### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 

### For Table of Contents, see home page: http://ntp.niehs.nih.gov/go/roc13 

## Naphthalene CAS No. 91-20-3 Reasonably anticipated to be a human carcinogen First listed in the Eleventh Report on Carcinogens(2004)



### Carcinogenicity Naphthalene is reasonably anticipated to be a human carcinogen based on sufficient evidence from studies in experimental animals. Cancer Studies in Experimental Animals Exposure of rats to naphthalene by inhalation caused nasal tumors, which are rare in this species. Two types of nasal tumor were ob

served: olfactory epithelial neuroblastoma of the nose, which is a highly malignant and extremely rare tumor of the lining of the nose, and respiratory epithelial adenoma, which also is rare (NTP 2000). At the time the National Toxicology Program study was published, nei

ther type of tumor had been observed in the historical controls (299 males and females) in NTP two-year studies that used the same feed as the naphthalene bioassay. (As of 2010, no nasal tumors had been observed in 1,297 male or 1,247 female controls.) The incidence of neuroblastoma of the olfactory epithelium increased with increas

ing exposure level in both sexes and was significantly increased at the highest exposure level in females. Some of the neuroblastomas also invaded the brain. The incidence of respiratory epithelial adenoma was significantly increased in males, but not in females. These find

ings are supported by a significantly increased incidence of benign lung tumors (adenoma) in female B6C3F 1 mice exposed to naphtha

lene by inhalation (NTP 1992). The International Agency for Research on Cancer (2002) concluded that there was sufficient evidence for the carcinogenicity of naphthalene in experimental animals.
Cancer Studies in Humans The data available from epidemiological studies are inadequate to evaluate the relationship between human cancer and exposure spe

cifically to naphthalene. Two case-series studies of cancer in individ

uals exposed to naphthalene were identified; the first study reported cancer of the larynx and at other tissue sites among German work

ers occupationally exposed to naphthalene, and the second reported colorectal cancer among Africans who had used a naphthalene com

pound for medicinal purposes (Ajao et al. 1988, NTP 2002). Studies on Mechanisms of Carcinogenesis Naphthalene caused mutations in insects, but not in bacteria or cul

tured human lymphoblastoid cells (Sasaki et al. 1997, Grosovsky et al. 1999, NTP 2002). It caused other types of genetic damage in some but not all test systems. In newt larvae, naphthalene induced micro

nucleus formation. In cultured mammalian cells, it caused chro

mosomal aberrations, sister chromatid exchange, and formation of kinetochore-negative micronuclei, but did not cause DNA strand breaks, formation of kinetochore-positive micronuclei, or cell trans

formation. Inhalation exposure of rats to naphthalene caused oxi

dative stress and DNA damage in liver and brain tissue (IARC 2002, NTP 2002). When administered to experimental animals dermally, orally, or by inhalation, naphthalene is rapidly absorbed and metabolized (NTP 2000). Evidence suggesting that naphthalene is absorbed in humans comes from studies of workers in a coke plant, which found that con

centrations of naphthalene metabolites in the urine were significantly correlated with concentrations of naphthalene in personal air sam

ples (Bieniek 1994, 1997). The first step in the metabolism of naph

thalene is formation of naphthalene-1,2-oxide (as two stereo i somers, 1 R ,2 S -oxide and 1 S,2R -oxide) through the action of cytochrome P450 enzymes in the presence of the coenzyme NADPH. These oxides are metabolized further by three pathways: (1) hydration by epoxide hy

drolases into dihydrodiols, (2) conjugation by glutathione transferases, and (3)  spontaneous rearrangement into 1

- naphthol and 2

- naph

thol, which are converted to naphthoquinones (Chichester et al. 1994, Shultz et al. 1999). Naphthalene is excreted in the urine as the un

changed parent compound or as metabolites, including 1

- naphthol, 2

- naphthol, naphthoquinones, dihydroxynaphthalenes, and conju

gated forms, including glutathione, cysteine, glucuronic acid, and sulfate conjugates (NTP 2002). The mechanism by which naphthalene causes cancer is unknown. A strong correlation has been observed between the rates of forma

tion of the stereoisomer (1 R ,2 S)-naphthalene oxide in various tissues and the selective toxicity of naphthalene to these tissues, suggesting that this metabolite may play a role in naphthalene’s toxicity to the lung and other tissues (Buckpitt and Franklin 1989). Oxidative dam

age and DNA breakage, observed in rat liver and brain tissue, may contribute to naphthalene’s toxicity and carcinogenicity. 

### Properties Naphthalene is a polycyclic aromatic hydrocarbon that exists at room temperature as a white crystalline solid with an aromatic odor. It is insoluble in water but soluble in methanol, ethanol, benzene, toluene, olive oil, turpentine, chloroform, carbon tetrachloride, ether, hydro

naphthalenes, fixed and volatile oils, and ethylene dichloride. It is sta

ble in closed containers under normal temperatures and pressures (Akron 2009). Physical and chemical properties of naphthalene are listed in the following table. Property Information Molecular weight 128.2 Density 1.162 g/cm 3 at 20°C Melting point 80.2°C Boiling point 217.9°C Log K ow 3.3 Water solubility 0.031 g/L at 25°C Vapor pressure 0.085 mm Hg at 25°C Vapor density relative to air 4.42 Source: HSDB 2009. 

### Use The principal use of naphthalene in the United States is as an inter

mediate in the production of phthalic anhydride, which in turn is an intermediate in the production of phthalate plasticizers, pharmaceuti

cals, insect repellents, and other materials. Naphthalene has also been used as an intermediate in the production of 1

- naphthyl- N -methyl

carbamate insecticides, β-naphthol, synthetic leather-tanning chem

icals, surfactants (e.g., naphthalene sulfonates), moth repellents, and toilet-bowl deodorizers (ATSDR 2005, HSDB 2009). In 1999, 59% of naphthalene was used for production of phthalic anhydride, 21% for production of surfactant and dispersant chemicals, 11% for produc

tion of insecticides, and 9% in moth repellents and for other purposes (CMR 1999). The Naphthalene Panel of the American Chemistry Council reported in 2002 that naphthalene was no longer used di

rectly in tanneries, in the textile industry, or in the production of toilet-bowl deodorizers and that β-naphthol was not manufactured in the United States (ACC 2002).

### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 2 

### Production Naphthalene is produced from either coal tar (which contains approx

imately 10% naphthalene), by condensation and separation of coal tar from coke-oven gases, or from petroleum, by dealkylation of methyl

naphthalenes. In the United States, most naphthalene was produced from petroleum through the 1980s. U.S. production of naphthalene peaked in 1968, at 900 million pounds, decreasing to 222 million pounds by 1994 (ATSDR 2005). In 2000, production was 235 mil

lion pounds, of which over 90% (219 million pounds) was from coal tar (CEH 2000). In 2002, estimated U.S. production capacity was 215 million pounds (ATSDR 2005). In 2009, two U.S. producers of naph

thalene were identified (SRI 2009). From 1989 to 1998, U.S. demand for naphthalene grew 0.5% per year. Demand was 246 million pounds in 1998 and 248 million pounds in 1999. Demand for naphthalene sulfonates, used primarily as su

perplasticizer additives to increase the flowability of concrete, grew steadily in the late 1990s (CMR 1999). In 2000, estimated consump

tion of naphthalene was 241 million pounds (ATSDR 2005). In 2009, naphthalene was available from 28 U.S. suppliers (ChemSources 2009). Between 1989 and 2003, U.S. imports of naphthalene ranged from a high of 18.5 million kilograms (40.9 million pounds) in 1989 to a low of 1.1 million kilograms (2.5 million pounds) in 1999. In 2008, imports totaled 8.1 million kilograms (17.9 million pounds). Between 1989 and 2008, U.S. exports of naphthalene ranged from a low of 2.5 million liters (660,000 gallons) in 1993 to a high of 64.9 million liters (17.1 million gallons) in 1998; in 2009, exports were 4.8 million liters (1.3 million gallons) (USITC 2009). 

### Exposure The general population potentially is exposed to naphthalene through inhalation of ambient and indoor air. Accidental ingestion of house

hold products containing naphthalene, mainly by children, has been reported. Dermal exposure to naphthalene may occur through han

dling or wearing of clothing stored with moth repellents containing naphthalene. The average daily intake of naphthalene from ambient air was estimated at 19 μg, based on an average naphthalene concen

tration of 0.95 μg/m 3 in urban and suburban air and an inhalation rate of 20  m 3 /day (ATSDR 2005). According to the U.S. Environ

mental Protection Agency’s Toxics Release Inventory, environmen

tal releases of naphthalene have decreased annually since 1998, when almost 6 million pounds was released. In 2007, 983 facilities released over 2.7 million pounds of naphthalene, of which more than half was released to air (TRI 2009). The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that 112,700 workers potentially were exposed to naphthalene (NIOSH 1990). Workers identified by EPA as poten

tially exposed to naphthalene include beta-naphthol makers, cellu

loid makers, coal-tar workers, dye-chemical makers, fungicide makers, hydro na phthalene makers, moth-repellent workers, phthalic anhy

dride makers, smokeless-powder makers, tannery workers, textilechemical workers, and aluminum reduction plant workers (EPA 1980). No more recent occupational exposure surveys were found. However, industry estimates in 2002 indicated that about 1,000 workers were employed by the largest U.S. tar-distillation and wood-preservation company and that fewer than 50 workers in the moth-repellent in

dustry potentially were exposed to naphthalene (ACC 2002). These estimates did not include workers potentially exposed to naphthalene in production of phthalic anhydride and other uses. Workplace air concentrations of naphthalene have been measured in many studies and vary by industry. In the vulcanization step of tire manufacturing, naphthalene was measured at concentrations of up to 1.09 mg/m 3 , re sulting in an estimated daily intake of 0.0029 mg/kg of body weight (Durmusoglu 2007). A survey by the National Institute for Occupa

tional Safety and Health in 1980 reported air concentrations of naph

thalene as high as 10.2 μg/m 3 in an area sample and 19.3 μg/m 3 in a personal sample (ATSDR 2005).. 

### Regulations Coast Guard, Department of Homeland Security Minimum requirements have been established for safe transport of nitrobenzene on ships and barges. Department of Transportation (DOT) Naphthalene is considered a hazardous material, and special requirements have been set for marking, labeling, and transporting this material. Environmental Protection Agency (EPA) Clean Air Act Mobile Source Air Toxics:Listed as a substance for which regulations are to be developed. National Emission Standards for Hazardous Air Pollutants:Listed as a hazardous air pollutant. Clean Water Act Effluent Guidelines:Listed as a toxic pollutant. Designated a hazardous substance. Comprehensive Environmental Response, Compensation, and Liability Act Reportable quantity (RQ) = 100 lb. Emergency Planning and Community Right-To-Know Act Toxics Release Inventory:Listed substance subject to reporting requirements. Resource Conservation and Recovery Act Listed Hazardous Waste:Waste codes for which the listing is based wholly or partly on the presence of naphthalene = U165, F024, F025, F034, K001, K035, K087, K145. Listed as a hazardous constituent of waste. Occupational Safety and Health Administration (OSHA) While this section accurately identifies OSHA’s legally enforceable PELs for this substance in 2010, specific PELs may not reflect the more current studies and may not adequately protect workers. Permissible exposure limit (PEL) = 10 ppm (50 mg/m 3 ). 

### Guidelines American Conference of Governmental Industrial Hygienists (ACGIH) Threshold limit value – time-weighted average (TLV-TWA) = 10 ppm (50 mg/m 3 ). Potential for dermal absorption. National Institute for Occupational Safety and Health (NIOSH) Recommended exposure limit (REL) = 10 ppm (50 mg/m 3 ). Short-term exposure limit (STEL) = 15 ppm (75 mg/m 3 ). Immediately dangerous to life and health (IDLH) limit = 250 ppm (1,250 mg/m 3 ). 

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### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 3 Grosovsky AJ, Sasaki JC, Arey J, Eastmond DA, Parks KK, Atkinson R. 1999. Evaluation of the potential health effects of the atmospheric reaction products of polycyclic aromatic hydrocarbons. Res Rep Health Eff Inst 84: 1-22. HSDB. 2009. Hazardous Substances Data Bank. National Library of Medicine. http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB and search on CAS number. Last accessed: 8/12/09. IARC. 2002. Naphthalene. In Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene

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