p-Toluenesulfonamide is formed from chloramine-T, an antimicrobial agent used by the aquaculture industry to treat fish intended for human consumption. Chloramine-T is also widely used as a disinfectant in the medical, dental, veterinary, food processing, and agricultural industries. Because of its low degree of cytotoxicity, chloramine-T has been used in direct contact with tissues, including treatment for burns, in whirlpools for wounds, and as an oral mouthwash. In the agricultural industry, it is used as a broad-spectrum biocide for foot-and-mouth disease, swine vesicular disease, and poultry diseases. Chloramine-T was nominated by a private individual for toxicology studies based on its current status as an Investigational New Animal Drug for controlling proliferative gill disease and bacterial gill disease in aquaculture and the need for additional toxicology studies to support its safe use. p-Toluenesulfonamide was studied for toxicity by the NTP because it has been shown to be the major product formed from chloramine-T. For the 2-week studies, male and female F344/N rats and B6C3F1/N mice were exposed to p-toluenesulfonamide (greater than 99% pure) in feed. For the 3-month studies, male and female F344/NTac rats and B6C3F1/N mice were exposed to p-toluenesulfonamide (greater than 99% pure) in feed. Genetic toxicology studies were conducted in Salmonella typhimurium, rat peripheral blood erythrocytes, and mouse peripheral blood erythrocytes.
In the 2-week studies, groups of five male and five female F344/N rats and mice were fed diets containing 0, 750, 1,500, 3,000, 10,000, or 30,000 ppm p-toluenesulfonamide (equivalent to average daily doses of approximately 95, 185, 370, 1,170, or 3,135 mg p-toluenesulfonamide/kg body weight to male F344/N rats, 80, 170, 335, 1,050, or 2,645 mg/kg to female F344/N rats, 150, 300, 700, 2,035, or 7,690 mg/kg to male mice, and 125, 280, 635, 2,410, or 6,000 mg/kg to female mice) for 15 days. All animals survived to the end of the studies. For F344/N rats, the final mean body weights of the 10,000 and 30,000 ppm groups were 91% and 71% that of male controls, respectively, and 94% and 83% that of female controls, respectively. Body weight gains were also decreased in 10,000 and 30,000 ppm rats. For mice, the final mean body weights of the 30,000 ppm groups were 86% that of male controls and 85% that of female controls. Body weight gains were also decreased in 30,000 ppm male mice and in all exposed female mice. Groups of mice exposed to 30,000 ppm lost weight during the study. In F344/N rats, feed consumption by 10,000 and 30,000 ppm males and 30,000 ppm females was less than that by the controls. In mice, feed consumption by exposed groups of mice was generally similar to that by the controls. No clinical observations or histopathologic findings were attributed to p-toluenesulfonamide exposure in the 2-week studies in F344/N rats or mice.
In the 2-week studies, absolute and relative kidney weights of 10,000 and 30,000 ppm female mice and relative kidney weights of 1,500 and 3,000 ppm female mice were significantly increased compared to those of the controls. There were no corresponding histologic lesions in the 2-week studies in F344/N rats or mice.
In the 3-month studies, groups of 10 male and 10 female F344/NTac rats and mice were fed diets containing, 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm p-toluenesulfonamide (equivalent to average daily doses of approximately 50, 100, 200, 380, or 725 mg/kg to male F344/NTac rats, 30, 110, 210, 400, or 780 mg/kg to female F344/NTac rats, 120, 230, 420, 770, or 1,760 mg/kg to male mice, and 90, 210, 380, 780, or 1,890 mg/kg to female mice) for 14 weeks. Groups of 10 male and 10 female clinical pathology F344/NTac rats were exposed to the same concentrations for up to 22 days. All F344/NTac rats and male mice survived to the end of the studies; one 10,000 ppm female mouse died during week 6. For F344/NTac rats, the final mean body weights of the 10,000 ppm groups were 93% that of male controls and 92% that of female controls. Body weight gains were also decreased in 2,500 ppm or greater male F344/NTac rats and in 5,000 and 10,000 ppm female F344/NTac rats. The mean body weight gains of 5,000 and 10,000 ppm male F344/NTac rats were significantly less than that of the controls. The final mean body weight of 1,250 ppm female F344/NTac rats was significantly greater (109%) than that of the controls; mean body weight gain was also increased in 1,250 ppm female F344/NTac rats. Feed consumption by 5,000 ppm male F344/NTac rats and 10,000 ppm male and female F344/NTac rats was less than that by controls early in the study, but generally recovered to near control values later in the study. Feed consumption by 625 and 1,250 ppm male mice was greater than that by the controls early in the study but returned to near control values later in the study. No clinical observations or histopathologic findings were attributed to p-toluenesulfonamide exposure in the 3-month studies in F344/NTac rats or mice.
p-Toluenesulfonamide was not mutagenic in Salmonella typhimurium strains TA98, TA100, or TA102 with or without exogenous metabolic activation. In vivo, no increases in micronucleated reticulocytes (polychromatic erythrocytes) or erythrocytes (normochromatic erythrocytes) were observed in peripheral blood of male or female F344/NTac rats or B6C3F1/N mice from the 3-month studies, and no biologically significant changes in the percentage of reticulocytes among total erythrocytes were seen, suggesting that p-toluenesulfonamide did not induce bone marrow toxicity.
Under the conditions of these 3-month feed studies, there were no treatment-related lesions in male or female F344/NTac rats or mice exposed to p-toluenesulfonamide in the feed at 625, 1,250, 2,500, 5,000, or 10,000 ppm. The most sensitive measures of p-toluenesulfonamide exposure in each species and sex were increased relative kidney weights in male F344/NTac rats [lowest observed effect level (LOEL) 2,500 ppm; 200 mg/kg], decreased body weight in female F344/NTac rats (LOEL 10,000 ppm; 780 mg/kg), increased relative lung weight in male mice (LOEL 10,000 ppm; 1,760 mg/kg), and increased relative liver weight and absolute and relative kidney weights in female mice (LOEL 10,000 ppm; 1,890 mg/kg). It is uncertain if these body weight or organ weight effects would compromise the survival or well-being of the animal after longer exposures.