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Draft TR-601: Di(2-Ethylhexyl) Phthalate (CASRN 117-81-7)

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Draft TR-601: Di(2-Ethylhexyl) Phthalate (CASRN 117-81-7) 1 NTP Technical Report on the 2 Toxicology and Carcinogenesis Studies of 3 Di(2-ethylhexyl) Phthalate (CASRN 117-81-7) 4 Administered in Feed to Sprague Dawley ® ® 5 (Hsd:Sprague Dawley SD ) Rats 6 Technical Report 601 7 February 2021 8 National Toxicology Program 9 Public Health Service 10 U.S. Department of Health and Human Services 11 ISSN: 2378-8925 12 Research Triangle Park, North Carolina, USA NOTICE This DRAFT Technical Report is distributed solely for the purpose of predissemination peer review under the applicable information quality guidelines. It has not been formally disseminated by NTP. It does not represent and should not be construed to represent NTP determination or policy. Peer Review Draft NOT FOR ATTRIBUTION 1 Foreword 2 The National Toxicology Program (NTP), established in 1978, is an interagency program within 3 the Public Health Service of the U.S. Department of Health and Human Services. Its activities 4 are executed through a partnership of the National Institute for Occupational Safety and Health 5 (part of the Centers for Disease Control and Prevention), the Food and Drug Administration 6 (primarily at the National Center for Toxicological Research), and the National Institute of 7 Environmental Health Sciences (part of the National Institutes of Health), where the program is 8 administratively located. NTP offers a unique venue for the testing, research, and analysis of 9 agents of concern to identify toxic and biological effects, provide information that strengthens 10 the science base, and inform decisions by health regulatory and research agencies to safeguard 11 public health. NTP also works to develop and apply new and improved methods and approaches 12 that advance toxicology and better assess health effects from environmental exposures. 13 The Technical Report series began in 1976 with carcinogenesis studies conducted by the 14 National Cancer Institute. In 1981, this bioassay program was transferred to NTP. The studies 15 described in the NTP Technical Report series are designed and conducted to characterize and 16 evaluate the toxicological potential, including carcinogenic activity, of selected substances in 17 laboratory animals (usually two species, rats and mice). Substances (e.g., chemicals, physical 18 agents, and mixtures) selected for NTP toxicity and carcinogenicity studies are chosen primarily 19 on the basis of human exposure, level of commercial production, and chemical structure. The 20 interpretive conclusions presented in NTP Technical Reports are derived solely from the results 21 of these NTP studies, and extrapolation of the results to other species, including characterization 22 of hazards and risks to humans, requires analyses beyond the intent of these reports. Selection for 23 study per se is not an indicator of a substance’s carcinogenic potential. 24 NTP conducts its studies in compliance with its laboratory health and safety guidelines and the 25 Food and Drug Administration Good Laboratory Practice Regulations and meets or exceeds all 26 applicable federal, state, and local health and safety regulations. Animal care and use are in 27 accordance with the Public Health Service Policy on Humane Care and Use of Laboratory 28 Animals. Studies are subjected to retrospective quality assurance audits before they are presented 29 for public review. Draft reports undergo external peer review before they are finalized and 30 published. 31 The NTP Technical Reports are available free of charge on the NTP website and cataloged in 32 PubMed, a free resource developed and maintained by the National Library of Medicine (part of 33 the National Institutes of Health). Data for these studies are included in NTP’s Chemical Effects 34 in Biological Systems database. 35 For questions about the reports and studies, please email NTP or call 984-287-3211. ii Peer Review Draft NOT FOR ATTRIBUTION 1 Table of Contents 2 Foreword ......................................................................................................................................... ii 3 Tables ...............................................................................................................................................v 4 Figures............................................................................................................................................ vi 5 About This Report........................................................................................................................ viii 6 Explanation of Levels of Evidence of Carcinogenic Activity ...................................................... xii 7 Peer Review ................................................................................................................................. xiv 8 Publication Details .........................................................................................................................xv 9 Acknowledgments..........................................................................................................................xv 10 Abstract ........................................................................................................................................ xvi 11 Perinatal and Postweaning Study in Rats (Study 1) ................................................................ xvi 12 Postweaning-only Study in Rats (Study 2) ............................................................................ xvii 13 Comparative Carcinogenic Benchmark Dose Analyses ........................................................ xvii 14 Genetic Toxicology ................................................................................................................ xvii 15 Conclusions ............................................................................................................................ xvii 16 Overview .................................................................................................................................... xxiv 17 Introduction ......................................................................................................................................1 18 Chemical and Physical Properties ...............................................................................................1 19 Production, Use, and Human Exposure ......................................................................................1 20 Regulatory Status ........................................................................................................................2 21 Absorption, Distribution, Metabolism, and Excretion ................................................................3 22 Experimental Animals .........................................................................................................3 23 Humans ................................................................................................................................4 24 Toxicity .......................................................................................................................................6 25 Experimental Animals .........................................................................................................6 26 Humans ................................................................................................................................7 27 Reproductive and Developmental Toxicity ................................................................................7 28 Experimental Animals .........................................................................................................7 29 Humans ................................................................................................................................9 30 Immunotoxicity ...........................................................................................................................9 31 Experimental Animals .........................................................................................................9 32 Humans ..............................................................................................................................10 33 Carcinogenicity .........................................................................................................................10 34 Experimental Animals .......................................................................................................10 35 Humans ..............................................................................................................................11 36 Genetic Toxicity ........................................................................................................................11 37 Study Rationale .........................................................................................................................13 38 Materials and Methods ...................................................................................................................14 39 Procurement and Characterization of Di(2-ethylhexyl) Phthalate ............................................14 40 Preparation and Analysis of Dose Formulations .......................................................................14 iii Peer Review Draft NOT FOR ATTRIBUTION 1 Animal Source ...........................................................................................................................15 2 Animal Welfare .........................................................................................................................15
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