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EC number: 272-945-9 | CAS number: 68921-53-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Key value for chemical safety assessment
- Bioaccumulation potential:
- low bioaccumulation potential
Additional information
Justification for grouping of substances and read-across
The PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of six members, which are either well-defined mono-constituent substances or related UVCB substances, with varying fatty alcohol chain lengths. The distinguishing feature of this category of chemicals is that its members are diester derivatives of fumaric acid (CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally falls in the C8-C22 carbon number range, including linear, even numbered alcohols. The available studies providing information on the human health hazard assessment within the PFAE fumarates category were conducted with the category member Didodecyl fumarate (CAS 2402-58-6). This substance was selected for testing, because it represents the category member with the shortest fatty alcohol side chain, and consequently with the lowest molecular weight, which is regarded as worst-case approach in terms of hazard assessment of the PFAE fumarates for the local as well as for systemic effects.
The category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This supporting chemical is used to cover toxicological endpoints, exclusively. The read across of Bis(2-ethylhexyl) adipate (CAS 103-23-1) to the PFAE fumarate category is justified due to their similar structural and physico-chemical properties, as well as their toxicological, ecotoxicological profiles.
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 reaction products of esterification of alcohols (e.g. dodecanol) with a dicarboxylic organic acid (i.e. fumaric 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 fumarates.
List of category members of the PFAE fumarates including CAS number and molecular weight (range):
ID# |
CAS |
Chemical name |
Molecular weight [g/mol] |
Carbon number of alcohol moiety |
Carbon number in acid |
Substance type |
1 |
2402-58-6 (a) |
Didodecyl fumarate |
452.72 |
C12 |
C4 unsatd. |
M |
2 |
10341-03-4 |
Ditetradecyl fumarate |
508.82 |
C14 |
C4 unsatd. |
M |
3 |
68610-90-2 |
2-Butenedioic acid (E)-, di-C8-18-alkyl esters |
340.50 - 621.03 |
C8-18 |
C4 unsatd. |
UVCB |
4 |
68921-51-7 |
2-Butenedioic acid (E)-, di-C12-18-alkyl esters |
452.71 - 621.03 |
C12-C18 |
C4 unsatd. |
UVCB |
5 |
68921-52-8 |
2-Butenedioic acid (E)-, di-C16-18-alkyl esters |
564.92 - 621.03 |
C16; C18 |
C4 unsatd. |
UVCB |
6 |
68921-53-9 |
2-Butenedioic acid (E)-, di-C18-22-alkyl esters |
621.03; 733.24 |
C18-C22 |
C4 unsatd. |
UVCB |
7 |
103-23-1 (b) |
Bis(2-ethylhexyl) adipate (DEHA) |
370.64 |
C8 branched |
C6 |
M |
M = Mono-constituent substance
(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.
(b) Analogue substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category. These substances are not subject to the REACh Phase-in registration deadline of 31 May 2013 and 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 fumarates and the supporting chemical are esters with the ester group being the common functional group of all substances. The substances are diesters of fumaric acid with varying linear alcohol moieties (carbon chain lengths C8-C22, even numbered). The supporting chemical, Bis(2-ethylhexyl)adipate is a diester of adipic acid with a C8 alcohol moiety; 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 fumaric acid (or adipic acid for Bis(2-ethylhexyl) adipate). Esterification is, in principle, a reversible reaction (hydrolysis). Thus, the fatty alcohol and fumaric 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 results in structurally similar chemicals. Following hydrolysis, the fatty alcohol is, in general, enzymatically oxidized to the corresponding carboxylic acid, which can be further degraded by β-oxidation, the second cleavage product fumaric acid is , as it is also an endogenous metabolite, incorporated into the citric acid cycle and rapidly degraded to CO2 (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, 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 of the alcohol.
a) Physicochemical properties:
The molecular weight of the category members ranges from 340.50 (C8 component of 2-Butenedioic acid (E)-, di-C8-18-alkyl esters) to 733.24 (C22 component of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters) g/mol. PFAE fumarates are pasty solids with melting points in the range from 32 °C (C8-18 diester) to 70 °C (C18-22 diester). All category substances decompose before boiling. For all substances the calculated vapour pressure is < 0.0001 Pa (at 20 °C) (SPARC v4.6). The substances are very poorly soluble or insoluble, i.e. their solubility is < 0.15 mg/L. Octanol/water partition coefficient (calculated with KOWWIN v1.68) increases with molecular weight: from 8.09 (C8 component of 2-Butenedioic acid (E)-, di-C8-18-alkyl esters) to ca. 22 (C22 component of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters). The analogue substance bis(2-ethylhexyl) adipate (CAS 103-23-1; DEHA) has a molecular weight of 370.64 g/mol and is a liquid due to the branching of the fatty alcohol. The boiling point of this analogue substance is given with 214 °C at reduced pressure which makes decomposition before boiling probable at normal pressure. The log Pow of DEHA is 8.12 (calculated with KOWWIN v1.68), the vapour pressure is low (< 0.001 Pa at 20 °C). The water solubility of the analogue substance is also low (0.0032 mg/L).
b) Environmental fate and ecotoxicological properties:
All members of the category are readily biodegradable according to OECD criteria or readily but failing 10-day window. 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. All substances exhibit log Kow values > 8 (the majority even > 10). Thus they will mainly distribute into soil and sediment. Nevertheless, since all members of the category are rapidly biodegradable, they will not be persistent in the sediment and the terrestrial environment. Based on the rapid environmental biodegradation and metabolism via enzymatic hydrolysis, relevant uptake and bioaccumulation in aquatic organisms is not expected. Enzymatic breakdown will initially lead to the free fumaric acid and the free fatty alcohol. From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (for further information please see chapter 5.3 of the technical dossier). This is supported by low calculated BCF values for all category members (BCF < 10 L/kg wet weight; BCFBAF v3.01; Arnot-Gobas, including biotransformation, upper trophic).
Based on the experimental data, all category members exhibit no acute and chronic toxicity to aquatic organisms. Due to their rapid biodegradability and expected enzymatic hydrolysis, also no adverse effects are anticipated in sediment organisms. Furthermore based on the available information on uses and the rapid degradability for these substances, direct and indirect exposure to soil can be excluded for all members of the category PFAE fumarates.
The presented environmental fate and ecotoxicological properties are also applicable for the analogue substance Bis(2-ethylhexyl) adipate (CAS 103-23-1), although this substance is not used for read across within the environmental fate and ecotoxicological context.
c) Toxicological properties:
The toxicological properties show that all category members and the structurally related analogue substance Bis(2-ethylhexyl) adipate share similar toxicokinetic behaviour (i.e. hydrolysis of the ester bond before absorption followed by absorption and metabolism of the breakdown products) and that the constant pattern consists in a lack of potency change of properties across the category, explained by the common metabolic fate of aliphatic diesters, independent of the chain length of the dicarboxylic acid moiety (C4 unsatd. or C6) and the length/branching of the alcohol moiety. Thus, considering all available data from category members and the analogue substance the category members show no acute oral or dermal toxicity, no skin irritation, eye irritation or sensitizing properties, no human hazard for systemic toxicity after repeated oral exposure, 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.
CAS 68921-53-9
Basic toxicokinetics
There are no studies available in which the toxicokinetic behaviour of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters (CAS 68921-53-9) 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 2-Butenedioic acid (E)-, di-C18-22-alkyl esters 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 physicochemical 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 fumarate category.
The substance 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is a diester of two C18-22 alkyl residues and fumaric acid (2-Butenedioic acid (E)) and meets the definition of an UVCB substance based on the analytical characterization.
2-Butenedioic acid (E)-, di-C18-22-alkyl esters is a white solid at room temperature and has a molecular weight between 621.03 and 733.24 g/mol and a water solubility < 0.05 mg/L at 20 °C (Frischmann, 2012). The log Pow is calculated to be > 10 (Hopp, 2011) and the vapour pressure is estimated to be 4.87E-16 Pa and 4.16E-23 Pa (Szymoszek, 2012).
Absorption
Absorption is i.a. 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:
The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). As the molecular weight of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is between 621.03 and 733.24 g/mol, absorption of the molecule in the gastrointestinal tract is assumed possible but limited.
Absorption after oral administration of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is also considered limited when the “Lipinski Rule of Five” (Lipinski et al., 2001; Ghose et al., 1999) is applied. The log Pow is above the given range of -0.4 to 5.6, the total number of atoms exceeds 70 and the molecular weight is above the upper limit of 480 g/mol.
The log Pow of > 10 suggests that 2-Butenedioic acid (E)-, di-C18-22-alkyl esters 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).
After oral ingestion, the members of the PFAE fumarates category undergo stepwise hydrolysis of the ester bonds by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the fatty acid is formed. The physicochemical 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 physicochemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for the resulting cleavage products with a high water solubility (i.e. fumaric acid), it is anticipated that they are absorbed in the gastrointestinal tract. In case of long carbon chains and thus rather low water solubility they are absorbed mainly by micellar solubilisation (Ramirez et al., 2001).
Overall, systemic bioavailability of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.
Dermal:
The smaller the molecule, the more easily it may be taken up via the dermal route. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large to penetrate the skin (ECHA, 2012). As the molecular weight of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is between 621.03 and 733.24 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 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is considered not to be skin irritating based on the category approach, enhanced penetration of the substance due to local skin damage can be excluded.
Based on a QSAR calculated dermal absorption a value of < 0.00001 mg/cm²/event (very low) was predicted for 2-Butenedioic acid (E)-, di-C18-22-alkyl esters (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. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is less than 0.05 mg/L, dermal uptake is likely to be (very) low.
Overall, the calculated low dermal absorption potential, the low water solubility, the molecular weight (>100), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters in humans is considered as very limited.
Inhalation:
2-Butenedioic acid (E)-, di-C18-22-alkyl esters has a low vapour pressure between 4.87E-16 Pa and 4.16E-23 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). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like 2-Butenedioic acid (E)-, di-C18-22-alkyl esters can be taken up by micellar solubilisation.
Overall, a systemic bioavailability of 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm.
Bioccumulation
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 > 5 implies that 2-Butenedioic acid (E)-, di-C18-22-alkyl esters may have the potential to accumulate in adipose tissue (ECHA, 2012).
However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, leading to the cleavage products the respective alcohol (C18-22) and fumaric acid (CAS 110-17-8).
The first cleavage product, the alcohol (C18-22), is only slightly water-soluble. However, fatty alcohols have limited potential for retention or bioaccumulation as they are efficiently metabolised (OECD SIDS, 2006). The second cleavage product, fumaric acid, has a log Pow of 0.46 and a water solubility of 7 g/L (HSDB, 2011; ESIS, 2000). As it is an intermediate of the citric acid cycle, it will not accumulate in adipose tissue, but will be rapidly metabolised (HSDB, 2011; Lehninger, 1970).
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 and/or the cleavage products in adipose tissue is expected.
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).
2-Butenedioic acid (E)-, di-C18-22-alkyl esters undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products alcohol (C18-22) and fumaric acid.
Aliphatic fatty alcohols are widely distributed within the body and efficiently eliminated (OECD SIDS, 2006). Due to its low molecular weight and moderate log Pow, fumaric acid will also be distributed within the body (HSDB, 2011).
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 labeled 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% of administered radioactivity at 24 h. In other tissues the radioactivity declined with time after 6 h. The blood contained about 1% of the administered radioactivity after 6-12 h which 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% of the administered radioactivity after 24 h of dosing and it decreased to about 2% and 0.5% of administered radioactivity 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 2-Butenedioic acid (E)-, di-C18-22-alkyl esters and its cleavage products, alcohol (C18-22) and fumaric acid, will be distributed within the organism.
Metabolism
Dicarboxylic acid esters are expected have the same metabolic fate as fatty acid esters. Esters of carboxylic acids are hydrolysed to the corresponding alcohol and carboxylic 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 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. During the first step of biotransformation the alcohols are oxidised to the corresponding carboxylic acids, followed by a stepwise elimination of C2-units in the mitochondrial beta-oxidation process (OECD SIDS, 2006). The second cleavage product fumaric acid is , as it is also an endogenous metabolite, incorporated into the citric acid cycle and rapidly degraded to CO2 (ESIS, 2000).
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% of the administered dose; mono-(2-ethylhexyl)adipate (MEHA) was the second metabolite found, but to a very little extent. Thus, cleavage of parent substance was shown in vivo within 6 hours into adipic acid (20-30% of the administered dose in urine, 1% of the administered dose in blood, 2-3% of the administered dose in liver) and MEHA to a lower 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 rats and mice DEHA is rapidly converted to primarily 2-Ethylhexanoic acid (EHA), 2-ethyl-5-hydroxyhexanoic acid and 2-ethylhexan-1,6-dioic acid and their glucuronides. However in monkeys, large amounts of MEHA glucuronide and 2-ethylhexanol glucuronide are excreted and only a very small proportion of the dose is converted to EHA and other downstream metabolites. Apart from MEHA, monoester metabolites have not been identified (Elcombe, 1981).
In a publication on fumaric acid esters depletion of glutathione (GSH) after administration of dimethyl fumaric ester is described indicating conjugation with GSH catalyzed by GSH-transferases (GST) as Phase-II metabolism (Rostami Yazdi and Mrowietz, 2008). The reason for this pathway is the double bond of the α,β-unsaturated carbonyl group of fumaric acid as substrate for GST whereas saturated dicarboxylic acid esters like adipic acid diester are glucuronidated directly at the carbonyl group (Takahashi et al., 1981).
Overall, 2-Butenedioic acid (E)-, di-C18-22-alkyl esters is hydrolyzed and the cleavage products are metabolized by beta oxidation and/or conjugation with GSH.
Excretion
For 2-Butenedioic acid (E)-, di-C18-22-alkyl esters and its cleavage products, the main route of excretion is expected to be by expired air as CO2 after metabolic degradation (beta-oxidation). Further routes of excretion might be via faeces and renal excretion after conjugation with GSH of the substance itself or its metabolites.
Experimental data of the structurally similar Bis(2-ethylhexyl) adipate (CAS 103-23-1) indicate rapid excretion via urine or expired air, too (Takahashi et al., 1981).
Thus, renal excretion after conjugation with GSH and exhalation as CO2 are the most relevant routes of excretion of the parent substance or its metabolites.
A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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