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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 Fatty acids, C14-18 and C16-18-unsatd., mixed esters with castor oil, castor oil fatty acids, 2-ethylhexanoic acid and 2,2-bis(hydroxymethyl)-1-butanol (CAS 92113-48-9) 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 theoretical hydrolysis product 2-ethylhexanoic acid.

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

After oral ingestion, esters of the respective polyol and fatty acids will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In the gastrointestinal (GI) tract, metabolism prior to absorption via endogenous enzymes and/or enzymatic activity of the gut 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 (Mattsson and Volpenhein, 1972a). In general, it is assumed that the hydrolysis rate of fatty acid esters with polyols varies in particular depending on the fatty acid chain length and grade of esterification (Mattson and Volpenhein, 1969; Mattson and Volpenhein, 1972a,b). With regard to other polyol esters, a lower rate of enzymatic hydrolysis in the GI tract was observed for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b). In vitro hydrolysis rate of polyol esters (e.g. pentaerythritol esters) 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). Based on this, polyol esters are enzymatically hydrolysed to generate alcohol and the corresponding fatty acids. The esters may show varying rates of enzymatic hydrolysis depending on the number of ester bonds and the alcohol involved.

If hydrolysis occurs, prediction of 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 (trimethylolpropane, 2-ethylhexanoic acid, long-chain fatty acids, and the mixed mono- and diesters) may become relevant. The molecular weight of the trimethylolesters (> 512.75 g/mol) indicates that oral absorption of the parent substance is not favoured. In addition, the low water solubility (< 10 mg/L) and the log Pow of > 2 of the substance indicate that the absorption may be limited by the inability to dissolve into gastrointestinal fluids. However, micellar solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow of > 4 and low water solubility (Aungst and Shen, 1986).

When considering the expected hydrolysis product trimethylolpropane, absorption may occur. Based on the low molecular weight, low log Pow and the high water solubility of this alcohol, the substances may pass through aqueous pores or may be carried through the epithelial barrier by the bulk passage of water.

Furthermore, fatty acids are expected as hydrolysis products resulting from ester hydrolysis. Medium-chain fatty acids (MCFA) are readily absorbed from the small intestine directly into the bloodstream and transported to the liver for hepatic metabolism, while long-chain fatty acids (LCFA) are less readily absorbed, are incorporated into chylomicrons and enter the lymphatic system (Stryer, 1994). Branched short-chain fatty acids, such as 2-ethylhexanoic acid (molecular weight 144.21 g/mol; water solubility approximately 2 g/L; log Pow of approximately 2.7) are well absorbed 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 in welcher Spezies? (EPA, 1986).

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Fatty acids, C14-18 and C16-18-unsatd., mixed esters with castor oil, castor oil fatty acids, 2-ethylhexanoic acid and 2,2-bis(hydroxymethyl)-1-butanol. On the basis of the following considerations, the dermal absorption of Fatty acids, C14-18 and C16-18-unsatd., mixed esters with castor oil, castor oil fatty acids, 2-ethylhexanoic acid and 2,2-bis(hydroxymethyl)-1-butanol is considered to be low. Regarding the molecular weight of > 512.75 g/mol and the octanol/water partition coefficient of >2 in combination with the low water solubility, a low dermal absorption rate is anticipated based on expert judgement.

The hazard assessment of the hydrolysis products via the dermal route is secondary, as low hydrolysis of Fatty acids, C14-18 and C16-18-unsatd., mixed esters with castor oil, castor oil fatty acids, 2-ethylhexanoic acid and 2,2-bis(hydroxymethyl)-1-butanol in the skin is assumed. Similarly, this principle can also be applied to all analogue substances used for assessment of human health, as their physico-chemical properties will determine their hazard assessment.

Inhalation

The test substance has a very low vapour pressure of < 0.18 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 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 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 the test substance reaches the alveolar region. 

Therefore, inhalative absorption of the test substance is considered to be not higher than through the intestinal epithelium, but still likely to happen.

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).

Polyols such as Trimethylolpropane or Pentaerythritol are very polar (log Kow <0), thus being distributed mainly within the water compartment and do not accumulate in the body but are readily excreted via urine. Alternatively, one or several hydroxyl groups can be oxidized to a carboxylic acid moiety prior to urinary excretion.

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).

Metabolism and excretion

The fatty acids as cleavage products are stepwise degraded via beta–oxidation in the mitochondria. Even numbered fatty acids are degraded via beta-oxidation to carbon dioxide and acetyl-CoA, with release of biochemical energy. The metabolism of the odd numbered 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, 1994). The alternative pathways of alpha- and omega-oxidation can be found in the liver and the brain, respectively (CIR, 1987).

Polyol alcohols (e.g. TMP) 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).

The polyols are readily excreted via urine either unchanged or after one or several hydroxyl groups are oxidized to a carboxylic acid moiety.

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). 

In all 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 (BG Chemie, 2000).

 

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