NTP technical report on the toxicity studies of 1-Nitropyrene (CAS No. 5522-43-0) Administered by Inhalation to F344/N Rats.

1-Nitropyrene is a by-product of combustion. It is the predominant nitrated polycyclic aromatic hydrocarbon emitted in diesel engine exhaust and has been found at concentrations of up to 57 pg/m(3) in the air over urban and suburban areas. 1-Nitropyrene is detoxified mainly to 1-aminopyrene by nitro reduction. 1-Nitropyrene can also undergo ring oxidation, depending on the concentration of oxygen. Aryl nitrenium ions generated by nitro reduction or K-region nitropyrene epoxides generated by ring oxidation can react with DNA, forming adducts. 1-Nitropyrene was nominated for toxicity study because it is mutagenic, it is found in the environment, and it has potential for human exposure. Administration by inhalation was chosen because humans are exposed to 1-nitropyrene mainly by inhalation. Nose-only inhalation was chosen because whole-body inhalation exposure would require a large quantity of purified 1-nitropyrene that is expensive and difficult to procure. The study was performed in rats because of technical problems with conducting nose-only inhalation studies in mice and because mice are known to be more resistant to 1-nitropyrene toxicity. In the base study, groups of 10 male and 10 female 7-week-old F344/N rats were exposed to 0, 0.5, 2, 8, 20, or 50 mg/m(3) 1-nitropyrene aerosol, 6 hours per day, 5 days per week, for 13 weeks. At 13 weeks, rats were evaluated for histopathology, clinical pathology, and reproductive system effects. In a supplemental evaluation, toxicokinetic effects were assessed in male F344/N rats exposed to 1-nitropyrene for 13 weeks. All rats survived to the end of the 13-week exposure. For all groups, body weight gains of exposed rats were similar to those of concurrent controls (but lower than those of historical whole body inhalation study control rats); however, liver weights of exposed male rats were higher than those of the controls. There were slight variations in certain hematology and clinical chemistry parameters for some groups, but these were not considered related to 1-nitropyrene exposure. Squamous metaplasia of the respiratory mucosa was observed in the larynx of male rats exposed to 1-nitropyrene at a concentration of 2 mg/m(3) or greater and of female rats at all exposure concentrations. Squamous metaplasia of the bronchial epithelium also occurred in male and female rats in the higher exposure groups. Cytoplasmic alteration of the nasal respiratory epithelium was observed in both sexes exposed to 1-nitropyrene at a concentration of 8 mg/m(3)or greater. No treatment-related effects on sperm motility or vaginal cytology were noted. However, testicular atrophy was observed in all male rats and was considered a secondary effect resulting from the daily confinement within the exposure tubes. The elimination half-life of 1-nitropyrene in the lungs was about 1 hour for rats exposed to 8 mg/m(3)and 6 hours for rats exposed to 50 mg/m(3). Lung burdens of 1-nitropyrene in rats exposed to 8 mg/m(3) remained the same for the 13-week duration; however, lung burdens in rats exposed to 50 mg/m(3) increased with time indicating that the rats were unable to clear the 1-nitropyrene between exposures. The half-life of 1-nitropyrene in the plasma of rats exposed to 50 mg/m(3) was about 1 hour. Based on data contained in this report and previously published reports on the genetic toxicity, carcinogenicity, and toxicokinetics of 1-nitropyrene, it is the opinion of the National Toxicology Program (NTP) that 1-nitropyrene has a high likelihood of being carcinogenic to the respiratory tract, particularly under exposure conditions that lead to significant accumulations of 1-nitropyrene in the lungs, and perhaps other organs of F344/N rats. In summary, nose-only inhalation exposure to 1-nitropyrene for 13 weeks induced squamous metaplasia of the laryngeal and bronchial respiratory epithelium in male and female rats. Cytoplasmic alteration in the nasal respiratory epithelium were also induced in male and female rats. The no-observed-adverse-effect level (NOAEL) for male rats was 0.5 mg/m(3). A NOAEL for female rats could not be determined from these studies. Synonyms: 3-Nitropyrene; Pyrene, 1-nitro.