N-1-naphthylaniline

Carcinogenicity

Description of key information

Three animal studies are available, however they are all disregarded due to methodical deficiencies. An increased occurence of cancers was observed in one limited epidemiological study of occupationally exposed humans. However, because of the small number of excess deaths and concomitant exposure to other chemicals, it is not possible to attribute this finding solely to N-phenyl-1 -naphthylamine. Based on toxicokinetic considerations and taking into account that PANA is not genotoxic, there is currently no concern regarding carcinogenicity.

Justification for classification or non-classification

Not classified.

Additional information

Animal data

In a dermal carcinogenicity study an estimated amount of 0.75 mg/kg bw N-phenyl-1-naphthylamine (dissolved in 50 µL toluene) was applied to the skin of 50 male mice twice a week for 80 weeks. Data concerning the purity of the test substance or the formulation applied were not provided. No adverse effects on survival or increased incidence of skin tumours were observed; however, pigmentation, fibrosis, scar formation, acanthosis, and hyperkeratosis were noted. Histopathological examination of organs other than the skin were not performed (Kettering Laboratories, 1985).

Wang et al. (1984) observed an increased incidence of malignant tumours in male ICR and TA-1 mice following repeated subcutaneous administration of N-phenyl-1-naphthylamine (technical grade or pure; no additional data provided). The authors reported an increase of lung carcinomas and kidney hemangiosarcomas, with an increase of the incidence of kidney hemangiosarcomas in unilaterally nephrectomized rats. However, in they same study they reported similar results also for N-Phenly-2-naphthylamine, which was shown to be not carcinogenic in a 2-year NTP study in F344 rats and in male B6C3F1 mice. Threrefore, the reliability of the study performed by Wang et al. is questionable. In addition, the study is characterized by several pitfalls, i.e. the use of small numbers of animals of a single sex, limited dose groups, the absence of data on mortality and morbidity, use of a non-physiologically relevant route of exposure and insufficient characterisation of the test substance.

In a long-term study in which three dogs were orally administered 290 mg N-phenyl-1 -naphthylamine 5 days per week for up to 3.5 years, bladder tumours were not observed (DuPont, 1945; Gehrmann et al., 1948; McCormick, 1971). Owing to the limited number of animals and the examination for tumours only in the bladder, this study is inadequate for evaluation of the carcinogenic potential of N-phenyl-1-naphthylamine following oral administration.

Human data

An increased occurence of cancers in a small packaging unit in a Swedish engineering company was reported in a cohort study (Järvholm & Lavenius, 1981). A special anticorrosive oil, which contained 0.5 % N-phenyl-1 -naphthylamine in addition to other chemicals including white spirit as a major component had been used in this study. The female staff was mainly in contact with the oil. In 12 of 78 women cancers were diagnosed in several organs (predominantly the uterus and ovary). Morbidity and mortality from cancer were 3.1- and 3.5 -fold higher, respectively, than expected, based upon age-specific and sex-specific data from the Swedish Cancer Register. Among 20 male staff, no significant differences were established. When no anticorrosive oil had been used, morbidity and mortality from cancer were not elevated. The authors concluded that, apart from exposure to N-phenyl-1-naphthylamine, the formation of N-nitroso-N-phenyl-1-naphthylamine from sodium nitrite originating from the packaging paper used may be a possible explanation for the increased frequency of cancer. However, because of the small number of excess deaths and concomitant exposure to other chemicals, it is not possible to attribute this finding solely to N-phenyl-1 -naphthylamine. In addition, the mayour component white spirit is suspected to be carcinogenic so that the findings could be attributed to that chemical.

Assessment

Two studies are available in mice and dogs showing that after repeated exposure to PANA the tumor incidences are not increased. However, methodical deficiencies do not allow for a sound conclusion. In the study presented by Wang et al (1984), increases in hemangiosarcomas and lung carcinoma incidences have been observed after repeated subcutaneous application of PANA (of unknown purity) to male mice. However, in this study similar tumors haven also been reported for the isomer N-phenly-2-naphthylamine (PBNA). These tumors could not be confirmed in a 2-year NTP study with PBNA in both mice and rats. Therefore, the positive results observed with PANA are extremely questionable. Increases in tumor incidences in female workers can also not be exclusively correlated to PANA exposure, since they were also exposed to another mineral oil of unknown composition. One potential activation step is metabolic dephenylation of PANA to 1-naphthylamine. However, after incubation of rat hepatocytes with PANA, a dephenylation reaction could not be observed in vitro (Xuanxian et al. 1992). Similarly, Sikka et al. only reported hydroxylated derivatives in vitro (1981). Therefore, the dephenylation of PANA is rather unlikely. Apparently, dephenylation is generally not an expected metabolic reaction for this family of substances, since in their review from 2007 Weiss et al. concluded that dephenylation also of PBNA is occurring only at very low rates, explaining the lack of direct evidence of carcinogenicity of PBNA in both experimental and epidemiological studies. In addition, the potential PANA metabolite 1-naphthylamine is much less potent regarding genotoxicity than the known human carcinogen 2-naphthylamine, the dephenylation product of PBNA. Based on these considerations, and taking into account that PANA itself is not genotoxic based on various negative test results available, there is currently no concern in regard to carcinogenicity for PANA.