Hemolytic anemia and
methemoglobinemia induced by exposure to certain arylamines, such as
aniline and
dapsone, are known to be mediated by their N-
hydroxylamine metabolites. The arylamide
propanil (3,4-dichloropropionanilide), a
herbicide used extensively in rice fields, is also thought to induce
methemoglobinemia through the action of metabolites. However, the hemolytic potential of this compound has not previously been reported. The present studies were undertaken to determine the hemolytic potential of
propanil, and, if positive, the role of metabolites in this hemotoxicity. The survival of previously administered 51Cr-labeled erythrocytes in rats was reduced in a dose-dependent manner by ip administration of both
propanil and its deacylated metabolite,
3,4-dichloroaniline (ED50 for both ca. 1.8 mmol/kg). When labeled erythrocytes were exposed in vitro to
propanil or
3,4-dichloroaniline and then readministered to rats, no decrease in erythrocyte survival was observed, which indicated that these compounds were not direct-acting
hemolytic agents. In contrast, erythrocyte survival was markedly reduced by ip administration or in vitro exposure to
N-hydroxy-3,4-dichloroaniline. In addition,
N-hydroxy-3,4-dichloroaniline was detected in the blood of
propanil-treated rats in amounts sufficient to account for the hemolytic activity of the parent compound. These data indicate that
N-hydroxy-3,4-dichloroaniline mediates
propanil-induced
hemolytic anemia, and that occupational exposure to
propanil may result in an increased risk of hemolytic episodes.