Alcohols, C8-10-iso-, C9-rich

Endpoint summary

Additional information

Following a single oral dose in rats, Isooctanol (68526 -83 -0) is nearly completely absorbed following oral administration and excreted primarily in the urine. Accordingly, tissue concentrations are highest in the tissues associated with oral administration and urinary excretion, but [14C]-isooctanol and/or its metabolites were detected in all tissues, usually at low or equivalent concentrations relative to the plasma. There appeared to be little affinity for whole blood cells or any tissues types, and the majority of the [14C]-isooctanol derived radioactivity was excreted in the first 24 hours postdose. There was no notable difference in the absorption, distribution, or excretion of [14C]-isooctanol equivalents with respect to the sex of the rats. In a repeat dose study, oral administration of Isooctanol (68526 -83 -0) for 13 consecutive days and a single dose of [14C]-isooctanol equivalents to rats at dosage levels of 50 and 400 mg/kg/day was well tolerated. Isooctanol was nearly completely absorbed following oral administration and excreted primarily in the urine. Accordingly, tissue concentrations were highest in the tissues associated with oral administration and urinary excretion, but [14C]-isooctanol equivalents and/or its metabolites were detected in all tissues, usually at low or equivalent concentrations relative to the plasma. There appeared to be little affinity for whole blood cells or any tissues types, and the majority of the Isooctanol was excreted in the first 24 hours postdosing. In an in vitro comparative metabolism study in rat and rabbit hepatocytes, metabolism of [14C]-isooctanol was rapid and extensive in both species tested with complete depletion of parent compound observed at 120 min. The metabolic profiles showed 21 areas of radioactivity being detected and quantified. Metabolism of [14C]-isooctanol was found to occur via oxidation and Phase II conjugation (glucuronidation and sulphation). The following structures were identified as metabolites in rat and rabbit: direct glucuronide conjugate(s) of [14C]-isooctanol, hydroxy glucuronide conjugate(s), sulphate conjugates of hydroxy [14C]-isooctanol, isomers of hydroxy [14C]-isooctanol, with the exception of carboxylic acid conjugate of [14C]-isooctanol (rabbit only).

 

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.

 

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 normally 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 their corresponding aldehydes and further to their 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 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.

 

Based on substance specific test data on isooctanol and isotridecanol, as well as general knowledge from the peer reviewed literature, it is expected that isononanol is nearly completely absorbed within 24 hrs, rapidly metabolized via beta-oxidation to aldyhydes and subsequently to correponding carboyxlic acids with selective conjugation to glucuoronic and sulfate compounds that can be excreted via urine and feces.