Reaction mass of 2,2-bis(hydroxymethyl)propane-1,3-diyl bis(2-ethylhexanoate) and 3-[(2-ethylhexanoyl)oxy]-2-{[(2-ethylhexanoyl)oxy]methyl}-2-(hydroxymethyl)propyl 2-ethylhexanoate and 3-[(2-ethylhexanoyl)oxy]-2,2-bis{[(2-ethylhexanoyl)oxy]methyl}propyl 2-ethylhexanoate

Endpoint summary

Description of key information

Absorption of pentaerythritol esters with 2-ethylhexanoic acid (CAS No. former 7299-99-2) may be the highest after oral exposure, but may be limited at all due to the low water solubility. After enzymatic hydrolysis, the hydrolysis products may be absorbed and well distributed within the body. Alcohol hydrolysis products are incorporated in standard metabolic pathways. 2-Ethylhexanoic acid may be metabolised by omega and omega-1 oxidation or by glucuronidation and following renal excretion.

Additional information

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 behaviour of the substance Multi constituent ester of pentaerythritol 2-ethylhexanoate (CAS No. former 7299-99-2) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies evaluating the toxicokinetic properties of the substance available. Some information is available for the hydrolysis products ethylhexanoic acid and pentaerythritol.

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) 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

When assessing the potential of Multi constituent ester of pentaerythritol 2-ethylhexanoate to be absorbed in the gastrointestinal (GI) tract, it has to be considered that carboxylic acid esters will undergo enzymatic hydrolysis by ubiquitous expressed GI esterases (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). The rate of hydrolysis is dependent on the structure of the ester, and may therefore be rapid or rather slow.

Thus, due to hydrolysis predictions on oral absorption based on the physico-chemical characteristics of the intact parent substance alone may no longer apply. Instead, the physico-chemical characteristics of the breakdown products of the ester (pentaerythritol and the carboxylic acid 2-ethylhexanoic acid and the mono-, di-, triesters) may become relevant. The molecular weight range of Multi constituent ester of pentaerythritol 2-ethylhexanoate (388.6-640.9 g/mol) indicates that oral absorption is favoured or is at least possible. In contrast, the low water solubility (< 0.05 mg/L) and the range of log Pow values of the multiconstituent compound (diester: 4.99; triester: 8.46; tetraester: 12.34) indicate that the absorption may be limited by the inability to dissolve into GI fluids. However, micellar solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986).

When considering the hydrolysis product pentaerythritol, absorption may occur. The molecular weight of 136.15 g/mol, log Pow of -1.7, and the water solubility of 62 g/L indicate that the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Passive diffusion is not favoured due to the log Pow of -1.7, but cannot be excluded.

The other hydrolysis product 2-ethylhexanoic acid (molecular weight 144.21 g/mol; water solubility approximately 2 g/L; log Pow approximately 2.7) is absorbed well via the gastrointestinal tract. Peak plasma concentrations of 85.1 µg 2-ethylhexanoic acid equivalents per g blood were reached after 18.8 min following oral administration of 100 mg/kg bw of 2-ethylhexanoic acid (EPA, 1986).

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Multi constituent ester of pentaerythritol 2-ethylhexanoate. On the basis of the following considerations, the dermal absorption of Multi constituent ester of pentaerythritol 2-ethylhexanoate is considered to be low. Regarding the molecular weight range of 388.6-640.9 g/mol and the range of octanol/water partition coefficient of 4.99 – 12.34 in combination with the low water solubility, a low dermal absorption rate is anticipated. With log Pow values above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6, will slow the rate of transfer between the stratum corneum and the epidermis and therefore absorption across the skin will be limited and uptake into the stratum corneum itself is slow. 

The hazard assessment of the hydrolysis products via the dermal route is secondary, as low hydrolysis of Multi constituent ester of pentaerythritol 2-ethylhexanoate in the skin is anticipated.  

Inhalation

Multi constituent ester of pentaerythritol 2-ethylhexanoate has a very low vapour pressure of <0.0001 Pa at 20 °C (calculated) 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 significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated 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).

As discussed above, absorption after oral administration of Multi constituent ester of pentaerythritol 2-ethylhexanoate may mainly be driven by enzymatic hydrolysis of the ester bond to the respective metabolites and subsequent absorption of the breakdown products. As the presence of esterases and lipases in the mucus lining fluid of the respiratory tract is expected to be lower in comparison to the gastrointestinal tract, absorption of the hydrolysis products in the respiratory tract is considered to be less effective than in the gastrointestinal tract. Nevertheless, absorption of the parent substance itself cannot be excluded if Multi constituent ester of pentaerythritol 2-ethylhexanoate reaches the alveolar region. 

Therefore, inhalative absorption of Multi constituent ester of pentaerythritol 2-ethylhexanoate is considered to be not higher than through the intestinal epithelium, but still likely to happen.

In an acute inhalation study with an analogue substance fatty acids, C5-10, esters with pentaerythritol             , rats were exposed to 5 mg/L test substance for 4 h (Parr-Dobrzanski, 1994). No mortality and no clinical signs were observed that could be related to systemic toxicity.

Distribution and accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. 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).

As the parent compound Multi constituent ester of pentaerythritol 2-ethylhexanoate is likely to be hydrolysed before absorption as discussed above, the distribution of intact Multi constituent ester of pentaerythritol 2-ethylhexanoate is not relevant but rather the distribution of the breakdown products of hydrolysis. The absorbed products of hydrolysis, pentaerythritol and its mono-, di-, and trimester, and 2-ethylhexanoic acid can all be distributed within the body.

The distribution of free ethyl hexanoic acid was monitored following intraperitoneal administration to male Balb/C mice and male Wistar rats. In the mouse most of the radioactivity was detected in the kidneys, the liver, and the gastrointestinal tract 30 minutes after administration. At one hour small amounts were observed in the salivary gland, skin, and olfactory bulb. In the rat the highest levels were found in the blood, liver and kidneys. Small amounts were observed in the brain (BG Chemie, 2000).

In summary, the available information on Multi constituent ester of pentaerythritol 2-ethylhexanoate indicates that no significant bioaccumulation of the parent substance in adipose tissue is expected.

Metabolism

Metabolism of Multi constituent ester of pentaerythritol 2-ethylhexanoate may occur initially via enzymatic hydrolysis of the ester bonds resulting in 2-ethylhexanoic acid, pentaerythritol and/or pentaerythritol mono-, di-, and triester.

2-Ethylhexanoic acid metabolism was found to take place via conjugation with glucuronic acid as well as cytochrome P-450-dependent omega and omega-1 oxidation. The major urinary metabolites identified were the glucuronide of 2-ethylhexanoic acid as well as 2-ethyl-1,6-hexanedioic acid, 6-hydroxy-2-ethylhexanoic acid and their respective glucuronides. With increasing single dose the fraction of glucuronidated 2-ethylhexanoic acid increased while the percentage of cytochrome P-450 dependent, more highly oxidized metabolites decreased (BG Chemie, 2000).

Polyol alcohols are - due to their physico-chemical properties (low molecular weight, low log Pow, and solubility in water) - easily absorbed and can either remain unchanged or are expected to be further metabolized or conjugated (e.g. glucuronides, sulfates, etc.) into polar products that are excreted via urine (Di Carlo et al., 1965; Bevan, 2001; Bisesi, 2001). For pentaerythritol no further metabolism is expected.

Excretion

In all available studies with 2-ethylhexanoic acid, irrespective of the route of administration employed, the radioactivity was predominantly excreted in the urine and faeces within 24 h, with half-lives of elimination ranging from 4.2 to 6.8 h.

Pentaerythritol is readily excreted unchanged via urine (Di Carlo et al., 1965; Bevan, 2001; Bisesi, 2001).