Pentaerythritol, mixed esters with linear and branched fatty acids

Bioaccumulation: aquatic / sediment

Additional information

Experimental bioaccumulation data are not available for the target substance Tetraesters of pentaerythritol with linear and branched fatty acids. The high log Kow (> 10) as an intrinsic chemical property of the substance indicates a potential for bioaccumulation. However, the information gathered on environmental behavior, bioavailability 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 the substance is 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) by biodegradation and by sorption to organic matter. An assessment of bioaccumulation for possible degradation products is not considered to be necessary. Due to the ready biodegradability rapid and ultimate biodegradation under most environmental conditions is assumed. Thus, according to ECHA Guidance R.7b, no further investigation of the bioaccumulation of transformation products is required (ECHA, 2016). The low water solubility (<0.01 mg/L at 25 °C) and high estimated log Kow (> 10) indicate that the substance is highly lipophilic. If released into the aquatic environment, the substance undergoes extensive biodegradation and sorption on organic matter. Thus, the bioavailability in the water column is reduced rapidly. The relevant route of uptake of Tetraesters of pentaerythritol with linear and branched fatty acids in aquatic organisms is expected to be predominantly by ingestion of particle bound substance.

Metabolism of aliphatic esters

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2014). As the molecular weight of Tetraesters of pentaerythritol with linear and branched fatty acids ranges from 640.93- 697.04 g/mol absorption of the molecule is considered to be limited. Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance Tetraesters of pentaerythritol with linear and branched fatty acids, as the substance fails two rules for good bioavailability (molecular weight is >500 and the log Pow is >5). Thus, oral absorption is expected to be limited. Please refer to the toxicokinetic statement in IUCLID section 7.1 for further information.

However, should the substance be taken up by fish during the process of digestion and absorption in the intestinal tissue, aliphatic esters like Tetraesters of pentaerythritol with linear and branched fatty acids are expected to be initially metabolized via enzymatic hydrolysis to the corresponding free fatty acids and the free fatty alcohols (here: pentaerythritol). 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 reliable literature data have clearly shown that esters do not readily bioaccumulate in fish (Rodger & Stalling, 1972; 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 of

Fatty alcohols

Pentaerythritol is the product from the enzymatic reaction of Tetraesters of pentaerythritol with linear and branched fatty acids catalyzed by carboxylesterases. Pentaerythritol is absorbed rapidly but mainly excreted unchanged. DiCarlo et al. (1965) reported that 10 mg/kg C14-labled pentaerythritol orally administered to mice was absorbed and excreted rapidly from the gastrointestinal tract. Almost half of the administered dose left the gastrointestinal tract within 15 min and 68% of the dose appeared as unchanged PE in the urine and feces after 4 hours already. In addition the cleavage product has a very low potential for bioaccumulation based on the very low log Kow of -1.767 (estimated by KOWWIN v1.68)

Fatty acids

The metabolism of fatty acids in mammals is well known and has been investigated intensively in the past (Stryer, 1994). The free fatty acids can either be stored as triglycerides or oxidized via mitochondrial ß-oxidation removing C2-units to provide energy in the form of ATP (Masoro, 1977). Acetyl-CoA, the product of the ß-oxidation, can further be oxidized in the tricarboxylic acid cycle to produce energy in the form of ATP. As fatty acids are naturally stored as trigylcerides in fat tissue and re-mobilized for energy production it can be concluded that even if they bioaccumulate, bioaccumulation will not pose a risk to living organisms. Fatty acids (typically C14 to C24 chain lengths) are also a major component of biological membranes as part of the phospholipid bilayer and therefore part of an essential biological component for the integrity of cells in every living organism (Stryer, 1994). Saturated fatty acids (SFA; C12 - C24) as well as mono-unsaturated (MUFA; C14 - C24) and poly-unsaturated fatty acids (PUFA; C18 - C22) were naturally found in muscle tissue of the rainbow trout (Danabas, 2011) and in the liver (SFA: C14 - C20; MUFA: C16 - C20; PUFA: C18 - C22) of the rainbow trout (Dernekbasi, 2012).

Data from QSAR modeling

Tetraesters of pentaerythritol with linear and branched fatty acids are predicted to have a low potential for bioconcentration, based on evaluation of the five tetra-ester components possible in the reaction mixture. Additional information on bioaccumulation could be gathered using the (Q)SAR model BCFBAF v3.01. The estimated BCF values for Tetraesters of pentaerythritol with linear and branched fatty acids indicate negligible bioaccumulation in organisms. All of these have similar estimated BCF in both the regression based method as well as the Arnot-Gobas method. When including biotransformation, low BCF/BAF values of 0.893-0.893 resulted (Arnot- Gobas estimate, including biotransformation, upper trophic). The biotransformation rate in fish is estimated using structural fragments of the representative components to estimate the half-life, the (Q)SAR calculations can be used as supporting indication that the potential of bioaccumulation is low. Moreover, the results support the tendency that substances with high log Kow values (> 10) have a lower potential for bioconcentration as summarized in the ECHA Guidance R.11 and they are not expected to meet the B/vB criterion (ECHA, 2014).

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 Tetraesters of pentaerythritol with linear and branched fatty acids 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 Tetraesters of pentaerythritol with linear and branched fatty acids will not be bioaccumulative (all well below 2000 L/kg). The cleavage product pentaerythritol has a low potential for bioaccumulation based on the low log Kow (<3) and fatty acids are metabolised by common physiological processes. Moreover, the bioavailability of the substance in the environment is limited due to its high lipophilicity and adsorption to organic matter. Taking all these information into account, it can be concluded that the bioaccumulation potential of Tetraesters of pentaerythritol with linear and branched fatty acids is low.