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Dose Response Study with N-Nitrosomorpholine in Drinking Water of F-344 Rats¹

National Cancer Institute-Frederick Cancer Research Facility, Biometics Research, Inc.-Basic Research Program, Frederick, Maryland 21701

A dose-response study in carcinogenesis was carried out with N-nitrosomorpholine in female F344 rats. The compound was administered in drinking water, which was supplied in controlled amounts of 20 ml per day per rat, 5 days a wk. At the two highest dose rates, 100 mg/liter and 40 mg/liter, treatment lasted 25 and 40 wk, respectively. At the other dose rates, which differed by a factor of 2.5, treatment lasted 50 or 100 wk. The average total dose received by each rat ranged from 250 mg to 0.7 mg. There were 100 animals per group at the lowest dose rates and 24 animals per group at the highest dose rates. Total doses of nitrosomorpholine above approximately 30 mg per rat caused a statistically significant decrease in survival, but at lower doses survival was similar to that of untreated controls. In nearly all of the treated groups there was a statistically significant increase in the incidence of benign or malignant hepatocellular neoplasms, with a highly significant dose-related trend. At the higher doses there was a significant incidence of hemangiosarcomas of the liver. Both hepatocellular carcinomas and hemangiosarcomas metastasized to the lungs and other organs. At the highest doses there was a significant incidence of neoplasms of the tongue and esophagus, which were rarely seen at the lower doses. The results suggest that even the lowest dose of nitrosomorpholine received by the rats, 0.7 mg or approximately 3 mg/kg body weight, was not a no-effect dose during the 2-yr lifetime of a rat. Probit analysis of the results indicate a dose estimated to cause tumors in 50% of the population of 25 mg nitrosomorpholine for liver neoplasms.

¹ Sponsored by the National Cancer Institute, Department of Health and Human Services, under Contract N01-CO-23909 with Bionetics Research, Inc. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

² Present address: Pathology Associates, Inc., 10075 Tyler Place, Hyatt Park II, Ijamsville, MD 21754.

³ Present address: Data Management Services, Inc., National Cancer Institute-Frederick Cancer Research Facility, Frederick, MD 21701.

Received 6/ 2/87. Revised 12/18/87. Accepted 1/22/88.