore, respiratory absorption of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate in humans is considered possible after inhalation but is not expected to be higher than following oral exposure.

Accumulation

Generally highly lipophilic substances 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 > 10 implies that 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as absorption of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is considered to be very low, the potential of bioaccumulation is very low as well.

Nevertheless, as further described in the section metabolism below 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate will undergo to slow esterase-catalyzed hydrolysis, leading to the cleavage products pentaerythritol and fatty acids.

The log Pow of the first cleavage 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 cleavage products, the fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized 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 cleavage 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 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, 2012).

Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption.

As discussed above, absorption of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is considered very low based on its physicochemical characterisation as poor water solubility and high molecular weight.

Nevertheless, esters of pentaerythritol and fatty acids will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products pentaerythritol and the different fatty acids.

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).

Overall, the available information indicates that the cleavage products, pentaerythritol and fatty acids can be distributed in the organism.

Metabolism

On the basis of the properties of the test substance a very low absorption of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is anticipated.

As discussed above, hydrolysis of an esterified alcohol with more than three ester groups is assumed to be slow. In in-vivo studies in rats, a decrease in absorption was observed with an increasing esterification grade. For example, for pentaerythritol tetraoleate an absorption rate of 64% and 90% was observed, when ingested at 25% and 10% of dietary fat, 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 about 2000 times 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 of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation unchanged before entering the liver where hydrolysis will basically take place. 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate will be hydrolysed to pentaerythritol and fatty acids, even though it was shown in-vitro that the hydrolysis rate of PE esters was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a).

The first cleavage products, fatty acids, is stepwise metabolized by beta-oxidation, following the same pattern as other odd carbon number, straight-chain, aliphatic acids (Bingham et al 2001; HSDB, 2013). The metabolism of the uneven fatty acids results in carbon dioxide and an activated C3-unit, which undergoes a conversion into succinyl-CoA before entering the citric acid cycle (Stryer, 1996). The second cleavage product, pentaerythritol, is absorbed rapidly but excreted unchanged. 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.

Excretion

On the basis of the low absorption of the test substance 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is expected to be excreted via faeces.

However based on the hydrolysis described above, fatty acids and pentaerythritol as breakdown products will occur in the body. The fatty acid components will be metabolized for energy generation, stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). 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. The other cleavage product, pentaerythritol is not metabolized but excreted unchanged via urine. 10 mg/kg C14-labled PE orally administered to mice was absorbed from the gastrointestinal tract to almost 50% within 15 minutes. 68% of the dose was excreted via urine and faeces after 4 hours (DiCarlo et al., 1965). The amount found in faeces was assumed to arise from contamination with urine due to the setup of the metabolic cages. Additionally, Kutscher (1948) found 85-87% of unaltered PE in the urine of humans ingesting a radiolabeled PE.