EFFECT OF CHEMICAL FORM, ROUTE OF ADMINISTRATION AND VEHICLE ON 3,5-DICHLOROANILINE-INDUCED NEPHROTOXICITY IN THE FISCHER-344 RAT

Chloroanilines are widely used chemical intermediates for the manufact ure of dyes, agricultural chemicals and industrial compounds. Nephroto xicity occurs as one toxicity following intraperitoneal (i.p.) adminis tration of chloroaniline hydrochlorides to rats. The purpose of this s tudy was to examine the effect of chemical form, route of administrati on and vehicle on 3,5-dichloroaniline-induced nephrotoxicity. In one s et of studies, male Fischer 344 rats (four to eight per group) were ad ministered a single i.p. injection of 3,5-dichloroaniline free base or hydrochloride salt, cysteine hydrochloride or ornithine hydrochloride (0.8, 1.0 or 1.5 mmol kg(-1)) or an appropriate vehicle and renal fun ction monitored for 48 h. Only 3,5-dichloroaniline hydrochloride induc ed nephrotoxicity that was characterized as acute renal failure. When 3,5-dichloroaniline free base (0.8 mmol kg(-1)) was administered in di methyl sulfoxide (DMSO), all rats died within 24 h. In a second experi ment, the free base or hydrochloride form of 3,5-dichloroaniline (1.5 mmol kg(-1)) or vehicle (0.9% saline or sesame oil, respectively) were administered orally and renal function monitored for 48 h. No evidenc e of nephrotoxicity was observed following either treatment. However, when the hydrochloride salt was given in 25% DMSO in 0.9% saline, all rats died within 24 h, with two rats demonstrating increased proteinur ia, glucosuria and hematuria within the first 6 h after treatment. The se results demonstrate that 3,5-dichloroaniline nephrotoxicity is pote ntiated by the administration of systemic acid, but that acid alone ha s no effect on renal function at the dose tested. Also, 3,5-dichloroan iline (hydrochloride or free base form) is less toxic orally than when administered i.p. In addition, when DMSO is used as part of the vehic le, 3,5-dichloroaniline toxicity is potentiated. Thus, chemical form, route of administration and vehicle are all important factors in 3,5-d ichloroaniline-induced toxicity.