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TR-485: Oxymetholone

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TR-485: Oxymetholone NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF OXYMETHOLONE (CAS NO. 434-07-1) IN F344/N RATS AND TOXICOLOGY STUDIES OF OXYMETHOLONE IN B6C3F1 MICE (GAVAGE STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 August 1999 NTP TR 485 NIH Publication No. 99-3975 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. Listings of all published NTP reports and ongoing studies are available from NTP Central Data Management, NIEHS, P.O. Box 12233, MD E1-02, Research Triangle Park, NC 27709 (919-541-3419). The Abstracts and other study information for 2-year studies are also available at the NTP’s World Wide Web site: http://ntp-server.niehs.nih.gov. NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF OXYMETHOLONE (CAS NO. 434-07-1) IN F344/N RATS AND TOXICOLOGY STUDIES OF OXYMETHOLONE IN B6C3F1 MICE (GAVAGE STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 August 1999 NTP TR 485 NIH Publication No. 99-3975 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health 2 Oxymetholone, NTP TR 485 CONTRIBUTORS National Toxicology Program NTP Pathology Working Group Evaluated and interpreted results and reported findings Evaluated slides, prepared pathology report (29 July 1997) W.C. Eastin, Ph.D., Study Scientist J.C. Seeley, D.V.M., Chairperson D.A. Bridge, B.S. PATHCO, Inc. J.R. Bucher, Ph.D. B. Bullock, D.V.M. R.E. Chapin, Ph.D. Bowman Gray J.R. Hailey, D.V.M. B.J. Davis, D.V.M., Ph.D. National Toxicology Program J.R. Hailey, D.V.M. R.A. Herbert, D.V.M., Ph.D. J.K. Haseman, Ph.D. National Toxicology Program J. Mahler, D.V.M. G.D. Jahnke, D.V.M., Ph.D., Observer R.R. Maronpot, D.V.M. National Toxicology Program G.N. Rao, D.V.M., Ph.D. J.R. Leininger, D.V.M., Ph.D. J.H. Roycroft, Ph.D. National Toxicology Program C.S. Smith, Ph.D. J. Mahler, D.V.M. National Toxicology Program G.S. Travlos, D.V.M. C.C. Shackelford, D.V.M., M.S., Ph.D. K.L. Witt, M.S., Integrated Laboratory Systems Experimental Pathology Laboratories, Inc. Battelle Columbus Laboratories Analytical Sciences, Inc. Conducted 14-day and 14-week studies, evaluated pathology findings Provided statistical analyses P.J. Kurtz, Ph.D., Principal Investigator R.W. Morris, M.S., Principal Investigator R.L. Persing, D.V.M. K.P. McGowan, M.B.A. M.J. Ryan, D.V.M., Ph.D. M.A. Mauney, M.S. B.A. Trela, Ph.D. N.G. Mintz, B.S. J.T. Scott, M.S. Conducted 2-year studies, evaluated pathology findings Biotechnical Services, Inc. P.J. Kurtz, Ph.D., Principal Investigator Prepared Technical Report M.R. Hejtmancik, Ph.D., Principal Investigator J.D. Johnson, Ph.D. S.R. Gunnels, M.A., Principal Investigator B.A. Trela, Ph.D. L.M. Harper, B.S. J.T. Yarrington, D.V.M., Ph.D. J.P. Hogan, M.S. A.M. Macri-Hanson, M.A., M.F.A. S.M. Swift, B.S. Experimental Pathology Laboratories, Inc. Provided pathology quality assurance J.F. Hardisty, D.V.M., Principal Investigator C.C. Shackelford, D.V.M., M.S., Ph.D. Dynamac Corporation Prepared quality assurance audits S. Brecher, Ph.D., Principal Investigator 3 CONTENTS ABSTRACT ............................................................. 5 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY ............. 11 TECHNICAL REPORTS REVIEW SUBCOMMITTEE ................................ 12 SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS .......... 13 INTRODUCTION ......................................................... 15 MATERIALS AND METHODS ................................................ 23 RESULTS ............................................................... 37 DISCUSSION AND CONCLUSIONS ............................................ 77 REFERENCES ........................................................... 85 APPENDIX A Summary of Lesions in Male Rats in the 2-Year Gavage Study of Oxymetholone ............................................... 95 APPENDIX B Summary of Lesions in Female Rats in the 2-Year Gavage Study of Oxymetholone ............................................... 139 APPENDIX C Genetic Toxicology ............................................. 181 APPENDIX D Hematology and Clinical Chemistry Results ............................. 187 APPENDIX E Tissue Weights and Tissue-Weight-to-Body-Weight Ratios ................... 193 APPENDIX F Reproductive Tissue Evaluations and Estrous Cycle Characterization ........... 197 APPENDIX G Chemical Characterization and Dose Formulation Studies ................... 201 APPENDIX H Ingredients, Nutrient Composition, and Contaminant Levels in NIH-07 Rat and Mouse Ration ................................... 213 APPENDIX I Sentinel Animal Program ......................................... 217 APPENDIX J Single-Dose Toxicokinetic Studies in F344/N Rats and B6C3F1 Mice ............ 221 4 Oxymetholone, NTP TR 485 5 ABSTRACT H3C OH CH3 H3C H HO H H O H OXYMETHOLONE CAS No. 434-07-1 Chemical Formula: C21 H32 O3 Molecular Weight: 332.5 Synonyms: Adroidin; anadroyd; anasteron; anasteronal; anasterone; androstan-3-one, androstano[2,3-c]1,2,5-oxadiazol-17-ol, 17-methyl-, (5-",17-$)-; becorel; 4,5-dihydro-2-hydroxymethylene-17-"-methyltestosterone; dynasten; HMD; 17$-hydroxy-2­ (hydroxymethyl)-17-methyl-5-"-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-(5-",17-$)-; 17-hydroxy­ 2-(hydroxymethylene)-17-methyl-5-"-17-$-androst-3-one; 17$-hydroxy-2-(hydroxymethylene)-17-"-methyl-5-"-androstan-3-one; 17$-hydroxy-2-(hydroxymethylene)-17-methyl-5"-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-5-"-17­ $-androstan-3-one; 17$-hydroxy-2-hydroxymethylene-17"-methyl-3-androstanone; 2-hydroxymethylene-17-"-methyl-5­ "-androstan-17-$-ol-3-one; 2-hydroxymethylene-17"-methyl dihydrotestosterone; 2-hydroxymethylene-17-"-methyl-17-$­ hydroxy-3-androstanone; methabol; 17"-methyl-2-hydroxymethylene-17-hydroxy-5-"-androstan-3-one; oximetholonum; oximetolona; oxitosona-50; oxymethenolone; roboral; zenalosyn Trade names: Adroyd; Anadrol; Anapolon; Anapolon 50; Nastenon; Pardroyd; Pavisoid; Plenastril; Protanabol; Synasteron Oxymetholone is a synthetic anabolic steroid used to by gavage for 16 days or 14 weeks. Genetic toxi­ treat a variety of conditions, including hypogonadism cology studies were conducted in Salmonella typhi­ and delayed puberty. It is also used to correct hered­ murium, cultured Chinese hamster ovary cells, and itary angioneurotic edema, manage carcinoma of the mouse peripheral blood erythrocytes. breast, promote a positive nitrogen balance following injury or surgery, and stimulate erythropoiesis. Considerable amounts of androgens are consumed by athletes in attempts to improve athletic performance. 16-DAY STUDY IN RATS The National Institute of Environmental Health Groups of five male and five female F344/N rats were Sciences and the National Cancer Institute nominated administered 0, 160, 315, 625, 1,250, or 2,500 mg oxymetholone for study based on its extensive illicit oxymetholone/kg body weight in 0.5% methyl­ pharmaceutical use and the limited evidence that it is cellulose by gavage for 16 days. All male rats sur­ a potential human carcinogen.
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