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Toxicity Effects

CAS Registry Number: 91-57-6

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

  • 2-Methylnaphthalene
  • Naphthalene, 2-Methyl-

Human Toxicity Excerpts

  • GENOTOXICITY: Chromosome analyses were carried out in human lymphocytes treated in vitro with 1- and 2-methylnaphthalene (1-MN, 2-MN) in the presence and absence of the mammalian metabolic activation system, S9 mix. Without S9 mix there was no indication of induction of any significant cytogenetic effect by either compound. With S9 mix a weak clastogenic effect was apparent at 4 mM 2-MN only and sister-chromatid exchange frequencies were significantly increased at each dose of 1- and 2-MN, yet always less than twice the control level. The present observations do not indicate that 1- and 2-MN must be classified as potential genotoxic substances. [Kulka U et al; Mutat Res. 208 (3-4): 155-8 (1988)] **PEER REVIEWED** PubMed Abstract
  • HUMAN EXPOSURE STUDIES: In contrast to naphthalene, the only reported effects of methylated naphthalene in man are skin irritation and skin photosensitization. /Methylated naphthalene/[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-309] **PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ALTERNATIVE and IN VITRO TESTS: Cultured rat hepatocytes were challenged with benzo[a]pyrene (BaP; 0.3-30 um), naphthalene (NAPH; 0.1-100 um), 2-methylnaphthalene (2-MNAPH; 0.1-100 um), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0.001-1 nm ), 2,3,7,8-tetrachlorodibenzofuran (TCDF; 0.005-5 nm) or pentachlorophenol (PCP; 0.1-100 um) for 4-24 hr to define class-specific differences in hepatotoxic potential. Mitochondrial fragility and GSH status were monitored as indices of hepatocyte injury.The aryl hydrocarbon receptor agonists upregulated hepatocyte GSH levels by 24 hr ... NAPH and 2-MNAPH transiently decreased hepatocyte GSH levels at 12 hr, but were without effect at later time points ...[Zhao W et al; Toxicology in Vitro 12 (2): 175-182 (1998)] **PEER REVIEWED**
  • GENOTOXICITY: Tobacco smoke condensates, 239 compounds representative of the gaseous and semivolatile phase of tobacco smoke, were assayed for mutagenicity towards 4-histidine requiring mutants of Salmonella typhimurium. 1- and 2-Methylnaphthalene were tested quantitatively using TA98 and TA100 with and without S9 from 3-methylcholanthrene induced rats the concentration used were 3 umol/plate. 1- and 2-methylnaphthalene were not mutagenic.[Florin I et al; Toxicol 15 (3): 219-32 (1980)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: ...Single doses of 0 or 300 mg/kg 2-methylnaphthalene /were administered/ to male Swiss-Webster mice (5/group) by intraperitoneal injection, with sacrifice 24 hours later. Histological examinations identified bronchiolar necrosis in all treated animals, and no lesions among controls. Pulmonary necrosis was considered moderate (bronchiolar epithelial cell swelling, vacuolization, and exfoliation) for 3/5 mice and severe (extensive sloughing in terminal and larger airways with widespread exfoliation) for 2/5 mice. For this study, the LOAEL for bronchiolar necrosis in male Swiss Webster mice is 300 mg/kg 2-methylnaphthalene.[EPA; Toxicological Review of 2-Methylnaphthalene (CAS No. 91-57-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) p.25 (December 2003). Available from, as of December 18, 2014: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showToxDocs] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: 2-Methylnaphthalene /admin orally at concn 5.00 mg/kg/ is lethal to /rats/.[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3338] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Both 1- and 2-methylnaphthalene produced depression of the respiratory rate in rats under acute inhalation exposure.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 341] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Male Swiss-Webster mice were exposed to naphthalene, 1-methyl-, 2-methyl-, 1-nitro- and 2-nitronaphthalene by intraperitoneal injection of peanut oil solutions over a dose range of 0.5-3.0 mmol kg-1 body weight. Treated mice were killed at times from 6 hours to 14 days post-treatment. Tissues were analyzed for cytotoxic effects by optical and electron microscopy, and for cell proliferation by autoradiography following in vitro labeling of lung slices with 3(H)-thymidine. The naphthalene derivatives varied widely in their cytotoxic effects. The most toxic was 1-nitronaphthalene with no mice surviving doses greater than 1 mmol kg-1. Naphthalene and 2-methylnaphthalene were about equally toxic, followed by 2-nitro- and 1-methylnaphthalene, in decreasing order of toxicity. In all cases the first evidence of cytotoxic effects was seen in the Clara cells of the bronchiolar epithelium, and, at the highest doses, toxic effects were found in the adjacent ciliated cells. Changes could be detected at the ultrastructural level at all doses, and within 6 hours after treatment. Only slight effects were seen in other cell types. Increased cell proliferation following chemical treatment was seen only in the bronchiolar epithelium, among cells tentatively identified as Clara cells or their precursors. Cytotoxic effects of naphthalene and its 1- and 2-methyl derivatives were confined to the lung, with minimal evidence of toxicity in the liver and kidney. The mononitronaphthalenes both produce small areas of centrizonal necrosis in the liver, but no discernible effects in the kidney. The experiments demonstrate the effect of small structural differences on the cytotoxicity of this group of environmental pollutants and also illustrate the sensitivity of the Clara cell as a target for xenobiotics.[Rasmussen RE et al; J Appl Toxicol 6 (1): 13-20 (1986)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: Neurotoxic and sensory respiratory irritation effects of 1-methylnaphthalene and 2-methylnaphthalene in male rats and male Balb/C mice were investigated under conditions of acute inhalation exposure. Rotarod performance and pain sensitivity behavior were tested in rats exposed to 1-methylnaphthalene at concentrations of 152-407 mg/cu m, and 2-methylnaphthalene at concentrations of 229-522 mg/cu m immediately after termination of a 4 hr exposure. The respiratory rate was measured in mice by the whole body pletysmographic method in 6 min duration exposure to various concentrations of 1-methylnaphthalene and 2-methylnaphthalene. Exposure to both methylated naphthalene derivatives resulted in concentration-dependent decrease in pain sensitivity in rats and depression of respiratory rate in mice. At the concentrations applied no statistically significant disturbances in rotarod performance behavior were observed. The concentrations depressing the respiratory rate to 50% (RD50) were 129 mg/cu m and 67 mg/cu m, for 1-methylnaphthalene and 2-methylnaphthalene, respectively. As based on RD50 values, the MAC values of 4 mg/cu m for 1-methylnaphthalene, and of 2 mg/cu m for 2-methylnaphthalene are suggested.[Korsak Z et al; Int J Occup Med Environ Health 11 (4): 335-42 (1998)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: Pulmonary toxicity of naphthalene (NAP), 2-methylnaphthalene (2-MN), 2-isopropylnaphthalene (2-IPN) and 2,6-diisopropylnaphthalene (2,6-DIPN) was studied in mice. Twenty four hr after the intraperitoneal (i.p.) administration of NAP (200 mg/kg (1.6 mmol) or 2-MN (400 mg/kg (2.8 mmol), pulmonary damage was detected. Prior treatment with diethyl maleate resulted in enhancement of NAP and 2-MN-induced bronchiolar damage. In contrast to the effects of NAP and 2-MN, injections of 2-IPN (3000 mg (17.6 mmol)/kg) and 2,6-DIPN (3000 mg (14.2 mmol)/kg) did not cause detectable pulmonary damage. Injections of NAP and 2-MN caused considerable depletion of pulmonary reduced glutathione (GSH), while injections of 2-IPN and 2,6-DIPN caused only a slight depletion. There were general decreases in the binding of the compounds to lung slices with increasing number of carbons of the alkyl substituent. Pretreatment with a cytochrome P-450 inducer (beta-naphthoflavone) increased the binding of NAP, 2-MN, and 2-IPN to lung slices. Treatments with NAP, 2-MN, 2-IPN and 2,6-DIPN did not affect the lipid peroxidation or phospholipid contents in the lung. These results suggest that the difference in pulmonary toxicity among NAP, 2-MN, 2-IPN, and 2,6-DIPN may be dependent on the ability of these compounds to irreversibly bind to lung tissue.[Honda T et al; Chem Pharm Bull 38 (11): 3130-5 (1990)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Acute Exposure: The effects of 1-methylnaphthalene (pure and practical grade) and 2-methylnaphthalene (pure and practical grade) on the hematocrit values, total and differential white blood cell counts, and reticulocyte counts were determined in intact and splenectomized dogs. Each compound was dispersed in the atmosphere in a refined kerosene base using a fogger. Exposures occurred on four consecutive mornings. Based on the information presented, it was not possible to determine the exposure concentration. Pure 1-methylnaphthalene increased the reticulocyte counts in the splenectomized dogs but not the intact dogs. Reticulocyte values remained elevated for 10 days after the fogging ceased. Practical grade 1-methylnaphthalene increased leukocyte counts in intact and splenectomized dogs and neutrophil counts in intact dogs, but pure 1-methylnaphthalene had no effect on these parameters. 2-Methylnaphthalene had no effect on any of the parameters monitored. Neither 1-methylnaphthalene nor 2-methylnaphthalene had an effect on hematocrit values, suggesting that these compounds do not cause hemolysis under the conditions of the study. Since the increased reticulocyte counts were seen only in splenectomized dogs, it is difficult to interpret whether or not this change signifies increased hematopoiesis in response to 1-methylnaphthalene exposure.[HHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene p.41 (August 2005). Available from, as of December 15, 2014: http://www.atsdr.cdc.gov/toxprofiles/index.asp] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Pulmonary alveolar proteinosis was induced at a 100% incidence in B6C3F1 female mice by twice weekly painting the back skin with methylnaphthalene for 30 weeks to give a total dose of 7.14 g/kg b.wt. Semithin sections were used for defining areas of type II pneumocyte hyperplasia and hypertrophy and associated proteinosis. Ultrastructurally, alveolar spaces were found to be filled with numerous myelinoid structures resembling the lamellar bodies of type II pneumocytes. Mononucleated giant cells (balloon cells) containing numerous myelinoid structures, lipid droplets and many electron dense amorphous acicular crystals were closely associated with this extracellular membranous material. Stacks of elastic fibers stained with tannic acid and bundles of collagen fibers were loose and discontinuous in the interstitium of affected areas.[Murata Y et al; Exp Toxicol Pathol 44 (1): 47-54 (1992)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: The toxicity and carcinogenic potential of 2-methylnaphthalene (2-MN) were examined in B6C3F1 mice. Groups of 50 male and 50 female mice were given diets containing 0, 0.075, and 0.15% 2-MN for 81 weeks. Both 0.075 and 0.15% 2-MN caused pulmonary alveolar proteinosis at high incidence: 55.1 and 45.8% in females and 42.9 and 46.9% in males, respectively. The incidences of total lung tumors, including bronchiolar/alveolar adenomas and carcinomas, were 20.4 and 12.2% in male mice given 0.075 and 0.15% 2-MN, respectively, the former value being significantly increased compared with the 4. 1% in control males. However, in the respective incidences of the adenomas and carcinomas, neither intergroup differences nor dose dependencies were observed. The incidences of other tumors did not differ between mice treated with 2-MN and the controls. The results indicated that 2-MN induces pulmonary alveolar proteinosis but does not possess unequivocal carcinogenic potential in B6C3F1 mice.[Murata Y et al; Fundam Appl Toxicol 36 (1): 90-3 (1997)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... The ability of 2-methylnaphthalene to induce cataract formation in rats /was evaluated/. While no cataracts were found in a group of 5 weanling F344 rats fed a diet of 2% 2-methylnaphthalene (equivalent to 2,000 mg/kg-day) for at least 2 months, cataracts were detected in rats fed an equivalent concentration of naphthalene. Evaluation of this study is limited by the lack of experimental details. In this study, 2,000 mg/kg-day was an apparent NOAEL for cataract formation.[EPA; Toxicological Review of 2-Methylnaphthalene (CAS No. 91-57-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) p.16 (December 2003). Available from, as of December 18, 2014: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showToxDocs] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: 2-Methylnaphthalene is an eye and skin irritant in rabbits.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 341] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: This paper presents toxic effects of 2-methylnaphthalene (2-MN) in laboratory animals under conditions of 4-week inhalation exposure to 2-MN vapors. Male Wistar rats were exposed to 2-MN vapors at a nominal concentration of 0, 2, 10 or 50 mg/cu m in dynamic inhalation chambers for 4 weeks (6 hr/day, 5 days/week). After 4 weeks of inhalation exposure the animals were necropsied. Blood samples were collected and selected organs were weighted and prepared for histological examinations. The effects of the increased levels of exposure to 2-MN experienced by the experimental rats were as follows: a) increasing gamma-glutamylotransferase activity, b) stimulation of the hematopoietic system, c) lower cholesterol concentrations, d) higher number of goblet cells in lobar bronchi, e) hyperplasia of hepatic bile ducts. Four-week exposure of the animals to 2-MN at 2 mg/cu m proved to be the no-observed-adverse-effect-level (NOAEL), while 10 mg/cu m appeared to represent the lowest-observed-adverse-effect-level (LOAEL).[Swiercz R et al; Int J Occup Med Environ Health 24 (4): 399-408 (2011)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: Intraperitoneal doses of 2-methylnaphthalene (2-MN) have been shown to cause pulmonary toxicity in DBA/2J mice. Pretreatment with the monooxygenase inducers sodium phenobarbital and 3-methylcholanthrene (3-MC) failed to protect the DBA/2J mice from the toxic effect of 2-methylnaphthalene. Pretreatment of DBA/2J mice with the monooxygenase inhibitors, SKF 525-A and piperonyl butoxide also failed to enhance or attentuate the pulmonary lesions. Pulmonary and hepatic microsomes from DBA/2J mice metabolized 2-methylnaphthalene to three dihydrodiols, 2-naphthyl alcohol and other unidentified metabolites. Kidney microsomes produced 2-naphthyl alcohol but no detectable dihydrodiols. In comparison to control animals, hepatic microsomes from animals pretreated with sodium phenobarbital produced more of the least polar dihydrodiol, while amounts of the other two dihydrodiols were unaffected. 3-Methylcholanthrene, piperonyl butoxide and diethylmaleate failed to affect dihydrodiol formation in both pulmonary and hepatic microsomes. After the administration of a lung toxic dose (400 mg/kg, i.p.) of 2-MN, irreversible binding was highest in the liver, followed by the kidney, the lung and lastly skeletal muscle. Of the pretreatments given to the mice, only phenobarbital demonstrated a significant effect, and this elevation was apparent only in the liver. A pulmonary toxic dose of 2-MN (400 mg/kg, i.p.) administered to DBA/2J mice significantly depleted reduced GSH in the liver and lung and to a lesser extent, in the kidney. There appeared no good correlation between the pulmonary toxicity of 2-MN-dihydrodiol and/or alcohol formation or the in vivo irreversible binding to macromolecules. These results are compared with those reported previously in C57BL/6J mice.[Griffin KA et al; Toxicology 26 (3-4): 213-30 (1983)] **PEER REVIEWED** PubMed Abstract

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 1630 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2268] **PEER REVIEWED**

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Absorption, Distribution And Excretion

  • ... Single intraperitoneal injections of 400 mg/kg (14)C-2-methylnaphthalene /were administered/ to male C57BL/6J mice. Groups of 4 mice were sacrificed at 0.5, 1, 3, 6, 12, or 24 hours after injection for measurement of radioactivity in fat, kidney, liver, and lung. Blood 2-methylnaphthalene concentrations decreased with a reported elimination half-life of 3 hours, indicative of rapid distribution to other tissues or elimination from the body. Peak tissue concentrations of 2-methylnaphthalene equivalents (nmol/mg wet weight) were attained about 1 hour after injection in the liver, 2 hours after injection in the fat, and 4 hours after injection in the kidney and the lung. Peak concentrations were highest in fat (13 nmol/mg), followed by lower concentrations in liver (3.5 nmol/mg), kidney (2.9 nmol/mg), and lung (0.7 nmol/mg). The results demonstrate that 2-methylnaphthalene did not preferentially accumulate in the lung although the lung was the only site of toxicity. Histological examination found that the single 400 mg/kg dose induced bronchiolar necrosis (minimal to prominent sloughing of lining cells in the bronchiolar lumen as revealed by light microscopy) in all exposed mice. No lesions were found in the liver or kidney of exposed mice at any time point. Consistent with the attainment of peak lung tissue concentration at 4 hours after injection, no lesions were evident until 8 hours after injection. The authors also evaluated distribution by measurement of irreversible binding of label from (14)C-2-methylnaphthalene to various tissues over a dose (0, 50, 100, 300, and 500 mg/kg; intraperitoneal injection) and time course (1, 2, 4, 8, 12, and 24 hrs). Maximum irreversible binding of 2-methylnaphthalene metabolites was observed in lung, liver, and kidney tissues at 8 hours post administration. The binding was dose- dependent in all tissues between 50-500 mg/kg and concentrations of bound radioactivity were higher in the liver and kidney than in the lung (the only tissue where lesions were found).[EPA; Toxicological Review of 2-Methylnaphthalene (CAS No. 91-57-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) p.7-8 (December 2003). Available from, as of December 18, 2014: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showToxDocs] **PEER REVIEWED**
  • 2-Methylnaphthalene was identified by gas chromatography/mass spectrometry in flesh extract of eels (Anguilla japonica temminck et schlegel) maintained in controlled laboratory environment of water with suspension of crude oil.[Ogata M et al; Water Res 13 (7): 613-8 (1979)] **PEER REVIEWED**
  • English sole were exposed to oiled (Alaskan north slope crude oil) sediments over 4 months to assess bioavailability and tissue hydrocarbon distribution kinetics in flatfish. Crude oil was mixed with aromatic hydrocarbon free sediments to a concentration of 700 ug/g dry weight at the beginning of the experiment. During the first month, this concentration decreased to 400 ug/g dry weight, and remained relatively stable during the remainder of the 4 month period. Flatfish accumulated alkane and aromatic hydrocarbons in skin, muscle and liver. 1- and 2-methylnaphthalene was accumulated to greater extent than other aromatic hydrocarbons. Tissue levels decreased with time, after 27 day continuous exposure only liver contained detectable levels.[McCain BB et al; J Fish Res Board Can 35 (5): 657-64 (1978)] **PEER REVIEWED**
  • The accumulation and elimination of (14)C in rainbow trout tissues following short and long term exposures to aqueous (14)C-labeled 2-methylnaphthalene was studied.[Melancon MJ JR, Lech JJ; Arch Environ Contam Toxicol 7 (2): 207-20 (1978)] **PEER REVIEWED** PubMed Abstract
  • The aim of the study was to evaluate the toxicokinetics of 2-methylnaphtalene (2-MN) during and after inhalation exposure. Male Wistar rats were exposed to 2-MN vapors at nominal concentrations of 200 or 400 mg/cu m in the dynamic inhalation chamber for 6 hours or 5 days (6 hr/day). Blood samples were collected during and after exposure. Blood concentrations of 2-MN were estimated by gas chromatography using the headspace technique. During a 6-hour exposure to 200 or 400 mg/cu m, blood 2-MN concentration increased rapidly within the first or second hour of exposure, respectively, after reaching a plateau. The elimination of 2-MN from blood followed an open two-compartment model. 2-MN was rapidly eliminated from blood of the animals exposed by inhalation to 2-MN. During exposure, lung retention of the chemical was found to decrease. Under conditions of repeated 2-MN exposure, no significant systemic 2-MN accumulation could be observed.[Swiercz R et al; Int J Occup Med Environ Health 23 (4):385-9 (2010)] **PEER REVIEWED** PubMed Abstract
  • The available animal data indicate that 2-methylnaphthalene is absorbed rapidly following ingestion (approximately 80% within 24 hours). Once absorbed, it is widely distributed among tissues, reaching peak concentrations in less than 6 hours. It is quickly metabolized by the liver, lungs, and other tissues. 2-Methylnaphthalene is rapidly excreted (approximately 70-80% within 48 hours in guinea pigs and 55% in rats), primarily as urinary metabolites.[EPA; Toxicological Review of 2-Methylnaphthalene (CAS No. 91-57-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) p.5 (December 2003). Available from, as of December 18, 2014: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showToxDocs] **PEER REVIEWED**
  • The tissue distribution of 2-methylnaphthalene was measured in guinea pigs 3, 6, 24, and 48 hours after oral administration of tritium-labeled 2-methylnaphthalene (10 mg/kg; 59 uCi/kg). The highest concentration of label was present in the gallbladder with 20.17 ug at 3 hours and 15.72 ug at 6 hours. (All concentrations are expressed in ug equivalents of (3)H/g wet tissue.) At 24 hours, the value fell to 0.43 ug and at 48 hours, to 0.04 ug. The presence of label in the gallbladder presumably reflects the excretion of hepatic metabolites in the bile. The values for the kidney were 5.64 ug at 3 hours, 7.62 ug at 6 hours, 0.29 ug at 24 hours, and 0.09 ug at 48 hours. Radiolabelled compound was detected in the liver immediately after exposure. When converted to units of mass, hepatic concentrations were 1.71 ug at 3 hours and 2.66 ug at 6 hours, falling to 0.18 ug at 24 hours. Lung concentrations were similar to those for blood at all time points. The amount in blood at 3 hours was 0.75 ug and that for the lungs was 0.69 ug; at 6 hours, the blood had a concentration of 0.71 ug and the lung had 0.76 ug. The half-life of 2-methylnaphthalene in the blood was 10.4 hours. The decay of naphthalene in the other tissues examined was described as biphasic.[HHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene p.96-7 (August 2005). Available from, as of December 15, 2014: http://www.atsdr.cdc.gov/toxprofiles/index.asp] **PEER REVIEWED**

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Metabolism/Metabolites

  • Intraperitoneal doses of 2-methylnaphthalene (2-MN) have been shown to cause pulmonary toxicity in DBA/2J mice. Pretreatment with the monooxygenase inducers sodium phenobarbital and 3-methylcholanthrene (3-MC) failed to protect the DBA/2J mice from the toxic effect of 2-methylnaphthalene. Pretreatment of DBA/2J mice with the monooxygenase inhibitors, SKF 525-A and piperonyl butoxide also failed to enhance or attentuate the pulmonary lesions. Pulmonary and hepatic microsomes from DBA/2J mice metabolized 2-methylnaphthalene to three dihydrodiols, 2-naphthyl alcohol and other unidentified metabolites. Kidney microsomes produced 2-naphthyl alcohol but no detectable dihydrodiols. In comparison to control animals, hepatic microsomes from animals pretreated with sodium phenobarbital produced more of the least polar dihydrodiol, while amounts of the other two dihydrodiols were unaffected. 3-Methylcholanthrene, piperonyl butoxide and diethylmaleate failed to affect dihydrodiol formation in both pulmonary and hepatic microsomes. After the administration of a lung toxic dose (400 mg/kg, i.p.) of 2-MN, irreversible binding was highest in the liver, followed by the kidney, the lung and lastly skeletal muscle. Of the pretreatments given to the mice, only phenobarbital demonstrated a significant effect, and this elevation was apparent only in the liver. A pulmonary toxic dose of 2-MN (400 mg/kg, i.p.) administered to DBA/2J mice significantly depleted reduced GSH in the liver and lung and to a lesser extent, in the kidney. There appeared no good correlation between the pulmonary toxicity of 2-MN-dihydrodiol and/or alcohol formation or the in vivo irreversible binding to macromolecules. These results are compared with those reported previously in C57BL/6J mice.[Griffin KA et al; Toxicology 26 (3-4): 213-30 (1983)] **PEER REVIEWED** PubMed Abstract
  • Metabolism of 2-methylnaphthalene in rats (in vivo and in vitro) ... was investigated. Conversion of 2-methylnaphthalene to both monohydroxylated compound and dihydrodiols was decreased by incubation with carbon monoxide, omission of NADPH or use of denatured microsomes, implying involvement of cytochrome(s) p450-linked mixed function oxidase activity. Pretreatment ... with phenobarbital and beta-naphthoflavone selectively altered the rate of formation of specific dihydrodiols by rat liver microsomes. Although phenobarbital had no significant effect on rate of dihydrodiol formation, beta-naphthoflavone was strong inducer.[Breger RK et al; Drug Metab Dispos 9 (2): 88-93 (1981)] **PEER REVIEWED** PubMed Abstract
  • 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. 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 or liver slices of male ddY mice observed a similar dependence of binding on CYP activity (i.e., inhibited by cold temperature, nitrogen atmosphere, piperonyl butoxide, and SKF 525A).[EPA; Toxicological Review of 2-Methylnaphthalene (CAS No. 91-57-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) p.11-2 (December 2003). Available from, as of December 18, 2014: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showToxDocs] **PEER REVIEWED**
  • The NADPH-dependent metabolism of naphthalene and 2-methylnaphthalene to covalently bound metabolites in lung or liver microsomal incubations occurred at easily measurable rates. Renal microsomal NADPH-dependent metabolism of either substrate was not detected. The formation of covalently bound naphthalene or 2-methylnaphthalene metabolites was dependent upon NADPH and was inhibited by the addition of reduced glutathione, piperonyl butoxide, and SKF 525A. Covalent binding of radioactivity from (14)C2-methylnaphthalene also was strongly inhibited by incubation in a nitrogen atmosphere or at 2 degree. The arachidonic acid-dependent formation of reactive metabolites from naphthalene or 2-methylnaphthalene was undetectable in microsomal incubations from lung, liver or kidney. Indomethacin, 1 hr before and 6 hr after the administration of 300 mg/kg naphthalene or 2-methylnaphthalene, failed to block the pulmonary bronchiolar injury induced by these aromatic hydrocarbons. These studies suggest that the major enzymes involved in the metabolic activation of naphthalene or 2-methylnaphthalene in vitro are the cytochrome P-450 monooxygenases and that cooxidative metabolism by the prostaglandin synthetases appears to play little role in the formation of reactive metabolites in vitro.[Buckpitt A et al; Biochem Pharmacol. 35 (4): 645-50 (1986)] **PEER REVIEWED** PubMed Abstract
  • The metabolism of 2-methylnaphthalene (2-MN) in guinea pigs (in vivo and in vitro) was investigated. Excretion of 2-MN from guinea pigs took place rapidly. In the first 24 hr, nearly 80% of the orally administered 2-(3H)-MN was excreted in the urine in the form of several metabolites, and about 10% of it was recovered in the feces. The major metabolites in the urine were oxidative products of the methyl group of 2-MN (naphthoic acid and its glycine and glucuronic acid conjugates) and accounted for 76% of the total urinary radioactivity in the first 24 hr. S-(7-Methyl-1-naphthyl)cysteine and glucuronic acid and sulfate conjugates of 7-methyl-1-naphthol were also identified as minor metabolites (18% of the total urinary radioactivity). As an in vitro metabolite, the formation of S-(7-methyl-1-naphthyl)glutathione was indicated using the 9,000g supernatant of the homogenate of guinea pig liver. The oral administration of 2-MN (500 mg/kg) to guinea pigs significantly lowered the trichloroacetic acid-soluble sulfhydryl content in the liver.[Teshima R et al; Drug Metab Dispos. 11(4): 152-7 (1983)] **PEER REVIEWED** PubMed Abstract
  • The oxidative metabolites of 2-methylnaphthalene (2-MN) were extracted from rat liver microsome suspensions. One monohydroxylated and three isomeric dihydrodiol metabolites of 2-MN were isolated and purified by HPLC. The metabolites were characterized by GC-MS together with 1H Fourier transform (1HFT) NMR. The identification of a 2-MN-monohydroxylated product as 2-hydroxymethylnaphthalene was confirmed by comparison of its HPLC retention time and NMR spectrum with that of a synthetic standard. The three isomeric dihydrodiol metabolites had different HPLC retention times, fragmentation patterns, ultraviolet, and 1H NMR spectra. GC-MS of the silylated dihydrodiols revealed the consistent presence of an ion peak at m/z 320, indicative of a disilylated dihydrodiol. Analysis of the 1H FT NMR spectra revealed the metabolites to be the 3,4-dihydrodiol, 5,6-dihydrodiol, and 7,8-dihydrodiol of 2-methylnaphthalene.[Breger R et al; Drug Metab Dispos 11(4): 319-23 (1983)] **PEER REVIEWED** PubMed Abstract
  • The uptake, disposition, biotransformation, and elimination of (14)C-labeled 2-methylnaphthalene was studied in several species of fish. (14)C /in bile/ from rainbow trout, carp, and sheepshead which had been exposed was present mainly /in/ metabolites. Most metabolites appeared to be conjugated. The disposition and metabolism of 2-methylnaphthalene in rainbow trout were affected by pretreatment with inducer of microsomal enzymes beta naphthoflavone. Biliary (14)C was higher in induced trout and tissues contained greater proportion of (14)C as metabolites in the induced trout than in the controls.[Melancon MJ JR, Lech JJ; Astm Spec Tech Publ; Iss Stp 667, Aquat Toxicol 5-22 (1979)] **PEER REVIEWED**
  • Urine was collected from four female rats for 3 days after two subcutaneous injections with 0.3 mg of 2-methyl(8-(14)C)naphthalene per kg. Of the (14)C injected, 55% was found in the urine. The urine was solvent-fractionated into a toluene fraction (4.9% of urine (14)C), a chloroform fraction (11.7%), two ethyl acetate fractions (41.7%), and a methanol fraction (37.8%). Only about 3-5% of urine (14)C appeared to be unchanged 2-methylnaphthalene. A major radioactive peak which was isolated from the chloroform fraction was further subdivided into three peaks by HPLC. These metabolites, which may be three isomeric dihydrodiols of 2-methylnaphthalene, represented 6-8% of urine (14)C. The more polar fractions contained several radioactive peaks when examined by TLC. One of these peaks was hydrolyzed with base to glycine and a 14C-labeled material which was similar to 2-naphthoic acid by TLC and by HPLC. Mass spectrometry of this latter material and of the unhydrolyzed metabolite confirmed the presence of 2-naphthoic acid and 2-naphthoylglycine, respectively. In total, 2-naphthoylglycine accounted for 30-35% of urine (14)C.[Melancon M et al; Drug Metab Dispos 10(2): 128-33 (1982)] **PEER REVIEWED** PubMed Abstract
  • Yields 2-naphthylcarbinol in pseudomonas. /from table/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. M-33] **PEER REVIEWED**
  • Yields cis-1,2-dihydro-1,2-dihydroxy-7-methylnaphthalene and trans-1,2-dihydro-1,2-dihydroxy-7-methylnaphthalene in pseudomonas. /from table/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. M-33] **PEER REVIEWED**

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Footnotes

1 Source: the NTP's CEBS database.

2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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