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TR-494: Anthraquinone

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TR-494: Anthraquinone NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF ANTHRAQUINONE (CAS NO. 84-65-1) IN F344/N RATS AND B6C3F1 MICE (FEED STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Triangle Park, NC 27709 September 2005 NTP TR 494 NIH PUblication No. 05-3953 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, abstracts of all NTP Technical Reports, and full versions of the completed reports are available at the NTP’s World Wide Web site: http://ntp.niehs.nih.gov. In addition, printed copies of these reports are available from NTP as supplies last by contacting (919) 541­1371. NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF ANTHRAQUINONE (CAS NO. 84-65-1) IN F344/N RATS AND B6C3F1 MICE (FEED STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 September 2005 NTP TR 494 NIH PUblication No. 05-3953 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, prepared pathology report on rats (November 10, 1998) R.D. Irwin, Ph.D., Study Scientist J.C. Seely, D.V.M., Chairperson Study Pathologist R.R. Maronpot, D.V.M., PATHCO, Inc. G.M. Blumenthal, Ph.D. G.P. Flake, M.D., Observer J.R. Bucher, Ph.D. E.T. Gaillard, D.V.M., M.S. R.E. Chapin, Ph.D. Experimental Pathology Laboratories, Inc. J.R. Hailey, D.V.M. R.A. Herbert, D.V.M., Ph.D. J.K. Haseman, Ph.D. National Toxicology Program G.N. Rao, D.V.M., Ph.D. N. Izumisawa, D.V.M., Ph.D. J.H. Roycroft, Ph.D. Yamanouchi, USA M.P. Jokinen, D.V.M. C.S. Smith, Ph.D. Pathology Associates International G.S. Travlos, D.V.M. R.R. Maronpot, D.V.M. K.L. Witt, M.S. National Toxicology Program A.W. Singer, D.V.M., Ph.D. Battelle Columbus Laboratories Battelle Columbus Laboratories Conducted studies, evaluated pathology findings Evaluated slides, prepared pathology report on mice (September 17, 1998) P.J. Kurtz, Ph.D., Principal Investigator, 14­week studies J.C. Seely, D.V.M., Chairperson M.R. Hejtmancik, Ph.D., Principal Investigator, PATHCO, Inc. 2­year studies R. Cattley, V.M.D., Ph.D. M.J. Ryan, D.V.M., Ph.D. Chemical Industry Institute of Toxicology A.W. Singer, D.V.M., Ph.D. E.T. Gaillard, D.V.M., M.S. Experimental Pathology Laboratories, Inc. Experimental Pathology Laboratories, Inc. R.A. Herbert, D.V.M., Ph.D. Provided pathology review National Toxicology Program N. Izumisawa, D.V.M, Ph.D., Observer J.F. Hardisty, D.V.M., Principal Investigator Yamanouchi, USA E.T. Gaillard, D.V.M., M.S. R.R. Maronpot, D.V.M. National Toxicology Program Dynamac Corporation A. Nyska, D.V.M. Prepared quality assurance audits National Toxicology Program S. Rehm, D.V.M. S. Brecher, Ph.D., Principal Investigator SmithKline Beecham M.J. Ryan, D.V.M., Ph.D. Analytical Sciences, Inc. Battelle Columbus Laboratories Provided statistical analyses Biotechnical Services, Inc. R.W. Morris, M.S., Principal Investigator Prepared Technical Report D.E. Kendrick, M.S. S.R. Gunnels, M.A., Principal Investigator K.P. McGowan, M.B.A. L.M. Harper, B.S. J.T. Scott, M.S. A.M. Macri­Hanson, M.A., M.F.A. D.C. Serbus, Ph.D. R.A. Willis, B.A. 3 CONTENTS ABSTRACT ............................................................................ 7 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY ................ 13 TECHNICAL REPORTS REVIEW SUBCOMMITTEES ...................................... 14 SUMMARIES OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS .......... 17 INTRODUCTION ....................................................................... 23 MATERIALS AND METHODS ........................................................... 27 RESULTS .............................................................................. 37 DISCUSSION AND CONCLUSIONS ....................................................... 83 REFERENCES .......................................................................... 95 APPENDIX A Summary of Lesions in Male Rats in the 2-Year Feed Study of AnthraqUinone ......................................................... 103 APPENDIX B SUmmary of Lesions in Female Rats in the 2-Year Feed StUdy of AnthraqUinone ......................................................... 147 APPENDIX C Summary of Lesions in Male Mice in the 2-Year Feed Study of AnthraqUinone ......................................................... 185 APPENDIX D Summary of Lesions in Female Mice in the 2-Year Feed Study of AnthraqUinone ......................................................... 215 APPENDIX E Genetic Toxicology ........................................................ 245 APPENDIX F Clinical Pathology Results .................................................. 265 APPENDIX G Organ Weights and Organ-Weight-to-Body-Weight Ratios ....................... 275 APPENDIX H Reproductive Tissue Evaluations and Estrous Cycle Characterization .............. 279 APPENDIX I Pharmacokinetic Model and Toxicokinetic ResUlts .............................. 283 APPENDIX J Chemical Characterization and Dose FormUlation StUdies ....................... 305 APPENDIX K Feed and Compound Consumption in the 2-Year Feed Studies of Anthraquinone .... 317 4 Anthraquinone, NTP TR 494 APPENDIX L Ingredients, Nutrient Composition, and Contaminant Levels in NIH-07 Rat and Mouse Ration ............................................ 325 APPENDIX M Sentinel Animal Program .................................................. 329 APPENDIX N Single-Dose Toxicokinetic Studies in F344/N Rats and B6C3F1 Mice ............... 333 APPENDIX O 32-Day Feed Study of Anthraquinone in F344/N Rats ........................... 349 Anthraquinone, NTP TR 494 5 6 Anthraquinone, NTP TR 494 Summary Background: Anthraquinone is used to make dyes and paper and as a bird repellant. We studied anthraquinone to determine if it caused cancer in rats or mice. Methods: We fed groups of 50 male and female rats feed containing 469, 938, 1,875, or 3,750 parts per million (ppm) anthraquinone for 2 years. Similar groups of male and female mice received feed containing 833, 2,500, or 7,500 ppm anthraquinone. Groups of 50 male and female rats and mice receiving undosed feed served as the control groups. Tissues from more than 40 sites were examined for every animal. Results: In each group, the group receiving the highest dose of anthraquinone weighed less than its control group. Male and female rats given anthraquinone had higher rates of tumors of the kidney and urinary bladder. Liver tumors also were increased in female rats and slightly increased in male rats. In male and female mice given anthraquinone, the rates of liver tumors were greatly increased, and a few of these animals developed thyroid gland tumors. Conclusions: We conclude that anthraquinone caused cancer of the kidney and urinary bladder in male and female rats and of the liver in female rats. The occurrence of some liver tumors in male rats may have been related to anthraquinone exposure. We conclude that anthraquinone caused liver cancer in
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