Toxicological Review for 2-Methylnaphthalene (CAS No. 91-57-6 ...

Three additional minor metabolites are formed via the 7,8-epoxide pathway. 1-Glutathionyl-7-
methylnaphthalene was identified in the urine of guinea pigs and by in vitro experiments with guinea pig
microsomes (Teshima et al., 1983). 7-Methyl-1-naphthol and 7-methyl-2-naphthol were identified in
the urine of 4 species (rats, mice, guinea pigs, and rabbits)
following oral exposure (Grimes and Young, 1956). The mammalian metabolism of 2-
methylnaphthalene has been analyzed in two quantitative experiments (Melancon et al., 1982; Teshima
et al., 1983). Melancon et al. (1982) administered single subcutaneous injections of 0.3 mg/kg
2-methyl[8- 14 C]naphthalene to 4 female Sprague-Dawley rats. In collected urine, 3-5% of the
administered dose was unchanged 2-methylnaphthalene, 30-35% was naphthuric acid, 6-8% were
other conjugates of naphthoic acid, 6-8% were dihydrodiols of 2-methylnaphthalene, 4-8% were other
nonconjugated metabolites, and 36-45% were other high-polarity unidentified metabolites. Teshima
et al. (1983) administered single oral doses of 10 mg/kg 2-[ 3 H]methyl-naphthalene to male Hartley
guinea pigs (3/group). At 24 hours, 78.6% of the total administered dose had been excreted in urine as
metabolites. Sixty-one percent of radioactivity in urine was accounted for by 2-naphthuric acid, 11%
by glucuronide conjugates of 2-naphthoic acid, 4% by unconjugated 2-naphthoic acid, 10% by
S-(7-methyl-1-naphthyl)cysteine, and at least 8% by metabolites of 7-methyl-1-naphthol. Additionally,
unquantified glutathione conjugates were detected in the livers of treated guinea pigs (Teshima et al.,
1983). Taken together, these reports indicate that the metabolism of 2-methylnaphthalene is rapid
(approximately 55% in rats within 3 days and approximately 80% in guinea pigs within 1 day) and that
80-85% of the metabolism occurs via oxidation of the 2-methyl group, with ring epoxidation accounting
for only 15-20%.
Standard assays in microsomal preparations (from male Sprague-Dawley rat liver, C57BL/J6
mouse liver and lung, and Swiss-Webster mouse liver, lung, and kidney tissues) demonstrate that the
initial steps of 2-methylnaphthalene metabolism are mediated by CYP enzymes (Breger et al., 1981;
Griffin et al., 1982; Melancon et al., 1985). The experiments further demonstrate that catalysis of 2-
methylnaphthalene metabolism to either dihydrodiols (the ring epoxidation pathway) or 2-
hydroxymethylnaphthalene (the alkyl-group oxidation pathway) required the cofactor NADPH and are
inhibited by heat denaturation or carbon monoxide. Other studies that measured covalent binding of
label from 2-methyl[8- 14 C]naphthalene to liver, lung, and kidney microsomal proteins of male Swiss-
Webster mice (Buckpitt et al., 1986) or liver slices of male ddY mice (Honda et al., 1990) observed a
similar dependence of binding on CYP activity (i.e., inhibited by cold temperature, nitrogen
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