Fatty acids, montan-wax, stearyl esters

Endpoint summary

Description of key information

Fatty acids, montan-wax, stearyl esters (CAS 68308-30-5) is expected to have a low potential for bioaccumulation based on its high log Kow (> 10.0), environmental fate and toxicokinetic behaviour as well as its estimated BCF values obtained by five different QSAR models.

Additional information

There are no experimental studies available, in which the bioaccumulation potential of Fatty acids, montan-wax, stearyl esters (CAS 68308-30-5) was assessed. The estimated log Kow of the substance is high (> 10.0, QSAR, VEGA v1.1.3), which may be indicative of a potential for bioaccumulation since it is above the trigger value of 3.0 set out in Regulation (EC) No 1907/2006 (Annex IX, column 2, 9.3.2).

However, the screening criterion based solely on the log Kow value most likely overestimates the true bioaccumulation potential of a substance because it does not account for environmental and toxicokinetic behavior. In fact, current knowledge suggests that log Kow values of 10 or above are indicators of reduced bioconcentration, as stated in the Guidance R.7c (ECHA, 2017) and R.11 (PBT/vPvB assessment v3.0, ECHA, 2017). The interaction between lipophilicity, bioavailability and membrane permeability is considered to be the main reason why the relationship between the bioaccumulation potential of a substance and its hydrophobicity is commonly described by a relatively steep Gaussian curve with a bioaccumulation peak approximately between log Kow of 6.0 – 7.0. Substances with log Kow values above 10, which has also been calculated for the present substance, are considered to have a low bioaccumulation potential. Furthermore, for those substances with a log Kow value of > 10.0 it is unlikely that they reach the pass level for bioaccumulative substances according to OECD criteria for the PBT assessment (BCF > 2000; ECHA, 2017).

Furthermore, additional data compiled on the environmental and toxicokinetic behavior of the substance, in combination with QSAR predictions for BCF values, provide additional evidence that the potential for bioaccumulation is likely to be low.

Environmental behavior

The substance has a low water solubility (< 0.539 mg/L, OECD 105), a high estimated adsorption potential (log Koc > 5.0) and a high estimated log Kow (> 10.0), indicating that it is highly lipophilic.

If released into the aquatic environment, only low concentrations of the substance are expected to dissolve in the water phase. Rather, the substance is expected to sorb to organic matter, leading to an effective reduction of its bioavailability in the water column. Thus, the most relevant potential route of uptake by aquatic organisms is expected to occur via contact with or ingestion of particle-bound substance. However, its bioavailability in the sediment compartment is presumably very low based on its intrinsic physico-chemical properties (e.g. high sorption).

Toxicokinetic behaviour

According to ECHA Guidance R7.c (2017), accumulation is a general term for the net result of absorption (uptake), distribution, metabolism and excretion of a substance in an organism. These processes are addressed in more detail below. For further details and references, refer to the IUCLID section on “Toxicokinetics, metabolism and distribution”.

 

Mammalian organisms

Absorption.Based on the molecular weight, log Kow, vapour pressure and water solubility of the substance, inhalation is considered a negligible uptake route and only limited oral as well as low dermal absorption is expected to occur in mammalian organisms. The physico-chemical properties of the substance indicate poor absorption from the gastrointestinal (GI) tract following oral ingestion and/or low acute toxicity (based on acute oral toxicity data on target substance and source substances). However, its highly lipophilic properties indicate that the substance could be taken up via micellar solubilisation by bile salts, which may affect the overall absorption rate of the substance.

Distribution and metabolism. Fatty acids, montan-wax, stearyl esters (CAS 68308-30-5) is a long-chain aliphatic ester. Thus, it is expected to undergo esterase-catalysed hydrolysis, which yields the corresponding fatty alcohol and alcohol components of the substance. Esterases are ubiquitous and as such, present in most tissues and organs, but particularly so in the GI tract and the liver. Thus, enzymatic hydrolysis may occur prior to uptake across biological membranes in the gastrointestinal (GI) tract, or after the absorption of (intact) esters via the inhalation or dermal route, in different places in the body, depending on the route of exposure. Therefore, the hydrolysis products (fatty acids and alcohols) are considered more relevant for distribution and accumulation processes of the substance.

Based on the generic information on hydrolysis of alkyl esters, Fatty acids, montan-wax, stearyl esters (CAS 68308-30-5) is expected to be enzymatically hydrolysed to the C18-alcohol moiety and the respective C22-, C24-, C26-, C28-, and C30- fatty acid moieties. Generally, free fatty acids and alcohols are readily absorbed by the intestinal mucosa, the rate of which is chain-length dependent.

Based on experimental data from an in vivo study with rats, most of the resulting fatty acids are absorbed by adipose tissue and (re-)esterified along with other fatty acids to form triglycerides for storage. Triglycerides are released in chylomicrons into the lymphatic system, or taken up by muscle tissue and oxidized to derive energy or released into the systemic circulation and returned to the liver, where they are metabolized, stored or re-enter the circulation (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1993; NTP, 1994; Stryer, 1996; WHO, 2001). There is a continuous turnover of stored fatty acids, which are constantly metabolized to generate energy and then excreted as CO₂. Thus, accumulation of fatty acids only occurs if their intake exceeds the caloric requirements of the organism.

Based on experimental data from an in vivo study with rats, the absorbed alcohols undergo the same metabolism routes as the fatty acids, but are first converted into the corresponding fatty acids by oxidation and then distributed in the form of triglycerides after (re-)esterification (Lehninger, 1993; WHO, 1999). Thus, the metabolites of alcohols also serve as energy source or are used for storage in adipose tissue.

The C18-alcohol which represents the hydrolysis product of the substance, as well as the corresponding fatty acids of the substance are expected to be metabolized via oxidation to the corresponding carboxylic acids via the formation of transient aldehyde intermediates (Lehninger, 1993). Both the alcohol and the aldehyde can also be conjugated (e.g. with glutathione) and then excreted after additional metablization steps. Fatty acids can also be further metabolized directly after absorption, or after the oxidation of an alcohol or after the de-esterification of triglycerides. Other major metabolic pathways for linear and branched fatty acids include the beta-oxidation pathway for energy generation, the omega-oxidation pathway at high dose level or conjugation (e.g. by glucuronides, sulfates) to increased polarity for excretion via urine. Based on the available experimental data, there is no indication that the substance is metabolized into reactive species that could negatively affect DNA and proteins.

Excretion. Based on experimental data with rats, excretion is expected to largely occur in the form of CO2 via expired air (40 – 70%) but to a certain extent also via faeces (7 – 20%) and urine (2%) (Bookstaff et al., 2003). Furthermore, the alcohol components may undergo conjugation with e.g. glutathione, to form more water-soluble molecules which are more readily excreted via urine (WHO, 1999). The remaining fraction of unabsorbed substance in the GI will be excreted via faeces.

 

Overall, low bioaccumulation is expected because the constituent fatty alcohol and alcohol components resulting from the enzymatically catalyzed hydrolysis of the original substance take on various different functions within the mammalian organism such as energy supply and storage or cell membrane formation. For further details, refer to toxicokinetic data on metabolism and distribution (IUCLID section 5.1).

 

Aquatic organisms

The biochemical processes involved in the metabolization of aliphatic esters, comprising enzymatic hydrolysis and subsequent metabolization of the corresponding hydrolysis products carboxylic acid and alcohol components, are ubiquitous in the animal kingdom. Thus, in the unlikely event of uptake and absorption by fish, the substance is expected to be rapidly metabolized via enzymatic hydrolysis into its corresponding fatty acids and fatty alcohols. It is well known from literature that the resulting hydrolysis products will also be effectively metabolized and excreted by fish (Heymann, 1980; Lech & Bend, 1980; Lech & Melancon, 1980; Murphy & Lutenske, 1990; Sand et al., 1973).

 

QSAR predictions on BCF values

All models consistently predicted very low BCF values of maximally 28.18 L/kg, which are clearly below the threshold values of 2000 L/kg and 5000 L/kg for bioaccumulative and very bioaccumulative substances, respectively, as laid down by REACH Regulation (EC) 1907/2006 (Annex XIII, section 1).

Even though the predicted molecules did not fall within the applicability domains of the respective models, the obtained results taken as a whole were considered acceptable in a weight-of-evidence approach according to 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.

 

Conclusion

Based on all the available information taken together, it is thus concluded that Fatty acids, montan-wax, stearyl esters (CAS 68308-30-5) has a low potential for bioaccumulation and that the compiled data provide sufficient evidence (in accordance with 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.

 

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