National Toxicology Program

National Toxicology Program
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Abstract for TR-501 - p,p'-Dichlorodiphenyl Sulfone (CASRN 80-07-9)

Toxicology and Carcinogenesis Studies of
p,p'-Dichlorodiphenyl Sulfone (CAS NO. 80-07-9) in F344/N Rats and B6C3F1Mice (Feed Studies)

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Chemical Formula: C12H8Cl2O2S   

p,p'-dichlorodiphenylsulfone 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,p'-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 to p,p'-dichlorodiphenylsulfone (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,p'-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 2, 6, 19, 65, or 200 mg p,p'-dichlorodiphenylsulfone/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 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,p'-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,p'-dichlorodiphenyl sulfone for 104 to 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,p'-dichlorodiphenylsulfone-containing diets for 18 months and bled for plasma determinations of p,p'-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,p'-dichlorodiphenylsulfone for 105 to 106 weeks. Dietary concentrations of 30, 100, and 300 ppm delivered average daily doses of approximately 3.8, 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,p'-dichlorodiphenylsulfone-containing diets for up to 12 months; three mice in each group were bled for plasma determinations of p,p'-dichlorodiphenylsulfone 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,p'-DICHLORODIPHENYL SULFONE

p,p'-Dichlorodiphenyl sulfone is rapidly absorbed from the gut and metabolized by a saturable process. Although some p,p'-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,p'-dichlorodiphenyl sulfone induces enzymes involved in its metabolism.

GENETIC TOXICOLOGY

p,p'-dichlorodiphenylsulfone 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,p'-dichlorodiphenylsulfone 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,p'-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,p'-dichlorodiphenyl sulfone in male or female B6C3F1 mice exposed to 30, 100, or 300 ppm.

Exposure to p,p'-dichlorodiphenyl sulfone for 2 years caused increased incidences of nonneoplastic lesions of the liver in male and female rats and mice.


Synonyms: Bis (4-chlorophenyl) sulfone; bis (p-chlorophenyl) sulfone; 4-chloro-1-(4-chlorophenylsulfonyl) benzene; 4-chlorophenyl sulfone; p-chlorophenyl sulfone; 4,4'-dichlorodiphenyl sulfone; 4,4'-dichlorodiphenyl sulphone; di-4-chlorophenyl sulfone; di-p-chlorophenyl sulfone; 1,1'-sulfonylbis (4-chlorobenzene)


Summary of the 2-Year Carcinogenesis Studies
of p,p'-dichlorodiphenylSulfones
 

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1Mice

Female
B6C3F1 Mice

Concentrations
in feed
0, 10, 30, or 100 ppm 0, 30, 100, or 300 ppm 0, 30, 100, or 300 ppm 0, 30, 100, or 300 ppm
Body weights 30 and 100 ppm groups less than control group 100 and 300 ppm groups less than control group 300 ppm group less than control group 300 ppm group less than control group
Survival rates 24/50, 30/50, 20/50, 28/50 36/50, 38/50, 35/50, 35/50 40/50, 45/50, 44/50, 42/50 42/50, 40/50, 43/50, 45/50
Nonneoplastic effects Liver: centrilobular hypertrophy (0/50, 1/50, 3/50, 16/50) Liver: centrilobular hypertrophy (0/50, 2/50, 24/50, 38/50); bile duct hyperplasia (5/50, 12/50, 21/50, 32/50); centrilobular degeneration (1/50, 5/50, 10/50, 7/50) Liver: centrilobular hypertrophy (1/50, 24/50, 43/50, 45/50) Liver: centrilobular hypertrophy (0/50, 0/50, 9/50, 29/50); eosinophilic focus (2/50, 1/50, 4/50, 14/50)
Neoplastic effects None None None None
Level of evidence of carcinogenic activity No evidence No evidence No evidence No evidence
Genetic Toxicology of p,p'-dichlorodiphenylSulfones
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium gene mutations: Negative in strains TA97, TA98, TA100, and TA1535 with and without S9
Sister chromatid exchanges Cultured Chinese hamster ovary cells in vitro: Negative with S9; equivocal without S9
Chromosomal aberrations Cultured Chinese hamster ovary cells in vitro: Negative with and without S9
Micronucleated erythrocytes Mouse bone marrow in vivo: Positive when administered by intraperitoneal injection

 


Report Date: September 2001

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies


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