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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Justification for grouping of substances


The PFAE Linear (Polyfunctional Aliphatic Ester) category consists of 16 substances, well-defined mono-constituent substances as well as related UVCB substances, respectively with varying fatty alcohol chain lengths and branching. The distinguishing feature of this category of chemicals is that they are diester derivatives of common dicarboxylic acids: namely adipic (C6), azelaic (C9) and sebacic (C10) acids. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched, even and odd numbered alcohols. 

Carboxylic acid esters are generally produced by chemical reaction of an alcohol with an organic acid in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by the transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. The carboxylic acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to the carbonyl carbon of the acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester (Liu et al., 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Diesters are the final products of esterification of alcohols (e.g. octanol) with a dicarboxylic organic acid (e.g. adipic acid).

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substances listed below are allocated to the category of PFAE linear.

List of category members including CAS and molecular weight (range):



Chemical name

Molecular weight

Carbon number in alcohol

Carbon number in acid

Substance type


6938-94-9 (a)

Diisopropyl adipate


C3 iso





Dibutyl adipate







Dihexyl adipate







Diisooctyl adipate


C8 iso




123-79-5 (b)

Dioctyl adipate







Bis(2-ethylhexyl) adipate / DEHA


C8 branched





Hexanedioic acid, di-C7-9-branched and linear alkyl esters


C7-C9 linear and branched





Diisononyl adipate


C9 iso





Bis(tridecyl) adipate







Bis(2-octyldodecyl) adipate


C20 branched





Bis(2-ethylhexyl) azelate


C8 branched





Bis(2-octyldodecyl) azelate


C20 branched





Diisopropyl sebacate


C3 iso





Dibutyl sebacate







Bis(2-ethylhexyl) sebacate


C8 branched





Bis(2-octyldodecyl) sebacate


C20 branched



(a) Category members OR substances subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.


Category specific similarities/trends:

Grouping of substances into this category is based on:

(1) common functional groups: all members of the category PFAE linear are diester derivatives of the common saturated diacids: namely adipic (C6), azelaic (C9) and sebacic (C10) acid. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched alcohols; and

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: all members of the category result from esterification of the alcohol with the respective dicarboxylic acid. Esterification is, in principle, a reversible reaction (hydrolysis). Thus, the fatty alcohol and dicarboxylic acid moieties are simultaneously precursors and breakdown products of the category members. For the purpose of grouping of substances, enzymatic hydrolysis in the gastrointestinal tract and/or liver is identified as the biological process, by which the breakdown of the category members result in structurally similar chemicals (Takahashi et al., 1981). Following hydrolysis, the fatty alcohol is, in general, enzymatically oxidized to the corresponding carboxylic acid, which can be further degraded by β-oxidation. Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids (for further information please see chapter 7.1 of the technical dossier); and

(3) constant pattern in the changing of the potency of the properties across the category: the available data show similarities and trends within the category in regard to (a) physicochemical, (b) environmental fate, ecotoxicological and (c) toxicological properties. For those individual endpoints showing a trend (d), the pattern in the changing of potency is clearly and expectedly related to the carbon chain length of the dicarboxylic acid and the carbon chain length and/or branching of the alcohol.

a) Physicochemical properties:

The molecular weight of the category members ranges from 230 g/mol (CAS 6938-94-9, Diisopropyl adipate) to 763 g/mol (CAS 69275-01-0, Bis(2-octyldodecyl) azelate). Category substances are characterized with low melting points: they are liquid under ambient conditions. All category substances decompose before boiling and they are non-volatile. Calculated vapour pressures exceed 0.01 Pa (at 20 °C) only for two compounds with the lowest molecular weight: Diisopropyl adipate (MW = 230 g/mol, VP = 0.26 Pa) and Dibutyl adipate (MW = 258 g/mol, VP = 0.02 Pa – both experimental and calculated). The same two compounds are soluble in amounts exceeding 10 mg/L (i.e: 180 mg/L and 35 mg/L, respectively). The remaining substances with <10 mg/L are very poorly soluble or insoluble in water. The calculated octanol/water partition coefficient increases with molecular weight accordingly: from log Pow = 3.2 (Diisopropyl adipate) to log Pow = 21.4 (Bis(2-octyldodecyl) azelate).

b) Environmental fate and ecotoxicological properties:

All members of the category are readily biodegradable according to the OECD criteria. Therefore, the category members will not be persistent in the environment. The abiotic degradation via hydrolysis is not considered to be a relevant degradation pathway in the environment. Relatively good water soluble (approximately > 10 mg/L) members of the category exhibit log Kow values < 5. Substances with log Kow < 5 are expected to distribute in the aquatic, sediment and soil compartment. In contrast, substances with log Kow values > 5, will mainly distribute into soil and sediment exclusively. Nevertheless, since all members of the category are readily biodegradable, they will not be persistent in the terrestrial environment. Based on the rapid environmental biodegradation and metabolisation via enzymatic hydrolysis, relevant uptake and bioaccumulation in aquatic organisms is not expected. Enzymatic breakdown will initially lead to the free dicarboxylic acid and the free alcohol. From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (see expert statement on bioaccumulation chapter 5.3 of the technical dossier). This is supported by low calculated BCF values calculated for all category members (BCF < 1 - 29 L/kg ww; BCFBAF v3.01; Arnot-Gobas, including biotransformation, upper trophic).

Based on the experimental data, the majority of category members exhibit no acute or chronic toxicity to aquatic organisms. Only two “water soluble” esters with Adipic acid (C6) as dicarboxylic acid component and short chain alcohols, exhibit toxic or harmful effects (CAS 105-99-7, Dibutyl adipate and CAS 6938-94-9, Diisopropyl adipate). Due to their rapid biodegradability and rapid metabolization, no adverse effects are anticipated in sediment and soil organisms. This assumption is supported by three short term tests to earthworm for Bis(2-ethylhexyl) adipate (CAS 103-23-1), Dibutyl adipate (CAS 105-99-7) and Bis(tridecyl) adipate (CAS 16958-92-2) showing LC50 values above 800 mg/kg soil dw.

c) Toxicological properties:

The toxicological properties show that all category members have similar toxicokinetic behaviour (enzymatic hydrolysis of the ester bond leading to the corresponding dicarboxylic acid and alcohol, then absorption and further metabolism to polar products that are excreted in the urine or exhalation as CO2).  There is consistently low toxicity among the category members which can be explained by the common metabolic fate of all aliphatic diesters, independent of the lengths of the dicarboxylic acid backbone (C6, C9 or C10) or the alcohol side chains (C3 to C20). Thus, considering all available evidence and expert judgement the category members showed no acute oral, dermal or inhalation toxicity, no skin irritation, eye irritation or sensitizing properties, no human hazard for systemic toxicity after repeated oral, inhalative and dermal exposure and are not mutagenic or clastogenic and have shown no relevant reproduction toxicity and have no effect on intrauterine development.

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).


Toxikokinetics, metabolism and distribution:


CAS 6938-94-9

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Diisopropyl adipate (CAS 6938-94-9) 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, 2012), assessment of the toxicokinetic behaviour of the substance Diisopropyl 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 on the PFAE linear category.

Diisopropyl adipate is a diester of two isopropanols and adipic acid and meets the definition of a mono-constituent substance based on the analytical characterization.

Diisopropyl adipate is liquid at room temperature and has a molecular weight of 230.30 g/mol and the water solubility is 180 mg/L at 25 °C (Meylan, 1996). The log Pow is 2.85 (Bargallo, 2011) and the vapour pressure is estimated to be 0.26 Pa at 20 °C (Nagel, 2011).


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, 2012).


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 Diisopropyl adipate is 230.30 g/mol, absorption of the molecule in the gastrointestinal tract is in general anticipated.

Absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski et al., 2001; refined by Ghose et al., 1999) is applied to the substance Diisopropyl adipate, as all rules are fulfilled.

The log Pow of 2.85 suggests that Diisopropyl 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).

Data from an acute oral toxicity study are available. A LD50 > 5000 mg/kg bw was determined in mice (Dufour, 1993).Slight clinical signs directly after administration were observed; thus, oral absorption of the substance is assumed.

After oral ingestion, the members of the PFAE linear category undergo stepwise hydrolysis of the ester bonds by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the dicarboxylic acid is formed. The physico-chemical characteristics of the cleavage 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, 2012). However, also for both cleavage 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 by micellar solubilisation (Ramirez et al., 2001), and for small and water soluble cleavage products by dissolution into the gastrointestinal fluids (IARC, 1987).

Overall, a systemic bioavailability of Diisopropyl adipate and/or the respective cleavage products in humans is considered likely after 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, 2012). As the molecular weight of Diisopropyl adipate is 230.30 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, 2012). As Diisopropyl adipate is not skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculated dermal absorption a value of 0.00200 mg/cm²/event (low) was predicted for Diisopropyl adipate (Danish EPA, 2010). 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. 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 Diisopropyl adipate is 180 mg/L, dermal uptake is possible.

Overall, the calculated low dermal absorption potential, the moderate water solubility, the molecular weight (>100 g/mol), the log Pow and the fact that the substance is not irritating to skin imply that dermal uptake of Diisopropyl adipate in humans is considered possible but limited.


Diisopropyl adipate has a low vapour pressure of 0.26 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 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, 2012). Compounds of moderate lipophilicity with a log Pow between -1 and 4, that are moderately soluble in water, like Diisopropyl adipate, can be absorbed directly across the respiratory tract epithelium by passive diffusion.

Overall, a systemic bioavailability of Diisopropyl adipate in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15μm.


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 log Pow < 3 implies that accumulation of Diisopropyl adipate in adipose tissue is not likely (ECHA, 2012).

However, as further described in the section metabolism below, esters of alcohols and dicarboxylic acids undergo esterase-catalysed hydrolysis, leading to the cleavage products isopropanol and adipic acid.

The log Pow of the first cleavage product isopropanol is 0.05, indicating a high solubility in water. The second cleavage product, adipic acid, has a similar log Pow of 0.08 and is water-soluble, too (HSDB, 2011).Consequently, there is no potential for isopropanol and adipic acid to accumulate in adipose tissue, either. 

This assumption is supported by results from studies performed with the structurally similar substance Bis(2-ethylhexyl) adipate (CAS 103-23-1) indicating no potential for bioaccumulation (Elcombe, 1981; Takahashi et al., 1981).

Overall, the available information indicates that no significant bioaccumulation of the parent substance or the cleavage products in adipose tissue is anticipated.


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).

Diisopropyl adipate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products isopropanol and adipic acid. As both cleavage products are water-soluble and have log Pow values of 0.05 and 0.08, they will be distributed in aqueous compartments of the organism.

As described in the following chapter, the distribution of Bis(2-ethylhexyl) adipate (DEHA, CAS 103-23-1), 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 evident 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 is very rapid and there is no specific organ affinity under these experimental conditions (Takahashi et al., 1981).

Overall, the available information indicates that Diisopropyl adipate and its cleavage products, isopropanol and adipic acid, will be distributed within the organism.


Dicarboxylic acid esters are expected have the same metabolic fate as fatty acid esters. Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012; Lehninger, 1970). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and dicarboxylic acids undergo stepwise enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances that are 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, isopropanol, is oxidized by the non-specific alcohol dehydrogenase (ADH) to acetone, which is either excreted directly or further metabolized, depending on the substance level in the organism. It can be oxidized to hydroxyl-acetone, which is then further metabolized. A minor metabolic pathway was found leading to beta-isopropyl-glucuronide, which is excreted in the urine (glucuronidation) (EFSA, 2010; IARC, 1987; Wiley online library, 2012).

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 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, CAS 103-23-1) are regarded exemplarily. The elimination, distribution and metabolism were assessed in rats according to a protocol similar to OECD Guideline 417 (Takahashi et al., 1981). 14C-DEHA in DMSO was administered to male Wistar rats by oral gavage. Adipic acid was found as main metabolite in urine in 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 to a very less extent. Thus, cleavage of parent substance was shown in vivo within 6 hours into adipic acid (20-30% in urine, 1% in blood, 2-3% in liver) and MEHA to a lesser extent. From these results, it is clear that orally ingested DEHA is rapidly hydrolyzed 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. 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).

Overall, Diisopropyl adipate is hydrolyzed and the cleavage products are metabolized by beta oxidation and/or glucuronidation.


For Diisopropyl adipate, 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. Due to the low molecular weight and the high water solubility, a large proportion of isopropanol is excreted unchanged via exhalation and urinary excretion. Acetone, the metabolism product of isopropanol after enzymatic oxidation, is also excreted via exhaled air (IARC, 1987). Adipic acid can be found unchanged in the urine, too (HSDB, 2011).


Experimental data of the structurally similar DEHA (CAS 103-23-1) are available. In monkeys, large amounts of 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 urine 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 and exhalation as CO2 are the most relevant routes of excretion of the substance itself or its metabolites.

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