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TR-508: Riddelliine (CASRN 23246-96-0) in F344/N Rats and B6c3f1mice (Gavage Studies)

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TR-508: Riddelliine (CASRN 23246-96-0) in F344/N Rats and B6c3f1mice (Gavage Studies) NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF RIDDELLIINE (CAS NO. 23246-96-0) IN F344/N RATS AND B6C3F1 MICE (GAVAGE STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 May 2003 NTP TR 508 NIH Publication No. 03-4442 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health FOREWORD The National Toxicology Program (NTP) is made up of four charter agencies of the U.S. Department of Health and Human Services (DHHS): the National Cancer Institute (NCI), National Institutes of Health; the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center for Toxicological Research (NCTR), Food and Drug Administration; and the National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention. In July 1981, the Carcinogenesis Bioassay Testing Program, NCI, was transferred to the NIEHS. The NTP coordinates the relevant programs, staff, and resources from these Public Health Service agencies relating to basic and applied research and to biological assay development and validation. The NTP develops, evaluates, and disseminates scientific information about potentially toxic and hazardous chemicals. This knowledge is used for protecting the health of the American people and for the primary prevention of disease. The studies described in this Technical Report were performed under the direction of the NIEHS and were conducted in compliance with NTP laboratory health and safety requirements and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use were in accordance with the Public Health Service Policy on Humane Care and Use of Animals. The prechronic and chronic studies were conducted in compliance with Food and Drug Administration (FDA) Good Laboratory Practice Regulations, and all aspects of the chronic studies were subjected to retrospective quality assurance audits before being presented for public review. These studies are designed and conducted to characterize and evaluate the toxicologic potential, including carcinogenic activity, of selected chemicals in laboratory animals (usually two species, rats and mice). Chemicals selected for NTP toxicology and carcinogenesis studies are chosen primarily on the bases of human exposure, level of production, and chemical structure. The interpretive conclusions presented in this Technical Report are based only on the results of these NTP studies. Extrapolation of these results to other species and quantitative risk analyses for humans require wider analyses beyond the purview of these studies. Selection per se is not an indicator of a chemical’s carcinogenic potential. Details about ongoing and completed NTP studies are available at the NTP’s World Wide Web site: http://ntp-server.niehs.nih.gov. Abstracts of all NTP Technical Reports and full versions of the most recent reports and other publications are available from the NIEHS’ Environmental Health Perspectives (EHP) http://ehp.niehs.nih.gov (866-541-3841 or 919-653-2590). In addition, printed copies of these reports are available from EHP as supplies last. A listing of all the NTP Technical Reports printed since 1982 appears on the inside back cover. NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF RIDDELLIINE (CAS NO. 23246-96-0) IN F344/N RATS AND B6C3F1 MICE (GAVAGE STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 May 2003 NTP TR 508 NIH Publication No. 03-4442 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health 2 CONTRIBUTORS National Toxicology Program NTP Pathology Working Group Evaluated and interpreted results and reported findings Evaluated slides and prepared pathology report on rats (September 14, 2000) P.C. Chan, Ph.D., Study Scientist M.P. Jokinen, D.V.M., Chairperson D.W. Bristol, Ph.D. Pathology Associates International J.R. Bucher, Ph.D. S.A.M. Chandra, B.V.Sc., Ph.D. J.R. Hailey, D.V.M. Experimental Pathology Laboratories, Inc. J.K. Haseman, Ph.D. G.P. Flake, M.D. R.A. Herbert, D.V.M., Ph.D. National Toxicology Program R.R. Maronpot, D.V.M. J.E. Heath, D.V.M. A. Nyska, D.V.M. Southern Research Institute S.D. Peddada, Ph.D. R.A. Herbert, D.V.M., Ph.D. National Toxicology Program G.N. Rao, D.V.M., Ph.D. P.W. Mellick, D.V.M., Ph.D., Observer J.H. Roycroft, Ph.D. Pathology Associates International C.S. Smith, Ph.D. A. Nyska, D.V.M. G.S. Travlos, D.V.M. National Toxicology Program K.L. Witt, M.S., ILS, Inc. K. Ozaki, D.V.M., Ph.D. National Toxicology Program Southern Research Institute H.G. Wall, D.V.M., Ph.D. Conducted studies and evaluated pathology findings Glaxo Wellcome, Inc. Evaluated slides and prepared pathology report on mice J.D. Prejean, Ph.D., Principal Investigator (August 22, 2000) W.R. Richter, D.V.M., M.S., Principal Investigator J.B. Nold, D.V.M., Ph.D., Chairperson D.R. Farnell, D.V.M. Pathology Associates International J.E. Heath, D.V.M. S.A.M. Chandra, B.V.Sc., Ph.D. Experimental Pathology Laboratories, Inc. National Center for Toxicological Research, G.P. Flake, M.D. Food and Drug Administration National Toxicology Program Conducted DNA adduct characterization studies J.R. Hailey, D.V.M. National Toxicology Program M.W. Chou, Ph.D., Principal Investigator R.A. Herbert, D.V.M., Ph.D. P.P. Fu, Ph.D., Principal Investigator National Toxicology Program R.D. Beger, Ph.D. P.N. Long, D.V.M., Ph.D. D.R. Doerge, Ph.D. Pathology Associates International J. Nichols, B.S. A. Nyska, D.V.M. Q. Xia, Ph.D. National Toxicology Program K. Ozaki, D.V.M., Ph.D., Observer J. Yan, M.S. National Toxicology Program Y.-C. Yang, Ph.D. H.G. Wall, D.V.M., Ph.D. Glaxo Wellcome, Inc. Experimental Pathology Laboratories, Inc. Provided pathology quality assurance Dynamac Corporation Prepared quality assurance audits J.F. Hardisty, D.V.M., Principal Investigator S. Brecher, Ph.D., Principal Investigator S.A.M. Chandra, B.V.Sc., Ph.D. Biotechnical Services, Inc. Analytical Sciences, Inc. Prepared Technical Report Provided statistical analyses S.R. Gunnels, M.A., Principal Investigator P.W. Crockett, Ph.D., Principal Investigator L.M. Harper, B.S. L.J. Betz, M.S. E.S. Paal, M.S.J. K.P. McGowan, M.B.A. D.C. Serbus, Ph.D. J.T. Scott, M.S. W.D. Sharp, B.A., B.S. 3 CONTENTS ABSTRACT . 5 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY . 9 TECHNICAL REPORTS REVIEW SUBCOMMITTEE . 10 SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS . 11 INTRODUCTION . 13 MATERIALS AND METHODS . 19 RESULTS . 27 DISCUSSION AND CONCLUSIONS . 55 REFERENCES . 63 APPENDIX A Summary of Lesions in Male Rats in the 2-Year Gavage Study of Riddelliine . 69 APPENDIX B Summary of Lesions in Female Rats in the 2-Year Gavage Study of Riddelliine . 93 APPENDIX C Summary of Lesions in Male Mice in the 2-Year Gavage Study of Riddelliine . 139 APPENDIX D Summary of Lesions in Female Mice in the 2-Year Gavage Study of Riddelliine . 183 APPENDIX E Genetic Toxicology . 211 APPENDIX F Chemical Characterization and Dose Formulation Studies . 225 APPENDIX G Ingredients, Nutrient Composition, and Contaminant Levels in NTP-2000 Rat and Mouse Ration . 237 APPENDIX H Sentinel Animal Program . 241 APPENDIX I DNA Adduct Characterization Studies . 245 4 Riddelliine, NTP TR 508 SUMMARY Background Riddelliine is a naturally occurring alkaloid found in certain plants in the western United States rangeland. Traces of riddelline have been found in the meat of animals grazing on these plants, and cattle, horses, and sheep have died from such exposure. Methods We deposited solutions of riddelliine through a tube directly into the stomachs of male and female rats and mice five days per week for two years. Male and female rats received concentrations of 1 milligram of riddelliine per kilogram of body weight, and male and female mice received concentrations of 3 milligrams of riddelliine per kilogram of body weight. Other groups of female rats and male mice also received 1/3, 1/10, or 1/30 as much as the highest concentration. Results Of 100 rats receiving 1 mg/kg, all but three died before the end of the study. Liver tumors were the cause of death for most of these animals; the incidences of mononuclear cell leukemia were also increased in exposed rats. Over half the male and female mice receiving 3 mg/kg also died before the end of the study. Male mice had more liver tumors and female mice more lung tumors than did animals not exposed to the chemical. Conclusions We conclude that riddelliine caused liver neoplasms in male and female rats and male mice and lung neoplasms in female mice, and also leukemia in male and female rats. 5 ABSTRACT H CH2 OH C C CH2 C C CH2OH H C C 3 O CH2 C O O O N RIDDELLIINE CAS No. 23246-96-0 Chemical Formula: C18H 23NO 6 Molecular Weight: 349.4 Synonyms: 13,19-Didehydro-12,18-dihydroxy senecionan-11,16-dione; 3-ethylidine-3,4,5,6,9,11,13,14,14a,14b-decahydro-6-hydroxy-6­ (hydroxymethyl)-5-methylene(1,6)di-oxacyclododecino(2,3,4-gh)-pyrrolizidine-2,7-dione; trans-15-ethylidine-12b-hydroxy-12a­ hydroxymethyl-13-methylenesenec-1-enine Riddelliine belongs to a class of toxic pyrrolizidine alka­ obtained from female rats admininstered riddelliine for loids and is isolated from plants of the genera 3 or 6 months. Crotalaria, Amsinckia, and Senecio that grow in the western United States. Cattle, horses, and sheep that ingest these plants succumb to their toxic effects.
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