Bis(2-(2-butoxyethoxy)ethyl) adipate

Endpoint summary

Description of key information

No in vivo studies available, investigating the toxicokinetic behaviour of Bis(2-(2-butoxyethoxy)ethyl) adipate (CAS 141-17-3). One in vitro study is available, showing rapid hydrolysis of of Bis(2-(2-butoxyethoxy)ethyl) adipate in intestinal fluid simulants under formation of 2-(2-n-Butoxyethoxy)ethanol (CAS 112-34-5) and Adipic acid (124-04-9). Based on molecular structure, molecular weight, water solubility and octanol-water partition coefficient, absorption via the oral and inhalation routes is likely. In contrast, absorption via the dermal route is considered possible but limited. Distribution of the metabolites in the body is wide, and elimination via the renal pathway and exhalation in form of CO2 are considered to be the predominant routes of excretion. Bioaccumulation in adipose tissue is not anticipated.

Additional information

There are no in vivo studies available, in which the toxicokinetic behaviour of bis(2-(2-butoxyethoxy)ethyl) adipate (CAS 141-17-3) has been investigated. One in vitro study is available, which investigates the hydrolysis of bis(2-(2-butoxyethoxy)ethyl) adipate in intestinal fluid simulants as described in the EFSA guidelines ‘Note for Guidance for Food Contact Materials’ (Oßberger, 2013).

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, 2012), assessment of the toxicokinetic behaviour of the substance Bis(2-(2-butoxyethoxy)ethyl) adipate 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, 2012) and taking into account further available information.

Bis(2-(2-butoxyethoxy)ethyl) adipate is a diester of two 2-(2-Butoxyethoxy)ethanol (CAS 112-34-5) and adipic acid and meets the definition of a monoconsituent substance based on the analytical characterisation.

Bis(2-(2-butoxyethoxy)ethyl) adipate is liquid at room temperature and has a molecular weight of 434.45 g/mol and a water solubility of 0.57 mg/L (Frischmann, 2012).The octanol/water partition coefficient (log Pow) value was calculated to be 3.24 (Hopp, 2011) and the vapour pressure is estimated to be < 0.0001 Pa at 20 °C (Nagel, 2011).

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 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 favourable for oral absorption (ECHA, 2012). As the molecular weight of bis(2-(2-butoxyethoxy)ethyl) adipate is 434.45 g/mol, absorption of the molecule in the gastrointestinal tract after oral intake is in general anticipated. Absorption after oral administration of bis(2-(2-butoxyethoxy)ethyl) adipate is also expected when the “Lipinski Rule of Five” (Lipinski et al. 2001; Ghose et al. 1999) is applied to the substance. Except for the total number of atoms that exceeds the given range of 20 - 70, all rules are fulfilled. The log Pow of 3.24 suggests that bis(2-(2-butoxyethoxy)ethyl) adipate is favourable for absorption by passive diffusion, as this mechanism is of importance for substances with a moderate log Pow between -1 and 4, unless they are not very hydrophilic (> 10000 mg/L) (ECHA, 2012).

After oral ingestion bis(2-(2-butoxyethoxy)ethyl) adipate undergoes hydrolysis of the ester bonds by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972).In vitro data are available, showing that about 97% of bis(2-(2-butoxyethoxy)ethyl) adipate are hydrolysed within one hour, whereas recovery experiments even indicate a far quicker hydrolysis (Oßberger, 2013). During hydrolysis, two equivalents of the alcohol 2-(2-n-butoxyethoxy) ethanol (CAS 112-34-5) and one equivalent of the dicarboxylic acid adipic acid (CAS 124-04-9) are released. The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) are 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). However, also for both cleavage products, it is anticipated that they are absorbed in the gastrointestinal tract. Since the cleavage products are small in size and water soluble, absorption by dissolution into the gastrointestinal fluids is anticipated. Substances with a molecular weight below 200 g/mol may even pass through aqueous pores (ECHA, 2012). Overall, a systemic bioavailability of bis(2-(2-butoxyethoxy)ethyl) adipate and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

Dermal:

Dermal absorption of the molecule cannot be excluded as the molecular weight of bis(2-(2-butoxyethoxy)ethyl) adipate is 434.45 g/mol. Based on a QSAR calculated dermal absorption, a value of 0.00002 mg/cm²/event was predicted for bis(2-(2-butoxyethoxy)ethyl) adipate (Danish EPA, 2010). Based on this value the substance has a low potential for dermal absorption. For substances with a log Pow between 1 and 4, dermal absorption is favoured, if the substance is sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of bis(2-(2-butoxyethoxy)ethyl) adipate is 0.57 mg/L and the log Pow is 3.24, dermal uptake is likely to be low. Overall, the calculated low dermal absorption potential, the moderate water solubility, the molecular weight (> 100), the log Pow and the fact that the substance is not irritating to skin imply that dermal uptake of bis(2-(2-butoxyethoxy)ethyl) adipate in humans is possible but considered to be limited.         

Inhalation:

Bis(2-(2-butoxyethoxy)ethyl) adipate has a low vapour pressure of < 0.0001 Pa at 20 °C thus being of very 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 considered negligible. 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. Compounds of moderate lipophilicity with a log Pow between -1 and 4, that are moderately soluble in water, like bis(2-(2-butoxyethoxy)ethyl) adipate, can be absorbed directly across the respiratory tract epithelium by passive diffusion (ECHA, 2012). Overall, a systemic bioavailability of bis(2-(2-butoxyethoxy)ethyl) adipate in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm.

Accumulation

Lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. As bis(2-(2-butoxyethoxy)ethyl) adipate has a log Pow value of 3.24, accumulation in adipose tissue is not likely but cannot be excluded in case of continuous exposure. However, as shown in the available in vitro test and further discussed in the metabolism section below, bis(2-(2-butoxyethoxy)ethyl) adipate undergoes esterase-catalysed hydrolysis, resulting in the cleavage products 2-(2-n-butoxyethoxy) ethanol and adipic acid. Thus, accumulation potential of the cleavage products is regarded to be of more relevance than that of the parent substance. The log Pow of the first cleavage product 2-(2-n-butoxyethoxy) ethanol is 0.56, indicating a high solubility in water (HSDB, 2011). The second cleavage product, adipic acid, has log Pow of 0.08 and is very water-soluble, too. Consequently, there is no potential for 2-(2-n-Butoxyethoxy) ethanol and adipic acid to accumulate in adipose tissue. Overall, the available information indicates that distribution of the cleavage products in various body tissues occurs but no significant bioaccumulation of the parent substance in adipose tissue is 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).

Bis(2-(2-butoxyethoxy)ethyl) adipate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products 2-(2-n-Butoxyethoxy)ethanol and Adipic acid. As both cleavage products are water-soluble and have log Pow values of 0.56 and 0.08, they will be distributed in aqueous compartments of the organism.

Overall, the available information indicates that the cleavage products, 2-(2-n-Butoxyethoxy)ethanol and Adipic acid will be distributed in the organism.

Metabolism

The available in vitro study investigates the hydrolysis of bis(2-(2-butoxyethoxy)ethyl) adipate in intestinal fluid simulants as described in the EFSA guidelines ‘Note for Guidance for Food Contact Materials’ (EFSA, 2008; Oßberger, 2013). The data indicate that after oral ingestion, bis(2-(2-butoxyethoxy)ethyl) adipate undergoes hydrolysis of the ester bonds by gastrointestinal enzymes. The results show that about 97% of bis(2-(2-butoxyethoxy)ethyl) adipate are hydrolysed within one hour, whereas recovery experiments even indicate a far quicker hydrolysis. The experimental result is consistent with the data published by Fukami and Yokoi (2012) which demonstrates that esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid by esterases. 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 stepwise enzymatic hydrolysis already in the gastrointestinal fluids. In contrast, substances 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. In the first step of hydrolysis, the monoester is produced that is further hydrolysed to the alcohol and the dicarboxylic acid. The first cleavage product, 2-(2-n-butoxyethoxy) ethanol is oxidized by the non-specific alcohol dehydrogenase (ADH) and then further metabolized (HSDB, 2011). Metabolism of alkylglycol ethers takes place predominantly in the liver where mixed function oxidase cleave the ether linkage, yielding alkylglycol and the alcohol. These two byproducts may be consumed in intermediary metabolism to CO2 and water (OECD SIDS, 2006). Data obtained from a subchronic repeated dose toxicity study with rats indicate increased liver metabolism after administration of 2-(2-n-butoxyethoxy) ethanol in drinking water (Johnson et al., 2005). At study termination, rats given 1000 mg/kg bw/day showed increased liver metabolic enzyme activation, including the hepatic Phase II enzyme UDP-glucuronosyltransferase (UGT) together with increased relative liver weights. The second cleavage product, adipic acid, is metabolized by beta-oxidation to succinic and acetic acid and further metabolites (HSDB, 2011). Beta-oxidation is the degradation pathway of fatty acids based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acetyl-CoA, the entry molecule for the citric acid cycle. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987). Details of adipic acid metabolism in the rat was reported by Rusoff et al. (1960). Radioactively labelled adipic acid was fed to fasted rats, and the metabolites detected in the urine were analysed as urea, glutamic acid, lactic acid, β-ketoadipic acid, and citric acid, as well as adipic acid. Results from this study also indicate that adipic acid is metabolised by beta-oxidation. Overall, bis(2-(2-butoxyethoxy)ethyl) adipate is hydrolyzed and the cleavage products are metabolized by beta oxidation and/or glucuronidation.

Excretion

For bis(2-(2-butoxyethoxy)ethyl) adipate, the main route of excretion is expected to be via expired air as CO2 after metabolic degradation (beta-oxidation) and via biliary excretion with the faeces. The metabolism products of bis(2-(2-butoxyethoxy)ethyl) adipate that are produced predominantly in the liver may be consumed in intermediary metabolism to CO2 and water, with the latter ultimately being excreted in expired air. Alternatively, the alcohol (or intermediate metabolite) may be conjugated in the liver with glucuronic acid, sulfate, or glutathione for ultimate excretion, predominantly in the urine (OECD SIDS, 2006). Beside excretion after metabolic degradation, adipic acid also can be found unchanged in the urine (Rusoff et al., 1960, HSDB, 2011). Data obtained from a subchronic repeated dose toxicity study with 2-(2-n-butoxyethoxy) ethanol in rats revealed increased relative and absolute kidney weights in the high dose group (1000 mg/kg bw/day), indicating the importance of the renal pathway (Johnson et al., 2005). Thus, renal excretion after glucuronidation and exhalation as CO2 are the most relevant routes of excretion of the substance itself or its metabolites.

 

References:

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* Danish EPA (2010). Danish (Q)SAR Database Report powered by OASIS Database.http://130.226.165.14/index.html

* ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

* Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

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* Mattson F.H. and Volpenhein R.A., 1972: 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

*OECD SIDS (2006):SIDS Initial Assessment Profile:Long Chain Alcohols (C6-22 primary aliphatic alcohols)

http://webnet.oecd.org/hpv/UI/handler.axd?id=03441f78-d135-4cab-b832-edfb1d0d677e

* Rusoff, II et al. (1960). Intermediary metabolism of adipic acid. Toxicol. Appl. Pharmacol. 2:316-330