Toxicology and carcinogenesis studies of p,p'-dichlorophenyl sulfone (CAS No. 80-07-9) in F344/N rats and B6C3F1 mice (feed studies).
p,pN-Dichlorodiphenyl sulfone is used as a starting material in the production of polysulfones and polyethersulfones and as a component in reactive dyes in the textile industry; it is also a by-product of pesticide production. p,pN-Dichlorodiphenyl sulfone was nominated for study by the National Cancer Institute because of its history of high production and use, the prospect of increased production and use, and the absence of adequate toxicity testing. Male and female F344/N rats and B6C3F1 mice were exposed top,pN-dichlorodiphenyl sulfone (greater than 99% pure)in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,cultured Chinese hamster ovary cells, and mouse bone marrow. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 2, 6, 19, 65, or 200 mgp,pN-dichlorodiphenyl sulfone/kg body weight) for 14 weeks. All rats survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 100 ppm or greater and kidney weights of 1,000 and 3,000 ppm male rats were significantly greater than those of the controls. Centrilobular hepatocyte hypertrophy of the liver was observed in most male rats exposed to 100 ppm or greater and in all female rats exposed to 300 ppm or greater, and the severities were increased in 300 ppm males and 1,000 and 3,000 ppm males and females. The incidences of nephropathy in 1,000 and 3,000 ppm female rats were significantly increased. Dose-related increases in severity of nephropathy were observed in male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 3.5, 15, 50, 165,or 480 mg/kg) for 14 weeks. All mice survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 300 ppm or greater were significantly increased. Centrilobular hypertrophy of the liver was observed in most males exposed to 100 ppm or greater and in all females exposed to 1,000 or 3,000 ppm, and the severities generally increased with increasing exposure concentration. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 10 (males), 30, 100, or 300 (females) ppm p,pN-dichlorodiphenyl sulfone for 105 weeks. Dietary concentrations of 10, 30, and 100 ppm resulted in average daily doses of approximately 0.5, 1.5, and 5.0 mg/kg to males. Dietary concentrations of 30, 100,and 300 ppm resulted in average daily doses of approximately 1.6, 5.4, and 17 mg/kg to females. Additional groups of 10 male and 10 female rats were fed the same p,pN-dichlorodiphenyl sulfone-containing diets for 18 months and bled for plasma determinations of p,pN-dichlorodiphenyl sulfone at approximately 2 weeks and 3, 12, and 18 months. Survival of all exposed groups of male and female rats was similar to that of the control groups. Mean body weights of 30 and 100 ppm males were generally less than those of the controls during the latter part of the study, and mean body weights of 100 and 300 ppm female rats were less from weeks 30 and 18,respectively. Feed consumption by the exposed groups was similar to that by the controls throughout the study. The incidences of centrilobular hepatocyte hypertrophy in 100 ppm male and 100 and 300 ppm female rats were significantly greater than those in the controls. The incidences of bile duct hyperplasia and centrilobular degeneration were also significantly increased in 100 and 300 ppm females. No neoplasms were related to chemical exposure. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 30, 100, or 300 ppm p,pN-dichlorodiphenyl sulfone for 105 to 106 weeks. Dietary concentrations of 30, 100, and 300 ppm delivered average daily doses of approximately 4, 13, and 40 mg/kg to males and approximately 3, 10, and 33 mg/kg to females. Additional groups of 10 male and 10 female mice were fed the same p,pN-dichlorodiphenyl sulfone-containing diets for up to 12 months;three mice in each group were bled for plasma determinations of p,pN-dichloro-diphenyl sulfone at approximately 2 weeks or 3 or 12 months. Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of 300 ppm mice were less than those of the controls throughout most of the study. Feed consumption by the exposed groups was similar to that by the controls throughout the study. The incidences of centrilobular hepatocyte hypertrophy in all exposed groups of male mice and in 100 and 300 ppm females were significantly greater than those in the controls. The incidence of eosinophilic foci in 300 ppm females was significantly increased. No neoplasms were related to chemical exposure. PHARMACOKINETICS OF p,pN-DICHLORODIPHENYL SULFONE: p,pN-Dichlorodiphenyl sulfone is rapidly absorbed from the gut and metabolized by a saturable process. Although some p,pN-dichlorodiphenyl sulfone is eliminated unchanged in feces and urine, most of the elimination is via metabolism. Mathematical modeling of the toxicokinetics supports the view that p,pN-dichlorodiphenyl sulfone induces enzymes involved in its metabolism.


RESULTS
p,pN-Dichlorodiphenyl sulfone was not mutagenic in any of several strains of Salmonella typhimurium, with or without metabolic activation enzymes (S9). Results of the sister chromatid exchange test in cultured Chinese hamster ovary cells were judged to be negative in the presence of S9 and equivocal in the absence of S9, but no induction of chromosomal aberrations was noted, with or without S9. In contrast to the in vitro results, positive results were obtained in an acute in vivo mouse bone marrow micronucleus assay with p,pN-dichlorodiphenyl sulfone administered by intraperitoneal injection three times over a dose range of 200 to 800 mg/kg.


CONCLUSIONS
Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity* of p,pN-dichlorodiphenyl sulfone in male F344/N rats exposed to 10, 30, or 100 ppm or in female F344/N rats exposed to 30, 100, or 300 ppm. There was no evidence of carcinogenic activity of p,pN-dichlorodiphenyl sulfone in male or female B6C3F1 mice exposed to 30,100, or 300 ppm. Exposure to p,pN-dichlorodiphenyl sulfone for 2 years caused increased incidences of nonneoplastic lesions of the liver in male and female rats and mice.
D000284:Administration, Oral; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015162:Micronucleus Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013450:Sulfones / Q000008:administration & dosage / Q000633:toxicity*
D002273:Carcinogens; D009153:Mutagens; D013450:Sulfones; C034224:4,4'-dichlorodiphenyl sulfone