Fatty acids, C16-18 and C18-unsatd., esters with propylene glycol

Endpoint summary

Additional information

The target substance Fatty acids, C16-18 and C18-unsatd., esters with propylene glycol represents a UVCB substance predominantly comprised of diesters of an aliphatic diol (1,2-propyleneglycol (PG)) chemically linked to mainly oleic acid (C18:1) but as well to palmitic acid (C16), palmitoleic acid (C16:1), stearic acid (C18) and/or linoleic acid (C18:2).

Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. propyleneglycol) with an organic acid (e.g. oleic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by a transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. The acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to a carbonyl carbon of acid. An intermediate product is formed. This intermediate product loses a water molecule and a proton to give an ester (Liu et al, 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000).

 

The key points that the analogue substances share are:

 (1) common functional groups: Source and target substances are esters with the ester group being the common functional group of all substances. The substances are mono- or/and diesters of aliphatic diols (ethylene glycol (EG), 1,2-propylene glycol (PG) or 1,3-butyleneglycol (1,3-BG)) and fatty acids with the chain length C6 to C18.  The fatty acid chains comprise carbon chain lengths ranging from C6 (e.g. Fatty acids, C612, esters with propylene glycol, CAS 85883-73-4) to C18 (e.g.Fatty acids, C16-18, esters with ethylene glycol, CAS 91031-31-1), saturated but also unsaturated C16 and C18 (e.g. Fatty acids, C16-18 and C18-unsatd., esters with propylene glycol, CAS 85049-34-9 or Fatty acids, C14-18 and C16-18 unsatd., esters with propylene glycol, CAS 84988-75-0), branched C18 (e.g. 1-methyl-1,2ethanediyl diisooctadecanoate, CAS 68958-54-3) and epoxidized C18 (e.g. Fatty acids, C18 and C18 unsatd., epoxidized, esters with ethylene glycol, CAS 151661-88-0), are used as analogue substances for read across.

 

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: glycol esters are expected to be initially metabolized via enzymatic hydrolysis in the corresponding free fatty acids and the free glycol alcohols such as ethylene glycol and propylene glycol. The hydrolysis represents the first chemical step in the absorption, distribution, metabolism and excretion (ADME) pathways expected to be similarly followed by all glycol esters. The hydrolysis is catalyzed by classes of enzymes known as carboxylesterases or esterases (Heymann, 1980). Ethylene and propylene glycol are rapidly absorbed from the gastrointestinal tract and subsequently undergo rapid biotransformation in liver and kidney (ATSDR, 1997; ICPS, 2001; WHO, 2002; ATSDR, 2010). Propylene glycol will be further metabolized in liver by alcohol dehydrogenase to lactic acid and pyruvic acid which are endogenous substances naturally occurring in mammals (Miller & Bazzano, 1965, Ritchie, 1927). Ethylene glycol is first metabolised by alcohol dehydrogenase to glycoaldehyde, which is then further oxidized successively to glycolic acid, glyoxylic acid, oxalic acids by mitochondrial aldehyde dehydrogenase and cytosolic aldehyde oxidase (ATSDR, 2010; WHO, 2002). The anabolism of fatty acids occurs in the cytosol, where fatty acids esterified into cellular lipids that are the most important storage form of fatty acids (Stryer, 1994). The catabolism of fatty acids occurs in the cellular organelles, mitochondria and peroxisomes via a completely different set of enzymes. The process is termed ß-oxidation and involves the sequential cleavage of two-carbon units, released as acetyl-CoA through a cyclic series of reaction catalyzed by several distinct enzyme activities rather than a multienzyme complex (Tocher, 2003).

 

(3) Physico-chemical properties: The pattern observed depends on the fatty acid chain length and the degree of esterification (mono- or diesters). The molecular weight ranges from 202.29 to 622.97 g/mol. The physical appearance is related to the chain length of the fatty acid moiety, the degree of saturation and the number of ester bonds. Thus, mono- and diesters of short-chain fatty acids and unsaturated fatty acids (C6-14 and C16:1, C18:1) as well as diesters of branched fatty acids (C18iso) are liquid, while mono- and diesters of long-chain fatty acids are waxy solids. All substances are non-volatile (vapour pressure: ≤ 0.1 Pa). The n-octanol/water partition coefficient of all substances is higher than 3. It is in the agreement with knowledge about the chemical structure of the substances. Most of the substances are chemicals with high molecular weight, with long carboxylic chains, which result in hydrophobic properties of these substances. The latter is also confirmed by low solubility of the substances in water.

 

(4) Environmental fate and ecotoxicological properties: Considering the low water solubility and the potential for adsorption to organic soil and sediment particles, the main compartment for environmental distribution is expected to be the soil and sediment. Nevertheless, persistency in these compartments is not expected since the substances are readily biodegradable. Evaporation into air and the transport through the atmospheric compartment is not expected since the substances are not volatile based on the low vapour pressure. All analogue substances did not show any effects on aquatic organisms in acute and chronic up to the limit of water solubility. Moreover, bioaccumulation is assumed to be low based on available metabolism data.

 

(5) Toxicological properties: The toxicological properties show that analogue substances have a similar toxicokinetic behaviour (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, explained by the common metabolic fate of glycol esters independently of the fatty acid chain length and degree of glycol substitution. Thus, no substance showed acute oral, dermal or inhalative toxicity, no skin or eye irritation properties, no skin sensitisation, are of low toxicity after repeated oral exposure and are not mutagenic or clastogenic and have shown no indications for reproduction toxicity and have no effect on intrauterine development.

 

The available data allows for an accurate hazard and risk assessment of the target substance and the analogue approach 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) (read-across approach) 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.

 

A detailed justification for the analogue approach and read-across is provided in the technical dossier (see IUCLID Section 13).

 Several experimental studies confirmed that the target substance is readily biodegradable according to the OECD criteria (79.9 % biodegradation after 28 d). Therefore, the target substance will not be persistent in the environment. The degradation via abiotic hydrolysis is not considered to be a relevant degradation pathway in the environment since QSAR results using HYDROWIN v2.00 resulted in DT50 > 1 yr at pH 7.

 

Considering the low water solubility (< 0.05 mg/L) and the potential for adsorption to organic soil and sediment particles (log Koc: 9.0, MCI method, KOCWIN v2.00), the main compartment for environmental distribution is expected to be the soil and sediment. Nevertheless, persistency in these compartments is not expected since the target substance are readily biodegradable. Evaporation into air and the transport through the atmospheric compartment is not expected since the substance is not volatile based on the low vapour pressure (VP:≤ 0.1 Pa). Accumulation in air and the subsequent transport to other environmental compartments is not anticipated. Due to the low water solubility, rapid environmental biodegradation and metabolisation via enzymatic hydrolysis of the glycol esters, a relevant uptake and bioaccumulation in aquatic organisms is not expected. Enzymatic breakdown will initially lead to the free fatty acid and the free glycol alcohol (e. g. propylene glycol). From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (Heymann, 1980; Lech & Bend, 1980; Lech & Melancon, 1980; Murphy & Lutenske, 1990). This is supported by low calculated BCF values of 0.893 - 89.4 L/kg ww (BCFBAF v3.01, Arnot-Gobas, including biotransformation, upper trophic).

For a detailed reference list please refer to IUCLID section 13.