VOL.: 82 (2002) (p. 367)
5. Summary of Data Reported and Evaluation
5.1 Exposure data
Naphthalene is a commercially important aromatic hydrocarbon which is produced from coal tar and petroleum. It is used mainly as an intermediate in the production of phthalic anhydride, naphthalene sulfonates and dyes and to a lesser extent as a moth-repellent. Human exposure to naphthalene can occur during its production, in creosote treatment of wood, in coal coking operations, during its use as an industrial intermediate, as a result of its use as a moth-repellent, and as a result of cigarette smoking.
5.2 Human carcinogenicity data
The only data available to the Working Group were two case series. No inference on the carcinogenicity of naphthalene could be drawn from these.
5.3 Animal carcinogenicity data
Naphthalene was tested for carcinogenicity by oral administration in one study in rats, by inhalation in one study in mice and one in rats and in one screening assay in mice, by intraperitoneal administration in newborn mice and in rats, and by subcutaneous administration in two studies in rats. Exposure of rats by inhalation was associated with induction of neuroblastomas of the olfactory epithelium and adenomas of the nasal respiratory epithelium in males and females. Both of these tumours were considered to be rare in untreated rats. In the screening assay study by inhalation using only female mice, there was an increase in lung adenomas per tumour-bearing mouse. In the inhalation study in mice, there was an increase in the incidence of bronchiolo-alveolar adenomas in female mice. An apparent increase in the incidence of these tumours in male mice was not statistically significant. The studies by oral administration in rats, intraperitoneal administration in mice and subcutaneous administration in rats were too limited for an evaluation of the carcinogenicity of naphthalene.
5.4 Other relevant data
Animal studies suggest that naphthalene is readily absorbed following oral or inhalation exposure. Although no data are available from human studies on absorption of naphthalene, the determination of metabolites in the urine of workers indicates that absorption does occur, and there is a good correlation between exposure to naphthalene and the amount of 1-naphthol excreted in the urine. A number of metabolites, including quinones, naphthols and conjugates (glucuronides, sulfates, glutathione) are derived from the 1,2-epoxide either directly or through multiple metabolic steps.
Naphthalene causes cataracts in humans, rats, rabbits and mice. Humans accidentally exposed to naphthalene by ingestion develop haemolytic anaemia, but there is no evidence of haemolytic anaemia in rodents. Cases of haemolytic anaemia have been reported in children and infants after oral or inhalation exposure to naphthalene or after maternal exposure during pregnancy.
Naphthalene causes lung toxicity in mice, but not rats, following either intraperitoneal injection or inhalation exposure. In mice, the injury is dose-dependent and Clara cell-specific. After repeated administration of naphthalene, mouse Clara cells become tolerant to the naphthalene-induced injury that occurs following a single dose of naphthalene. Acute and chronic exposure to naphthalene caused nasal toxicity in both mice and rats.
In isolated mouse Clara cells, 1,4-naphthoquinone and naphthalene 1,2-oxide were more toxic than naphthalene. Injury to Clara cells in perfused lungs occurred at lower concentrations of naphthalene 1,2-oxide compared with naphthalene or its other metabolites.
There is some evidence of developmental toxicity in rats and mice at dose levels that caused clear maternal toxicity. Clara cells of neonatal mice are more sensitive than those of adult mice to the cytotoxic effects of naphthalene.
There is little evidence for induction of gene mutations by naphthalene. In contrast, positive results were obtained in assays for micronucleus formation, chromosomal aberrations and chromosomal recombinations in vitro, which are consistent with a clastogenic potential.
Overall, the proposed mechanism of carcinogenic action is that the higher rates of metabolism of naphthalene in mice lead to cytotoxic metabolites in the lung, causing increased cell turnover and tumours. The absence of lung tumours in rats is entirely consistent with this mechanism. The maximal rates of metabolism measured in human lung microsomes are about 10–100 times lower than those in mice.
There is inadequate evidence in humans for the carcinogenicity of naphthalene.
There is sufficient evidence in experimental animals for the carcinogenicity of naphthalene.
Naphthalene is possibly carcinogenic to humans (Group 2B).For definition of the italicized terms, see Preamble Evaluation.
See Also: Toxicological Abbreviations Naphthalene (ICSC) Naphthalene (PIM 363)