Abstract for TR-500

Toxicology and Carcinogenesis Studies of Naphthalene in F344/N Rats (Inhalation Studies)

CASRN: 91-20-3
Chemical Formula: C10H8
Molecular Weight: 128.18
Synonyms/Common Names: Mothballs; moth flakes; naphthalin; naphthaline; naphthene; tar camphor; white tar
Report Date: December 2000

Full Report PDF


Naphthalene was previously tested in B6C3F1 Mice via inhalation (See TR-410 reported April 1992)

Naphthalene is used as an intermediate in the synthesis of phthalic and anthranilic acids, naphthols, naphthylamines, sulfonic acid, synthetic resins, celluloid, and hydronaphthalenes; it is also used in the preparation of anthraquinone, indigo, salicylic acid, and 1-naphthyl-N-methylcarbamate insecticide. It is an ingredient in some moth repellants and toilet bowl deodorants; it is also used in veterinary medicine in antiseptics for irrigating animal wounds and as an external medication to control lice on livestock and poultry. Naphthalene was selected for study by the National Toxicology Program because previous inhalation studies with naphthalene in mice were positive and existing studies in rats were either considered inadequate or were conducted via routes other than inhalation. Male and female F344/N rats were exposed to naphthalene (greater than 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells.

Two-year study

Groups of 49 male and 49 female rats were exposed to naphthalene by inhalation at concentrations of 0, 10, 30, or 60 ppm for 6 hours plus T90(12 minutes) per day, 5 days per week for 105 weeks. Additional groups of nine male and nine female rats were exposed to 10, 30, or 60 ppm for up to 18 months for evaluation of toxicokinetic parameters.

Survival, body weights, and gross observations

The survival of all exposed groups of male and female rats was similar to that of the chamber controls. Mean body weights of all exposed groups of males were less than those of the chamber control group throughout most of the study. Masses were observed in the nose of male and female rats. These masses frequently partially occluded the nasal passages or obliterated the normal architecture of the nasal turbinates.

Pathology findings

The incidences of neuroblastoma of the olfactory epithelium, a rare neoplasm, occurred with positive trends in males and females. Because this neoplasm did not occur in chamber control rats or in male rats exposed to 10 ppm and because this neoplasm has not been seen in the historical chamber control rats in NTP 2-year inhalation studies, the increased incidences of neuroblastoma were considered to be related to naphthalene exposure. In males, the incidences of adenoma of the respiratory epithelium of the nose, another rare neoplasm, occurred with a positive trend and were significantly increased in all exposed groups; none occurred in the chamber controls. In females, these neoplasms occurred in the 30 and 60 ppm groups but not in the chamber control or 10 ppm groups. Because these neoplasms did not occur in the chamber controls and have not been observed in the historical chamber control rats in NTP 2-year inhalation studies, the incidences of nasal adenoma were considered to be related to naphthalene exposure.

Increased incidences of nonneoplastic lesions of the nose associated with exposure to naphthalene included atypical hyperplasia, atrophy, chronic inflammation, and hyaline degeneration of the olfactory epithelium; hyperplasia, squamous metaplasia, hyaline degeneration, and goblet cell hyperplasia of the respiratory epithelium; and glandular hyperplasia and squamous metaplasia.

Toxicokinetic results model

A physiologically based toxicokinetic model was developed to characterize the disposition of inhaled naphthalene in rats. Because of its low vapor pressure and high blood-to-air partition coefficient, essentially all of the naphthalene that is absorbed into the general circulation is metabolized. At the exposure concentrations used in the 2-year study, approximately 20% to 30% of the inhaled dose was metabolized by male and female rats. Naphthalene that was not absorbed during exposure was assumed to be exhaled. The respective estimated daily doses metabolized by rats exposed to 10, 30, or 60 ppm for 6 hours (i.e., the internalized doses) are 3.6, 10.7, and 20.1 mg naphthalene/kg body weight for males and 3.9, 11.4, and 20.6 mg/kg for females.

Genetic toxicology

Naphthalene was not mutagenic in any of four strains of Salmonella typhimurium with or without induced liver S9 enzymes. However, in cytogenetic tests with cultured Chinese hamster ovary cells, naphthalene induced significant increases in sister chromatid exchanges with and without metabolic activation (S9) and in chromosomal aberrations with S9. Naphthalene did not induce chromosomal aberrations in the absence of S9 activation.


Under the conditions of this 2-year inhalation study, there was clear evidence of carcinogenic activity of naphthalene in male and female F344/N rats based on increased incidences of respiratory epithelial adenoma and olfactory epithelial neuroblastoma of the nose.

In male and female rats, exposure to naphthalene caused significant increases in the incidences of nonneoplastic lesions of the nose.


 Summary of the Two-year Carcinogenesis Studies of Naphthalene


F344/N Rats

F344/N Rats

Concentrations in air

Chamber control, 10, 30, or 60 ppm

Chamber control, 10, 30, or 60 ppm

Body weights

Exposed groups less than the chamber control group

Exposed groups similar to the chamber control group

Survival rates

24/49, 22/49, 23/48, 21/49

28/49, 21/49, 28/49, 24/49

Nonneoplastic effects

Nose: olfactory epithelium, hyperplasia, atypical (0/49, 48/49, 45/48, 46/48); olfactory epithelium, atrophy (3/49, 49/49, 48/48, 47/48); olfactory epithelium, inflammation, chronic (0/49, 49/49, 48/48, 48/48); olfactory epithelium, degeneration, hyaline (3/49, 46/49, 40/48, 38/48); respiratory epithelium, hyperplasia (3/49, 21/49, 29/48, 29/48); respiratory epithelium, metaplasia, squamous (0/49, 15/49, 23/48, 18/48); respiratory epithelium, degeneration, hyaline (0/49, 20/49, 19/48, 19/48); respiratory epithelium, hyperplasia, goblet cell (0/49, 25/49, 29/48, 26/48); glands, hyperplasia (1/49, 49/49, 48/48, 48/48); glands, metaplasia, squamous (0/49, 3/49, 14/48, 26/48) Nose: olfactory epithelium, hyperplasia, atypical (0/49, 48/49, 48/49, 43/49); olfactory epithelium, atrophy (0/49, 49/49, 49/49, 47/49); olfactory epithelium, inflammation, chronic (0/49, 47/49, 47/49, 45/49); olfactory epithelium, degeneration, hyaline (13/49, 46/49, 49/49, 45/49); respiratory epithelium, hyperplasia (0/49, 18/49, 22/49, 23/49); respiratory epithelium, metaplasia, squamous (0/49, 21/49, 17/49, 15/49); respiratory epithelium, degeneration, hyaline (8/49, 33/49, 34/49, 28/49); respiratory epithelium, hyperplasia, goblet cell (0/49, 16/49, 29/49, 20/49); glands, hyperplasia (0/49, 48/49, 48/49, 42/49); glands, metaplasia, squamous (0/49, 2/49, 20/49, 20/49)

Neoplastic effects

Nose: respiratory epithelium, adenoma (0/49, 6/49, 8/48, 15/48); olfactory epithelium, neuroblastoma (0/49, 0/49, 4/48, 3/48) Nose: respiratory epithelium, adenoma (0/49, 0/49, 4/49, 2/49); olfactory epithelium, neuroblastoma (0/49, 2/49, 3/49, 12/49)

Level of evidence of carcinogenic activity

Clear evidence

Clear evidence

Genetic Toxicology of Naphthalene
Assay Test System Results
Bacterial mutagenicity Salmonella typhimurium gene mutations: Negative in strains TA98, TA100, TA1535, and TA1537 with and without S9
Sister chromatid exchanges Cultured Chinese hamster ovary cells in vitro: Positive with and without S9
Chromosomal aberrations Cultured Chinese hamster ovary cells in vitro: Positive with S9, negative without S9