Isononanoic acid, C16-18 (even numbered)-alkyl esters

Bioaccumulation: aquatic / sediment

Description of key information

The potential for bioaccumulation of isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) is low based on all available data.

Additional information

Experimental bioaccumulation data are not available for isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2). The high log Kow of 11.07 - 12.05 (KOWWIN v1.68; Müller, 2011) as an intrinsic chemical property of the substance indicates a potential for bioaccumulation. However, the information gathered on environmental behaviour and metabolism, in combination with QSAR-estimated values, provide enough evidence (in accordance to the 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 to state that these substances are likely to show negligible bioaccumulation potential.

Environmental behavior

Due to ready biodegradability and high potential of adsorption, the substance can be effectively removed in conventional sewage treatment plants (STPs) either by biodegradation or by sorption to biomass. The low water solubility (< 0.05 mg/L) and high estimated log Kow values indicate that the substance is highly lipophilic. If released into the aquatic environment, it will undergo extensive biodegradation and sorption on organic matter, as well as sedimentation. Thus, the bioavailability of isononanoic acid, C16-18 alkyl esters in the water column is reduced rapidly. The relevant route of uptake of the substance in organisms is considered predominately by ingestion of particle bounded substance. 

Metabolism of aliphatic esters

Should the substance be taken up by fish during the process of digestion and absorption in the intestinal tissue, aliphatic esters like isononanoic acid, C16-18 alkyl esters is expected to be initially metabolized via enzymatic hydrolysis to the corresponding free isononanoic acid and the free C16-18 fatty alcohol. The hydrolysis is catalyzed by classes of enzymes known as carboxylesterases or esterases (Heymann, 1980). The most important of which are the B-esterases in the hepatocytes of mammals (Heymann, 1980; Anders, 1989). Carboxylesterase activity has been noted in a wide variety of tissues in invertebrates as well as in fish (Leinweber, 1987; Soldano et al, 1992; Barron et al., 1999, Wheelock et al., 2008). The catalytic activity of this enzyme family leads to a rapid biotransformation/metabolism of xenobiotics which reduces the bioaccumulation or bioconcentration potential (Lech & Bend, 1980). It is known for esters that they are readily susceptible to metabolism in fish (Barron et al., 1999) and literature data have clearly shown that esters do not readily bioaccumulate in fish (Rodger & Stalling, 1972; Murphy & Lutenske, 1990; Barron et al., 1990). In fish species, this might be caused by the wide distribution of carboxylesterase, high tissue content, rapid substrate turnover and limited substrate specificity (Lech & Melancon, 1980; Heymann, 1980). The metabolism of the enzymatic hydrolysis products is presented in the following chapter.

 

Metabolism of enzymatic hydrolysis products

Fatty alcohols

Fatty alcohols ranging from C16 (hexadecan-1-ol) to C18 (octadecan-1-ol) are the expected main corresponding alcohol hydrolysis products from the enzymatic reaction of isononanoic acid, C16-18 alkyl esters catalyzed by carboxylesterases. The metabolism of alcohols is well known. The free alcohols can either be esterified to form wax esters which are similar to triglycerides or they can be metabolized to fatty acids in a two-step enzymatic process by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) using NAD+ as coenzyme as shown in the gourami (Trichogaster cosby) (Sand et al., 1973). The responsible enzymes ADH and ALDH are present in a large number of animals, plants and microorganisms (Sund & Theorell, 1963; Yoshida et al., 1997). They were found among others in the zebrafish (Reimers et al., 2004; Lassen et al., 2005), carp and rainbow trout (Nilsson, 1988; Nilsson, 1990). The alcohol metabolism was investigated in the zebrafish Danio rerio, which is a standard organisms in aquatic ecotoxicology. Two cDNAs encoding zebrafish ADHs were isolated and characterized. A specific metabolic activity was shown in in-vitro assays with various alcohol components ranging from C4 to C8. The corresponding aldehyde can be further oxidized to the fatty acid catalyzed by an ALDH. Among the ALDHs the ALDH2, located in the mitochondria is the most efficient. The ALDH2 cDNA of the zebrafish was cloned and a similarity of 75% to mammalian ALDH2 enzymes was found. Moreover, it exhibits a similar catalytic activity for the oxidation of acetaldehyde to acetic acid compared to the human ALDH2 protein (Reimers at al., 2004). The same metabolic pathway was shown for longer chain alcohols like stearyl- and oleyl alcohol which were enzymatically converted to its corresponding acid, in the intestines (Calbert et al., 1951; Sand et al., 1973; Sieber, et al., 1974). Branched alcohols like 2-hexyldecanol or 2-octyldodecanol show a high degree of similarity in biotransformation compared to the linear alcohols. They will be oxidized to the corresponding carboxylic acid followed by the ß-oxidation as well. A presence of a side chain does not terminate the ß-oxidation process (OECD, 2006). The influence of biotransformation on bioaccumulation of alcohols was confirmed in GLP studies with the rainbow trout (according to OECD 305) with commercial branched alcohols with chain lengths of C10, C12 and C13 as reported in de Wolf & Parkerton, 1999. This study resulted in an experimental BCF of 16, 29 and 30, respectively for the three alcohols tested. The 2-fold increase of BCF for C12 and C13 alcohol was explained with a possible saturation of the enzyme system and thus leading to a decreased elimination.

 

Fatty acids

The metabolism of fatty acids in mammals is well known and has been investigated intensively in the past (Stryer, 1994). A major metabolic pathway for linear and branched fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). A similar metabolic pathway can be expected for aquatic organisms.

Data from QSAR calculation

Additional information on bioaccumulation could be gathered through BCF/BAF calculations using BCFBAF v3.01. The estimated BCF values for the substance indicate negligible bioaccumulation in organisms (BCF: 34.3 - 44.7 L/kg, regression based). When including biotransformation, BCF and BAF values of 0.9547 - 1.217 and 62.03 - 143.6 L/kg, respectively were obtained (Arnot-Gobas estimate, including biotransformation, upper trophic). Even though the substance is outside the applicability domain of the model the calculated values can be used as supporting indication that the potential of bioaccumulation is low. The model training set is only consisting of substances with log Kow values of 0.31 - 8.70. But it supports the tendency that substances with high log Kow values have a lower potential for bioconcentration as summarized in the ECHA Guidance R.11 and that they are not expected to meet the B/vB criterion (ECHA, 2012).

 

Conclusion

The biochemical process metabolizing aliphatic esters is ubiquitous in the animal kingdom. Based on the enzymatic hydrolysis of aliphatic esters and the subsequent metabolism of the corresponding carboxylic acid and alcohol, it can be concluded that the high log Kow, which indicates a potential for bioaccumulation, overestimates the true bioaccumulation potential of isononanoic acid, C16-18 alkyl esters since it does not reflect the metabolism of substances in living organisms. BCF/BAF values estimated with the BCFBAF v3.01 program also indicate that the substance will not be bioaccumulative (all well below 2000 L/kg). Taking all these information into account, it can be concluded that the bioaccumulation potential of isononanoic acid, C16-18 alkyl esters is low.

References

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