Subacute Inhalation Toxicity of 2-Chloro-4-Toluidine in Rats

Abstract

This article addresses results from a 4-wk inhalation exposure study in Wistar rats with the vapor and/or aerosol atmospheres of 2-chloro-4-toluidine. Groups of 10 rats/sex were nose-only exposed to mean analytical concentrations of 19.1, 115.1, and 702.3 mg/m³ using an exposure regimen of 6 h/day and 20–22 exposures within a time period of 4 wk. These concentrations were selected based on results from a repeated 5 × 6 h/day pilot study using concentrations of 27.1, 104.8, 381.6, and 1283.7 mg/m³. In a single 4-h exposure study at the maximum tested concentration of 7620 mg/m³, 1 of 10 female rats succumbed (no mortality in males), while no mortality occurred at 3293 mg/m³. In the 1- and 4-wk studies mortality occurred at 1283.7 and 702.3 mg/m³, respectively. Rats exposed for 4 wk to 702.3 mg/m³ displayed characteristic signs of toxicity that included cyanosis, respiratory distress, and significantly decreased body weights. Rectal temperatures were significantly decreased at 115.1 mg/m³ and above. Dark and enlarged spleens occurred at 702.3 mg/m³. At this concentration, prominent treatment-related effects included methemoglobinemia, reticulocytosis, red blood cells with Heinz bodies, decreased hemoglobin, hematocrit, and red blood cell counts. Borderline evidence of erythrocytotoxicty was noticed at 115.1 mg/m³ (based on a minimal increase in Heinz bodies). Spleen and liver weights were significantly increased at 702.3 mg/m³, whereas the thymus weight was decreased at 115.1 mg/m³ and above. Microscopic changes were found in the spleen (hemosiderosis) at 702.3 mg/m³. An atrophy of the olfactory epithelium in the nasal cavities occurred at 115.1 mg/m³ and above. Clinical pathology revealed changes pathognostic of hepatic effects, although microscopic examinations did not reveal any specific changes. The no-observed-adverse-effect level (NOAEL) of the 4-wk study was 19.1 mg/m³ and is based on the predominant atrophic changes of the olfactory epithelium and the minimal to borderline erythrocytotoxic effects at 115.1 mg/m³.