Share This:
https://ntp.niehs.nih.gov/go/20475

Abstract for TR-533 - Benzophenone (CASRN 119-61-9)

Abstract

Toxicology and Carcinogenesis Studies of Benzophenone (CAS No. 119-61-9) in F344/N Rats and B6C3F1 Mice (Feed Studies)

Link to the full study report in PDF. If you have difficulty accessing the document, please send email to the NTP Webmaster [ Send Email ] and identify documents/pages for which access is required.  

 

Structure

 

Chemical Formula: C13H10O - Molecular Weight: 182.22

Benzophenone is used as a photoinitiator, a fragrance enhancer, an ultraviolet curing agent, and occasionally as a flavor ingredient; it is also used in the manufacture of insecticides, agricultural chemicals, and hypnotics, antihistamines, and other pharmaceuticals; and it is used as an additive in plastics, coatings, and adhesive formulations. Benzophenone was nominated for study by the National Institute of Environmental Health Sciences based on its potential for occupational and consumer exposure and the lack of long-term toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to benzophenone (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse bone marrow cells, and mouse peripheral blood erythrocytes. Results of 14-week toxicity studies in F344/N rats and B6C3F1 mice were reported earlier (NTP, 2000).

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were fed diets containing 0, 312, 625, or 1,250 ppm benzophenone (equivalent to average daily doses of approximately 15, 30, and 60 mg benzophenone/kg body weight to males and 15, 30, and 65 mg/kg to females) for 105 weeks. Survival of 1,250 ppm males was significantly less than that of controls. Mean body weights of 1,250 ppm males were markedly less than those of the controls during year 2 of the study, and weights of exposed females were consistently less than controls throughout the study. Feed consumption by 1,250 ppm males was less than that by the controls after week 70; feed consumption by 1,250 ppm females was generally less than that by the controls throughout the study.

There was a positive trend in the incidences of renal tubule adenoma in males, and the incidences in 625 and 1,250 ppm males exceeded the historical control range for all routes; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Due to these findings, additional kidney sections were evaluated; results indicated additional renal tubule adenomas in all groups of males and renal tubule hyperplasia in all groups of males and females. The incidences of pelvic transitional epithelium hyperplasia and the severity of nephropathy were significantly increased in all exposed groups of male rats.

Increased incidences of mononuclear cell leukemia in all exposed groups of females exceeded the historical control range from feed studies, and the incidence in 625 ppm females was significantly greater than that in the controls. Male rats exposed to 312 or 625 ppm had significantly increased incidences of mononuclear cell leukemia. One 625 ppm female and two 1,250 ppm females had histiocytic sarcomas, and the incidence in the 1,250 ppm group exceeded the range in the historical controls.

Liver lesions included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of males and females, cystic degeneration in 625 and 1,250 ppm males, and bile duct hyperplasia in all exposed groups of females.

Incidences of mammary gland fibroadenoma in females exposed to 625 or 1,250 ppm were lower than expected after adjusting for body weight.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were fed diets containing 0, 312, 625, or 1,250 ppm benzophenone (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg body weight to males and 35, 70, and 150 mg/kg to females) for 105 weeks. Survival of all exposed groups of mice was generally similar to that of the control groups. Mean body weights of exposed females were less than vehicle controls. Feed consumption by exposed males and females was similar to that by the controls.

In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups, and these incidences exceeded the historical control range. All hepatocellular neoplasms combined occurred with a positive trend. In female mice, the incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. Incidences of centrilobular hepatocyte hypertrophy were significantly increased in all exposed groups of males and females. All exposed groups of male mice had significant increases in the incidences of multinucleated hepatocytes and chronic active inflammation. The incidences of cystic degeneration of hepatocytes in 625 and 1,250 ppm males were significantly increased. The incidence of histiocytic sarcoma in 625 ppm females was significantly increased and exceeded the historical control range.

The incidences of kidney nephropathy and mineralization in exposed groups of females and the severity of nephropathy in exposed groups of males were significantly increased.

The incidences of metaplasia of the olfactory epithelium were significantly increased in 1,250 ppm males and females. The incidences of hyperplasia of lymphoid follicles in the spleen were significantly increased in all exposed groups of males and in 312 and 625 ppm females.

GENETIC TOXICOLOGY

Benzophenone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without hamster or rat liver activation enzymes. No significant increases in the frequencies of micronucleated polychromatic erythrocytes were seen in bone marrow samples from male mice administered benzophenone three times by intraperitoneal injection. In addition, no increases in micronucleated normochromatic erythrocytes were noted in peripheral blood of male or female mice administered benzophenone for 14 weeks in dosed feed.

CONCLUSIONS

Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma; mononuclear cell leukemia in male F344/N rats may have been related to benzophenone exposure. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginally increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F1 mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F1 mice may have been related to benzophenone exposure.

Administration of benzophenone in feed resulted in increased incidences and/or severities of nonneoplastic lesions in the kidney and liver of male and female rats and in the liver, kidney, nose, and spleen of male and female mice. Decreased incidences of mammary gland fibroadenoma in female rats were related to benzophenone exposure.

Synonyms: Benzene, benzophenone (8CI); benzoyl; benzoylbenzene; benzoylbenzenephenyl; diphenyl ketone; diphenylmethanone; methanone, diphenyl-(9CI); α-oxodiphenylmethane; α-oxoditane; phenyl ketone


Summary of the 2-Year Carcinogenesis and Studies of Benzophenone

 


 
Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1 Mice
Female
B6C3F1 Mice
Concentrations in
feed
0, 312, 625, 1,250 ppm 0, 312, 625, 1,250 ppm 0, 312, 625, 1,250 ppm 0, 312, 625, 1,250 ppm
Body weights 625 and 1,250 ppm groups less than the control group 625 and 1,250 ppm groups less than the control group Exposed groups similar to the control group 312, 625, and 1,250 ppm groups less than the control group
Survival rates 22/50, 27/50, 31/50, 2/50 32/50, 38/50, 37/50, 34/50 44/50, 44/50, 44/50, 45/50 40/50, 42/50, 41/50, 31/50
Nonneoplastic effects

Kidney: renal tubule, hyperplasia (standard evaluation - 1/50, 5/50, 20/50, 23/50; standard and extended evaluations combined - 3/50, 11/50, 30/50, 40/50); pelvis, transitional epithelium, hyperplasia (1/50, 11/50, 29/50, 34/50); severity of nephropathy (1.3, 2.4, 3.3, 3.8)

Liver: hepatocyte, centrilobular, hypertrophy (0/50, 17/50, 31/50, 19/50); degeneration, cystic (8/50, 11/50, 20/50, 15/50)

Kidney: renal tubule, hyperplasia (standard evaluation - 0/50, 1/50, 1/50, 1/50; standard and extended evaluations combined - 1/50, 8/50, 10/50, 7/50); severity of nephropathy - (1.1, 1.4, 1.7, 2.0)

Liver: hepatocyte, centrilobular, hypertrophy (0/50, 27/50, 30/50, 33/50); bile duct, hyperplasia (10/50, 35/50, 39/50, 40/50)

Liver: hepatocyte, centrilobular, hypertrophy (0/50, 44/50, 50/50, 48/50); hepatocyte, multinucleated (0/50, 41/50, 47/50, 48/50); inflammation, chronic active (33/50, 47/50, 44/50, 42/50); hepatocyte, degeneration, cystic (0/50, 0/50, 5/50, 30/50)

Kidney: severity of nephropathy (1.2, 1.4, 1.7, 3.0)

Nose: olfactory epithelium, metaplasia (0/50, 2/50, 2/50, 24/50)

Spleen: lymphoid follicle, hyperplasia, lymphoid (17/50, 31/50, 34/50, 32/50)

Liver: hepatocyte, centrilobular, hypertrophy (0/50, 29/50, 44/50, 37/50)

Kidney: nephropathy (21/50, 33/50, 31/50, 30/50); mineralization (15/50, 31/50, 36/50, 49/50); severity of nephropathy - (1.2, 1.1, 1.5, 1.7)

Nose: olfactory epithelium, metaplasia (0/50, 0/50, 0/50, 39/50)

Spleen: lymphoid follicle, hyperplasia, lymphoid (24/50, 36/50, 37/50, 22/50)

Neoplastic effects

Kidney: renal tubule, adenoma (standard evaluation - 1/50, 1/50, 2/50, 4/50; standard and extended evaluations combined - 2/50, 2/50, 7/50, 8/50)

None

Liver: hepatocellular adenoma (11/50, 15/50, 23/50, 23/50); hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (18/50, 20/50, 25/50, 29/50)

Histiocytic sarcoma: (0/50, 0/50, 5/50, 3/50)

Equivocal findings

Mononuclear cell leukemia: (27/50, 41/50, 39/50, 24/50)

Mononuclear cell leukemia: (19/50, 25/50, 30/50, 29/50)

Histiocytic sarcoma: (0/50, 0/50, 1/50, 2/50)

None

Liver: hepatocellular adenoma (5/50, 4/50, 10/50, 8/50)

Decreased incidences

None

Mammary gland: fibroadenoma (27/50, 24/50, 15/50, 7/50)

None

None

Level of evidence of carcinogenic activity Some evidence Equivocal evidence Some evidence Some evidence
Genetic Toxicology of Benzophenone
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium gene mutations:
 
Negative in strains TA98, TA100, TA102, TA1535 and TA1537 with and without S9
Micronucleated erythrocytes Mouse marrow in vivo: Negative
Micronucleated erythrocytes Mouse peripheral blood in vivo: Negative

Report Date: February 2006

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

Target Organs & Incidences from 2-year Studies