Inhalation Toxicity of Propineb. Part I: Results of Subacute Inhalation Exposure Studies in Rats

Abstract

This article addresses results from repeated 1- and 4-wk inhalation exposure studies in Wistar rats with solid aerosol (dust) atmospheres of propineb, a zinc bisdithiocarbamate homopolymer that is used as an agrochemical fungicide. Groups of 10 rats/sex were exposed nose-only to mean concentrations of 3.97, 11.24, and 21.95 mg propineb/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 concentrations of 10.1, 19.9, 38.1, and 78.7 mg/m 3. Both studies demonstrated that with respect to muscular effects female rats were remarkably more susceptible as compared to males. Female rats exposed to 11.24 mg/m 3 and above displayed characteristic signs of toxicity that included weakness and flaccid paralysis of hindlegs and ensuing immobilization that was considered to be the cause of emaciation and ensuing mortality in some rats. There was an apparent reciprocal relationship of concentration and the manifestation of clinical evidence of muscular dysfunction; that is, the onset in female rats exposed to 11.24, 21.95, 38.1, and 78.7 mg/m 3 was on days 15, 8, 4, and 3, respectively. In contrast, none of the male rats elaborated comparable effects up to 38.1 mg/m 3. Neuromuscular measures included leg grip strength and supplemented the clinical findings, whereas the landing foot splay was only minimally affected. Hematology and clinical pathology endpoints, including those addressing thyroidal function, were unobtrusive up to and including 78.7 mg/m 3. Lung weights were significantly increased in groups exposed to 21.95 mg/m 3 and above, especially in male rats. The microscopic examinations made in the 4-wk study demonstrated an increased incidence of intraalveolar material and enlarged, foamy alveolar macrophages at 3.97 mg/m 3 and above. Especially in female rats an atrophy of thigh muscle fibers, including increased nuclei and focal degeneration, occurred at 11.24 mg/m 3 and above. TTCA (2-thiazolidinethione-4-carboxylic acid) in urine, a metabolite and biomarker of exposure to CS 2, which is a putative breakdown product of propineb, was overproportially higher in the female rats exposed to 11.24 mg/m 3 and above. This biomarker appears to accumulate with time. This finding provides indirect evidence that the etiopathologic cause of neuromuscular changes is related to intermediary levels of CS 2. The data of this investigation suggest that the toxicity of inhaled propineb is characterized by two independent effects, namely, responses occurring at the alveolar level and muscular weakness, especially in female rats. With respect to the latter finding, the no-observed-adverse-effect level (NOAEL) of the 4-wk study is 3.97 mg/m 3. Further study is needed to clarify whether the pulmonary response observed at this exposure level is consistent with an adaptive or an early adverse effect.