SUBCHRONIC NASAL TOXICITY OF HEXAMETHYLPHOSPHORAMIDE ADMINISTERED TO RATS ORALLY FOR 90 DAYS

Rats were administered hexamethylphosphoramide (HMPA) at dosages of 10 , 100, 300, and 1000 ppm in drinking water or at 15, 40, or 120 mg/kg/ day by gavage for approximately 90 days. Another group of rats was imp lanted subcutaneously with HMPA-filled osmotic minipumps, designed to deliver a dosage of 40 mg/kg/day to prevent the possibility of direct contact of HMPA with the nasal epithelium. After 90 days at 10 ppm in the drinking water, some rats had tracheas lined with regenerated epit helium, but no HMPA-related lesions were present in any other organs a nd tissues. At 100 ppm, nasal lesions (epithelial denudation, regenera tion, and squamous metaplasia) were mostly in the maxilloturbinates, t ips of nasoturbinates, and the adjacent septum in the anterior nasal c avity (level I), but the lesions were confined to the ventral region o f the mid-anterior nasal cavity (level II) and to recesses of the post erior nasal cavity (levels III and IV). At 300 ppm, nasal turbinates i n level I were partially adhered to the nasal septum by fibrous tissue . In level II the lesions were mainly confined to the ventral medial m eatus, but were scattered diffusely in levels III and IV. Denuded turb inates showed minimal bone proliferation. At 1000 ppm, the anterior na sal cavity was partially occluded by extensive adhesion of the turbina tes to the nasal septum by granulation tissue and proliferating turbin ate bone. The general architecture of the posterior nasal cavity was o bliterated by the marked proliferation of turbinate bone and fibrous t issue in the interturbinate spaces. Tracheas showed regenerated epithe lium and bronchi had focal epithelial denudation at 100, 300, and 1000 ppm. Foamy alveolar macrophages (histiocytosis) were increased in the lungs at 300 and 1000 ppm. Testicular atrophy occurred at 1000 ppm. N o other tissues were affected by HMPA treatment. Nasal lesions in rats given HMPA by gavage were identical in nature to, but sometimes sligh tly more severe than, the lesions in rats given HMPA in the drinking w ater. Rats given 40 mg/kg/day HMPA via an osmotic minipump had slightl y less severe nasal lesions than did the rats given the same dosage of HMPA by gavage. Testicular atrophy was present in the rats given 120 mg/kg/day by gavage. The results of this study show that, with the exc eption of bone proliferation, systemic delivery of HMPA or its metabol ites to the nasal tissue following oral administration causes tissue d amage similar to that caused by direct exposure of the nasal tissue vi a inhalation. Oral administration of HMPA is a less potent route for p roducing nasal lesions than is inhalation. (C) 1997 Society of Toxicol ogy.