National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Naphthalene
• NAPTHENE

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: Naphthalene ingestion or inhalation can result in massive hemolysis in glucose-6-phosphate dehydrogenase deficient subjects; hemolysis in normal individuals occurs only with exposure to very high levels. [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 301]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Poisoning may occur by ingestion of large doses, inhalation, or skin absorption. [Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1008]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: The development of cataracts and retinal hemorrhage in a 44 yr old man occupationally exposed to powdered naphthalene /was reported/. Unilateral chorioretinitis /developed/ in a coworker. .../Cataracts developed/ in 8/21 workers exposed to naphthalene fumes or dust for < or = 5 years in a manufacturing setting. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Toxic effects in infants have been associated with naphthalene exposure (level not reported) of the mother during gestation. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Diapers or clothes stored with mothballs and used directly on infants have caused skin rashes and systemic poisoning. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Severe naphthalene poisoning in humans resulted in hemoglobinuria, methemoglobinemia, the production of Heinz bodies, ... death, and/or kernicterus. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 3]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Chronic abuse of mothballs containing naphtalene and paradichlorobenzene was reported to cause peripheral neuropathy and chronic renal failure. Chronic sniffing of naphthalene containing mothballs can cause liver necrosis. [IPCS; Poisons Information Monograph 363: Naphthalene. (Date of last update: September 2000). Available from: http://www.inchem.org/documents/pims/chemical/pim363.htm as of July 17, 2003. ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: /It was/ reported that a 26-yr-old woman and her 4-yr-old daughter, as well as 7 relatives living in two other households, had anemia, jaundice, headache, confusion, nausea, and vomiting. In addition, visitors to the womans apartment also became ill with headache, nausea, and vomiting. Excessive numbers of mothballs (used for years to curb odors and control insects) were found in all three households. Analysis of air samples collected on charcoal in the womans apartment revealed exposure levels of 20 ppb naphthalene, but the author pointed out that levels may have been much higher when fresh supplies of mothballs were introduced. When the use of mothballs was discontinued, the above signs and symptoms disappeared. [USEPA; Toxicological Review of Naphthalene p. 7 (August 1998). Available from http://www.epa.gov/iris/toxreviews/0436-tr.pdf as of July 21, 2003. ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Acute effects can be the result of dermal and inhalation exposure from clothing stored in moth balls. [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 339]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Symptomatology: A. Surface contact: 1. Naphthalene cataracts and ocular irritation. 2. skin irritation and, in the case of a sensitized person, severe dermatitis. Lesions clear spontaneously, as soon as the exposure is terminated. 3. Percutaneous absorption ... inadequate to produce acute systemic reactions except in newborns. B. Inhalation of vapor: 1. Headache, confusion, and excitement. 2. Nausea and sometimes vomiting, and extensive sweating. 3. Dysuria, hematuria, & the acute hemolytic reaction described below. 4. Rarely optic neuritis is encountered. C. Ingestion: 1. Abdominal cramps with nausea, vomiting, and diarrhea. 2. Headache, profuse perspiration, listlessness, confusion. 3. In severe poisoning, coma with or without convulsions. 4. Irritation of the urinary bladder ... Signs & symptoms: urgency, dysuria, & the passage of a brown or black urine with or without albumin & casts. ... 5. Acute intravascular hemolysis is the most characteristic sign. ... It begins on the 3rd day & is accompanied by anemia, leukocytosis, fever, hemoglobinuria, jaundice, renal insufficiency, and sometimes, disturbances in liver function. 6. In the absence of adequate supportive treatment, death may result from acute renal failure in adults or kernicterus in young infants. [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**
  
• SIGNS AND SYMPTOMS: Conjunctivitis, swelling of parotid glands, hepatomegaly, splenomegaly, tenesmus, and lenticular opacities in peripheral portions. [ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988., p. 353]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: The neurologic symptoms of naphthalene ingestion reported in human case studies include confusion, altered sensorium, listlessness and lethargy, and vertigo. Muscle twitching, convulsions, decreased responses to painful stimuli, and coma occurred prior to death in individuals who ingested naphthalene. At autopsy, the brain has appeared edematous with separation of neural fibers and swelling of myelin sheaths being noted histologically. The neurologic symptomatology could result from the cerebral edema, which was probably secondary to acute hemolysis. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p.43 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 17, 2003. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: In severe cases, ingestion caused gastroenteric distress, tremors, and convulsions. ...The bone marrow may appear hyperplastic and show an increased proportion of nucleated erythrocytes. In some cases, hemoglobinuria, possible occlusion of the renal tubules, and altered renal functions may occur. Death may ensue due to respiratory failure. [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 339]**PEER REVIEWED**
  
• CASE REPORTS: A 69 yr old black female exposed to naphthalene and paradichlorobenzene developed aplastic anemia two months after exposure. [Harden RA, Baetjer AM; J Occup Med 20: 820 (1978) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene (Draft) p.C-21 (1980) ]**PEER REVIEWED**
  
• CASE REPORTS: Two Greek infants died as a consequence of acute hemolysis that resulted from exposure to naphthalene-treated materials (clothing, diapers, blankets, rugs, etc.) Both infants exhibited a severe form of jaundice (kemicterus) which often causes brain damage. One infant suffered from a glucose-6-phosphate dehydrogenase (G6PD) deficiency. The other infant was apparently heterozygous for this trait. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p.13 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 16, 2003. ]**PEER REVIEWED**
  
• CASE REPORTS: Transplacental transfer of naphthalene or its oxidation products can occur. In two instances where young women developed the habit of sucking moth balls during the last trimester of pregnancy, hemolytic anemia was discovered in one of them a few days before delivery. In the other hemolytic anemia was detected later when her infant developed jaundice. No abnormality was noted in the babies at birth but jaundice was noted in one after 7 hours and in the other on the 3rd day. The mothers and babies recovered [IPCS; Poisons Information Monograph 363: Naphthalene. (Date of last update: September 2000). Available from: http://www.inchem.org/documents/pims/chemical/pim363.htm as of July 17, 2003. ]**PEER REVIEWED**
  
• CASE REPORTS: Death has been documented in humans who intentionally ingested naphthalene. A 17 yr old male died 5 days after the ingestion of an unknown quantity of naphthalene mothballs. Death was preceded by vomiting, evidence of gastrointestinal bleeding, blood-tinged urine, and coma. A 30 yr old female died following similar sequelae 5 days after reportedly swallowing 40 mothballs (25 were recovered intact from the stomach upon autopsy). [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p.22 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 17, 2003. ]**PEER REVIEWED**
  
• CASE REPORTS: A 1-yr old child who had accidentally ingested naphthalene showed increasing lethargy and anorexia 2 weeks later, followed by hemolytic anemia. ...In a 6 yr old child, 2 g administered over a 2-day period caused death. [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 339]**PEER REVIEWED**
  
• CASE REPORTS: A clinical case of suicide attempt by means of oral self-giving of naphthalene-containing oil in an old man was reported. Clinical features showed hemolytic anemia supported by a decrease of hemoglobin concentration and red blood cell count, an increase of bilirubin (prevalently indirect) and lactate dehydrogenase and very low levels of haptoglobin. Methemoglobin (metHb) measured at admission to the Emergency Room and 19 days after poisoning was still above normal limits. No deficiency of glucose-6-phosphate dehydrogenase was detected. The clinical manifestations ameliorated after treatment with concentrated red blood cells and ascorbic acid, with fast normalization of metHb. The clinical picture appeared almost normal 1 month after poisoning. The clinical diagnosis was 'hemolytic anemia caused by naphthalene'. Absence of glucose-6-phosphate dehydrogenase deficiency probably reduced the severity of poisoning. [Trevisan A et al; J Appl Toxicol 21 (5): 393-6 (2001) ]**PEER REVIEWED**
  
• CASE REPORTS: Two case studies were reported in which humans experienced eye irritation and conjunctivitis as a result of naphthalene exposure. In one case a worker accidentally got naphthalene powder in his left eye. The exact amount was unknown but described by the worker as large. Despite immediate cleansing of the eye, the subject experienced conjunctivitis and pain shortly after exposure. Symptoms of irritation subsided but then reappeared 6 weeks later. At that time the subject noticed decreased vision in his left eye. When examined by a doctor, the eye had retinal lesions (one fresh and others seemingly older); the entire retina appeared clouded. The subject's vision in his left eye was poorer than that in the right. Five years earlier, vision in both eyes was the same. In the second case study, an adult male who worked in a storage area where naphthalene was used as a pesticide complained of ocular pain, conjunctivitis, and impaired vision. Neither the duration nor the mode of exposure were described. The subject most likely was exposed to naphthalene vapors. When examined by a doctor, the subject was found to have retinal bleeding and the beginning of a cataract. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p.51 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 17, 2003. ]**PEER REVIEWED**
  
• CASE REPORTS: A 36 yr old pharmacist was given 5 g of unpurified naphthalene in an emulsion of castor oil in divided doses in the course of thirteen hr. On awakening eight to nine hr later he had severe pain in the bladder, and found that he was nearly blind, although previously he had had good vision. ... A yr later /examination showed/ the vision to be reduced to finger counting at 1.5 meters, unimproved by glasses, & the visual fields were constricted to 30-50 degrees. In both lenses were seen countless fine whitish opacities arranged as a zonular cataract about the nucleus with a narrow clear zone at the equator. ... Fundi could not be seen clearly ... the retinas appeared pale and turbid, the vessels were narrowed, ... the temporal portions of the papillas seemed pale. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 651]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Six cases of malignant tumors occurred among 15 workers exposed to vapors of naphthalene and coal tar for a period of up to 32 years at a coal tar naphthalene production facility: 4 individuals contracted laryngeal carcinoma and all were smokers; the other 2 workers developed neoplasms of the pylorus and cecum. No control group was examined. [Wolf O; Deutche Gesundheitwesen 31: 996 (1976) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: ...A 10-yr retrospective chart review of 160 patients with G-6-PD deficiency and/or anemia and an analysis of 24 hospitalized African-American children with an episode of acute hemolysis associated with G-6-PD deficiency were conducted. The parents of 330 children cared for in the pediatric emergency departments (EDs) of two tertiary care centers were questioned regarding domestic mothball (naphthalene) use. ...Fourteen of 24 (58.3%) of the children identified with G-6-PD deficiency presented with hemolysis associated with exposure to naphthalene-containing moth repellents. The remaining 10 had /infection-associated hemolysis/ (IAH). 79% of the /naphthalene-associated hemolysis/ (NAH) group required transfusion, compared with 60% of the IAH group. Mothballs were reportedly used by 27% of the families surveyed in one inner-city population with a 2-13% incidence of G-6-PD deficiency and by 15% in a more culturally diverse city. ... [Santucci K, Shah B; Acad Emerg Med 7 (1): 42-7 (2000) ]**PEER REVIEWED**
  
• BIOMONITORING: ...Concentrations of naphthalene and naphthols in breathing-zone air during a workshift and 1-naphthol and 2-naphthol in urine collected after the workshift were determined for 102 male workers. Gas chromatography with a flame ionization detector (GC-FID) was used to determine the air concentration. Urine naphthols were extracted after acid hydrolysis by solid-phase extraction and separated by the GC-FID method. Naphthalene homologues in air and their metabolites in urine samples were identified by gas chromatography-mass spectrometry. ...1-Naphthol, 2-naphthol and 1,4-naphthoquinone were identified in the urine samples. The time-weighted average concentrations of naphthalene and naphthols in the breathing-zone air showed that the exposure level of the workers was rather low. The geometric mean values were as follows: 0.77 and 0.87 mg/cu m for naphthalene, 0.016 and 0.034 mg/cu m for 1-naphthol, 0.012 and 0.067 mg/cu m for 2-naphthol during tar distillation and naphthalene oil distillation, respectively. The corresponding urinary concentrations of 1- and 2-naphthols were 693.1 and 264.4 umol/mol and 264.4 and 297.7 umol/mol creatinine, respectively. The correlation coefficients between the naphthol concentrations in urine and the breathing-zone air concentrations of naphthalene were statistically significant, varying in the range of 0.64-0.75 for 1-naphthol and 0.70-0.82 for 2-naphthol. There was linear dependence (r= 0.76) between the summary concentration of naphthols in urine and the naphthalene concentration in air. ... [Bieniek G; Scand J Work Environ Health 23 (6): 414-20 (1997) ]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: ...Mice and rats were exposed for 4 hr to naphthalene vapor at concentrations of 0-110 ppm. In rats, no injury was observed in the lung epithelium at exposure concentrations up to 100 ppm. Exposures as low as 2 ppm produced proximal airway injury in mice, with increased severity in a concentration-dependent fashion up to 75 ppm. Terminal airways of exposed mice exhibited little or no injury at low concentrations (13 ppm). Exposures of 8.5 ppm or higher were required to produce injury to Clara cells in the terminal airways. In contrast, administration of naphthalene (200 mg/kg ip) caused Clara cell cytotoxicity, which was limited to distal airways in mice. Higher doses (>300 mg/kg) extended the injury pattern toward the lobar bronchus. [West JAA et al; Toxicology and Applied Pharmacology 173 (2): 114-119 (2001) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Rats injected ip with 40 mg/kg naphthalene for 3 days exhibited arylhydroxylase inhibition. [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 336]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ...Naphthalene... was administered to mice (200 mg/kg) by ip injection. Shortly after injection (1, 2, and 3 hr), intracellular GSH content was assessed by high performance liquid chromatography or quantitative epifluorescent imaging microscopy and compared with the degree of cytotoxicity as assessed by high resolution histopathology. In highly susceptible airways (distal bronchioles), GSH decreased by 50% in 1 hr. Cytoplasmic vacuolization was not visible until 2 hr, when GSH had decreased by an additional 50%. By 3 hr, cytoplasmic blebbing was extensive. In minimally susceptible airways (lobar and proximal bronchi), GSH depletion varied widely within the population; a small proportion of the cells lost >50% of their GSH by 2 hr and a significant percentage of the cells retained most of their GSH throughout the entire 3 hr. Cytoplasmic vacuolization was apparent in some of the cells at 2 hr but not visible in any cells at 3 hr. ... [Plopper CG et al; Am J Respir Cell Mol Biol 24 (3): 272-81 (2001) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Whole-mount airway preparations isolated from the lungs of mice treated by ip injection of naphthalene and allowed to recover for 5 days were examined for the distribution and abundance of solitary pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) along the main axial pathway of the right middle lobe. Sham mice treated with corn oil vehicle were examined in a similar manner. An antibody to calcitonin gene-related peptide, a neuroendocrine cell marker, was used to identify the location, size, and number of PNECs and NEBs in the airways. After naphthalene treatment and epithelial repair, NEBs were significantly increased along the walls of the airways as well as on branch point ridges. The surface area covered by NEBs composed of 20 or fewer PNECs was significantly enlarged after naphthalene treatment compared with control NEBs of an equivalent cell number. The PNEC number per square millimeter was also increased more than threefold above control values after naphthalene treatment. ... [Peake JL et al; Am J Pathol 156 (1): 279-286 (2000) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Rabbits fed naphthalene exhibited browning of the lenses and eye humors, inhibition of the ciliary body and ascorbic acid transport, and the development of cataracts. [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 336]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: 225 mg/kg ip injection of naphthalene to C57BL/6J mice produced significant (30-70%) and prolonged (8-15 days) impairment in pulmonary microsomal monooxygenase activities without altering these activities in liver microsomes. [Tong SS et al; Exp Mol Pathol 37 (3): 358-69 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Naphthalene (0.05-2.0 mmol/kg) was administered in corn oil ip to C57B1/6J mice. Lung tissue from interim sacrificed animals was rapidly fixed and examined by electron microscopy. Mice in the higher dosage groups developed necrosis of secretory nonciliated bronchiolar cells. Epithelial structure returned to normal within seven days in all cases. No changes were noted in either untreated or corn oil-treated control group. [Mahvi D et al; Am Jour Pathol 86: 559 (1977) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Following the ip administration of naphthalene (200 mg/kg) to mice, the lung, in comparison with other organs, was selectively damaged. Histological exam of the lung showed that it was the non-ciliated, bronchiolar epithelial cells (Clara cells) which were damaged. At higher doses (400 mg/kg and 600 mg/kg, ip), there was also damage to the cells in the proximal tubules of the kidney. In contrast to the effect in mice, doses of naphthalene as high as 1600 mg/kg (ip) caused no detectable pulmonary or renal damage in the rat. This difference in toxicity between the mouse and rat was reflected by the ability of naphthalene to more severely deplete the non-protein sulfhydryls in the mouse lung and kidney than in the rat. ... [O'Brien KA et al; Chem Biol Interact 55 (1-2): 109-22 (1985) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Necropsy findings /in Sprague Dawley rats/ (study deaths): Multiple lesions of the stomach mucosa; and discolored lungs, adrenals, and intestines. [Papciak RJ, Mallory VT; J Am Coll Toxicol Pt B: Acute Toxicity Data 1 (1): 17 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: /Dermal sensitization/ study /was/ conducted /in Hartley guinea pigs/. ... Results: Induced and challenged at 100%. Challenge scores: incidence = 0/20; severity = 0.0 @ 48 hours. Naphthalene is considered to be non-sensitizing. [Papciak RJ, Mallory VT; J Am Coll Toxicol Pt B: Acute Toxicity Data 1 (1): 17 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: /Dogs/ administered 420 and 1530 mg/kg naphthalene (in a solid form) in a single oral dose /showed/ decreases of 29 and 33%, respectively, in blood hemoglobin concentrations. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-8 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Naphthalene produces selective injury to Clara cells in the mouse in vivo and in the isolated perfused lung. To investigate the role of circulating reactive metabolites in lung injury, the stability, metabolism and cytotoxicity of naphthalene oxide, a reactive intermediate, were examined in the perfused mouse lung. The t1/2 of naphthalene oxide is 4 min in Waymouth's medium. Addition of 5% bovine serum albumin of the medium increased the half-life of the epoxide to 11 min. Perfusion of the lung with 0.2 or 2 umol of naphthalene oxide decreased pulmonary reduced glutathione levels of 62 and 42% of control, respectively. 1,4-Naphthoquinone and naphthol glucuronide represented 36 and 25% of the total polar metabolites isolated after infusion of naphthalene oxide, whereas dihydrodiol and thioether conjugates were minor metabolites. In comparison, thioethers and dihydrodiol were the primary metabolites isolated from lungs perfused with (14)C naphthalene. Histologic examination of the lungs fixed 4 hr after infusion of naphthalene oxide (0.25-1.0 umol/60 min) revealed selective vacuolation and necrosis of Clara cells, significant decreases in the mass of bronchiolar Clara cells and increases in the mass of vacuolated cells. Injury to lungs perfused with naphthalene or secondary metabolites such as naphthoquinones, 1-naphthol and 1,2-dihydroxynaphthalene was less dramatic. In contrast to other studies implicating quinones as mediators of aromatic hydrocarbon toxicity, the current work suggests that epoxides play a significant role in naphthalene-induced lung injury. This investigation also demonstrates that circulating epoxides are capable of eliciting selective Clara cell injury. /Naphthalene oxide/ [Kanekal S et al; J Pharmacol Exp Ther 256(1): 391-401 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Pulmonary toxicities of naphthalene, 2-methylnaphthalene, 2-isopropylnaphthalene and 2,6-diisopropylnaphthalene were studied in mice. Twenty four hr after ip administration of naphthalene (200 mg/kg (1.6 mmol)) or 2-methylnapthalene (400 mg/kg (2.8 mmol)), pulmonary damage was detected. Prior treatment with diethyl maleate resulted in enhancement of naphthalene and 2-methylnaphthalene induced bronchiolar damage. In contrast to the effects of naphthalene and 2-methylnaphthalene, injections of 2-isopropylnaphthalene (3000 mg (17.6 mmol)/kg) and 2,6-diisopropylnaphthalene (3000 mg (14.2 mmol)/kg) did not cause detectable pulmonary damage. Injections of naphthalene and 2-methylnaphthalene caused considerable depletion of pulmonary reduced glutathione, while injections of 2-isopropylnaphthalene and 2,6-diisopropylnapthalene 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 p450 inducer (beta-naphthoflavone) increased the binding of naphthalene, 2-methylnaphthalene, and 2-isopropylnaphthalene to lung slices. Treatments with naphthalene, 2-methylnaphthalene, 2-isopropylnaphthalene and 2,6-diisopropylnaphthalene did not affect the lipid peroxidation or phospholipid contents in the lung. These results suggest that the differences in pulmonary toxicity among naphthalene, 2-methylnaphthalene, 2-isopropylnaphthalene and 2,6-diisopropylnaphthalene 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**
  
• LABORATORY ANIMALS: Acute Exposure: Maximum /dermal/ irritation score (erythema) was 2 (days 1 to 4); considered to be slightly irritating. /Dermal scoring was according to Draize/. No edema was observed. Slight fissuring of the skin was noted. All scores returned to normal by day 6. [Papciak RJ, Mallory VT; J Am Coll Toxicol Pt b: Acute Toxicity Data 1 (1): 17 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Draize ocular irritation scores = 0 of 110 (rinsed) and 3.8/110 (unrinsed); considered minimally irritating. All scores returned to normal by 72 hours. [Papciak RJ, Mallory VT; J Am Coll Toxicol Pt B: Acute Toxicity Data 1 (1): 17 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Dogs administered 3 g of naphthalene developed distemper-like attacks and moderate anemia. [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 336]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ...To address whether male and female mice are equally susceptible to naphthalene, mice were injected with naphthalene, and lungs were examined 1, 2, 3, 6, and 24 hr after treatment. By analysis of acute injury using differential permeability to fluorescent nuclear dyes and high-resolution histopathology, injury in female mice was found to be more extensive, occur earlier, and include permeable cells in proximal airways, including airway bifurcations. HPLC analysis of the products of cytochrome P-450 (CYP)-mediated metabolism in microdissected airways indicated that although both genders produced a predominance of products from CYP2F2, female mice produced more naphthalene dihydrodiol in distal airways, the primary sites of injury. ... [Van Winkle LS et al; Am J Physiol Lung Cell Mol Physiol 282 (5): 1122-34 (2002) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ...Adult, 14-day postnatal (DPN) and 7DPN male mice were given a single ip dose (25, 50, or 100 mg/kg) of naphthalene and killed 24 hr later. Epithelial damage, as assessed by quantitative histopathology, included cellular swelling, vacuolization, and exfoliation. In 7DPN mice, bronchiolar epithelium was severely injured at the lowest dose of naphthalene tested, 25 mg/kg. Bronchiolar epithelium in 14DPN mice was moderately injured at 25 mg/kg; injury severity was greatest at 50 and 100 mg/kg. Minimal bronchiolar epithelial injury occurred in adult mice at 50 mg/kg and moderate injury at 100 mg/kg. In proximal bronchi, epithelium of 7DPN mice showed signs of injury only at 100 mg/kg. Bronchial epithelium of adult mice was not injured at any dose. Isolated distal airways from 7DPN and 14DPN mice were more sensitive to naphthalene exposure than isolated distal airways from adult mice. Despite the low levels of P450 activity, differentiating Clara cells in neonatal mice are more susceptible to injury by the bioactivated cytotoxicant naphthalene than are differentiated Clara cells in adult mice. [Fanucchi MV et al; Toxicol Appl Pharmacol 144 (1): 96-104 (1997) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Severe bronchiolar epithelial-cell necrosis was reported in mice after intraperitoneal injection of naphthalene. Lung, liver, and kidney macromolecules were shown by a radiolabelling technique to be the main targets. Maximal binding of naphthalene was found 2-4 hr after application, and a threshold was found at 200-400 mg/kg bw, corresponding to glutathione depletion. Covalent binding was highest in tissues with high cytochrome P450 mono-oxygenase activity, i.e. lung, liver, and kidney. [WHO; Environ Health Criteria 202: Selected Non-heterocyclic Policyclic Aromatic Hydrocarbons p.513 (1998). Available from: http://www.inchem.org/documents/ehc/ehc/ehc202.htm as of July 17, 2003. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Oral administration of 1 g/kg/day to rabbits leads to lenticular changes, initially observed as swelling in peripheral portion of lens. ...Within 2 wk the whole lens is affected with mature cataract. ...Biochemical basis for cataract ...shown to be related to liver metabolite of naphthalene, 1,2-dihydro-1,2-dihydroxynaphthalene. [Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991., p. 536]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: After oral administration of naphthalene for 10 days to rats biochemical alterations occurred. Changes were significant in the liver where increases in liver weight, lipid peroxidation and aniline hydroxylase activity were noted. [Rao GS, Pandya KP; Toxicol Lett 8 (6): 311 (1981) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Short-term exposure: Adverse effects, associated ... with 267 mg/kg/day /for 14 days/ included increased mortality and decreased terminal body weights in male and female /CD-1/ mice, decreased absolute thymus weight (30%) in males, and increased bilirubin and decreased absolute and relative spleen and lung weights in females. There were no effects on hexobarbital sleeping time or on various immunological screening tests, with the exception that high-dose females had decreased response to concanavalin A in lymphocytes. A NOAEL of 53 mg/kg was identified. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-8 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: A NOAEL /in F344 rats/ was observed to be 50 mg/kg /5 days/week for 13 weeks by gavage/. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-8 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: A NOAEL /in B6C3F1 mice/ of 200 mg/kg/day /5 days /week for 13 weeks by gavage/ was ... identified. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-9 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ...Groups of 30 female A/J strain mice (6-8 weeks old) were exposed to 0, 10, or 30 ppm naphthalene (98%-99% pure) vapors for 6 hr/day, 5 days/wk for 6 months. After the 6-month exposure period, excised lungs were examined for tumors. Tumors were examined histologically. ...Survival was not different between the exposed and control groups. Lung tumors were found in all 20 positive control mice given single ip injections of 1 g urethane/kg; the mean number of tumors per mouse in the positive control was 28.9. Increased numbers of lung tumors were found in the naphthalene-exposed groups compared with the control group, but the differences were not statistically significant (6, 10, and 11 for the 0, 10, and 30 ppm groups, respectively). Tumors were described as alveolar adenomas consisting of large cuboidal or columnar epithelial cells supported by a sparse fibroblastic stroma and arranged in poorly defined acinar structures with papillary formations. No carcinomas were found. Naphthalene exposure did not significantly increase the percentage of animals with tumors (21%, 29%, and 30% for 0, 10, and 30 ppm mice, respectively). Statistically significant increases in the number of adenomas per tumor-bearing lung were observed in the exposed mice, but there was no increase in response with increasing dose. Mean numbers of tumors per tumor-bearing lung (standard deviation noted in parentheses) were 1.00 (0.00), 1.25 (0.07), and 1.25 (0.07) for 0, 10, and 30 ppm mice, respectively. [USEPA; Toxicological Review of Naphthalene p. 16 (August 1998). Available from http://www.epa.gov/iris/toxreviews/0436-tr.pdf as of July 21, 2003. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ...No evidence for immunotoxicity has been demonstrated /in mice/ despite prolonged exposure. Recently it has been suggested that this lack of effect may be related to the inability of splenocytes to metabolize naphthalene and/or to relatively low concentrations of metabolites that may be generated in the liver and diffuse to the spleen. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 442]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Feeding /naphthalene/ daily to Black-Hooded rats for 79 days caused gradual progressive development of cataract. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 957]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Daily oral administration of 1 g/kg of naphthalene to rabbits, produced lenticular opacity and peripheral swelling of the lens, slightly visible after three doses, and causing marked changes after 20 doses. Naphthalene causes changes in amino acid, ascorbic acid, protein, and carbohydrate metabolism of the eye, producing calcium oxalate crystals. [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 336]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: There was lympoid depletion of the thymus in 2 of 10 female rats exposed to 400 mg/kg/day naphthalene for 13 weeks. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene. p.42 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 17, 2003. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ...We have assessed the oral, low dose (0.05 LD50) chronic effects of naphthalene (110 mg/kg/day /orally/ in corn oil) for 120 consecutive days on lipid peroxidation and DNA fragmentation in the liver and brain tissues of female Sprague-Dawley rats. The animals were sacrificed on 0, 15, 30, 45, 60, 75, 90, 105 and 120 days of treatment. Maximum increases in hepatic and brain lipid peroxidation and DNA fragmentation were observed between 90 and 105 days of treatment. Following administration of naphthalene for 90 days, approximately 1.4- and 1.3-fold increases in lipid peroxidation were observed in the hepatic and brain tissues, respectively, while under the same conditions and time points 1.9- and 2.5-fold increases in hepatic and brain DNA fragmentation were observed, respectively. ... [Bagchi D et al; Res Commun Mol Pathol Pharmacol 101 (3): 249-57 (1998) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ...A 10% solution of naphthalene dissolved in paraffin oil was given every other day by gavage to 31 pigmented rabbits for 5 weeks, at a dose of 1 g/kg bw. Four rabbits who received only paraffin oil served as controls. The eyes were clinically followed up by means of ophthalmoscopy and retinal fluorangiography. At selected intervals, the eyes were examined with light microscopy and transmission electron microscopy. ...The first lesions were focal and appeared in the periphery of the fundus about 3 weeks after the beginning of treatment and tended to spread over the entire retina. Histologically, there was a degeneration of photoreceptors, accompanied by a reaction and proliferation of retinal pigment epithelium (RPE) that phagocytized the damaged visual cells. After about 3 months, the proliferation of RPE was followed by subretinal neovascularization (SRN). Both mature fenestrated and thick-walled non-fenestrated capillaries penetrated Bruch's membrane, enveloped by abundant fibrous extracellular matrix and accompanied by pericytes. As a consequence of this process, the retina was focally transformed into a "neovascular complex" in which a vascular plexus was intermingled with pseudo-acinar cavities lined by RPE. There were no signs of SRN at retinal fluorangiography, possibly because of the dense microenvironment of extracellular matrix and RPE cells of the neovascular complexes. ... [Orzalesi N et al; Invest Ophthalmol Vis Sci 35 (2): 696-705 (1994) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: A NOAEL /in BDI and BDIII rats/ was found to be 41 mg/kg/day (10 g/0.35 kg/700 days assuming a body weight of 0.35 kg). /Naphthalene was administered in the diet/. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-9 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: No carcinogenic response was observed ... in rats given oral doses of 10 to 20 mg/day naphthalene, 6 days/week from day 100 to day 800 of age, or in rats given either sc or ip injections of 20 mg naphthalene, 1 day/week for 40 weeks, and observed for the remainder of their lives. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-11 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Naphthalene... is thought to be carcinogenically inactive. No carcinomas were seen in hairless mice. Naphthalene has low DNA- and RNA-binding capacities. Naphthalene inhibits the tumorigenic potential of tobacco smoke condensate. It also inhibited the induction of skin tumors in mice that received naphthalene and benzo(a)pyrene. [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 338]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: 1-Methylnaphthalene did not damage the lung epithelium of rats when doses of up to 142 mg/kg were given by ip injection but there was increased vacuolization of the Clara cells in mice with a dose of 71 mg/kg. At comparable molar doses, cytotoxicity of 1-methylnaphthalene in mice was about one fourth that caused by naphthalene and 2-methylnaphthalene. Chronic oral exposure to 71.6-143.7 mg/kg/day 1-methylnaphthalene was associated with ...alveolar proteinosis in male and female mice. Proteinosis incidence ranged from 8.2% to 10% in the controls and from 34.7% to 46.0% in the treated mice, respectively. ...The lesions contained acidophilic amorphous material, foam cells, and cholesterol crystals. There was no apparent inflammation, edema, or fibrosis of the tissues. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p. 35, 78 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 16, 2003. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: The toxicologic and carcinogenic potential of naphthalene was studied by exposing groups of 49 male and 49 female F344 rats to atmospheres containing 0, 10, 30, or 60 ppm of the chemical for 6 hr daily, 5 days/wk for 2 yr. Mean body weights of exposed groups of male rats were less than for the control group throughout most of the study. Mean body weights of exposed female rats were generally similar to those of controls. Survival of exposed and control rats was similar. Under the conditions of this 2-yr inhalation study, naphthalene was carcinogenic to male and female F344/N rats, causing increased incidences of respiratory epithelial adenoma (males: control, 0%; low dose, 12%, mid dose, 17%; high dose, 31%; females: 0%; 0%; 8%; 4%) and olfactory epithelial neuroblastoma (males: control, 0%; low dose, 0%; mid dose, 8%; high dose, 6%; females: 0; 4%; 6%; 24%) of the nose. In both sexes of rats, exposure to naphthalene also caused significant increases in the incidences of nasal lesions including hyperplasia, atrophy, chronic inflammation, and hyaline degeneration of the olfactory epithelium and hyperplasia; squamous metaplasia, hyaline degeneration, and goblet-cell hyperplasia of the respiratory epithelium; and glandular hyperplasia and squamous metaplasia. [Abdo KM et al; Inhal Toxicol 13 (10): 931-50 (2001) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Treatment /of mated female CD-1 mice with 300 mg/kg/day of naphthalene by gavage/ began on gestation day 7 and continued for 8 consecutive days. Vehicle (corn oil) treated controls were maintained. Treatment was associated with maternal toxicity (increased mortality and reduced body weight gain) and fetotoxicity manifested as a reduced number of live young at birth. ...Offspring were not examined for malformations. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-10 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The administration to pregnant rabbits of 2-naphthol, a metabolite of naphthalene, has been associated with cataracts and evidence of retinal damage in the offspring. /2-naphthol/ [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-10 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Developmental toxicity and clastogenicity of naphthalene /was compared/ within an in vitro preimplantation mouse embryo culture system. Whole mouse embryos were collected 72 hr after conception and co-cultured in serum supplemented NCTC 109 medium containing 0.16 mM naphthalene. Embryos were harvested and karyotyped as a function of time over 48 hr post treatment. Chromosomal damage was greatest at 24 hr after exposure with a 10-fold incr observed in embryos exposed to naphthalene compared to untreated controls; a 30-fold incr in chromosomal damage was observed comparing untreated controls with cultures containing naphthalene & rodent hepatic S-9. These findings suggest that while naphthalene is minimally embryotoxic in the absence of exogenous biotransformation it is clastogenic; these observations indirectly indicate the presence of embryonic enzyme activity competent to metabolically activate naphthalene. Further, naphthalene clastogenicity markedly decr at 48 hr implicating the involvement of embryonic DNA repair. [Gollahon LS et al; Toxicologist 10 (1): 274 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The in vitro developmental toxicity of the bicyclic aromatic hydrocarbon naphthalene was characterized with a preimplantation mouse embryo culture system. Day 3 ICR mouse blastocysts were co-cultured with naphthalene for 1 hr either alone or in media supplemented with an Aroclor induced rat S-9 preparation and cofactors. Toxin treated blastocysts were subsequently cultured in NCTC 109 media with 10% fetal bovine serum for 72 hr to observe the developmental effects of exposure. Developmental parameters observed included viability, hatching, culture dish attachment and trophoblastic outgrowth with the presence of a distinct inner cell mass. At media concentrations up to 0.78 mM, naphthalene alone exhibited negligible toxic effects in culture; however naphthalene co-cultured with Aroclor induced rat hepatic S-9 fractions exhibited concn dependent embryolethality with an approximate LC50 of 0.18 mM in media. Naphthalene also induced concn dependent embryotoxicity at all observed parameters in S-9 supplemental media at concn ranging from 0.20 to 0.78 mM. These findings document the role of biotransformation in naphthalene's embryotoxicity to early mouse blastocysts and implicate naphthalene as a potentially embryotoxic and abortifacient component polycyclic aromatic hydrocarbon mixtures. [Iyer P et al; Toxicol 66 (3): 257-70 (1991) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In vitro embryotoxic effects of naphthalene /were monitored/ subsequent to in vivo exposure. Female ICR mice were injected on day 2 of gestation with naphthalene ip at either 14 mg/kg or 56 mg/kg. Embryos were collected on gestation day 3.5 and cultured in serum supplemented NCTC 109 medium for 72 hr. Embryos were examined during culture for viability, hatching, attachment and the presence of a distinct inner cell mass with trophoblastic outgrowth. Maternal napthalene doses at levels below the naphthalene LD50 inhibited the viability and implantation capability of fertilized embryos. Maternal exposure to naphthalene at 56 mg/kg and 14 mg/kg caused marked decreased in vitro attachment and embryonic growth; at the higher dose, delays in development were observed within 48 hr of culture. These findings support previous in vitro observations of naphthalene embryotoxicity and confirm the prenatal toxicity of this compound subsequent to in vivo exposure. [Iyer P et al; Toxicologist 10 (1): 274 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: No congenital abnormalities were observed after oral administration of naphthalene at 300 mg/kg/day to pregnant mice on days 7-14 of gestation, or at doses up to 400 mg/kg/day to pregnant rabbits on days 6-18 of gestation. Similarly, naphthalene was not teratogenic in rats at doses up to 450 mg/kg/day during gestation days 6-15. However, there was a slight, but dose-related, increase in fused sternebrae in female pups of rabbits administered doses of 20-120 mg/kg/day on days 6-19 of gestation. These effects were seen in 2 of 21 litters at 80 mg/kg/day and 3 of 20 litters at 120 mg/kg/day. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p.44 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 16, 2003. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Rats were exposed to 395 mg /naphthalene//kg bw by ip injections on days 1-15 of gestation. The treatment caused retardation of cranial ossification and developmental abnormalities in the cardiovascular system of pups from mothers treated with /naphthalene/. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 957]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: /Naphthalene/ (NAP)'s potential as a developmental toxicant was evaluated during the major period of organogenesis in the rat (/gestation day/ (gd) 6-15). NAP was administered in corn oil by gavage at 0, 50, 150, or 450 mg/kg/day. Dams were monitored daily for signs of toxicity, and on gd 20, fetuses were removed and examined for effects of NAP on growth, viability, and morphological development. All doses of NAP caused transient maternal CNS depresssion shortly after dosing. This effect persisted through gd 15 only in the 450 mg/kg/day group. Effects of NAP on maternal nutritional status and weight were confined to the 150 to 450 mg/kg/day groups. Feed and water intake was suppressed, but only on gd 6-9; water consumption then increased above normal from gd 9-18. During the dosing period, maternal body weight gain was decreased 31% and 53% relative to controls in the 150 and 450 mg/kg/day groups, respectively. Gestational (gd 0-20) and corrected (gestational weight-gravid uterine weight) maternal weight gains were also decreased at the mid and high doses. Liver weights (absolute and relative) were unaffected. NAP administration did not affect gravid uterine weight. The average number of corpora lutea/dam, implantation sites/litter, live fetuses/litter, and fetal body weight in the NAP-treated animals were within 95%-105% of controls. The incidence of malformations and variations in the NAP-treated groups were also compared to controls. These data indicate that the maternal NOAEL for NAP, based on CNS depression, was <50 mg/kg/day, and the developmental LOAEL, >450 mg/kg/day. [Navarro HA et al; Teratology 45 (5): 475 (1992) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Administration to rabbits of 0.1-1 mg/kg bw/day naphthalene by sc injection for 123 days resulted in severe edema and a high degree of vacuolar and collicular degeneration in the brain; necrosis of nerve cells also occurred. /It was/... suggested that hypoxemia resulting from hemolytic anemia was responsible for this finding. [WHO; Environ Health Criteria 202: Selected Non-heterocyclic Polycyclic Aromatic Hydrocarbons p.337 (1998). Available from: http://www.inchem.org/documents/ehc/ehc/ehc202.htm as of July 17, 2003. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Dose-related clinical signs of neurotoxicity were apparent in female Sprague-Dawley rats exposed to doses of 50, 150, or 450 mg/kg/day naphthalene for 10 days during organogenesis. Slow respiration and lethargy were observed in a large percentage of the exposed animals. Some rats were dazed, had periods of apnea, or were unable to move after exposure. In the lowest dose group, 73% of the animals were affected on the first day of dosing. In the two higher dose groups over 90% of the rats were affected. The animals in the lowest dose group acclimatized quickly. Symptoms were most apparent during the first 2 days of dosing. Signs of neurotoxicity persisted for longer periods in the higher dose groups. The severity and persistence of symptoms were related to dose. [DHHS/ATSDR; Toxicological Profile for Naphthalene, 1-Methylnapthalene, 2-Methylnapthalene p.44 (1995). Available from http://www.atsdr.cdc.gov/toxprofiles/tp67.html as of July 16, 2003. ]**PEER REVIEWED**
  
• GENOTOXICITY: The mutagenic activity from Cunninghamella elegans incubated 72 hr with various polycyclic aromatic hydrocarbons was evaluated in the Salmonella typhimurium reversion assay. All of the polycyclic aromatic hydrocarbons extracts were assayed in tester strains TA98 and TA100 both with and without metabolic activation using a liver fraction from Aroclor 1254 treated rats. None of the extracts from fungal incubations with the mutagenic polycyclic aromatic hydrocarbons ... naphthalene, ... displayed any appreciable mutagenic activity ... [Cerniglia CE et al; Arch Microbiol 143 (2): 105-10 (1985) ]**PEER REVIEWED**
  
• GENOTOXICITY: Naphthalene was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Naphthalene was tested at doses of 0.3, 1.0, 3.3, 10, 33, and 100 ug/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Naphthalene was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 100 ug/plate. Slight clearing of the background bacterial lawn occurred at /the highest/ dose in some cultures. [Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) ]**PEER REVIEWED**
  
• GENOTOXICITY: Naphthalene was not active in reverse mutation assays in ... Salmonella typhimurium with or without metabolic activation. Naphthalene was also not mutagenic in a Salmonella forward mutation assay with TM677. Negative results were reported for the Rec /Recombinational DNA Repair/ assay in Escherichia coli in the presence or absence of an exogenous mammalian metabolism system. ... No enhancement of /cell/ transformation was observed /in rat and mouse embryo cells infected with leukemia virus or in murine mammary gland organ cultures/. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-10 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• GENOTOXICITY: Naphthalene did not cause DNA damage in a rat hepatocyte alkaline elution assay. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-10 (1990) NTIS No. PB90-259821 ]**PEER REVIEWED**
  
• GENOTOXICITY: Incubation of human peripheral lymphocytes in medium containing naphthalene and a human liver metabolic activation system did not produce increased frequency of sister chromatid exchanges compared with controls. [USEPA; Toxicological Review of Naphthalene p. 7 (August 1998). Available from http://www.epa.gov/iris/toxreviews/0436-tr.pdf as of July 21, 2003. ]**PEER REVIEWED**
  
• GENOTOXICITY: /Naphthalene/ produces /chromosome aberrations/ in the somatic cells (threshold dose is 0.015 mg/kg bw). It is mutagenic for microorganisms. /Naphthalene/ was found to be positive in Salmonella mutagenicity test at concentrations of 5.0 and 10 ug/plate, but negative at 50, 100, or 1,000 ug/plate. There was no increase in forward mutation frequency in Salmonella. It was negative in a DNA damage Salmonella typhimurium strain TA1535/pSK1002 assay at a concentration of up to 83 ug/ml. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 957]**PEER REVIEWED**
  
• GENOTOXICITY: Naphthalene was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA135, TA1537, UTH8414 or UTH8413 either in the presence or absence of hamster or rat liver (S9) metabolizing system. No evidence for naphthalene mutagenesis was obtained in studies with culture embryonic rodent or mammary gland cells. Naphthalene was positive in culture chinese hamster ovary cell for the induction of chromosomal aberrations and sister-chromatid exchanges. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• GENOTOXICITY: Naphthalene was mutagenic in the marine bacterium Vibrio fischeri and in the Drosophila melanogaster wing somatic mutation and recombination test. [USEPA; Toxicological Review of Naphthalene p. 7 (August 1998). Available from http://www.epa.gov/iris/toxreviews/0436-tr.pdf as of July 21, 2003. ]**PEER REVIEWED**
  
• GENOTOXICITY: ...Naphthalene has not induced gene mutations in bacterial assays or in a metabolically competent human cell line. However, naphthalene has caused cytotoxicity in some cell lines, and induced clastogenicity in Chinese hamster ovary (CHO) cells, in a human lymphoblastoid cell line, and in preimplantation mouse embryos. Some naphthalene metabolites were cytotoxic, but only naphthoquinones produced chromosomal damage in vitro. No chromosomal damage was observed in vivo in bone marrow erythrocytes from treated mice; however, a positive response was reported in a Drosophila assay for wing somatic mutation and recombination. The five unpublished studies of naphthalene genotoxicity include three studies in vitro (two Ames bacterial assays and an in vitro unscheduled DNA synthesis assay) and two in vivo (mouse micronucleus and in vivo unscheduled DNA synthesis). Naphthalene was inactive in all five studies... . [Schreiner CA; J Toxicol Environ Health B Crit Rev 6 (2): 161-83 (2003) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: No carcinogenic activity was observed in an in vitro rat embryo cell/Rauscher leukemia virus test system at doses up to 0.1 g/l. [Freeman AE; JNCI 51: 799 (1973) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene (Draft) p.C-29 (1980) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: When a lens cell line from transgenic mice was exposed to the 1,2-dihydrodiol and 1,2-naphthoquinone metabolites of naphthalene, the dihydrodiol did not appear to be toxic but the naphthoquinone induced depletion of glutathione levels. Detoxification of naphthoquinone by the enzyme quinone oxidoreductase prevents formation of a semiquinone radical by two-electron reduction. /Naphthalene metabolites/ [WHO; Environ Health Criteria 202: Selected Non-heterocyclic Policyclic Aromatic Hydrocarbons p.492 (1998). Available from: http://www.inchem.org/documents/ehc/ehc/ehc202.htm as of July 17, 2003. ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: ...Both naphthalene and its metabolite 1-naphthol were bioactivated by human hepatic microsomes to metabolite(s) which were toxic to mononuclear leucocytes (MNL). However 1-naphthol was more cytotoxic than naphthalene (49.8 +/- 13.9% vs. 19.0 +/- 10.0% cell death; P<0.01), indicating that the toxicity of naphthalene is dependent on the bioactivation of 1-naphthol. CYP2E1-induced rat liver microsomes increased metabolism of naphthalene by 13% compared to control microsomes with a concomitant increase in both 1-naphthol and dihydrodiol formation. The cytotoxicity of naphthalene but not of 1-naphthol was increased by CYP2E1 induction, indicating that separate enzymes are involved in the bioactivation of 1-naphthol. The metabolites of 1-naphthol, 1,2-naphthoquinone (51.4 +/- 6.6% cell death) and 1,4-naphthoquinone (49.1 +/- 3.4% cell death) were directly toxic to MNL and depleted glutathione to 1.0% of the control levels. Both quinones were also genotoxic to human lymphocytes. In contrast, the primary metabolite of naphthalene, the 1,2-epoxide (0-100 microM) was neither cytotoxic nor genotoxic, and did not deplete glutathione. ... [Wilson AS et al; Toxicology 114 (3): 233-42 (1996) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: Selective lung damage and necrosis occurred in clara cells of mice admin naphthalene. It produced selective depression of pulmonary monooxygenase activities without accompanying changes in hepatic monooxygenase. A dose-dependent alteration of clara cells was noted. [Tong SS et al; Biochem Biophys Res Commun 100 (3): 944 (1981) ]**PEER REVIEWED**
  

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Human Toxicity Values

• A fatal /human/ dose from oral exposure /was reported/ to be approximately 2 g. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  

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Non-Human Toxicity Values

• LD50 Sprague Dawley rat oral 2.6 g/kg [Papciak RJ, Mallory VT; J Am Coll Toxicol Pt B: Acute Toxicity Data 1 (1): 17 (1990)]**PEER REVIEWED**
  
• LD50 New Zealand White rabbit dermal >2.0 g/kg [Papciak RJ, Mallory VY; J Am Coll Toxicol Pt B: Acute Toxicity Data 1 (1): 17 (1990)]**PEER REVIEWED**
  
• LD50 Male CD-1 mouse gavage 533 mg/kg [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990)]**PEER REVIEWED**
  
• LD50 Female CD-1 mouse gavage 710 mg/kg [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990)]**PEER REVIEWED**
  
• LD50 Male Sherman rat oral 2200 mg/kg [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• LD50 Female Sherman rat oral 2400 mg/kg [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-7 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• LD50 Mouse ip 150 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. 2373]**PEER REVIEWED**
  
• LD50 Mouse subcutaneous 969 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. 2373]**PEER REVIEWED**
  
• LD50 Mouse iv 100 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. 2373]**PEER REVIEWED**
  
• LD50 Guinea pig oral 1200 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. 2373]**PEER REVIEWED**
  
• LD50 Rat oral 490 mg/kg [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 336]**PEER REVIEWED**
  
• LD50 Rat dermal >20 g/kg [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 336]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Cutaneous absorption of naphthalene in infants is increased by baby oil. [Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972., p. 231]**PEER REVIEWED**
  
• When inhaled, naphthalene is rapidly absorbed... . [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 339]**PEER REVIEWED**
  
• At 100 mg/kg intraperitoneally, 20 to 30% was excreted in the rat urine, and 85 to 90% /of urinary excretion/ was in the form of acid conjugates; 5 to 10% was excreted in the bile and 70 to 80% /of biliary excretion/ was as acid conjugates. The major metabolite was naphthalene-1,2-dihydrodiol. [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 338]**PEER REVIEWED**
  
• In small oysters transport of naphthalene between tissues is primarily by diffusion. In intact oysters, accumulation in adductor muscle and body followed accumulation in gills after a large lag-time. In isolated tissues with no shell to impede water, there was no time lag. [Riley RT et al; Mar Biol (Berlin) 63 (3): 325 (1981) ]**PEER REVIEWED**
  
• The gills of Dolly Varden Char (Salvelinus malma) were the most important pathway for excretion of (14)C from (14)C-labeled naphthalene. In general, fish exposed to toluene excreted more (14)C than fish exposed to naphthalene. [Thomas RE, Rice SD; Biol Monit Mar Pollut, In Proc Symp Pollut Physiol Mar Org: 425 (1981) ]**PEER REVIEWED**
  
• English sole exposed to (3)H-benzo(a)pyrene and (14)C-naphthalene in sediment containing Prudhoe Bay crude oil. Bioconcentration value for (14)C-naphthalene was greater than values for (3)H-benzo(a)pyrene in tissues of fish exposed for 24 hr. [Varanasi U, Gmur DJ; Aquat Toxicol 1 (1): 49 (1981) ]**PEER REVIEWED**
  
• Naphthalene was readily taken up by tissue of laying pullets, swine, and dairy cattle after oral administration of a single dose or on a daily basis for 31 days. Adipose tissue, kidneys, livers, and lungs of pullets had the highest naphthalene levels after acute treatment; kidneys had high levels after chronic treatment. In swine, adipose tissues had high levels of naphthalene after acute treatment; lungs were highest with chronic treatment. In cattle, livers had the highest levels of naphthalene after both treatments. [Eisele GR; Bull Environ Contam Toxicol 34 (4): 549-56 (1985)]**PEER REVIEWED**
  
• Cutaneous and gastrointestinal absorption are facilitated when naphthalene is administered with oil or fat, respectively. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-4 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• Humans most absorb naphthalene by the inhalation route. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-4 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• Naphthalene and its metabolites have been reported to cross the human placenta in amounts sufficient to cause fetal toxicity. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-5 (1990) NTIS PB90-259821]**PEER REVIEWED**
  
• Reactive metabolites bind irreversibly with eye lens proteins and are associated with cataract formation. They also bind covalently with macromolecules in the lungs and may be associated with damage to the bronchiolar epithelium. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-6 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• Humans absorb naphthalene by pulmonary, gastrointestinal, and cutaneous routes. Naphthalene is found in the urine within a few days of ingestion. Naphthalene and its metabolites may be retained in adipose tissue. [Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1109]**PEER REVIEWED**
  
• Ingestion of naphthalene in the form of mothballs ... was eliminated unchanged in the feces. Greater danger exists when it is ingested in combination with fats, which facilitate the absorption of naphthalene. [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 339]**PEER REVIEWED**
  

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Metabolism/Metabolites

• It was shown: that 24-35% of an intraperitoneal dose of (14)C-naphthalene was eliminated as mercapturates by both mice and rats at 24 hours after dosing. For both species, this percentage was the same over a wide dose range (3.12-200 mg/kg body weight). In contrast, after inhalation exposure, the amounts of mercapturic acid in mouse urine were approximately twice those in rat urine at the same level of exposure. Over a 24 hour period, approximately 100-500 umol/kg body weight mercapturates were eliminated in urine of mice given intraperitoneal injections of 50-200 mg/kg body weight naphthalene. In mice exposed by inhalation to 1-100 ppm (5.24-524 mg/cu m) naphthalene for 4 hours, 1-240 umol/kg body weight total mercapturic acids were eliminated, while rats exposed to the same concentrations eliminated 0.6-67 umol/kg body weight. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V82 395 (2002)]**PEER REVIEWED**
  
• A 5 day old calf dosed orally with (14)C-propachlor excreted 70% dose in the urine as the cysteine conjugate; no mercapturic acid was detected. Rumen microflora were established in the calf (5 weeks older) and the experiment was repeated with the same results. When the same calf was dosed 1 week later with (14)C-naphthalene, 99% dose was excreted in the urine, mostly as the dihydrodiol glucuronide (34%) and the dihydrohydroxy cysteine conjugate (47%); no mercapturate was detected. ... Cysteine S-conjugate N-acetyltransferase activity in calf kidney and liver was about 10% of that n the corresponding rat tissues. [Bakke JE et al; Xenobiotica 20 (8): 801-8 (1990) ]**PEER REVIEWED**
  
• ...Metabolized via 1,2-epoxide into 1,2-dihydronaphthalene-1,2-diol, 1,2-dihydro-1-naphthol and N-acetyl-s-(2-hydroxy-1,2-dihydronaphthyl)-cysteine, which after further metabolism... Excreted in urine as 1-naphthylmercapturic acid ...and conjugates of 1,2-dihydronaphthalene-1,2-diol... 1- and 2-naphthols, and 1,2-dihydroxynaphthalene. [Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 219]**PEER REVIEWED**
  
• ...Naphthalene 1,2-oxide is intermediate in microsomal hydroxylation of naphthalene. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 329]**PEER REVIEWED**
  
• ...Naphthalene ...and monohalogenated benzenes are metabolized into mercapturic acids, conjugates in which n-acetylcysteine moiety replaces a hydrogen atom. [Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 92]**PEER REVIEWED**
  
• Naphthalene yields s-(1-naphthyl)glutathione in rabbit. Naphthalene yields s-(1-naphthyl)glutathione in rat, in mouse and in guinea pigs. /from table/ [Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. N-1]**PEER REVIEWED**
  
• Naphthalene yields cis-1,2-dihydro-1,2-dihydroxynaphthalene in pseudomonas. /from table/ [Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. N-1]**PEER REVIEWED**
  
• Fish were exposed to... Naphthalene in sediment containing prudhoe bay crude oil. Naphthalene was metab to 1,2-dihydro-1,2-dihydroxynaphthalene glucuronide. [Varanasi U, Gmur DJ; Aquat Toxicol 1 (1): 49 (1981) ]**PEER REVIEWED**
  
• Cunninghamella elegans (a filamentous fungus) is capable of oxidizing naphthalene to trans-1,2-dihydroxy-1,2-dihydronaphthalene. Other metabolites were identified as 1-napthol, 2-napthol and 4-hydroxy-1-tetralone. [Cerniglia CE et al; Chem Biol Interact 44 (1-2): 119-32 (1983)]**PEER REVIEWED**
  
• Ringed seals (Phoca hispida) were exposed experimentally to oil contamination by feeding of a (14)C naphthalene crude oil in fish for up to 4 days at a rate of 5 ml/day. Mixed function oxygenase activity, measured as aryl hydrocarbon hydroxylase in liver and kidney, was found to be induced; in particular, /activity in the kidney was induced 3-fold/ mixed function oxygenase induction correlated with a high degree of conversion of crude oil hydrocarbons to water-soluble metabolites. Most of the radioactivity was found in the polar fraction of the plasma and urine. [Engelhordt FR; Comp Biochem Physiol 72 (1): 133-6 (1982)]**PEER REVIEWED**
  
• Naphthalene is first metabolized by hepatic mixed function oxidases to the epoxide, naphthalene-1,2-oxide. The epoxide can be enzymatically converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydronaphthalene or conjugated with glutathione. The dihydrodiol can then be conjugated to form a polar compound with glucuronic acid or sulfate or be further dehydrogenated to form the highly reactive 1,2-dihydroxynaphthalene. This too can be enzymatically conjugated with sulfate or glucuronic acid or spontaneously oxidized to form 1,2-naphthoquinone. [Van Heyningen R; Exp Eye Res 28: 437 (1979) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene (Draft) p.C-7 (1980)]**PEER REVIEWED**
  
• The urinary excretion of mercapturic acids was considered as an indicator for human exposure. [Summer KH et al; Toxicol Appl Pharmacol 50 (2): 207-12 (1979)]**PEER REVIEWED**
  
• ... In rabbits 1,2-dihydroxynaphthalene ... is produced enzymatically and by autoxidation, and /it is/ the metabolic intermediate responsible for naphthalene cataractogenesis. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 653]**PEER REVIEWED**
  
• Conjugates of glutathione, cysteinylglycine and cysteine, intermediates in formation of mercapturic acids, are excreted, particularly in bile, as metabolites of... naphthalene. ... [Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 92]**PEER REVIEWED**
  
• In the presence of glutathione and glutathione transferases, microsomal fractions prepared from fresh samples of human lung tissue obtained at resection metabolized naphthalene to naphthalene dihydrodiol and 3 glutathione conjugates at easily measurable rates. [Buckpitt AR, Bahnson LS; Toxicology 41 (3): 333-41 (1986) ]**PEER REVIEWED**
  
• Naphthalene and 2-methylnaphthalene cause a highly organ and species selective lesion of the pulmonary bronchiolar epithelium in mice. Naphthalene but not 2-methylnaphthalene induced pulmonary bronchiolar injury is blocked by prior administration of the cytochrome p450 monooxygenase inhibitor piperonyl butoxide, thus suggesting that metabolism by enzyme other than the p450 monooxygenases may be important in 2-methylnaphthalene induced injury. Since many of the polycyclic aromatic hydrocarbons are metabolized by the prostaglandin endoperoxide synthetase system and because detectable xenobiotic metabolizing activity has been associated with the prostaglandin synthetases in the Clara cell, the studies reported here were done to compare reduced nicotinamide adenine dinucleotide phosphate versus arachidonate dependent metabolism of naphthalene in vitro and to determine whether indomethacin, a potent inhibitor of prostaglandin biosythesis, was capable of blocking the in vivo toxicity of these two aromatic hydrocarbons. 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)C 2-methylnaphthalene also was strongly inhibited by incubation in a nitrogen atmosphere . ... 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 organs. These studies suggest that the major enzymes involved in the metabolic activation of naphthalene or 2-methylnaphthalene in vitro are cytochrome p450 monooxygenases and that cooxidative metabolism by the prostaglandin synthetases appears to play little role in the formation of reactive metabolites in vitro. [Buckpitt AR et al; Biochem Pharmacol 35 (4): 645-50 (1986) ]**PEER REVIEWED**
  
• In an experimental animal study, doses of naphthalene ranging from 1 ug to 1 g were administered in the feed to 3 young pigs and their urine was collected in 2 sequential 24 hr specimens. The major urinary metabolite, conjugated 1-naphthol, was separated by gas chromatography and detected by electron capture. Most 1-naphthol excretion occurred during the first 24 hr period following dosing. Metabolic 1-naphthol could be detected after administration of as little as 100 ug naphthalene. A linear relationship was observed between urinary 1-naphthol and oral dose (both expressed on the log scale) in 24 hr specimen (r squared = 0.961, p<0.05) and 48 hr specimens (r squared = 0.906, p<0.05). [Keimig SD, Morgan DP; Appl Ind Hyg 1(1):61-4 (1986)]**PEER REVIEWED**
  
• In vitro studies of naphthalene indicate that oxidation to the epoxide, naphthalene 1,2-oxide, is the initial biotransformation reaction in rats. This intermediate may then be converted to a number of other oxidation products (eg, phenols, dihydrodiols) or be conjugated with glutathione. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-5 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• Urinary radioactivity /of a single 100 mg/kg ip dose of (14)C-naphthalene/ (collected for 72 hours) accounted for 60% of the administered dose. The ether extractable portion of the urine accounted for 6% of the administered dose and consisted primarily of 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene at 60 and 28%, respectively, of the ether extractable radioactivity. Water soluble metabolites included 1-naphthol; 1,2-dihydro-1,2-dihydroxy-1-naphthyl sulfate; 1,2-dihydro-2-hydroxy-1-naphthyl glucuronide and N-acetyl-S-(1,2-dihydro-2-hydroxy-1-naphthyl)cysteine at 5.0, 8.0, 16.8 and 65.0% of the nonether-extractable urinary radioactivity, respectively. ... Glutathione and mercapturic acid conjugation are major detoxification pathways in rats. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-5 (1990) NTIS No. 259821]**PEER REVIEWED**
  
• Following the ip administration of naphthalene (200 mg/kg) to mice, the lung, in comparison with other organs, was selectively damaged. Histological examination of the lung showed that it was the non-ciliated, bronchiolar epithelial cells (Clara cells) which were damaged. At higher doses (400 mg/kg and 600 mg/kg, ip), there was also damage to the cells in the proximal tubules of the kidney. In contrast to the effect in mice, doses of naphthalene as high as 1600 mg/kg ip caused no detectable pulmonary or renal damage in the rat. This difference in toxicity between the mouse and rat was reflected by the ability of naphthalene to more severely deplete the non-protein sulfhydryls in the mouse lung and kidney than in the rat. In order to investigate the species difference in toxicity, the metabolism of naphthalene by lung and liver microsomes of the mouse and rat was studied. In all cases, naphthalene was metabolized to a covalently bound product(s) and to two major methanol soluble products, which co-chromatographed with 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene. However, both the covalent binding and metabolism were approximately 10-fold greater in microsomes prepared from mouse lung compared with those from the rat. [O'Brien KA et al; Chem Biol Interact 55 (1-2): 109-22 (1985)]**PEER REVIEWED**
  
• Oral median lethal doses naphthalene ranged from around 350 mg/kg in mice to 2200 mg/kg in rats. The toxicity of naphthalene and 2-methylnaphthalene is due to a bronchiolar necrosis that develops rapidly after inhalation exposure. Clara cells in the bronchiolar epithelium are the primary target for low doses of naphthalene and 2-methylnaphthalene. When given in multiple doses to mice the bronchiolar epithelium appears to develop a tolerance to naphthalene. 2-Methylnaphthalene is less acutely toxic than naphthalene. Mice have tolerated intraperitoneal doses of 2-methylnaphthalene as high as 800 mg/kg. Both naphthalene and 2-methylnaphthalene must be metabolically activated to form enantiomeric epoxides and diol epoxides to express their toxicity. Stereochemical investigations in the case of naphthalene conducted in mice have shown that a major reason for the selective injury to the bronchiolar epithelium may be the high degree to which it is epoxidated. No specific naphthalene or 2-methylnaphthalene metabolite that can damage Clara cells has been identified nor has a close relationship between the metabolic binding and toxicity been established. The Clara cell toxicity of naphthalene and 2-methylnaphthalene may be due to circulating metabolites. [Buckpitt AR, Franklin RB; Pharmacol Therapeut 41 (1): 393-410 (1989)]**PEER REVIEWED**
  
• The fate of glutathione conjugates derived from naphthalene metabolism at various dose levels (5-80 mg/kg) were examined in an effort to explore the potential use of urinary mercapturic acids as biomarkers of exposure to naphthalene and as indicators of the activity and stereoselectivity of cytochrome p450 dependent naphthalene epoxidation. This approach extends previous studies which demonstrated a high degree of stereoselectivity in the formation of (+)-1R,2S-naphthalene oxide from naphthalene in target tissue microsomes (mouse lung), but not in microsomal preparations isolated from nontarget tissues such as mouse liver. To validate the use of mercapturic acids as indicators of epoxide formation in vivo, individual naphthalene oxide glutathione adduct isomers were administered iv to mice, and urinary metabolites were identified and quantified. Mercapturates accounted for 69-75% of the administered dose in the 8 hr urines of animals treated with trans-1-(S)-hydroxy-2-(S)-glutathionyl-1,2-dihydronaphthalene (adduct 1) and 76-84% for trans-1-(R)-hydroxy-2-(R)-glutathionyl-1,2-dihydronaphthalene (adduct 2). Only 39-57% of the dose of trans-1-(R)-glutathionyl-2-(R)-hydroxy-1,2-dihydronaphthalene (adduct 3) administered to mice was excreted as the mercapturic acid derivative; however, two additional metabolites were detected which were not present in the urine of animals treated with adducts 1 or 2. The first metabolite, accounting for 2-4% of the dose of adduct 3, was not identified. The second metabolite, isolated by HPLC and identified by mass spectrometry as (hydroxy-1,2-dihydronaphthalenylthio)pyruvic acid, accounted for 14-25% of the administered dose of adduct 3. [Buonarti M et al; Drug Metab Dispos 18 (2): 183-9 (1990)]**PEER REVIEWED**
  
• Naphthalene induced pulmonary and renal toxicity and polycyclic aromatic hydrocarbon induced carcinogenesis are known to be mediated by their reactive metabolites. Subchronic exposure (90 days) of mice to naphthalene does not alter humoral and cellular mediated immune responses, whereas polycyclic aromatic hydrocarbons, such as benzo(a)pyrene and 7,12-dimethylbenzanthracene, are known to be immunosuppressive. To understand these differences, the antibody forming cell responses of splenocyte cultures exposed to naphthalene (2, 20, and 200 uM) were evaluated. At these concentrations, the antibody forming cell response to sheep red blood cells (RBC) was not affected. To determine if reactive metabolites of naphthalene were immunosuppressive, splenocytes were exposed to naphthalene metabolites by direct addition or through the use of a metabolic activation system. The addition of 1-naphthol (70 and 200 uM) and 1,4-naphthoquinone (2, 7, and 20 uM) resulted in a decreased antibody forming cell response. Suppression of antibody forming cell responses was also obtained by culturing splenocytes with liver S9 and naphthalene. Since splenic metabolism of naphthalene to nonimmunosuppressive metabolites may account for the absence of immunotoxicity, the types of naphthalene metabolites generated by splenic microsomes were determined. It was observed that splenic microsomes were unable to generate any detectable naphthalene metabolites, whereas liver microsomes were able to generate both 1,2-naphthalene diol and 1-naphthol. Thus, the absence of an immunosuppressive effect by naphthalene exposure may be related to the inability of splenocytes to metabolize naphthalene. Moreover, the concentration of naphthalene metabolites generated within the liver that may diffuse to the spleen may be inadequate to produce immunotoxicity. [Kawabata TT, White KL Jr; J Toxicol Environ Health 30 (1): 53-67 (1990)]**PEER REVIEWED**
  
• Workers occupationally exposed to /naphthalene/ were found to have 1-naphthol (0.89-4.86 mg/L) in their urine. /Naphthalene/ was metabolized to cytotoxic, protein-reactive, and stable, but not genotoxic, metabolite by human liver cytochrome P-450 enzymes, which is probably a 1,2-epoxide. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 957]**PEER REVIEWED**
  
• In mice, a large part of /naphthalene/ is metabolized to a glutathione adduct which is then converted by hydrolysis, deamination, and decarboxylation into corresponding mercaptolactic and mercaptoacetic acids. Metylthioesters are also formed. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 957]**PEER REVIEWED**
  
• Conversion to the hemolytic agents , alpha- and beta-naphthol and alpha- and beta-naphthoquinone, is rapid in the adult and very slow in the newborn. [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 339]**PEER REVIEWED**
  
• Detoxification of naphthalene in rabbits by conjugation with glucuronic acid may have a protective influence against development of naphthalene cataract. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 653]**PEER REVIEWED**
  
• ...Metabolites obtained from murine isolated livers perfused with 5 or 10 micromoles carbon-14 (C14) labeled /naphthalene (NA)//hr were compared with urinary metabolites identified in male B6C3F1-mice treated with 50mg/kg C14-NA in-vivo. ...The highest covalent binding in perfused homogenized liver samples was found in the microsomal and mitochondrial fractions. The... metabolites in the liver perfusate were identified as sulfate conjugates of naphthol and dihydroxynaphthlene and a glucuronide conjugate of naphthol and naphthyl-dihydrodiol. A N-acetyl-glutathione conjugate of naphthalene-oxide (NAG) and a glucuronide conjugate of dihydroxynaphthalene were identified... . The majority of the metabolites seen in the urine from in-vivo NA treated animals were also found... . These were identified as naphthyl-dihydrodiol and sulfate conjugates of naphthol and dihydroxynaphthalene and a glucuronide conjugate of naphthol; however, these metabolites were not as prominent in the urine profile as they were in the liver perfusate. The most prominent peaks identified... from in-vivo treated animals were NAG conjugates along with less prominent peaks corresponding to the NAG conjugate of naphthalene-dihydrodiol-epoxide, a mixed sulfate/glucuronide conjugate of dihydroxynaphthalene, a mercaptolactic-acid conjugate of naphthalene-oxide, a diglucuronide conjugate of dihydroxynaphthalene, and two unknowns. ... [Tsuruda LS et al; Drug Metab Disp 23 (1): 129-36 (1995) ]**PEER REVIEWED**
  
• The fungal metabolism of aromatic hydrocarbons has been studied using naphthalene and biphenyl as model compounds. Using (14)C naphthalene and the fungus Cunninghamella elegans, the major free metabolites were trans-1,2-dihydroxy-1,2-dihydro-naphthalene, 4-hydroxy-l-tetralone and 1-naphthol. The sulfate and glucuronic acid conjugates of 1-naphthol were the major water soluble metabolites which were isolated by thin layer chromatography and ion pair high pressure liquid chromatography. Field Desorption Mass Spectrometry was used to identify the sulfate conjugate whereas the trimethylsilyl derivative of the glucuronic acid conjugate was characterized by Electron Impact Mass Spectrometry. Analogous metabolites were formed from biphenyl which was hydroxylated at the 4 position and then conjugated. [Hutson DH, Roberts TR (eds); Progress in Pesticide Biochemistry & Toxicology Vol# 4 p.156 (1985) ]**PEER REVIEWED**
  
• The metabolism of naphthalene in mammals has been extensively studied. Naphthalene is first metabolized by hepatic mixed function oxidases to the epoxide, naphthalene-1,2-oxide. ... The epoxide can be enzymatically converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydronaphthalene or conjugated with glutathione. The dihydrodiol can then be conjugated to form a polar compound with glucuronic acid or sulfate or be further dehydrogenated to form the highly reactive 1,2-dihydroxynaphthalene. This too can be enzymatically conjugated with sulfate or glucuronic acid or spontaneously oxidized to form another highly reactive compound, 1,2-naphthoquinone. /Naphthalene/ [USEPA; Ambient Water Quality Criteria Doc: Naphthalene p.30 (1980) EPA 440/5-80-059]**PEER REVIEWED**
  
• Single gavage doses of naphthalene of 0, 30, 75 or 200 mg/kg /were administered/ to two male and two female yearling chimpanzees and five adult male SPF Wistar rats, and urinary excretion of thioether /was determined/. At 0, 30, 75 and 200 mg/kg, thioether excretion in rats was 94.4, 185.6, 279.6 and 502.0 umol/24 hr/kg, respectively. Thioether excretion by chimpanzees (measured at 0 and 200 mg/kg) did not increase as a result of exposure to naphthalene. [USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p.I-5 (1990) NTIS No. PB90-259821]**PEER REVIEWED**
  
• Urinary excretion of premercapturic acids and mercapturic acids represents a major excretory path in mice and rats, but one study with chimpanzees and another with rhesus monkeys indicated that urinary excretion of mercapturic acids may not be as important in primates. [USEPA; Toxicological Review of Naphthalene p. 6 (August 1998). Available from http://www.epa.gov/iris/toxreviews/0436-tr.pdf as of July 21, 2003. ]**PEER REVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.