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Description of key information

There are no studies available in which the toxicokinetic behaviour of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid has been investigated.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of the substance Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is 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 Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014) and taking into account further available information on structurally analogue substances and hydrolysis products.

The substance Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is an organic liquid consisting of four main constituents with a molecular weight range of 584.82 - 668.98 g/mol. The measured water solubility and the predicted log Pow values are >0.09 - <10.65 µg/L at 20 °C (Schwarzkopf, 2016) and 10.67 - 13.06 (Mayer, 2016), respectively.

 

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

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, 2014). As the molecular weight of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid ranges from 584.82 - 668.98 g/mol absorption of the molecule in the gastrointestinal tract is considered to be limited.

If absorption occurs, the favourable mechanism will be 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) (Aungst and Shen, 1986) like Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid.

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 Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid, as the substance fails two rules for good bioavailability (molecular weight is >500 and the log Pow is >5). Thus, oral absorption is expected to be limited.

In the gastrointestinal tract (GIT), metabolism prior to absorption may occur. In fact, after oral ingestion, fatty acid esters with pentaerythritol are hydrolised by ubiquitously expressed esterases followed by absorption (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). In vitro hydrolysis rate of a 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). Based on this, it can be assumed that tetraesters of pentaerythritol will slowly be hydrolysed in the GIT by esterases and that absorption of the parent substance will be limited.

Additionally, 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%, 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). 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). Therefore, for Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid the absorption rate is expected to be low.

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, 2014).

Pentaerythritol, being 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. Moreover, the highly lipophilic fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides. The available data on oral toxicity of structurally related analogue substances are also considered for assessment of oral absorption.

The remaining fatty acid components, heptanoic acid and 3,5,5-trimethylhexanoic acid, will be absorbed and 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).

Acute oral toxicity studies were performed with the structurally similar analogue substances Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2), 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) and Isononanoic acid, mixed esters with 2-methylbutanoic acid, 3-methylbutanoic acid, pentaerythritol and valeric acid (CAS 146289-36-3), all indicating no signs of systemic toxicity resulting in acute oral LD50 values >2000 mg/kg bw.

Moreover, subacute and subchronic repeated dose toxicity studies conducted with the analogue substances Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7), 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) and Isononanoic acid, mixed esters with 2-methylbutanoic acid, 3-methylbutanoic acid, pentaerythritol and valeric acid (CAS 146289-36-3) did not induce overt toxicity resulting in NOAEL values ≥1000 mg/kg bw/day. For 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) a LOAEL of 1000 mg/kg bw/day was derived for male and female rats based on liver enlargement in animals of the high dose group (1000 mg/kg bw/day) and globular accumulations of eosinophilic material in males of the mid-dose group. Overall, the available data indicate low systemic toxicity, either due to low toxicity potency or low absorption potential correlated to low systemic toxicity. In conclusion, based on the available data, absorption of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is assumed to be limited. Due to the rather high number of ester bounds, only slow hydrolysis in the GIT is expected to occur in the GIT, resulting in breakdown products feasible for absorption.

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, 2014). As the molecular weight of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is 584.82 - 668.98 g/mol, dermal absorption of the molecule may be impeded due to its size.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). In vivo skin irritation studies with the analogue substance Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) and 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-1) revealed no skin irritating properties.

Acute dermal toxicity studies were performed with the analogue substance 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) and Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9) demonstrating no signs of systemic toxicity resulting in acute dermal LD50 values >2000 mg/kg bw.

A further subchronic (90-day) repeated dose toxicity study was performed with the analogue substance Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) identifying no signs of systemic toxicity 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.

Furthermore, QSAR based dermal permeability prediction (Episuite 4.1, DERMWIN V2.02.2012) using molecular weight, log Pow and water solubility for the four main constituents of the target substance was performed resulting in a dermal penetration rate of 1.19 to 95.4 µg/cm²/h for Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid. These values are considered as an indicator for a low to medium dermal absorption rate for Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid.

Overall, the low water solubility, the high molecular weight (>500 g/mol), the high log Pow value and the fact that the substance is not considered to be irritating to skin implies that dermal uptake of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid in humans is considered to be low.

Inhalation

Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid have a predicted low vapour pressure of 1.77E-11 to 1.1E-12 Pa at 20 °C (Mayer, 2016) 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 vapors, 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, 2014).

Lipophilic compounds with a log Pow >4, that are poorly soluble in water (1 mg/L or less) like Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid may be taken up by micellar solubilisation.

Additionally, as described above, Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid may be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher. However, as discussed above, enzymatic hydrolysis of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is considered to be slow and hence, only limited respiratory absorption of the respective breakdown products is considered likely.

Acute inhalation toxicity studies were performed with the structurally similar analogue substance Carboxylic 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) both indicating no hazard for systemic toxicity resulting in acute inhalation LC50 values ≥5.1 mg/L air.

Moreover, a subchronic (90-day) repeated dose toxicity study is available with the analogue substance Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2). 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 subchronic NOAEC is considered to be 0.5 mg/L air for male and female rats.

Overall, a systemic bioavailability of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid 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 >10 implies that Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid may have the potential to accumulate in adipose tissue (ECHA, 2014).

Absorption is a prerequisite for accumulation within the body. As absorption of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is considered to be low, the potential of bioaccumulation is considered as low as well. Nevertheless, as further described in the section metabolism below, esters of pentaerythritol and fatty acids may undergo slow esterase-catalyzed hydrolysis, leading to the cleavage products pentaerythritol and the respective fatty acid moities (3,5,5-trimethylhexanoic acid and heptanoic acid).

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 3,5,5-trimethylhexanoic acid and heptanoic acid moieties may be stored in adipose tissue. However, stored fatty acids underlie 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 cleavage products has to be considered.

 

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, 2014). 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 Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is considered based on its physicochemical characteristics thereby limiting its distribution. Esters of pentaerythritol and fatty acids can undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products pentaerythritol and the corresponding fatty acids which might be distributed within the body.

In regard to its physicochemical 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 breakdown products, 3,5,5-trimethylhexanoic acid and 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 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 cleavage products, pentaerythritol, 3,5,5-trimethylhexanoic acid and heptanoic.

 

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 rather high number of ester bounds and the complex structure of the molecule.

Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid will slowly be hydrolysed to the corresponding alcohol (pentaerythritol) 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 Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is low as well. Therefore, ester bond hydrolysis is expected to occur to a minor extent in the GIT and after systemic uptake. Nevertheless possible cleavage products are be discussed below.

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 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 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 second cleavage product pentaerythritol is absorbed rapidly but 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 part of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid that have become systemically available, might be hydrolysed and the cleavage products can be further metabolized.

 

Excretion

Low absorption is expected for Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid via the GIT, thus much of the ingested substance is assumed to be excreted in the feces. 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). The remaining fatty acid component, 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, 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 is not metabolized and excreted mainly unchanged via urine as previously described in the metabolism section. The amount found in feces was assumed to be contamination from urine due to the setup of the metabolic cages. Additionally, Kutscher (1948) found 85-87% of unaltered PE in the urine of humans ingesting pentaerythritol.

 

References

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DiCarlo F.J., Hartigan J.M. Jr., Couthino, C.B. and Phillips, G.E. (1965). Absorption, distribution and excretion of Pentaerythritol and Pentaerythritol Tetranitrate by mice. Proceedings of the Society for Experimental Biology and Medicine. 118: 311-314

ECHA (2014): Guidance on information requirements and chemical safety assessment, Endpoint specific guidance. European Chemicals Agency, Helsinki

Fukami, T. and Yokoi, T. (2012): The Emerging Role of Human Esterases. Drug Metab Pharmacokinet 27(5): 466-477.

Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.

Kutscher, W. (1948). Über das Verhalten des Pentaerythrits im Stoffwechsel. Hoppe-Seyler´s Zeitschrift für physiologische Chemie , Volume 283 (5-6)

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Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1993): Principles of Biochemistry. Second Edition. Worth Publishers, Inc., New York, USA. ISBN 0-87901-500-4.

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Mattson F.H. and Nolen G.A. (1972). Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171-1176.

Mattson F.H. and Volpenhein R.A., (1972a): Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of rat pancreatic juice. J Lip Res 13, 325-328

Mattson F.H. and Volpenhein R.A., (1972b): Digestion in vitro of erythritol esters by rat pancreatic juice enzymes. J Lip Res 13, 777-782

Mattson F.H. and Volpenhein R.A., (1972c): Rate and extent of absorption of the fatty acids of fully esterified glycerol, erythritol, xylitol, and sucrose as measured in thoracic duct cannulated rats. J Nutr 102, 1177-1180

OECD SIDS (1998): Pentaerythritol, CAS 115-77-5

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

WHO (1998): Safety evaluation of certain food additives and contaminants. Saturated Aliphatic Acyclic Branched-Chain Primary Alcohols, Aldehydes, and Acids. WHO food additives series 40.