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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS # 68604-38-6) 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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS # 68604-38-6) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

 

The substance Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is an UVCB substance based on the analytical characterisation. The organic liquid is an ester of Dipentaerythritol and C16-C18 and C18:1 fatty acids. It is poorly water soluble (< 0.15 mg/L, Frischmann, 2012) with a molecular weight of 1684 - 1853 g/mol, a log Pow > 10 based on QSAR predictions (Blum, 2011) and a vapour pressure of < 1.86E-50 Pa at 20 °C (Hinze, 2012).

 

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). As the molecular weight of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is > 1600 g/mol absorption of the molecule in the gastrointestinal tract is considered to be very limited.

 

Absorption after oral administration can be assessed applying the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)). The substance Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol fails three rules for good bioavailability ( more than 10 H-bond acceptors , the molecular weight is > 500 and the log Pow is > 5). Thus, oral absorption is again not expected to be high.

The log Pow of >10 of the substance Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol suggests that the absorption of such a highly lipophilic substance may be limited by the inability to dissolve into gastrointestinal (GI) fluids. It might be enhanced by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), which are poorly soluble in water (1 mg/L or less). However, for large molecules the gastrointestinal absorption is not likely to occur.

In the gastrointestinal 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 hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpenhein, 1972a). However, a lower rate of enzymatic hydrolysis in the GIT was 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, on the one hand, the hexaester of dipentaerythritol is not considered to be rapidly hydrolysed in the GIT by esterases and, on the other hand, absorption of the whole substance can be considered to be very low.

Even though hydrolysis is assumed to be slow, in 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, 2012).

Therefore it can be assumed that for Dipentaerythritol (diPE, parental Polyol, MW 254 g/mol, log Pow -2.0, water solubility 3 g/L), and the fatty acids (C16, C18 and C18:1) which may be formed as result of a previous slow stepwise hydrolysis, absorption in the gastro-intestinal tract can be anticipated. 

The available data on oral toxicity of structurally related analogue substances are also considered for assessment of oral absorption. Three acute oral toxicity studies with Pentaerythritol tetraoleate (CAS# 19321-40-5), Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7), and Dipentaerythritol with fatty acids, C5 and C9iso (CAS# 647028-25-9) at a concentration of 2000 mg/kg bw in rats showed no signs of systemic toxicity (Pels Rijcken, 1997; Robinson, 1991).

Futhermore data on the subacute repeated dose toxicity of structurally related substances Fatty acids, C8-10, mixed esters with Dipentaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS# 189200-42-8) and Dipentaerythritol with fatty acids, C5 and C9iso (CAS# 647028-25-9) showed no systemic effects in two 28-day studies and the NOAEL was set at 1000 mg/kg bw/day (Trimmer, 1995). In addition the analogue substance Pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS # 146289-36-3) showed no systemic effects in the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL = 1000 mg/kg bw/day; Müller, 1998). Therefore the intact parental compound or the respective metabolites occurred, resulted in a low order of systemic toxicity.

Most of the analogue substances are tetraesters, having a lower molecular weight in comparison with Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol and possibly higher rates of hydrolysis to the respective fatty acids and the respective polyol pentaerythritol. The absorption of the analogue substance is therefore assumed to be higher than the absorption of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol.

These results suggest that the test substances are 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 physical-chemical properties of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol and relevant data from available literature on fatty acid esters with more than 4 ester bonds do not indicate rapid hydrolysis before absorption of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol to the respective fatty acids and the polyols dipentaerythritol. On the basis of the above mentioned data, a low absorption of the test material and thus a limited systemic bioavailability is predicted.

 

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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is 1684 - 1853 g/mol, 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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol was not tested for skin irritation, read-across from Fatty acids, C16-18, esters with pentaerythritol (CAS# 85116-93-4, Steiling, 1991) was applied and the substance is not considered as skin irritating in humans. Therefore, an enhanced penetration of the substance due to local skin damage is not expected. Based on QSAR a dermal absorption value for Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol of 6.03E-22 to 5.63E-20 mg/cm2/event (very low) was calculated (Episuite 4.1, DERMWIN 2.01, 2012). Based on this value, the substance has a very low potential for dermal absorption.

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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is < 1 mg/L and log Pow is estimated to be >10, dermal uptake is likely to be very low.

The available data on dermal toxicity of the structurally related substances Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2), 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS#62125-22-8-) and Dipentaerythritol with fatty acids, C5 and C9iso (CAS# 647028-25-9) are also considered for assessment of dermal absorption.

Acute dermal toxicity studies were available for 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) (CAS# 62125-22-8-) and Dipentaerythritol with fatty acids, C5 and C9iso (CAS# 647028-25-9). At a concentration of up to 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Debets, 1984 and Allen, 1999).

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.

Thus, the toxicity of the substance is low and/or absorption after dermal exposure is low.

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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol in humans can be considered as very low.

Inhalation

Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol has a low vapour pressure of less than 1.86E-50 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 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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol can be taken up by micellar solubilisation. Additionally, as described above, theoretically, Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol can be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher. However, as discussed above, hydrolysis of fatty acid esters with more than 3 ester bounds is considered to be slow (Mattson and Volpenheim, 1972a). Therefore Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol will be slowly hydrolysed enzymatically to the respective metabolites and thus, their respiratory absorption is regarded to be low.

The available data on inhalation toxicity the structurally related substances, Fatty acids, C5-10, esters with pentaerythritol (CAS# CAS# 68424-31-7) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) are also considered for assessment of respiratory absorption. The acute inhalation toxicity read-across study conducted with Fatty acids, C5-10, mixed esters with pentaerythritol (CAS# 68424-31-7, Parr-Dobrzansk, 1994) in rats did not reveal any 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/mL in male and female rats.

Thus, the toxicity of the substance is low and/or absorption after inhalation exposure is low.

Overall, a systemic bioavailability of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol 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 following oral 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 of>10 implies that Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol may have the potential to accumulate in adipose tissue (ECHA, 2012).

Absorption is a prerequisite for accumulation within the body. As absorption of the Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is considered to be very low the potential of bioaccumulation is very low as well.

Nevertheless, as further described in the section metabolism below, esters of dipentaerythritol and fatty acids may undergo slow esterase-catalyzed hydrolysis, leading to the cleavage products dipentaerythritol and the fatty acids.

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. 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 can be 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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is considered very low based on its physico-chemical characterisation such as poor water solubility and high molecular weight.

Esters of dipentaerythritoland fatty acids can undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products dipentaerythritol and the different fatty acids.

Only the potential cleavage products of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol after chemical changes as a result of enzymatic hydrolysis, namely dipentaerythritol and the fatty acid, might be distributed within the body.

Dipentaerythritol, on the basis of its physico-chemical properties, 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).

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, dipentaerythritol and fatty acids can be distributed in the organism.

 

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, it is not anticipated that enzymatic hydrolysis of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is taking place in the gastrointestinal tract due to the high molecular weight and the complex structure of the molecule. Additionally, the hydrolysis of esterified alcohol with more than 3 ester groups is assumed to be slow as discussed above. In in vivo studies in rats, a decrease in absorption was observed with increasing esterification. For example, pentaerythritol tetraoleate ester had an absorption rate of 64% and 90% (25% and 10% of dietary fat), whereas the hexaester of sorbitol was not absorbed (Mattson and Nolen, 1972). As Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is a hexaester as well, the absorption rate is expected to be low.

In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol are slowly hydrolysed to the corresponding alcohol (dipentaerythritol) and fatty acids 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 Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol 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.

The first cleavage products, fatty acids are stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

The second cleavage product dipentaerythritol can either remain unchanged or may further be metabolized or conjugated (e.g. glucuronides, sulfates, etc.) to polar products that are excreted in the urine.

Overall, the part of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol that have become systemically available, might be hydrolysed and the cleavage products can be further metabolized. However, due to its high molecular weight, absorption of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol is not likely and thus, no extensive metabolism is expected but rather direct elimination.

 

Excretion

Low absorption is expected for Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol via the gastrointestinal tract, thus much of the ingested substance is assumed to be excreted in the faeces.

Absorbed fatty acid esters undergo rapid metabolisation. The fatty acid components (C16, C18 and C18:1) will be metabolized for energy generation or stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, excretion of the fatty acid components will occur presumably in the expired CO2.

The dipentaerythritol may either further be metabolized or conjugated to polar products or excreted unchanged via urine.

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