Triethanolamine (CASRN 102-71-6) in B6c3f1mice (Dermal Studies)
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NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF TRIETHANOLAMINE (CAS NO. 102-71-6) IN B6C3F1 MICE (DERMAL STUDY) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 May 2004 NTP TR 518 NIH Publication No. 04-4452 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 at the end of this Technical Report. NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF TRIETHANOLAMINE (CAS NO. 102-71-6) IN B6C3F1 MICE (DERMAL STUDY) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 May 2004 NTP TR 518 NIH Publication No. 04-4452 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 (April 1, 2002) F.A. Suarez, M.D., M.S., Study Scientist G.A. Parker, D.V.M., Ph.D., Chairperson R.A. Herbert, D.V.M., Ph.D., Study Pathologist ILS, Inc. D.W. Bristol, Ph.D. R. Bahnemann, D.V.M., Ph.D., Observer J.R. Bucher, Ph.D. BASF Corporation J.R. Hailey, D.V.M. W.R. Brown, D.V.M., Ph.D. J.K. Haseman, Ph.D. Research Pathology Services, Inc. R.R. Maronpot, D.V.M. G.P. Flake, M.D. D.P. Orzech, M.S. National Toxicology Program G. Pearse, B.V.M. & S. J.R. Hailey, D.V.M. S.D. Peddada, Ph.D. National Toxicology Program J.H. Roycroft, Ph.D. A. Nyska, D.V.M. 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., ILS, Inc. C.C. Shackelford, D.V.M., M.S., Ph.D. Experimental Pathology Laboratories, Inc. Battelle Columbus Operations G. Willson, B.V.M. & S. Conducted studies and evaluated pathology findings Experimental Pathology Laboratories, Inc. M.R. Hejtmancik, Ph.D., Principal Investigator Analytical Sciences, Inc. M.J. Ryan, D.V.M., Ph.D. Provided statistical analyses Experimental Pathology Laboratories, Inc. P.W. Crockett, Ph.D., Principal Investigator L.J. Betz, M.S. Provided pathology quality assurance K.P. McGowan, M.B.A. J.F. Hardisty, D.V.M., Principal Investigator J.T. Scott, M.S. C.C. Shackelford, D.V.M., M.S., Ph.D. G. Willson, B.V.M. & S. Biotechnical Services, Inc. Prepared Technical Report Dynamac Corporation S.R. Gunnels, M.A., Principal Investigator Prepared quality assurance audits B.F. Hall, M.S. S. Brecher, Ph.D., Principal Investigator L.M. Harper, B.S. D.C. Serbus, Ph.D. R.A. Willis, B.A., B.S. 3 CONTENTS ABSTRACT . 5 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY . 8 TECHNICAL REPORTS REVIEW SUBCOMMITTEE . 9 SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS . 10 INTRODUCTION . 11 MATERIALS AND METHODS . 19 RESULTS . 27 DISCUSSION AND CONCLUSIONS . 39 REFERENCES . 43 APPENDIX A Summary of Lesions in Male Mice in the 2-Year Dermal Study of Triethanolamine . 49 APPENDIX B Summary of Lesions in Female Mice in the 2-Year Dermal Study of Triethanolamine . 87 APPENDIX C Genetic Toxicology . 125 APPENDIX D Chemical Characterization and Dose Formulation Studies . 135 APPENDIX E Ingredients, Nutrient Composition, and Contaminant Levels in NTP-2000 Rat and Mouse Ration . 145 APPENDIX F Sentinel Animal Program . 149 APPENDIX G Absorption, Distribution, Metabolism, and Excretion Studies . 151 4 Triethanolamine, NTP TR 518 SUMMARY Background Triethanolamine is used to make many products, including household detergents and polishes, herbicides, vegetable and mineral oils, paraffin and waxes, plastics, resins, adhesives, and ointments. We studied the effects of triethanolamine on male and female mice to identify potential toxic or cancer-related hazards to humans. Methods We placed solutions of triethanolamine dissolved in acetone onto the shaved skin on the backs of male and female mice 5 days per week for 2 years. Male mice received concentrations of 200, 630, or 2,000 milligrams of triethanolamine per kilogram of body weight, and female mice received half those concentrations. Control groups received only acetone. Results The dosed animals did not have higher death rates than the control animals. The male mice receiving 2,000 mg triethanolamine per kg body weight weighed less than the male control animals. There was a slight increase in hemangiosarcomas (tumors of the vascular system) in the livers of males exposed to triethanolamine. In female mice exposed to triethanolamine, there was a significant increase in liver tumors. Conclusions We conclude that triethanolamine caused liver tumors in female mice and may have caused a slight increase in hemangiosarcomas of the liver in male mice. 5 ABSTRACT OH H2C CH2 H2 H2 C N C HO C C OH H2 H2 TRIETHANOLAMINE CAS No. 102-71-6 Chemical Formula: C6H15NO3 Molecular Weight: 149.19 Synonyms: Nitrilo-2,2N,2NN-triethanol; 2,2N,2NN-nitrilotriethanol; 2,2N,2NN-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; triethylolamine; tri(hydroxyethyl)amine; 2,2N,2NN-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; tris(2-hydroxyethyl)amine; trolamine Trade names: Daltogen, Sterolamide, Thiofaco T-35 Triethanolamine is widely used in the manufacturing of marginal increase in the incidence of renal tubule adeno household detergents and polishes, textiles, agricultural ma (NTP, 1991). Interpretation of the results from the herbicides, mineral and vegetable oils, paraffin and 2-year study in mice was complicated by Helicobacter waxes, pharmaceutical ointments, petroleum demulsi- hepaticus infection, prompting a repeat 2-year study in fiers, synthetic resins, plasticizers, adhesives, and mice. Male and female B6C3F1 mice received tri sealants. It is used as a chemical intermediate for anion- ethanolamine (greater than 99% pure) by dermal appli ic and nonionic surfactants, a vulcanization accelerator, cation for 2 years; a study of absorption, distribution, a humectant and softening agent and in many other metabolism, and excretion was performed in additional industrial applications. The National Cancer Institute mice. Genetic toxicology studies were conducted in nominated triethanolamine for study because of its wide- Salmonella typhimurium, cultured Chinese hamster spread use in cosmetics and other consumer products, its ovary cells, Drosophila melanogaster, and mouse high potential for worker exposure due to its many peripheral blood erythrocytes. industrial uses, and its potential for conversion to the carcinogen N-nitrosodiethanolamine. Previous 3-month and 2-year studies of triethanolamine were conducted by 2-YEAR STUDY the National Toxicology Program in F344/N rats and Groups of 50 male and 50 female mice received dermal B6C3F1 mice; results from the 2-year rat study indicated applications of 0, 200, 630, or 2,000 mg/kg (males) and equivocal evidence of carcinogenic activity based on a 0, 100, 300, or 1,000 mg/kg (females) triethanolamine in 6 Triethanolamine, NTP TR 518 acetone, 5 days per week, for 104 (males) or 104 to GENETIC TOXICOLOGY 105 (females) weeks. Triethanolamine was not mutagenic in any of the in vitro or in vivo tests. It did not induce mutations in Survival of all dosed groups was similar to that of the Salmonella typhimurium, and no induction of sister vehicle control groups.