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Additional information

Justification for the analogue approach (read-across)

The target substance Propyleneglycol dioleate (CAS 105-62-4) represents a UVCB substance comprised of diesters of an aliphatic diol (propyleneglycol (PG)) chemically linked to two molecules of oleic acid (C18´, mono unsaturated).

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 final products of the esterification reaction between propyleneglycol and oleic acid are diesters comprising of a ratio of propyleneglycol and oleic acid of 1:1.9).

Due to the structural similarities and consistent trend in physico-chemical, toxicological, ecotoxicological properties and toxicokinetic behaviour, the following source substances be considered as structural analogue substances, according to Regulation (EC) No. 1907/2006, Annex XI, 1.5.

The key points that the analogue substances share are:

 

(1) common functional groups: the substances are characterized by ester bond(s) between an aliphatic diol (ethylene glycol (EG), propylene glycol (PG) or 1,3-butyleneglycol (1,3-BG)) and one or two carboxylic fatty acid chains. The fatty acid chains comprise carbon chain lengths ranging from C6 to C18, mainly saturated but also mono unsaturated C16 and C18. 

 

(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 Propyleneglycol dioleate (CAS 105-62-4) 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).

Three studies are available investigating effects on different species of the terrestrial compartment for the read-across substances decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) and Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8). Acute toxicity studies with the earthworm resulted in no mortality up to a concentration of 1000 mg/kg soil dw. The read-across substance Butylene glycol dicaprylate / dicaprate exhibited effects on the freshweight of Avena sativa resulting in a NOEC of 39 mg/kg soil (EC50 of 263.79 mg/kg soil). This endpoint was the most sensitive among others tested in the available study.

No studies are available investigating the effects on soil microorganisms. 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, 1.2, to adapt the data requirements of Regulation (EC) No 1907/2006 Annex VII - X (ECHA guidance section R.7.11.5.3, page 121). Available read-across data in accordance to Regulation (EC) No 1907/2006 Annex XI, 1.5 from the structurally related substances butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) and decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) did not show any mortality to earthworms (Eisenia fetida) in acute terrestrial toxicity tests according to OECD 207 and EU Method C.8, respectively (LC50 > 1000 mg/kg soil dw). A plant study with butylene glycol dicaprylate/dicaprate according to OECD 208 with three species from different taxonomic groups resulted in an EC50 of > 100 mg/kg soil for all tested species (three plant species). Moreover, the read-across substance butylene glycol dicaprylate / dicaprate did not show any chronic effects up to the limit of water solubility on the water flea Daphnia magna in a study according to OECD 211 (Hertl, 2001) and no effects were observed on the respiration rate of activated sludge microorganisms (Diefenbach, 1997). Available reliable read-across data for toxicity to aquatic microorganisms supports the determination of a lack of toxicity to soil microorganisms. No inhibition of respiration rate of aquatic microorganisms was observed in any of the available studies. The Guidance Document (ECHA, 2012, page 122) states that a test on soil microbial activity will only be additionally necessary for a valid PNEC derivation if inhibition of sewage sludge microbial activity has occurred and this is clearly not the case. This is supported by further evidence from literature data. This data showed that soil microorganism communities are well capable of degrading fatty acid esters (Hita et al., 1996 and Cecutti et al., 2002) and use them as energy source (Banchio & Gramajo, 1997). Based on the available information, effects on soil microorganisms are not expected to be of concern, and consequently, no further testing is required. Acute studies with terrestrial organisms from different taxonomic groups are regarded sufficient for the assessment of terrestrial toxicity since the substance is readily biodegradable and chronic aquatic data indicated no effects up to the limit of water solubility.

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