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TR-446: 1-Trans-Delta9-Tetrahydrocannabinol (CASRN 1972-08-3) in F344 Rats and B6c3f1mice (Gavage Studies)

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TR-446: 1-Trans-Delta9-Tetrahydrocannabinol (CASRN 1972-08-3) in F344 Rats and B6c3f1mice (Gavage Studies) NATIONAL TOXICOLOGYPROGRAM Technical Report Series No. 446 TOXICOLOGY AND CARCINOGENESIS STUDIES OF 1-TRANS-DELTA'=TETRAHYDROCANNABINOL (CAS NO. 1972-08-3) IN F344/N RATS AND B6C3F, MICE (GAVAGE STUDIES) U.S. DEPARTMENT 1OF HEALTH AND HUMAS 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 Cancir 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. 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 anlayses for humans require wider analyses beyond the purview of these studies. Selection per se is not an indicator of a chemical's carcinogenic potential. These NTP Technical Reports are available for sale from the National Technical Information Service, U.S. Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161 (703-487-4650). Single copies of this Technical Report are available without charge while supplies last from NTP Central Data Management, NIEHS, P.O. Box 12233, MD El-02, Research Triangle Park, NC 27709 (919-541-3419). Listings of all published NTP reports and ongoing studies are also available from NTP Central Data Management. 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 1-TRANS-DELTA9-TETRAHYDROCANNABINOL (CAS NO. 1972-08-3) IN F344/N RATS AND B6C3Fl MICE (GAVAGE STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 November 1996 NTP TR 446 NIH Publication No. 97-3362 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health 2 1-Trans-Delta9-Tetrahydrocannabinol,NTP TR 446 CONTRIBUTORS National Toxicology Program NTP Pathology Working Group Evaluated and interpreted results and reported findings Evaluated slides, prepared pathology report on rats (13 October 1992) P.C. Chan, Ph.D., StudyScientist G.A. Boorman, D.V.M., Ph.D. J.C. Seely, D.V.M., Chairperson D.A. Bridge, B.S. PATHCO, Inc. J.R. Bucher, Ph.D. D. Dixon, D.V.M., Ph.D. National Toxicology Program M.R. Elwell, D.V.M., Ph.D. J.R. Hailey, D.V.M. T.J. Goehl, Ph.D. National Toxicology Program J.K. Haseman, Ph.D. B.F. Hamilton, D.V.M., Ph.D. G.N. Rao, D.V.M., Ph.D. Experimental Pathology Laboratories, Inc. J.H. Roycroft, Ph.D. C.C. Shackelford, D.V.M., M.S., Ph.D. R.C. Sills, D.V.M., Ph.D. National Toxicology Program G.S. Travlos, D.V.M. R.C. Sills, D.V.M., Ph.D. D.B. Walters, Ph.D. National Toxicology Program KL. Witt, M.S., Oak Ridge Associated Universities Evaluated slides, prepared pathology report on mice (30Ju& 1992) SRI International J.C. Seely, D.V.M., Chairperson Conducted 13- and 22-week studies, evaluated pathology findings PATHCO, Inc. R. Cattley, V.M.D., Ph.D. T.A. Jorgenson, M.S., Principal Investigator Chemical Industly Institute of Toxicology E.F. Meierhenry, Ph.D. B.F. Hamilton, D.V.M., Ph.D. R.J. Spanggord, Ph.D. Experimental Pathology Laboratories, Inc. C.C. Shackelford, D.V.M., M.S., Ph.D. National Toxicology Program R.C. Sills, D.V.M., Ph.D. TSI Mason Research Institute National Toxicology Program Conducted 2-year studies, evaluated pathology findings A.G. Braun, Sc.D., PrincipalInvestigator Analytical Sciences, Inc. F.A. Voelker, M.S., D.V.M. Provided statistical analyses M.E.P. Goad, D.V.M., Ph.D. R.W. Morris, M.S, Principal Investigator N.G. Mintz, B.S. Experimental Pathology Laboratories, Inc. S. Rosenblum, M.S. Provided pathology quality assurance J.F. Hardisty, D.V.M., PrincipalInvestigator Biotechnical Services, Inc. B.F. Hamilton, D.V.M., Ph.D. Prepared Technical Report D.D. Lambright, Ph.D., Principal Investigator Dynamac Corporation S.R. Gunnels, M.A. Prepared quality assurance audits T.A. King-Hunter, B.S. T.L. Rhoades, B.S. S. Brecher, Ph.D., PrincipalInvestigator 3 CONTENTS ABSTRACT ................................................................... 5 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTMTY ............... 9 TECHNICAL REPORTS REVIEW SUBCOMMITTEE ................................... 10 SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS ........... 11 INTRODUCTION .............................................................. 13 MATERIALSANDMETHODS .................................................... 29 RESULTS .................................................................... 41 DISCUSSION AND CONCLUSIONS ................................................ 73 REFERENCES ................................................................ 81 APPENDIXA Summary of Lesions in Male Rats in the 2-Year Gavage Study of 1-Trans-Delta9-Tetrahydrocannabinol ................................. 93 APPENDIX B Summary of Lesions in Female Rats in the 2-Year Gavage Study of 1-Trans-Delta9-Tetrahydrocannabinol ................................. 135 APPENDIX C Summary of Lesions in Male Mice in the 2-Year Gavage Study of 1-Trans-Delta9-Tetrahydrocannabinol ................................. 171 APPENDIXD Summary of Lesions in Female Mice in the 2-Year Gavage Study of 1-Trans-Delta9-Tetrahydrocannabinol ...;............................. 213 APPENDIX E Genetic Toxicology ................................................. 255 APPENDIX F Organ Weights and Organ-Weight-to-Body-WeightRatios .................... 265 APPENDIX G Hematology and Clinical Chemistry Results .............................. 277 APPENDIX H Reproductive Tissue Evaluations and Estrous Cycle Characterization ........... 285 APPENDIX I Chemical Characterization and Dose Formulation Studies ................... 291 APPENDIX J Ingredients. Nutrient Composition. and Contaminant Levels in NIH-07 Rat and Mouse Ration ..................................... 305 APPENDIX K Sentinel Animal Program ............................................ 311 4 l-Trans-Delta9-Tetrahydrocannabinol,NTP TR 446 ABSTRACT 1-TRANS-DELTA9-TETRAHYDROCANNABINOL CAS NO.1972-08-3 Chemical Formula: ~lH,,O, Molecular Weight: 314.5 Synonyms: 3-Pentyl-6,6,9-trimethyl-6a,7,8,lOa-tet~hyd~-6h-di~~o(b,d)pyran-l-ol;deltal-tetrahydrocannabinol; (-)-delta1-3,4-trans-tetrahydrocannabinok delta'4etrahydrocannabinon; THC; delta'-THC; delta9-THC Trade names: Dronabinol; Marinol 1-Trans-delta9-tetrahydrocannabinol (THC) was administration of THC. The absolute and relative nominated by the National Cancer Institute to the uterus weights of 50, 150, and 500 mgkg females NTP for study because it is the major psychoactive were significantly lower than those of the controls. component of marijuana and a widelyused Treatment-related multifocal atrophy was observed in Schedule I substance. Male and female F344/N rats the testes of 150 and 500 mgkg males; uterine and and B6C3F, mice received THC (97% pure) in corn ovarianhypoplasiaobservedin 150 and 500 mg/kg oil by gavage for 13 weeks, 13weeks with a 9-week femaleswas also considered to be related to THC recovery period, or 2 years. Genetic toxicology administration. Based on final mean body weights studies were conducted in Salmonella typhimurium, and mortality observed in the 13-week study, doses cultured Chinese hamster ovarycells, and mouse selected for the 2-year rat study were 12.5, 25, and peripheral blood cells. 50 mg/kg. ISWEEK STUDY IN RATS WWEEK STUDY IN MICE Groups of 10 male and 10 female rats received 0, 5, Groups of 10 male and 10 female mice received0,5, 15, 50, 150, or 500 mg THC/kg body weight in corn 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13weeks. Six male oil
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