Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic and n-heptanoic acids

Endpoint summary

Description of key information

Basic Toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acid (CAS No. 1379424-11-9, EC 945-883-1).

An assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information has been conducted (Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006). The Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) is used as a basis.

The available data on physico-chemical and toxicological properties of the substance are taken into account, as well as further available information on structurally analogue substances and on the hydrolysis products.

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

The substance Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and heptanoic acids is a liquid organic UVCB substance. Dipentaerythritol, with 6 -OH functional groups, is esterified with fatty acids heptanoic acid (C7) and 3,5,5, trimethylhexanoic acid to obtain hexaesters. The substance is poorly water soluble (<0.1 mg/L) with a molecular weight of 927 - 1095.6 g/mol, a log Pow of > 10 based on QSAR predictions and an estimated vapour pressure of < 0.0001 Pa at 20 °C.

 

Absorption

Absorption depends on the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the water solubility and the octanol/water partition coefficient (log Pow) value. The log Pow value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol and is a measure of lipophilicity (octanol is used as a surrogate for lipids).

Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is poorly water soluble (<0.1 mg/L) and with a high lipophilicity (calculated log Pow > 10) and high molecular weight. Therefore, the potential for absorption across biological membranes of the substance itself is expected to be very low.

Oral / Gastrointestinal absorption

There are no ionisable groups within the molecular structures of the constituents of the substance Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids.

Generally, the smaller the molecule, the more easily it may be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption while molecular weights above 1000 do not favour absorption. The molecular weight of the constituents of the substance Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and heptanoic acids are 927 - 1095 g/mol, hence absorption of the molecule in the gastrointestinal tract is considered to be very limited.

On the other side, the substance Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is very poorly water-soluble, it will not be easily dissolved in the gastrointestinal fluids.

The high Log P value of the substance (above 10) may limit its absorption by passive diffusion due to the inability to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. However, it may be taken up by micellar solubilisation, as this mechanism may be of particular importance for highly lipophilic compounds (log P>4), particularly those that are poorly soluble in water (1 mg/l or less). 

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 Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids, as the substance fails three rules for good bioavailability (more than 10 H-bond acceptors and the molecular weight is > 500 g/mol and the log Pow is > 5). Thus, oral absorption is expected to be very limited, too.

In the gastrointestinal tract (GIT), metabolism prior to absorption may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) have been shown to be rapidly hydrolised by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpnhein, 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) . 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 (Mattson and Volpenhein, 1972c). In vivo studies in rats showed that the hexaester of sorbitol is not absorbed (Mattson and Nolen, 1972). Based on this, it can be assumed that, hexaesters of dipentaerythritol will slowly be hydrolysed in the GIT by esterases and that absorption of the parent substance will be limited.

Even though hydrolysis is assumed to be slow, it needs to be addressed that the physico-chemical characteristics of the theoretical 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, 2017).

Therefore, it can be assumed that for Dipentaerythritol (MW 254 g/mol, log Pow -2.0, water solubility 3 g/L), and the fatty acids which may be formed as result of a previous slow stepwise hydrolysis, absorption in the gastro-intestinal tract occurs.

The available data on oral toxicity of structurally related analogue substances is also considered for assessment of oral absorption.

An acute oral toxicity study was available forDipentaerythritol with fatty acids, C5 and C9iso (EC 444-000-2). No signs of systemic toxicity were found at concentrations of 2000 mg/kg bw in rats. This substance neither showed systemic effects in a 28-day study, and the NOAEL was set at 1000 mg/kg bw/day (Jones, 2000). 

Repeated dietary administration (28-day) of the structurally related substance Fatty acids, C5-10, esters with pentaerythritol (EC 270-291-9, CAS No. 68424-31-7) to rats, up to and including a dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/day for female rats, did not produce any evidence of overt toxicity (Brammer, 1993). 

Therefore, if absorption of the intact parental compound or the respective metabolites occurred, it resulted in a low order of systemic toxicity.

The analogue substance is as well an hexaester, with two identical parent substances (diepentaerytrhitol and and 3,5,5-trimethylhexanoic acid) and the third parent substance very similar to target (pentanoic acid vs. heptanoic acid). Substance EC 270-291-9 is a tetraester, having a lower molecular weight in comparison with Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids, which is a hexaester, and possibly higher rates of hydrolysis to the respective fatty acids and the respective polyol pentaerythritol. The absorption of this structurally related substance is therefore assumed to be higher than the absorption of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids.

These results suggest that 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 summary, the above discussed physico-chemical properties of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids and relevant data from available literature on fatty acid esters with more than 4 ester bonds do not indicate rapid hydrolysis before absorption of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids to the respective fatty acids and dipentaerythritol. On the basis of the above mentioned data, a low absorption of the test material is predicted.

Dermal absorption

In general, a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2017). As the molecular weight of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is 759 - 1095 g/mol, dermal absorption of the molecule is not likely.

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. On the other side, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2017). Log Pow of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is > 10 and water solubility is less than 1 mg/L, therefore, dermal uptake of the substance is likely to be very low.

Based on QSAR a dermal absorption value for Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids of 2.88e-012 - 1.41e-014 mg/cm²/event (very low) was calculated (Episuite 4.11, DERMWIN 2.02, 2020). Based on this value, the substance has a very low potential for dermal absorption.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. (ECHA, 2017). As no skin irritation studies with Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids are available, read-across from analogue substance Dipentaerythritol hexaesters of pentanoic acid and 3,5,5-trimethylhexanoic acid (EC 444-000-2) was applied and the substance was not considered as skin irritating in humans. In addition, the analogue substance 3,5,5-trimethylhexanoic acid hexaester with dipentaerythritol EC 453-460-3 (Dipentaerythritol hexaester with one of the fatty acids that are present in Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids) is also considered not irritating to skin in humans. Therefore, an enhanced penetration of the substance Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids due to local skin damage is not expected.

On the other side, signs of systemic toxicity indicate that absorption has occurred. The acute dermal toxicity study with source substance Dipentaerythritol hexaesters of pentanoic acid and 3,5,5-trimethylhexanoic acid (EC 444-000-2) showed no signs of systemic toxicity resulting in acute dermal LD50 values >2000 mg/kg bw.

In regards of dermal toxicity data, a read-across from no signs of systemic toxicity were found in the acute oral toxicity study performed with the analogue source substance by dermal route

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 to skin implies that dermal uptake of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids in humans is considered as very low.

 Respiratory absorption - Inhalation

Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids 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.

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 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2017).

Absorption of highly lipophilic substances as Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids by passive diffusion is limited. However, absorption by mechanism of micellar solubilisation may be of particular importance.

In regards of water solubility, very low for Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids, similar criteria as for GI absorption apply for the absorption of deposited material.

Additionally, as described above, theoretically, Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids can be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher. However, hydrolysis of fatty acid esters with more than 3 ester bonds is considered to be slow (Mattson and Volpenheim, 1972a). Therefore, Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids will be slowly hydrolysed enzymatically to the respective metabolites and thus, their respiratory absorption is considered to be low.

The available data on inhalation toxicity for the structurally related substance Fatty acids, C5-10, esters with pentaerythritol (EC 270-291-9 CAS No. 68424-31-7, Parr-Dobrzansk, 1994) in rats showed no effects of systemic toxicity. Thus, the acute toxicity of the substance is low and/or absorption after inhalation exposure is low.

The available data on systemic toxicity data by oral route, as discussed above, showed no signs of systemic toxicity in analogue and structurally-related substances.

Overall, a systemic bioavailability of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids in humans cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15μm. However, it is not expected to be higher than following oral exposure.

 

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, 2017). 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 Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is considered very low based on its physicochemical characteristics thereby limiting its distribution.

Esters of dipentaerythritol and fatty acids can undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products dipentaerythritol and the different fatty acids. These potential cleavage products might be distributed within the body.

On the basis of its physicochemical properties, dipentaerythritol will be distributed in aqueous fluids by diffusion through aqueous channels and pores. There is no protein binding and it is distributed poorly in fatty tissues (OECD SIDS, 2009). Dipentaerythritol is likely to be rapidly absorbed and subject to extensive hepatic metabolism resulting in the renal excretion of water-soluble metabolites. The systemic distribution of di-Penta is therefore likely to be limited by its metabolism and excretion.

The remaining breakdown products, 3,5,5-trimethylhexanoic and n-heptanoic 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 parent compound, Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids, is not assumed to distribute throughout the body due to limited absorption. Dipentaerythritol is considered to distribute poorly in fatty tissues, while wide distribution within the body is expected for the other cleavage products 3,5,5-trimethylhexanoic and n-heptanoic acid.

 

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 gastrointestinal tract due to the high number of ester bounds and the complex structure of the molecule.

Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids are slowly hydrolysed to the corresponding alcohol (dipentaerythritol) and fatty acids moieties (3,5,5,-trimethylhexanoic acid and heptanoic acid) by esterases. It was shown in-vitro 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). Thus, it is assumed that the hydrolysis rate for Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is even lower in comparison with pentaerythritol esters. Therefore, ester bond hydrolysis is expected to occur to a minor extent in the gastrointestinal tract and after systemic uptake. Nevertheless, possible cleavage products should be discussed here.

Following hydrolysis of the ester bond, the breakdown products, fatty acids and polyol, will be absorbed and metabolised. A major metabolic pathway for linear and simply 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).

The cleavage product heptanoic acid is stepwise degraded via beta –oxidation in the mitochondria. 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 other cleavage product 3,5,5-trimethylhexanoic acid does not undergo beta oxidation due to an uneven methyl substitution. The metabolism is suspected to occur via omega- and omega- 1-oxidation, which lead to formation of various polar metabolites capable of excretion in the urine (WHO, 1998).

The polyol cleavage product dipentaerythritol is predicted to undergo sequential oxidative metabolism of the six hydroxy groups, based on known metabolic reactions and the elucidated pathways for other alcohol compounds; hydrolysis of the central ether linkage to yield pentaerythritol can also be predicted. There are no additional chemical groups known to be susceptible to mammalian metabolism. Rapid hepatic metabolism is indicated, which will facilitate excretion and therefore act to limit systemic exposure and toxicity.

Overall, the parts of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids that have become systemically available, might be hydrolysed and the cleavage products can be further metabolized.

However, absorption of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is not likely as previously discussed, and thus, no extensive metabolism is expected but rather direct elimination.

 

Excretion

Low absorption is expected for Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids via the gastrointestinal tract, thus much of the ingested substance is assumed to be excreted in the faeces.

Highly lipophilic substances, like Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells (exfoliation).

The expected low amount of absorbed fatty acid esters will undergo rapid metabolization.

The cleavage product heptanoic acid, will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994). Therefore, excretion of the fatty acid component will occur presumably in the expired CO2.

The other cleavage product, 3,5,5-trimethylhexanoic acid does not undergo beta oxidation due to an uneven methyl substitution, thus being expected to be excreted via bile or urine following omega- or omega-1-chain hydroxylation and subsequent formation of various polar metabolites (WHO, 1998).

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.

The dipentaerythritol may either further be metabolized or conjugated to polar products or excreted unchanged via urine. Rapid and extensive renal excretion of dipentaerythritol and/or its metabolites is likely, with no potential for bioaccumulation based on chemical properties.

 

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 >10 implies that Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids may have the potential to accumulate in adipose tissue (ECHA, 2017).

Absorption is a prerequisite for accumulation within the body. As absorption of Dipentaerythritol hexaesters with 3,5,5-trimethylhexanoic and n-heptanoic acids is expected to be very low, as discussed above, the potential of bioaccumulation is very low as well.

Nevertheless, as further described in the section metabolism above, esters of dipentaerythritol and fatty acids may undergo slow esterase-catalyzed hydrolysis, leading to the cleavage products dipentaerythritol and the respective fatty acid moieties (3,5,5-trimethylhexanoic and n-heptanoic acid).

The log Pow of the first cleavage product dipentaerythritol is -2.0 and it is highly soluble in water (3 g/L) (OECD SIDS, 2009). Consequently, there is no potential for dipentaerythritol to accumulate in adipose tissue. A rapid and extensive renal excretion of di-pentaerythritol and/or its metabolites is likely, with no potential for bioaccumulation based on chemical properties.

The other cleavage products, the fatty acids 3,5,5-trimethylhexanoic and n-heptanoic acid, may 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 for energy generation. Thus, 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 can be anticipated.

 

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