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Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Absorption: Likely after oral and inhalatory exposure, unlikely via the dermal route

Distribution: Wide distribution of bis(1-methylheptyl) adipate and its hydrolysis products is anticipated

Metabolism: Hydrolyisis to 2-octanol and adipic acid is expected

Excretion: Renal excretion after glucuronidation and exhalation as CO2

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of bis(1-methylheptyl) adipate (CAS 108-63-4) has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No. 1907/2006 and with the Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the substance 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 the Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on adequate analogue substances.

Bis(1-methylheptyl) adipate is a diester of two moles 2-octanol and one mole adipic acid (hexanedioic acid) and meets the definition of a mono-constituent substance based on the analytical characterisation. It is liquid at room temperature and has a molecular weight of 370.57 g/mol and a water solubility of 0.0042 mg/L at 20 °C, pH ca. 5.9 (OECD Guideline 105 adapted to slow stirring method based on OECD Guideline 123). The log Pow is > 8 at ca. 20 °C (Weight of Evidence: EU Method A.8, estimation method (solubility ratio) + (Q)SAR) and the vapour pressure is 8.4E-4 Pa at 25 °C (EU Method A.4, effusion method: Knudsen cell).


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, 2017).


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, 2017). As the molecular weight of bis(1-methylheptyl) adipate is 370.57 g/mol, absorption of the molecule in the gastro-intestinal tract is in general anticipated. Absorption after oral administration of bis(1-methylheptyl) adipate is also expected when the “Lipinski Rule of Five” (Lipinski et al., 2001; Ghose et al., 1999) is applied. Except for the log Pow, which is above the optimal range of -0.4 to 5.6, all rules are fulfilled.

The log Pow of > 8 suggests that bis(1-methylheptyl) adipate is favourable for 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).

After oral ingestion, bis(1-methylheptyl) adipate undergoes stepwise hydrolysis of the ester bonds by gastro-intestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the dicarboxylic acid is formed. The physico-chemical characteristics of the hydrolysis products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) are likely to 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, 2017). However, also for both hydrolysis products, it is anticipated that they are absorbed in the gastro-intestinal tract. In case of long carbon chains and thus rather low water solubility this will happen by micellar solubilisation (Ramirez et al., 2001), and for small and water soluble hydrolysis products this will happen by dissolution into the gastro-intestinal fluids. Substances with a molecular weight below 200 may even pass through aqueous pores (ECHA, 2017).

Overall, a high systemic bioavailability of bis(1-methylheptyl) adipate and/or the respective hydrolysis products in humans is considered likely following oral uptake of the substance.


The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2017). As the molecular weight of bis(1-methylheptyl) adipate is 370.57 g/mol, dermal absorption of the molecule cannot be excluded.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). As bis(1-methylheptyl) adipate is not expected to be skin irritating based on reliable data from adequate analogue substances, enhanced penetration of the substance due to local skin damage is not expected.

Based on a QSAR calculated dermal absorption a value of 0.0855 mg/cm²/event (low) was predicted for bis(1-methylheptyl) adipate (Dermwin version 2.02). Based on this value the substance has a 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, 2017). As the water solubility of bis(1-methylheptyl) adipate is 0.0042 mg/L, dermal uptake is likely to be low.

Overall, the calculated low dermal absorption potential, the water solubility, the molecular weight (> 100 g/mol) and the high log Pow value indicate that dermal uptake of bis(1-methylheptyl) adipate in humans is considered unlikely.


Bis(1-methylheptyl) adipate has a low vapour pressure of 8.4E-4 Pa at 25 °C and therefore 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 (ECHA, 2017). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of absorbed bis(1-methylheptyl) adipate in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15μm. Following the worst-case approach the absorption rate via the inhalation route is assumed to be as high as via the oral route.


Highly lipophilic substances tend in general 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 > 8 implies that bis(1-methylheptyl) adipate may have the potential to accumulate in adipose tissue (ECHA, 2017).

However, as further described in the section regarding metabolism below, esters of fatty alcohols and dicarboxylic acids undergo esterase-catalysed hydrolysis, leading for bis(1-methylheptyl) adipate to the formation of 2-octanol and adipic acid. The first hydrolysis product, 2-octanol, has a log Pow of 2.73 and a water solubility of 1.12 g/L (Danish QSAR Database, 2019). The second hydrolysis product, adipic acid, has a log Pow of 0.08 and is water-soluble. Consequently, there is no potential for 2-octanol and adipic acid to accumulate in adipose tissue. This assumption is supported by results from studies performed with the structurally similar substance bis(2-ethylhexyl) adipate (DEHA) indicating no potential for bioaccumulation (Elcombe, 1981; Takahashi et al., 1981).

Overall, the available information indicates that no significant bioaccumulation in adipose tissue is anticipated.


Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and the 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 its extracellular concentration particularly in fatty tissues (ECHA, 2017).

Bis(1-methylheptyl) adipate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the hydrolysis products 2-octanol and adipic acid. 2-octanol, a rather small (MW = 130.23 g/mol) substance of moderate water solubility, will be distributed in aqueous compartments of the organism and may also enter different tissues. Adipic acid is will be distributed in aqueous compartments of the organism.

As also described in the following section on metabolism, the distribution of bis(2-ethylhexyl) adipate (DEHA), a structurally similar substance, was assessed in rats treated with the radioactive labelled substance. Relatively high levels of radioactivity appeared in the liver, kidney, blood, muscle and adipose tissue apart from the stomach and intestine. All other tissues contained very little residual radioactivity. In liver, kidney, testicle and muscle, the amount of residual radioactivity reached a maximum in the first 6 - 12 h and reduced to less than 50% at 24 h. In other tissues the radioactivity declined with time after 6 h. The blood contained about 1% of the radioactivity after 6 - 12 h and then decreased to undetectable levels by the end of 2 days. It was also shown that total radioactivity in the tissues examined was about 10% after 24 h of dosing and it decreased to about 2% and 0.5% after 48 h and 96 h, respectively. From these results, it can be concluded that the elimination of radioactivity from tissues and organs was rapid and there was no specific organ affinity under these experimental conditions (Takahashi et al., 1981).

Overall, the available information indicates that bis(1-methylheptyl) adipate and its hydrolysis products, 2-octanol and adipic acid, will be distributed within the organism.


Dicarboxylic acid esters are expected to have the same metabolic fate as fatty acid esters. Esters of fatty acids are hydrolysed to the corresponding alcohol and carboxylic acid by esterases (Fukami and Yokoi, 2012; Lehninger, 199). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism. After oral ingestion, esters of fatty alcohols and dicarboxylic acids undergo stepwise enzymatic hydrolysis already in the gastro-intestinal 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 generally take place.

In the first step of hydrolysis, the monoester is produced that is further hydrolysed to the fatty alcohol and the dicarboxylic acid. The first hydrolysis product, 2-octanol, will undergo one of two general reactions in vivo, namely oxidation to carboxylic acid and direct conjugation with glucuronic acid (HSDB, 2019). The second hydrolysis product, adipic acid, is metabolised by beta-oxidation to succinic and acetic acid and further metabolites (HSDB, 2019). 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 off as acyl-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).

Experimental data of the structurally similar bis(2-ethylhexyl) adipate (DEHA) are considered to be relevant to bis(1-methylheptyl) adipate as well. The elimination, distribution and metabolism were assessed in rats according to a protocol similar to OECD guideline 417 (Takahashi, 1981). 14C-DEHA (labelled at the carbonyl carbon of the adipic acid) in DMSO was administered to male Wistar rats by oral gavage. Adipic acid was found as the main metabolite in urine within a short time and its excretion reached 20 - 30% of the administered dose within 6 h. In blood it was found at 1% and in liver at 2 - 3%; mono-2-ethylhexyl adipate (MEHA) was the second metabolite found, but at a very low concentration. Thus, hydrolysis of the parent substance DEHA was shown to occur in vivo within 6 hours into adipic acid (20 - 30% in urine, 1% in blood, 2  -3% in liver) and into MEHA to a lesser extent. From these results, it is clear that orally ingested DEHA is rapidly hydrolysed to MEHA and adipic acid which is the main intermediate metabolite.

In vitro, DEHA was hydrolysed to MEHA and adipic acid by tissue preparations from liver, pancreas and small intestine. When testing MEHA, the monoester was more rapidly hydrolysed to adipic acid than DEHA by these preparations, and the intestinal preparation was the most active one among them (Takahashi et al., 1981).

In another in vivo study in rats and mice, 2-ethylhexanoic acid (EHA), 2-ethyl-5-hydroxyhexanoic acid and 2-ethylhexan-1,6-dioic acid and their glucuronides were found in urine after administration of DEHA (labelled at the side chain). In monkey, however, large amounts of MEHA-glucuronide and 2-ethylhexanol glucuronide were excreted and only a very small proportion of the dose was converted to EHA and other downstream metabolites (Elcombe, 1981). A similar metabolic fate is anticipated in humans.

The metabolism of bis(1-methylheptyl) adipate is expected to follow the same pathways as those shown for DEHA. Overall, bis(1-methylheptyl) adipate is hydrolysed and the hydrolysis products are metabolised by beta-oxidation and/or glucuronidation.


For bis(1-methylheptyl) adipate and its hydrolysis products, the main routes of excretion are expected to be via expired air as CO2 after metabolic degradation (beta-oxidation) and by renal excretion via the urine. Adipic acid can also be found unchanged in the urine due to the low molecular weight and the high water solubility (HSDB, 2019).

Experimental data of the structurally similar bis(2-ethylhexyl) adipate (DEHA) are available. In monkeys, large amounts of mono-2-ethylhexyl adipate (MEHA)-glucuronide and 2-ethylhexanol-glucuronide were detected in urine (Elcombe, 1981). In in vivo and in vitro studies with DEHA, adipic acid was found as main metabolite in a short time and its excretion reached 20 - 30% of the administered dose within 6 h. In rats, excretion within 24 h amounted to 86% of the administered dose and almost all the dose was excreted in 48 h. The greater part of the excretion was recovered in breath and urine; excretion in faeces was small (Takahashi et al., 1981).

Thus, renal excretion after glucuronidation and exhalation as CO2 are the most relevant routes of excretion of bis(1-methylheptyl) adipate and its metabolites.


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