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ADME studies using C14 -radiolabelled sec-hexadecylnaphthalene indicate that oral absorption occurs to a low extent (~10% of radioactive dose) in rats (Huntingdon, 2002). Findings also indicated a low bioaccumulation potential in the tissues. The study substance was extensively metabolized to a large number of metabolites (28 discrete components) which were excreted in the urine. The metabolites have not been fully characterized in spite of extensive LC-MS and GC-MS analyses but preliminary data indicate that they are glucuronide or sulfate conjugates.

Metabolism of the sec-hexadecyl side-chain group rather than oxidation of the aromatic ring probably represent the major biotransformation pathway for the study substance. Literature review of metabolism and toxicity of long-chain alkylated naphthalenes (e.g., isopropyl and diisopropylnaphthalenes) (Hoke and Zellerhoff, 1998; Kojima et al. 1982) suggest that the sec-hexadecyl group in the study substance precludes biotransformation of the parent molecule into reactive and harmful intermediates (i.e. aromatic epoxides). Computational cytochrome P-450 modeling studies also predict that aromatic ring epoxidation of sec-hexadecylnaphthalene is not likely to occur due to poor substrate binding to the active site (i.e, bulky aliphatic group prevents fit) (Lewis et al 2002). Exclusive metabolism of the side-chain alkyl group in alkylnaphthalenes (e.g., alkyl group having more than 3 carbon atoms) has been postulated to account for the relative non-toxicity reported for diisopropylnaphthalene (DIPN) and thus, the favorable health safety properties of the parent material and its biotransformation products (see Hoke et al. 1998). Long chain alkyl groups in alkylnaphthalenes are believed to exclusively shunt metabolism of the parent chemical via side chain alkyl group pathway and not via the aromatic oxidation pathway. This precludes potential arene oxide formation or harmful/reactive metabolite involvement. Steric bulkiness of the long-chain alkyl group also contributes to poor substrate-active site binding with P450 metabolizing enzymes responsible for aromatic ring oxidation.

Elimination of water-soluble conjugated metabolites of the study substance occurs in the kidney with their ultimate excretion in the urine. Results from the oral radioactivity ADME studies indicate that urinary metabolites are comprised of glucuronide or sulfate conjugates (i.e., water-soluble, non-toxic). Extensive metabolism of the parent chemical and rapid excretion of metabolites in the urine suggest low bioaccumulation in the tissues (Huntingdon, 2002).

Dermal absorption is expected to be low or very limited based on extrapolation of the poor oral bioavailability results for the study substance. The physico-chemical properties of the study substance, particularly its high molecular weight and lipophilicity, may be limiting factors in the amount of material that is dermally absorbed. Owing to its low vapor pressure, exposure and respiratory absorption of the parent material via the lungs is not expected. The toxicokinetic and ADME characteristics of the study substance (i.e., low bioavailability, low bioaccumulation, exclusive metabolism via alkyl side-chain pathway to non-toxic biotransformation products) appear to be consistent with the low order of systemic toxicity observed in the acute and subchronic oral and dermal studies.