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TR-540: Methylene Blue Trihydrate (CASRN 7220-79-3) in F344/N Rats

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TR-540: Methylene Blue Trihydrate (CASRN 7220-79-3) in F344/N Rats NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF METHYLENE BLUE TRIHYDRATE (CAS NO. 7220-79-3) IN F344/N RATS AND B6C3F1 MICE (GAVAGE STUDIES) National Toxicology Program P.O. Box 12233 Research Triangle Park, NC 27709 May 2008 NTP TR 540 NIH Publication No. 08-4429 National Institutes of Health Public Health Service U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES FOREWORD The National Toxicology Program (NTP) is an interagency program within the Public Health Service (PHS) of the Department of Health and Human Services (HHS) and is headquartered at the National Institute of Environmental Health Sciences of the National Institutes of Health (NIEHS/NIH). Three agencies contribute resources to the program: NIEHS/NIH, the National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention (NIOSH/CDC), and the National Center for Toxicological Research of the Food and Drug Administration (NCTR/FDA) Established in 1978, the NTP is charged with coordinating toxicological testing activities, strengthening the science base in toxicology, developing and validating improved testing methods, and providing information about potentially toxic substances to health regulatory and research agencies, scientific and medical communities, and the public. The Technical Report series began in 1976 with carcinogenesis studies conducted by the National Cancer Institute. In 1981, this bioassay program was transferred to the NTP. The studies described in the Technical Report series are designed and conducted to characterize and evaluate the toxicologic potential, including carcinogenic activity, of selected substances in laboratory animals (usually two species, rats and mice). Substances selected for NTP toxicity and carcinogenicity studies are chosen primarily on the basis of human exposure, level of production, and chemical structure. The interpretive conclusions presented in NTP Technical Reports are based only on the results of these NTP studies. Extrapolation of these results to other species including characterization of hazards and risks to humans requires analyses beyond the intent of these reports. Selection per se is not an indicator of a substance’s carcinogenic potential. The NTP conducts its studies in compliance with its laboratory health and safety guidelines and FDA Good Laboratory Practice Regulations, and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use are in accordance with the Public Health Service Policy on Humane Care and Use of Animals. Studies are subjected to retrospective quality assurance audits before being presented for public review. NTP Technical Reports are indexed in the NIH/NLM PubMed database and are available free of charge electronically on the NTP website (http://ntp.niehs.nih.gov) or in hardcopy upon request from the NTP Central Data Management group at [email protected] or (919) 541-3419. NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF METHYLENE BLUE TRIHYDRATE (CAS NO. 7220-79-3) IN F344/N RATS AND B6C3F1 MICE (GAVAGE STUDIES) National Toxicology Program P.O. Box 12233 Research Triangle Park, NC 27709 May 2008 NTP TR 540 NIH Publication No. 08-4429 National Institutes of Health Public Health Service U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 2 CONTRIBUTORS National Toxicology Program NTP Pathology Working Group Evaluated and interpreted results and reported findings Evaluated slides and prepared pathology report on rats (December 8, 2004) D.W. Bristol, Ph.D., Study Scientist W.G. Lieuallen, D.V.M., Ph.D., Chairperson J.C. Peckham, D.V.M., M.S., Ph.D., Study Pathologist Pathology Associates International J.R. Bucher, Ph.D. M.F. Cesta, D.V.M., Observer R.S. Chhabra, Ph.D. National Toxicology Program B.J. Collins, M.S. K.J. Cimon, D.V.M., M.S. R.A. Herbert, D.V.M., Ph.D. Experimental Pathology Laboratories, Inc. A.P. King-Herbert, D.V.M. D. Dixon, D.V.M., Ph.D. G.E. Kissling, Ph.D. National Toxicology Program D.E. Malarkey, D.V.M., Ph.D. R.A. Herbert, D.V.M., Ph.D. R.R. Maronpot, D.V.M. National Toxicology Program S.D. Peddada, Ph.D. D.E. Malarkey, D.V.M., Ph.D. National Toxicology Program J.H. Roycroft, Ph.D. K. Mozzachio, D.V.M., Observer R.C. Sills, D.V.M., Ph.D. National Toxicology Program C.S. Smith, Ph.D. G. Pearse, B.V.M. & S. G.S. Travlos, D.V.M. National Toxicology Program K.L. Witt, M.S. J.C. Peckham, D.V.M., M.S., Ph.D. Experimental Pathology Laboratories, Inc. Battelle Columbus Operations A. Suttie, B.V.Sc., Ph.D. Conducted 1- and 3-month studies and evaluated pathology findings ILS, Inc. K. Yoshizawa, D.V.M., Ph.D., Observer P.J. Kurtz, Ph.D., Principal Investigator National Toxicology Program R.L. Persing, D.V.M. Evaluated slides and prepared pathology report on mice A.W. Singer, D.V.M. (January 26, 2005) J.D. Toff, D.V.M., M.S. W.G. Lieuallen, D.V.M., Ph.D., Chairperson Southern Research Institute Pathology Associates International Conducted 2-year studies and evaluated pathology findings M.F. Cesta, D.V.M., Observer National Toxicology Program W. Richter, D.V.M., Principal Investigator K.J. Cimon, D.V.M., M.S. Experimental Pathology Laboratories, Inc. C.D. Hébert, Ph.D., Principal Investigator D.R. Farnell, D.V.M., Ph.D. D. Dixon, D.V.M., Ph.D. National Toxicology Program J.E. Heath, D.V.M. G.P. Flake, M.D. National Toxicology Program Experimental Pathology Laboratories, Inc. R.A. Herbert, D.V.M., Ph.D. Provided pathology review National Toxicology Program D.E. Malarkey, D.V.M., Ph.D. J.F. Hardisty, D.V.M., Principal Investigator National Toxicology Program K.J. Cimon, D.V.M., M.S. A. Nyska, D.V.M. J.C. Peckham, D.V.M., M.S., Ph.D. National Toxicology Program G. Pearse, B.V.M. & S. National Toxicology Program Dynamac Corporation J.C. Peckham, D.V.M., M.S., Ph.D. Prepared quality assurance audits Experimental Pathology Laboratories, Inc. A. Suttie, B.V.Sc., Ph.D. S. Brecher, Ph.D., Principal Investigator ILS, Inc. Methylene Blue Trihydrate, NTP TR 540 3 Constella Group, Inc. Biotechnical Services, Inc. Provided statistical analyses Prepared Technical Report P.W. Crockett, Ph.D., Principal Investigator S.R. Gunnels, M.A., Principal Investigator L.J. Betz, M.S. B.F. Hall, M.S. K.P. McGowan, M.B.A. L.M. Harper, B.S. J.I. Powers, M.A.P. D.C. Serbus, Ph.D. 4 CONTENTS ABSTRACT ............................................................................. 7 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY................. 12 TECHNICAL REPORTS REVIEW SUBCOMMITTEE........................................ 13 SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS............. 14 INTRODUCTION ........................................................................ 15 MATERIALS AND METHODS ............................................................ 21 RESULTS ............................................................................... 35 DISCUSSION AND CONCLUSIONS........................................................ 81 REFERENCES........................................................................... 87 AP P E N D I X A Summary of Lesions in Male Rats in the 2-Year Gavage Study of Methylene Blue Trihydrate ................................................ 93 AP P E N D I X B Summary of Lesions in Female Rats in the 2-Year Gavage Study of Methylene Blue Trihydrate ................................................ 107 AP P E N D I X C Summary of Lesions in Male Mice in the 2-Year Gavage Study of Methylene Blue Trihydrate ................................................ 119 AP P E N D I X D Summary of Lesions in Female Mice in the 2-Year Gavage Study of Methylene Blue Trihydrate ................................................ 135 AP P E N D I X E Genetic Toxicology ......................................................... 149 AP P E N D I X F Clinical Pathology Results ................................................... 165 AP P E N D I X G Organ Weights and Organ-Weight-to-Body-Weight Ratios ....................... 193 AP P E N D I X H Reproductive Tissue Evaluations and Estrous Cycle Characterization .............. 199 AP P E N D I X I Chemical Characterization and Dose Formulation Studies ........................ 203 AP P E N D I X J Ingredients, Nutrient Composition, and Contaminant Levels in NTP-2000 Rat and Mouse Ration........................................... 217 AP P E N D I X K Sentinel Animal Program.................................................... 221 Methylene Blue Trihydrate, NTP TR 540 5 SUMMARY Background Methylene blue trihydrate has a variety of medical uses, including the treatment of methemoglobinemia and psychiatric disorders and as a disinfectant and biological stain. We studied the effects of methylene blue trihydrate on male and female rats and mice to identify potential toxic or cancer-related hazards. Methods We deposited solutions containing methylene blue trihydrate in aqueous methylcellulose directly into the stomachs of male and female rats and mice. Groups of 50 male and female rats received 5, 25, or 50 milligrams of methylene blue trihydrate per kilogram body weight five days per week for two years; groups of 50 male and female mice received 2.5, 12.5, or 25 milligrams of methylene blue per kilogram of body weight for the same duration. Groups of animals receiving methylcellulose alone served as the control groups. At the end of the study, tissues from more than 40 sites were examined for every animal. Results The two highest dose groups of male and female rats weighed less than the control animals, while the two highest dose groups of female mice weighed more than their corresponding control group. In male and female rats and mice, the blood of the animals was affected, with animals receiving the highest doses experiencing methemoglobinemia and anemia. This caused secondary injury to the spleen in these animals. Cancer of the pancreatic islets was increased in male rats receiving methylene blue trihydrate, and some uncommon tumors of the small intestine were seen in exposed male mice. There was a slight increase in malignant lymphomas in exposed male and female mice. Conclusions We conclude that exposure to methylene blue caused pancreatic islet tumors in male rats and small intestine tumors in male mice.
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