Alcohols, C11-14-iso-, C13-rich

Endpoint summary

Additional information

Isotridecanol is nearly completely absorbed following a single oral administration in rats and excreted in the urine, feces, and expired air. Plasma concentrations show proportionality relative to the administered dose. Isotridecanol and/or its metabolites were detected in all tissues; for the tissues with the highest concentration, AUClast values were often ≥ 3-fold higher relative to the plasma. There appeared to be little affinity for whole blood cells. The majority of the [14C]-isotridecanol equivalents–derived radioactivity was excreted in the first 24 hours postdose. There was no notable difference in the absorption, distribution, or excretion of [14C]-isotridecanol equivalents with respect to the sex of the rats. Based on the concentration of Isotridecanol equivalents remaining in tissue at 168 hours, approximately 4% to 6% of the dose was present in the in the animals at the end of the study. In addition, oral administration of Isotridecanol for 13 consecutive days and a single dose of [14C]- isotridecanol equivalents to Crl:CD(SD) rats at dosage levels of 50 and 400 mg/kg/day was well tolerated. Isotridecanol was nearly completely absorbed following oral administration and excreted primarily in the urine. The majority of the [14C]-isotridecanol equivalents were excreted in the first 24 hours postdose. There appeared to be little affinity for whole blood cells or any tissues types. Tissue concentrations were highest in the tissues associated with oral administration and urinary excretion, but [14C]-isotridecanol equivalents and/or its metabolites were also detected in notable concentrations in other tissues. [14C]-isotridecanol equivalents were still present in almost all tissues after 168 hours postdose. Overall, the exposure to tissues was generally usually low or equivalent relative to the plasma.

In an in vitro study designed to assess the metabolic stability and compare the metabolism of [¹⁴C]-isotridecanol representative structures and of isotridecanol whole product in cryopreserved hepatocytes from male Sprague Dawley rat and male New Zealand White rabbit, metabolic profiles were complex with the major differences observed between the test items and species were quantitative in nature rather than qualitative. Overall the metabolites observed following incubation of [¹⁴C]-isotridecanol representative structures with rat and rabbit hepatocytes were broadly comparable with oxidation and glucuronidation representing the two major metabolic routes. 

A follow-up study to the recent 90 -day studies on isotridecanol and isoundecanol were designed to evaluate the effects of isotridecanol and isounecanol on liver microsomal and peroxisomal enzyme activities. At termination in the 90-day study, liver tissue was taken, flash frozen and analyzed for enzymatic activity, measuring the following parameters: total protein content, total cytochrome P450 content and the activities of ethoxyresorufin-O-deethylation (EROD), pentoxyresorufin-O-depentylation (PROD), benzyloxyresorufin-O-debenzylation (BROD), benzyloxyquinoline-O-debenzylation (BQ), lauric acid hydroxylation (LAH), peroxisomal palmitoyl CoA oxidase (PCoA) activity and thyroxine (T4) glucuronidation (T4-GT). The data collected demonstrate that both isotridecanol and isoundecanol induce hepatic enzyme activity indicative of smooth endoplasmic reticulum (SER) and peroxisome proliferation in the rat (it is a weak inducer of EROD activity, a moderate inducer of BQ, LAH, PCoA and T4-GT activities, and a considerable inducer of PROD and BROD activities in male and female rats). These data ultimately support the hypothesis that thyroid effects observed in the isotridecanol and isoundecanol 90-day subchronic repeat dose study are secondary, adaptive changes to significant induction of liver enzymes.

 

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).

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).

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 in the longer branched-chain 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.