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Abstract for TR-466 - Ethylbenzene (CASRN 100-41-4)

Abstract

Toxicology and Carcinogenesis Studies of Ethylbenzene (CAS No. 100-41-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies)

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Chemical Formula: C8H10

 

Ethylbenzene is mainly used in the manufacture of styrene. Ethylbenzene is also a major component of mixed xylenes used as solvents in agricultural and home insecticide sprays, rubber and chemical manufacturing, and household degreasers, paints, adhesives, and rust preventives. Ethylbenzene is also used as an antiknock agent in aviation and motor fuels. Ethylbenzene was nominated for study by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) because of its potential for widespread human exposure and because of its structural similarity to benzene and toluene. Male and female F344/N rats and B6C3F1 mice were exposed to ethylbenzene (greater than 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. In previously reported 13-week toxicity studies in which F344/N rats and B6C3F1 mice were exposed to ethylbenzene by whole body inhalation exposure, no histopathologic changes were observed (NTP, 1992).

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female F344/N rats were exposed to 0, 75, 250, or 750 ppm ethylbenzene by inhalation, 6 hours per day, 5 days per week, for 104 weeks.

Survival, Body Weights, and Clinical Findings

Survival of male rats in the 750 ppm group was significantly less than that of the chamber controls. Mean body weights of 250 and 750 ppm males were generally less than those of the chamber controls beginning at week 20. Mean body weights of exposed groups of females were generally less than those of chamber controls during the second year of the study.

Pathology Findings

In male rats exposed to 750 ppm, the incidences of renal tubule adenoma and adenoma or carcinoma (combined) were significantly greater than the chamber control incidences. In addition, the incidence of renal tubule hyperplasia in 750 ppm males was significantly greater than that in the chamber controls.

The findings from an extended evaluation (step section) of the kidneys showed a significant increase in the incidences of renal tubule adenoma and hyperplasia in 750 ppm males and females; the incidence of renal tubule adenoma or carcinoma (combined) was significantly increased in 750 ppm males. The severities of nephropathy in 750 ppm male and all exposed female rats were significantly increased relative to the chamber controls.

The incidence of interstitial cell adenoma in the testis of 750 ppm males was significantly greater than that in the chamber control group and slightly exceeded the historical control range for inhalation studies.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 75, 250, or 750 ppm ethylbenzene by inhalation, 6 hours per day, 5 days per week, for 103 weeks.

Survival, Body Weights, and Clinical Findings

Survival of exposed groups of male and female mice was similar to that of the chamber controls. Mean body weights of female mice exposed to 75 ppm were greater than those of the chamber controls from week 72 until the end of the study.

Pathology Findings

In 750 ppm males, the incidences of alveolar/ bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly greater than those in the chamber control group but were within the NTP historical control ranges. The incidence of alveolar epithelial metaplasia in 750 ppm males was significantly greater than that in the chamber controls. In 750 ppm females, the incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly greater than those in the chamber control group but were within the historical control ranges. The incidence of eosinophilic foci in 750 ppm females was significantly increased compared to that in the chamber controls. There was a spectrum of nonneoplastic liver changes related to ethylbenzene exposure in male mice, including syncytial alteration of hepatocytes, hepatocellular hypertrophy, and hepatocyte necrosis.
The incidences of hyperplasia of the pituitary gland pars distalis in 250 and 750 ppm females and the incidences of thyroid gland follicular cell hyperplasia in 750 ppm males and females were significantly increased compared to those in the chamber control groups.

GENETIC TOXICOLOGY

Ethylbenzene gave little indication of mutagenicity, in vitro or in vivo . No induction of mutations was noted in Salmonella typhimurium strain TA97, TA98, TA100, or TA1535 with or without S9 metabolic activation, and no increases in sister chromatid exchanges or chromosomal aberrations were observed in cultured Chinese hamster ovary cells treated with ethylbenzene, with or without S9. In the mouse lymphoma assay, a significant mutagenic response was noted in the absence of S9, but only at the highest nonlethal dose tested and with accompanying cytotoxicity; the test was not performed with S9. No increases in the frequency of micronucleated erythrocytes were observed in vivo in peripheral blood samples from male and female mice exposed to ethylbenzene for 13 weeks.

CONCLUSIONS

Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity   of ethylbenzene in male F344/N rats based on increased incidences of renal tubule neoplasms. The incidences of testicular adenoma were also increased. There was  some evidence of carcinogenic activity of ethylbenzene in female F344/N rats based on increased incidences of renal tubule adenomas. There was  some evidence of carcinogenic activity of ethylbenzene in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. There was some evidence of carcinogenic activity of ethylbenzene in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms.

Exposure of male and female rats to ethylbenzene resulted in increased incidences of renal tubule hyperplasia and increased severities of nephropathy. Exposure of male mice to ethylbenzene resulted in increased incidences of alveolar epithelial metaplasia, syncytial alteration of hepatocytes, hepatocellular hypertrophy, hepatocyte necrosis, and thyroid gland follicular cell hyperplasia. In female mice, ethylbenzene exposure resulted in increased incidences of eosinophilic foci of the liver, pituitary gland pars distalis hyperplasia, and thyroid gland follicular cell hyperplasia.


Synonyms: EB; ethylbenzol; phenylethane

 


Summary of the 2-Year Carcinogenesis Studies of Ethylbenzene

 

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1 Mice

Female
B6C3F1 Mice


Concentrations in air


Chamber control, 75, 250, or 750ppm


Chamber control, 75, 250, or 750ppm


Chamber control, 75, 250, or 750 ppm


Chamber control, 75, 250, or 750 ppm


Body weights


250 and 750 ppm groups lower than chamber controls


Exposed groups less than chamber controls


Exposed groups similar to chamber controls


75 ppm group greater than chamber controls


Survival rates


15/50, 14/50, 13/50, 2/50


31/50, 31/50, 34/50, 35/49


28/50, 36/50, 32/50, 30/50


35/50, 38/50, 40/50, 37/50


Nonneoplastic effects


Kidney: renal tubule hyperplasia (standard evaluation - 2/50, 2/50, 4/50, 12/50; stabdard and extended evaluations combined - 11/50, 9/50, 11/50, 23/50; severity of nephropathy (2.3, 2.4, 2.3, 3.5)

Kidney: renal tubule hyperplasia (standard evaluation - 0/50, 1/50, 3/50, 3/49; standard and extended evaluations combined - 1/50, 2/50, 4/50, 10/49); severity of nephropathy (1.3, 1.6, 1.7, 2.3)


Lung: alveolar epithelial metaplasia (0/50, 1/50, 2/50, 6/50)

Liver: syncytial alteration (0/50, 5/50, 8/50, 23/50); hypertrophy (1/50, 0/50, 0/50, 17/50); necrosis (1/50, 1/50, 3/50, 10/50) Thyroid gland: follicular cell hyperplasia (21/50, 21/50, 29/50, 32/50)


Liver: eosinophilic focus (5/50, 7/50, 6/50, 22/50)

Pituitary gland (pars distalis): hyperplasia (10/48, 12/49, 23/47, 22/49) Thyroid gland: follicular cell hyperplasia (18/50, 23/50, 25/50, 35/50)


Neoplastic effects


Kidney: renal tubule adenoma (standard and extended evaluations combined - 3/50, 5/50, 7/50, 20/50); renal tubule adenoma or carcinoma (standard evaluation - 0/50, 3/50, 3/50, 7/50; standard and extended evaluations combined - 3/50, 5/50, 8/50, 21/50)

Testes: adenoma (36/50, 33/50, 40/50, 44/50)


Kidney: renal tubule adenoma (standard evaluation - 0/50, 0/50, 0/50, 1/49; standard and extended evaluations combined - 0/50, 0/50, 1/50, 8/49)


Lung: alveolar/ bronchiolar adenoma (5/50, 9/50, 10/50, 16/50); alveolar/ bronchiolar adenoma or carcinoma (7/50, 10/50, 15/50, 19/50)


Liver: hepatocellular adenoma (6/50, 9/50, 12/50, 16/50); hepatocellular adenoma or carcinoma (13/50, 12/50, 15/50, 25/50)


Level of evidence of carcinogenic activity


Clear evidence


Some evidence


Some evidence


Some evidence



Genetic Toxicology Studies of Ethylbenzene
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium gene mutations: Negative in strains TA97, TA98, TA100, and TA1535 with and without S9
Mammalian Cell Mutagenicity Mouse lymphoma gene mutations: Positive without S9
Sister chromatid exchanges Cultured Chinese hamster ovary cells in vitro: Negative with and without S9
Chromosomal aberrations Cultured Chinese hamster ovary cells in vitro: Negative with and without S9
Micronucleated erythrocytes Mouse peripheral blood in vivo: Negative

Report Date: January 1999

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

Target Organs & Incidences from 2-year Studies


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