Alcohols, C9-11-iso-, C10-rich

Endpoint summary

Additional information

Linear and branched chain alcohols exhibit similar patterns of absorption, metabolism, and excretion. Both linear and branched aliphatic alcohols are absorbed through the gastrointestinal tract and are rapidly eliminated from the blood (DeBruin, 1976; Lington and Bevan, 1994). Plasma half-lives are difficult to measure since many of the low molecular weight metabolites (e.g. aldehydes, carboxylic acids) are endogenous in humans (Lington and Bevan, 1994).

Toxicokinetic studies for Alcohols, C7-9-iso, C8-rich (Isooctanol; Exxal 8) CAS number 685266-83-0 and Alcohols, C11-14 iso, C13-rich (Isotridecanol: Exxal 13) CAS number 68526-86-3 will be conducted in 2016-2017 to determine the saturation of absorption and excretion. This data will be used as part of the integrated testing strategy as outlined in appendix 1 of the CSR.

 

Linear and branched chain alcohols are initially oxidized to corresponding aldehydes and further to corresponding carboxylic acids by high capacity NAD+/NADH-dependent enzymes, which are then metabolized to carbon dioxide via the fatty acid pathways and the tricarboxylic acid cycle (Feron et al., 1991; Parkinson, 1996a).

 

Alcohol dehydrogenase (ADH) enzymes are the cytosolic enzymes that are primarily responsible for the oxidation of alcohols to their corresponding aldehydes. Alcohols also can be oxidized to aldehydes by non-ADH enzymes present in the microsomes and peroxisomes, but these are generally quantitatively less important than ADH. Aldehyde dehydrogenases (ALDH) oxidize aldehydes to their corresponding carboxylic acids. Branched-chain aliphatic alcohols and aldehydes have been shown to be excellent substrates for ADH and ALDH (Albro, 1975; Blair & Bodley, 1969; Hedlund & Kiessling, 1969). As carbon chain length increases, the rates of ALD-mediated oxidation also increase (Nakayasu et al., 1978).

 

The metabolism of branched-chain alcohols, aldehydes, and carboxylic acids containing one or more methyl substituents is determined primarily by the position of the methyl group on the branched-chain. Alcohols and aldehydes are rapidly oxidized to their corresponding carboxylic acids. The branched-chain acids are metabolized via beta-oxidation followed by cleavage to yield linear acid fragments which are then completely metabolized in the fatty acid pathway or the tricarboxylic acid cycle. Higher molecular weight homologues (>C10), may also undergo a combination of ω-, ω-1 and β-oxidation, and selective dehydrogenation and hydration to yield polar metabolites which are excreted as the glucuronic acid or sulfate conjugates in the urine and, to a lesser extent, in the feces (Diliberto et al., 1990). Thus, the principal metabolic pathways utilized for detoxification of these branched-chain substances are determined primarily by four structural characteristics: carbon chain length, and the position, number, and size of alkyl substituents.

 

Discussion on bioaccumulation potential result:

Alkyl Alcohols C6 to C13 are broken down by mitochondrial beta-oxidation or by cytochrome P450-mediated ω- and ω-1-oxidation (may be followed by β-oxidation). The alcohol undergoes various oxidative steps to yield other alcohols, ketones, aldehydes, carboxylic acids and carbon dioxide (Mann, 1987). Data for monohydric, saturated alcohols show a systematic variation according to molecular weight in a manner similar to many other homologous series (Monick, 1968). The analogs 1-hexanol and 1-dodecanol follow similar metabolic pathways by undergoing oxidative steps to yield aldehydes, carboxylic acid and eventually undergoing intermediary metabolism (van Beilen et al., 1992). Undegraded alcohols are conjugated either directly or as a metabolite with glucuronic acid, sulfuric acid, or glycine and are rapidly excreted (Lington and Bevan, 1994). Glucuronidation and glutathione conjugation are means of rapid elimination (Mann, 1987).