Inhalation toxicity of 4-ethoxyaniline (p-phenetidine): Critical analysis of results of subacute inhalation exposure studies in rats

This article addresses results from a single 4-h and repeated 1- and 4-wk i nhalation exposure studies in Wistar rats with vapor and/or aerosol atmosph eres of 4-ethoxyaniline (p-phenetidine). Groups of 10 rats/sex were exposed nose-only to mean analytical concentrations of 11.1, 86.2, and 882.6 mg p- phenetidine/m(3) using an exposure regimen of 6 h/day, 5 days/wk for 4 wk. Concentrations were selected based on results from a pilot study in which r ats were exposed under identical conditions on 5 consecutive days for 6 h/d ay to mean analytical concentrations of 38.2, 133.0, and 1247.6 mg/m(3). In repeated exposure studies, the focus of endpoints was on hematotoxicity. T he LC50 was not determined, but no rats died following a single 4-h exposur e to 5085 mg/m(3) as a mixture of vapor and aerosol. No mortality was obser ved either in the 1- or 4-wk studies. Rats exposed to 882.6 mg/m(3) and abo ve evoked characteristic signs of toxicity that included cyanosis, with no apparent progression of findings during the exposure period. Animals expose d to 86.2 mg/m(3) and above exhibited a concentration-dependent, significan t increase in blood methemoglobin and reticulocyte counts as well as a sign ificant decrease in hemoglobin, hematocrit, and red blood cell counts. Sple en weights were significantly increased in groups exposed to 133.0 mg/m(3) and above. Microscopic changes demonstrated an increased hematopoiesis ( bo ne marrow smears) and splenic hemosiderosis at 86.2 and 882.6 mg/m(3) and a hepatic hemosiderosis only at 882.6 mg/m(3). These data suggest that the t oxicity of p-phenetidine is similar to that of its structural analog anilin e. Based on the erythrocytotoxicity occurring at 86.2 mg/m(3) and above, in cluding the apparent reactive changes in bone marrow ( increased erythropoi esis) and spleen ( increased erythroclasia), the no-observed-adverse-effect level (NOAEL) of the 4-wk study was 11.1 mg/m3 air and that of the 1-wk st udy was 38.2 mg/m3 air. This difference in NOAELs is considered to be relat ed to the selection of exposure concentrations rather than cumulative toxic ity.