Prechronic inhalation toxicity studies of isobutyl nitrite

Abstract

Isobutyl nitrite (IBN) is a volatile liquid that has become increasingly popular as an inhaled recreational drug. To investigate short-term toxic effects and establish exposure parameters for chronic inhalation studies, F344 N rats and B6C3F1 mice were exposed to IBN vapors on a 6 hr/day + t90,5 days/week schedule. Twelve exposures were administered at concentrations of 0, 100, 200, 400, 600, and 800 ppm IBN. This exposure series resulted in mortality in rats exposed to ≥600 ppm and mice exposed to 800 ppm. Animals exposed at the lower concentrations developed hyperplasia of the bronchiolar and nasal turbinate epithelium (rats and mice) and lymphocytic atrophy in the spleen and thymus (mice). Longer term, 13-week, subchronic exposures were conducted at concentrations of 0, 10, 25, 75, 150, and 300 ppm IBN. Exposure to 300 ppm IBN reduced the body weight gains in both sexes of rats and in female mice. IBN-related clinical pathology changes included reduced RBC counts accompanied by moderate increases in mean corpuscular volume and reticulocyte counts, increased WBC counts, and mildly increased methemoglobin concentration. Bone marrow hyperplasia was observed in all groups of IBN-exposed rats, while in mice only females at ≥150 ppm IBN displayed this change. Excessive splenic pulp hematopoiesis was noted in mice at all IBN exposure levels. Respiratory system changes included increased lung weights in rats and female mice at 300 ppm, hyperplasia of the nasal mucosa (male rats at ≥75 ppm and female rats at ≥150 ppm), and hyperplasia of the lung epithelium (male mice at ≥150 ppm and female mice at ≥75 ppm). The results suggested that a concentration of 150 ppm could be used as the highest exposure level for subsequent chronic inhalation tests.