Diffuse Vacuolar Epithelial Degeneration in Rats Receiving Subchronic Vapor Exposure to Bis[2-(Dimethylamino)Ethyl] Ether (Dmaee)

Abstract

Four groups of Sprague-Dawley rats (15 rats/sex/group) were exposed by whole body to analytically measured concentrations of 0 (control), 0.23, 1.25, or 5.8 ppm bis/2-(dimethylamino)ethyl ether (DMAEE) vapor for 6 h/day, 5 days/wk, for 14 wk. Ten rats/sex/group were euthanized after the exposure regimen, and 5 rats/sex/group were euthanized after a 6-wk recovery period. An additional 3 rats/sex, exposed to 0 and 5.8 ppm, were sequentially sacrificed following 1, 3, or 5 exposures for electron microscopic evaluation. The only systemic toxicity was reduced body weight gain for the 5.8 ppm group throughout the exposure regmen. Clinical signs of ocular and nasal tract irritation (swollen eyelids and periocular and perinasal encrustation) were observed, primarily in the 5.8 ppm group, during the exposure and recovery periods. An ophthalmic examination, following 13 wk of exposure, revealed keratitis in males from the 5.8 ppm group and females from the 1.25 and 5.8 ppm groups. At necropsy, diffuse corneal color change and/or swollen eyelids were observed for the 1.25 and/or 5.8 ppm groups. Exposure-related microscopic lesions were seen only in tissues having direct contact with DMAEE, including nonhaired skin, eyes, and the upper respiratory tract. These consisted of necrosis, inflammation, and vacuolar degeneration of the nasal cavity mucosa and submucosa, and vacuolar degeneration of the larynx, trachea, bronchial epithelium, corneas, and glabrous or sparsely haired skin (pinna, muzzle, and eyelids). Nasal cavity lesions were present in rats from all exposure groups including the recovery period, while lesions in other tissues were observed only in the 5.8 ppm group at the 14-wk sacrifice. Electron microscopy of the nasal mucosa of rats from the 5.8 ppm group showed the development of intracytoplasmic membrane-bound vacuoles in the mucosal epithelium after a single exposure, and in the mucosa and submucosa after 3 and 5 exposures. Vacuoles developed from the coalescence of small secretory vesicles budding from the Colgi apparatus.