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 inhalation exposure studies in Wistar rats with vapor and/or aerosol atmospheres 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 rats were exposed under identical conditions on 5 consecutive days for 6 h/day 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. The LC50 was not determined, but no rats died following a single 4-h exposure to 5085 mg/m(3) as a mixture of vapor and aerosol. No mortality was observed either in the 1- or 4-wk studies. Rats exposed to 882.6 mg/m(3) and above evoked characteristic signs of toxicity that included cyanosis, with no apparent progression of findings during the exposure period. Animals exposed to 86.2 mg/m(3) and above exhibited a concentration-dependent, significant increase in blood methemoglobin and reticulocyte counts as well as a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen weights were significantly increased in groups exposed to 133.0 mg/m(3) and above. Microscopic changes demonstrated an increased hematopoiesis (bone 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 toxicity of p-phenetidine is similar to that of its structural analog aniline. Based on the erythrocytotoxicity occurring at 86.2 mg/m(3) and above, including the apparent reactive changes in bone marrow (increased erythropoiesis) and spleen (increased erythroclasia), the no-observed-adverse-effect level (NOAEL) of the 4-wk study was 11.1 mg/m(3) air and that of the 1-wk study was 38.2 mg/m(3) air. This difference in NOAELs is considered to be related to the selection of exposure concentrations rather than cumulative toxicity.
Pauluhn
J
J
Institute of Toxicology, BAYER AG, Building No. 514, 42096 Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
Mohr
U
U
D000336:Aerosols; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D019570:Inhalation Exposure; D008297:Male; D008706:Methemoglobin / Q000032:analysis; D019055:No-Observed-Adverse-Effect Level; D010628:Phenetidine / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D017701:Reticulocyte Count; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014835:Volatilization
D000336:Aerosols; D010628:Phenetidine; D008706:Methemoglobin