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Environmental fate & pathways

Endpoint summary

Administrative data

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Additional information

No experimental data evaluating the bioaccumulation potential of the PFAE fumarates category members is available. Therefore, all available related data is combined in a Weight of Evidence (WoE) approach, which is in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2, to cover the data requirements of Regulation (EC) No. 1907/2006 Annex IX (ECHA, 2012c).

Environmental behaviour

The members of the PFAE fumarates category consist of main components with estimated high partition coefficients (calculated log Kow ≥ 8, for the majority of substances > 10). Based on the high log Kow and the measured strong water insolubility, determined to be below the detection limits of the used methods of 0.15 mg/L and 0.05 mg/L, respectively, one can conclude that the substances are hydrophobic and lipophilic (in nature).

In addition, the calculated log Koc values above 4 (in most cases > 5) indicate that the substances or the main components of the substances (in case of UVCBs) will adsorb to suspended organic particles, dissolved organic matter (DOM) and to some degree biota in the aquatic environment (e.g., see Jaffé, 1991). The substances are considered to be readily biodegradable or readily biodegradable, but failing 10 day window and therefore have shown enhanced ultimate biodegradability, which indicates that the substances will neither be persistent in the aquatic nor the terrestrial compartment. Hence the concentration of the analogue substances in the aquatic environment is expected to be low as they are in general effectively removed in conventional STPs either by biodegradation or by sorption to biomass. Considering this, one can assume that the availability of the substances in the aquatic environment are generally low, which reduces the probability of adsorption and uptake from the surrounding medium into organisms (e.g., see Björk, 1995, Haitzer et al., 1998).

If environmental concentrations facilitate exposure, the uptake of the analogue substances from medium into organisms is expected to be low based on the molecular weight, size and structural complexity of the substances. The substances are fumaric acid esters with two side chains of C12 to C22 carbon length. These large and complex structures in conjunction with their stereoisomerism around the butenedioic acid part assume a high degree of conformational flexibility. Dimitrov et al. (2002) revealed a tendency of decreasing log BCF with an increase in conformational flexibility of molecules, which they assumed to be related to the enhancement of the entropy factor on membrane permeability of chemicals. This concludes a high probability that a substance may encounter the membrane in a conformation which does not enable the substance to permeate.

Furthermore, several of the analogue substances consist of main components featuring high molecular weights of 453 to 733 g/mol. Even if dermal adsorption of substances cannot per se be excluded, it is conducive to say that with such molecular weights they may not be readily taken up due to the steric hindrance of crossing biological membranes.

This interaction between hydrophobicity, bioavailability and membrane permeability is considered to be the main reasons why the relationship between the bioaccumulation potential of a substance and its hydrophobicity is commonly found to be described by a relatively steep Gaussian curve with the bioaccumulation peak approximately at log Kow of 6-7 (e.g. see Dimitrov et al., 2002; Nendza & Müller, 2007; Arnot and Gobas 2003). Substances with log Kow values above 10, which have been calculated for almost all analogue substances and main components of substances, are, however, again considered to have a low bioaccumulation potential (e.g. see Nendza & Müller, 2007; 2010). Furthermore, for those substances with a log Kow value >10 it is recognized by the relevant authorities that it is unlikely that they accomplish the pass level of being bioaccumulative according to OECD criteria for the PBT assessment (log BCF = 2000; ECHA, 2011). Regarding the analogue substances, this assumption is supported by QSAR calculations using BCFBAF v3.01 (Nagel, 2014). BCF values were calculated to be between 46.3 and 5.05 L/kg (regression based method). A model which considered biotransformation calculated even lower BCF and BAF values between 0.90 - 0.89 and 1.55 – 1.09 L/kg, respectively (Arnot-Gobas, upper trophic). Even though the members of the fumarates category are, due to their high calculated log Kow values, in most cases outside the applicability domain of the used model (model training set is constituted of substances with log Kow values in the range of 0.31 to 8.70), the calculations (especially the low BCF values calculated using the Arnot-Gobas method) reflect the rapid biotransformation assumed for the category members.

Metabolism of aliphatic esters and metabolites

Given the physico-chemical properties and the subsequent behaviour in the environment the relevant route of uptake of the Fumarates in organisms is considered to be predominately by ingestion of particle bound substances. Following the ‘rule of 5’ (Lipinski et al., 2001), developed to identify drug candidates with poor oral absorption based on criteria in partitioning (log Kow >5), molecular weight (>500 g/mol) and hydrogen bonding (more than 5 hydrogen bond donors; more than 10 hydrogen bond acceptors), the category members can considered to be poorly absorbed after oral uptake.

If any of the Fumarates category members are uptaken by living organisms, aliphatic esters such as the members of the Fumarates category will be initially metabolized via enzymatic hydrolysis to the respective dicarboxylic acid and alcohol components as would other dietary fats (e.g. see Linfield et al., 1984). The hydrolysis is catalyzed by carboxylesterases and esterases, with B-esterases located in hepatocytes of mammals being the most important (Heymann, 1980; Anders, 1989). However, carboxylesterase activity has also been reported from a wide variety of tissues in invertebrates and fishes (e.g. see Leinweber, 1987; Suldano et al., 1992; Barron et al., 1999; Wheelock et al., 2008). In fish, the high catalytic activity, low substrate specificity and wide distribution of the enzymes in conjunction with a high tissue content lead to a rapid biotransformation of aliphatic esters, which significantly reduces its bioaccumulation potential (Lech & Melancon, 1980; Lech & Bend, 1980).

Fatty alcohols ranging from C12 (dodecan-1-ol) to C22 (docosan-1-ol) and fumaric acid are the expected hydrolysis products from the enzymatic reaction of the Fumarates catalyzed by carboxylesterase. The metabolism of fatty alcohols has been intensively reviewed in the literature (e.g. see Rizzo et al., 1987; Hargrove et al., 2004). The free alcohols can either be esterified to form wax esters (which are similar to triglycerides) or they can be transformed to fatty acids in a two-step enzymatic process catalyzed by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The responsible enzymes ADH and ALDH are present in a large number of animals including plants, microorganisms and fish (e.g. see Sund & Theorell, 1963; Nilson, 1990; Yoshida et al., 1997; Reimers et al., 2004; Lassen et al., 2005). 

The metabolism of alcohols in fish was intensively studied by Reimers et al. (2004). They isolated and characterized two cDNAs from the zebra fish, Danio rerio, encoding ADHs, which showed specific metabolic activity in in-vitro assays with various alcohol components ranging from C4 to C8. The emerging aldehydes were shown to be further oxidized to the corresponding fatty acid by ALDH enzymes. The most effective ALDH2, which is mainly located in the mitochondria of liver cells showed a similarity of 75% to mammalian ALDH2 enzymes and a similar catalytic activity (also see Nilsson, 1988). The same metabolic pathway was shown for longer chain alcohols, such as stearyl and oleyl alcohol in the intestines of rats (Sieber et al., 1974).

Furthermore, cleavage products with high water solubility like fumaric acid do not have the potential to accumulate in adipose tissue due to their low log Pow and are thus widely distributed within the body and rapidly eliminated via renal excretion.

Conclusion

Hence, fumarates are biotransformed to dicarboxylic acids and the corresponding alcohol component by the ubiquitous carboxylesterase enzymes in aquatic species. Based on the rapid metabolism it can be concluded that the high log Kow, which indicates a potential for bioaccumulation, overestimates the true bioaccumulation potential for the fumarates category members. Taking all these information into account, it can be considered that bioaccumulation of fumarates category members is unlikely to occur.

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