3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate

Categories

Category name:

Rationale & justification for the read across approach used in the registration dossier of Isononyl isononanoate IUPAC name : branched-nonyl 3,5,5 trimethylhexanoate

Justifications and discussions

Category rationale:

The present analogue approach contemplates isononyl isononanoate (IUPAC name branched-nonyl 3,5,5 trimethylhexanoate, previously CAS 42131-25-9) as target substance for read-across from the source substances listed in Table 1.
Isononyl isononanoate is a complex substance derived from 3,5,5 trimethylhexanoic acid and branched nonyl alcohol, the main components being structural isomers of C18H36O2 (see report in section 1.2).
Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. myristyl alcohol, stearyl alcohol) with an organic acid (e.g. myristic acid, stearic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by the transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. The carboxylic acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to the carbonyl carbon of the acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester (Liu et al., 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Mono-esters are the final products of the esterification.
Based on structural features and anticipated metabolism, suitable source substances for read-across are alkyl esters of fatty acids and alcohols with an analogue structure regarding branching and chain length, respectively. The common metabolic fate of fatty acid alkyl esters involves a stepwise hydrolysis of the ester bonds by gastrointestinal enzymes by which the breakdown results in structurally similar chemicals, the fatty acid component and the respective alcohol (Lehninger, 1993; Mattson and Volpenhein, 1972). Following hydrolysis of the ester bond, the breakdown products, fatty acid and alcohol, will be absorbed and metabolised. The fatty alcohol will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). 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). The branched fatty acids resulting from the oxidation of the corresponding alcohols are unlikely to be used for energy generation and storage, since saturated aliphatic, branched-chain acids are described to be subjected to omega-oxidation due to steric hindrance by the methyl groups at uneven position, which results in the formation of various diols, hydroxyl acids, ketoacids or dicarbonic acids. In contrast to the products of beta-oxidation, these metabolites may be conjugated to glucuronides or sulphates, which subsequently can be excreted via urine or bile or cleaved in the gut with the possibility of reabsorption (entero-hepatic circulation) (WHO, 1998).
The toxicological properties show that the target and source substances have similar toxicokinetic behaviour due to the common metabolic fate, which is independent of the chain length of the fatty acid and alcohol, respectively.
Due to the structural similarities and consistent trend in physico-chemical, toxicological and toxicokinetic behaviour, the selected source substances are considered suitable and human health effects can be directly read-across to isononyl isononanoate in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5.
The present analogue approach does not cover endpoints of the ecotoxicological section and therefore only points relevant for human health hazards are considered in the present analogue justification.