2-Butenedioic acid (E)-, di-C12-18-alkyl esters

Endpoint summary

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 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 byβ-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 indication for 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.

Aquatic toxicity of the PFAE fumarates category

ID#	CAS	Short-term toxicity to fish	Short-term toxicity to aquatic invertebrates	Toxicity to aquatic algae	Toxicity to microorganisms
1	2402-58-6	LC50 (96 h) = 2200 mg/L	EC50 (48 h) > 100 mg/L	ErC50 (72 h) > 100 mg/L	EC10 (0.5 h) > 10000 mg/L
2	10341-03-4	LC50 (96 h) > 100 mg/L	EC50 (48 h) > 100 mg/L	ErC50 (72 h) > 100 mg/L	EC50 (48 h) > 100 mg/L
3	68610-90-2	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9
4	68921-51-7	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9
5	68921-52-8	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9	RA: CAS 2402-58-6 RA: CAS 10341-03-4 RA CAS 68921-53-9
6	68921-53-9	LC50 (96 h) > 10000 mg/L	EC50 (48 h) > 100 mg/L	ErL50 (72 h) > 100 mg/L	EC10 (3 h) > 1000 mg/L

*Since no data on the chronic toxicity to aquatic invertebrates and fish are available for the category, these columns were excluded in this overview.

Discussion

The PFAE fumarates is a robust category with sufficient experimental data collectively covering fatty alcohol carbon numbers from C8 to C22 and total carbon numbers ranging from C12 to C26. Short-term aquatic toxicity data is available for all trophic levels within the PFAE fumarates category. Long-term data is available for algae. The read across approach used for the aquatic toxicity is performed under consideration for the acid chain length in particular, i.e. read across in aquatic toxicology is only performed within this fumaric acid ester category. Furthermore, the available studies cover the outer borders of this category so that the aquatic toxicity endpoints are covered by interpolation (i.e. studies are available for the lower alcohol chain length (C12, C14) and highest alcohol chain length (C18/C22), respectively). Only two constituents, i.e. C8 and C10 fatty acid ester components of 2-Butenedioic acid (E)-, di-C8-18-alkyl esters (CAS 68610-90-2) are not enclosed by the available data but can be covered by extrapolation since no trend in aquatic toxicity is observed due to the insolubility of the category members. Since the water solubility of this UVCB substance is below detection limit (equally to all category members) the influence of both components is regarded as negligible.

Based on the experimental data, all category members exhibit no acute and chronic toxicity to aquatic organisms up to the limit of water solubility. Therefore, in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5, grouping and read-across, the PFAE fumarates category members are not considered to be toxic or harmful to aquatic organisms.

In consequence, based on the current data, which is considered adequate for an accurate chemical safety assessment of the category, no category member is classified and labeled for environmental hazard according to the 2nd ATP of the Regulation (EC) No.1272/2008 (CLP).

No effect on microbial respiration or growth occurred for any member of the category. Thus disturbances in sewage treatment plants are not anticipated for any member of the category.

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