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Committee on Examining the Safety of Dietary Supplements for Horses, Dogs, and Cats Board on Agriculture and Natural Resources Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by a grant from The Department of Health and Human Services (U.S. Food and Drug Administration) under Contract No. 223-01-2460/0031. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. Library of Congress Cataloging-in-Publication Data National Research Council (U.S.). Committee on Examining the Safety of Dietary Supplements for Horses, Dogs, and Cats. Safety of dietary supplements for horses, dogs, and cats / Committee on Examining the Safety of Dietary Supplements for Horses, Dogs, and Cats, Board on Agriculture and Natural Resources, Division on Earth and Life Studies, National Research Council of the National Academies. p. cm. — (Animal nutrition series) Includes bibliographical references and index. 1. Animal nutrition. 2. Dietary supplements. I. Title. II. Series: Animal nutrition series (Washington, D.C.) SF95.N316 2008 636.08′52—dc22 2008042167 International Standard Book Number-13: 978-0-309-12570-3 International Standard Book Number-10: 0-309-12570-7 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu Copyright 2009 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distin- guished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is auton- omous in its administration and in the selection of its members, sharing with the National Acad- emy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and educa- tion. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering com- munities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON EXAMINING THE SAFETY OF DIETARY SUPPLEMENTS FOR HORSES, DOGS, AND CATS JIM E. RIVIERE, Chair, North Carolina State University, Raleigh DAWN M. BOOTHE, Auburn University, Auburn, Alabama GAIL L. CZARNECKI-MAULDEN, Nestle Purina PetCare PTC, St. Louis, Missouri DAVID A. DZANIS, Dzanis Consulting & Collaborations, Santa Clarita, California PATRICIA A. HARRIS, WALTHAM Centre for Pet Nutrition, Leicestershire, England WOUTER H. HENDRIKS, Wageningen University, Wageningen, The Netherlands CLAUDIA A. KIRK, University of Tennessee, Knoxville LORI K. WARREN, University of Florida, Gainesville Staff AUSTIN J. LEWIS, Study Director RUTHIE S. ARIETI, Senior Project Assistant 

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BOARD ON AGRICULTURE AND NATURAL RESOURCES W. REG GOMES, Chair, University of California (Emeritus), Oakland ROGER N. BEACHY, Donald Danforth Plant Science Center, St. Louis, Missouri H.H. CHENG, University of Minnesota (Emeritus), St. Paul DANIEL M. DOOLEY, University of California, Oakland JOAN H. EISEMANN, North Carolina State University, Raleigh KIRK C. KLASING, University of California, Davis VICTOR L. LECHTENBERG, Purdue University, West Lafayette, Indiana ROBERT PAARLBERG, Wellesley College, Watertown, Massachusetts KEITH PITTS, Curragh Oaks Consulting, Fair Oaks, California HAL SALWASSER, Oregon State University, Corvallis PEDRO A. SANCHEZ, The Earth Institute, Columbia University, Palisades, New York NORMAN R. SCOTT, Cornell University, Ithaca, New York Staff ROBIN A. SCHOEN, Director KAREN L. IMHOF, Administrative Assistant AUSTIN J. LEWIS, Senior Program Officer EVONNE P.Y. TANG, Senior Program Officer CAMILLA YANDOC ABLES, Associate Program Officer KARA N. LANEY, Associate Program Officer PEGGY TSAI, Associate Program Officer RUTH S. ARIETI, Research Associate JANET M. MULLIGAN, Research Associate KAMWETI MUTU, Research Associate ERIN P. MULCAHY, Program Assistant i

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Acknowledgments This report has been reviewed in draft form by persons The review of this report was overseen by George C. chosen for their diverse perspectives and technical expertise Fahey, Jr., University of Illinois. Appointed by the National in accordance with procedures approved by the National Research Council, he was responsible for making certain Research Council’s Report Review Committee. The purpose that an independent examination of this report was carried of this independent review is to provide candid and criti- out in accordance with institutional procedures and that all cal comments that will assist the institution in making its review comments were carefully considered. Responsibility published report as sound as possible and to ensure that the for the final content of this report rests entirely with the report meets institutional standards of objectivity, evidence, author committee and the institution. and responsiveness to the study charge. The review com- The committee wholeheartedly acknowledges the sup- ments and draft manuscript remain confidential to protect port of Dr. Austin Lewis, Program Officer for the com- the integrity of the deliberative process. We wish to thank mittee, who did an outstanding job of both keeping our the following for their review of this report: deliberations on track and focused on the final product. His gentle, but extremely insightful and effective, guidance dur- Kevin L. Armbrust, Mississippi State University ing meetings and conference calls is largely responsible for John E. Bauer, Texas A&M University, College Station the final product that emerged. The committee also owes William Bookout, National Animal Supplement Council, its deep gratitude to Ruthie Arieti, Senior Project Assistant, Valley Center, CA who managed to keep track of both our committee’s diverse George A. Burdock, The Burdock Group, Orlando, FL schedules and inputs in a manner that resulted in a smooth Cynthia A Cole, IDEXX Pharmaceuticals, Greensboro, NC flow for all activities associated with our work. Her active Mark E. Cook, University of Wisconsin, Madison maintenance of the committee website greatly facilitated David W. Freeman, Oklahoma State University, Stillwater our research and writing, as well as fostering a camaraderie George A. Graber, Center for Veterinary Medicine, Food amongst staff and committee members that was crucial to and Drug Administration (retired) allowing our committee to meet its objectives. We appreci- Robert H. Poppenga, University of California, Davis ate the efforts of Robin Schoen, Director of the Board on Jennifer Radosevich, Kemin Nutrisurance, Des Moines, IA Agriculture and Natural Resources, for her encouragement Kelly S. Swanson, University of Illinois, and support in allowing us to complete the project in a man- Urbana-Champaign ner and time frame both acceptable to us and our sponsor. Susan G. Wynn, Bells Ferry Veterinary Hospital, The technical editing by Paula Whitacre, Full Circle Com- Acworth, GA munications, was much appreciated. Finally, the committee wants to express its sincere thanks to the individuals listed Although the reviewers listed above have provided many in Appendix D who provided advice, data, and input into our constructive comments and suggestions, they were not deliberations. Several pet food companies also provided data asked to endorse the conclusions or recommendations, nor (via the Pet Food Institute) that were included in the report, did they see the final draft of the report before its release. but the individual companies prefer to remain anonymous. ii

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Contents SUMMARY 1 The Committee’s Task, 1 Key Findings, 1 Specific Findings and Recommendations, 2 Conclusions, 4 1 INTRODUCTION AND BACKGROUND 5 Significance of Animals and Dietary Supplements, 5 Regulation of Dietary Supplements, 5 Committee Charge, 6 General Terminology and Definition of Dietary Supplement, 7 Organization of the Report, 8 References, 9 2 REGULATION OF DIETARY SUPPLEMENTS IN THE UNITED STATES 11 Regulation of Dietary Supplements for Human Consumption, 11 Regulation of Animal Dietary Supplements, 13 Regulatory Assessment of Safety, 16 References, 18 3 ASSESSING SAFETY OF ANIMAL DIETARY SUPPLEMENTS 19 Adverse Events Defined, 19 Signals of Adverse Events to Animal Dietary Supplements, 21 Other Relevant Safety Assessment Terms, 21 Assessment of Nutrient Safety, 22 Adverse Event Detection and Reporting for Animal Dietary Supplements, 26 An Algorithm of Safety Assessment for Animal Dietary Supplements, 27 References, 30 4 FACTORS AFFECTING ANIMAL DIETARY SUPPLEMENT SAFETY 31 Extrinsic and Intrinsic Factors Affecting Animal Dietary Supplement Safety, 31 Biological Factors Affecting Animal Dietary Supplement Safety, 33 Summary, 58 References, 59 5 CATEGORIES OF SCIENTIFIC EVIDENCE 63 Evaluation Strategy, 63 Qualitative Evaluation, 66 Data From the Target Species, 66 Data From Other Animal Species, 68 ix

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x CONTENTS Data From Humans, 68 Active Compounds, 69 Data From Related Substances, 69 Ex Vivo Data, 70 In Vitro Data, 70 Limitations, 70 References, 71 6 LUTEIN 73 Description, 73 Biology, 79 Safety, 88 Current Regulatory Status of Lutein, 93 Limitations to the Assessment of Safety, 93 Risk Assessment, 94 Other Recommendations, 95 References, 96 7 EVENING PRIMROSE OIL 99 Description, 99 Biology, 111 Safety, 117 Current Regulatory Status, 127 Limitations to the Assessment of Safety, 127 Risk Assessment, 128 Other Recommendations, 129 References, 129 8 GARLIC 135 Description, 135 Biology, 142 Safety, 145 Current Regulatory Status, 161 Limitations to the Assessment of Safety, 161 Risk Assessment, 161 Other Recommendations, 163 References, 165 9 GENERAL CONSIDERATIONS IN DETERMINING SAFETY OF ANIMAL DIETARY SUPPLEMENTS 169 Findings and Recommendations, 169 Comments on Specific Animal Dietary Supplements Reviewed, 172 APPENDIXES A COMMITTEE STATEMENT OF TASK 179 B ABBREVIATONS AND ACRONYMS 181 C GLOSSARY OF TERMS 183 D CONTRIBUTORS 189 E COMMITTEE MEMBER BIOGRAPHIES 191 F RECENT PUBLICATIONS OF THE BOARD ON AGRICULTURE AND NATURAL RESOURCES 195 INDEX 197

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Tables, Figures, and Boxes TABLES 3-1 AAFCO Feeding Trial Protocols, 24 4-1 Feeding Ecology of Feral and Free-ranging Horses (Equus caballus), 35 4-2 Diet Composition of Gray Wolves (Canis lupus) in Different Countries (Percent of Total Diet), 36 4-3 Diet Composition of Feral Cats (Felis catus) in Different Countries, 37 4-4 Species Differences in Digestive Physiology and Eating Behavior, 38 4-5 Cytochrome P450 Families and Their Importance to Drug Metabolism in Humans and Orthologs in Other Species, 44 4-6 The Impact of Age-related Differences in Physiology on Xenobiotic Disposition in Humans, 46 4-7 Examples of the Potential Impact of Disease on Disposition of Xenobiotics, 50 4-8 Adaptations in Nutrient Metabolism of the Cat, 54 4-9 Potential Types of Interactions Involving Animal Dietary Supplements, 57 6-1 Lutein Content of Select Feeds and Feed Sources, 74 6-2 Lutein Dose and Plasma Concentration Relationship Among Different Species, 84 6-3 Historical Safe Intake (HSI) and Presumed Safe Intake (PSI) of Lutein in Horses, Dogs, and Cats (mg/kg BW per day), 95 7-1 Select Fatty Acid Composition of Evening Primrose Oil, 101 7-2 Detailed Fatty Acid Composition of a Single Sample of Evening Primrose Oil, 101 7-3 A Comparison of the Composition of Select Fatty Acids Present in Evening Primrose, Borage, Black Currant, Hemp Seed, and Fungal Oils, 107 7-4 Quality and Stability Characteristics of Evening Primrose Oil, 109 7-5 Summary of Published Studies Investigating the Use of Evening Primrose Oil as a Dietary Supplement in Canids, 120 γ-Linolenic Acid (GLA) Content of Select Animal and Poultry Products, 126 7-6 7-7 Historical Safe Intake (HSI) and Presumed Safe Intake (PSI) of Evening Primrose Oil in Horses, Dogs, and Cats (mg/kg BW per day), 128 8-1 Proximate Analysis for Various Garlic Forms (Percent Wet Weight), 136 8-2 Guide to Mineral and Trace Element Analysis for Garlic, 136 8-3 Suggested Differences Between Some of the Different Types of Garlic Preparations, 141 8-4 Examples of Tolerances for Residues (ppm), 142 xi

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xii TABLES, FIGURES, AND BOXES 8-5 Effect of Various Garlic Preparations on the Gastric Mucosa when Applied Directly via an Endoscope, 147 8-6 The LD50 Values of Synthetic S-Allyl cysteine (SAC) in Rats and Mice (mg/kg BW), 147 8-7 Examples of Studies Evaluating the Effect of Garlic Compounds on Physiological Response in Dogs and Cats, 151 8-8 Examples of Studies Reporting Potential Adverse Effects of Garlic in Dogs, 152 8-9 Examples of Dietary Garlic Supplements Marketed to be Fed to Horses in the United States by Addition to the Basal Ration, 154 8-10 Historical Safe Intake (HSI) and Presumed Safe Intake (PSI) of Garlic in Horses, Dogs, and Cats (mg/kg BW per day), 162 FIGURES 1-1 Annual expenditures on dogs and cats in the United States, 6 1-2 Categories of expenditures on dogs and cats in the United States in 2006, 6 1-3 Components or final products of animal diets, 8 3-1 Flow chart summarizing the definition of adverse events, 20 3-2 A proposed algorithm for assessing safety of animal dietary supplements, 28 4-1 Examples of extrinsic factors affecting animal dietary supplement safety, 32 4-2 Relationship between dose and plasma concentration and response to a xenobiotic, 39 4-3 Effect of various concentrations of xenobiotics and essential nutrients on animal health, 40 4-4 Factors determining plasma and tissue xenobiotic concentrations, 41 5-1 Evidence pyramid, 67 6-1 Synthesis of the xanthophylls, lutein and its sister isomer zeaxanthin, 76 6-2a Concentrations of plasma lutein + zeaxanthin in dogs fed diets containing 0, 5, 10, or 20 mg of lutein for 12 weeks, 83 6-2b Concentrations of plasma lutein + zeaxanthin in cats fed diets containing 0, 1, 5, or 10 mg of lutein for 12 weeks, 83 Chemical structures of γ-linolenic and linoleic acids, 100 7-1 7-2 Elongation and desaturation of essential fatty acids and their metabolism to leukotrienes, prostaglandins, and thromboxanes, 104 Pharmokinetics of γ-linolenic acid in serum in response to oral ingestion of 7-3 evening primrose oil in humans , 112 8-1 Guide to some of the effects of storage and other factors on one of the main compounds found in garlic, 137 BOXES 1-1 Statement of Task, 7 1-2 Legal Definition of a Dietary Supplement as Defined by the Dietary Supplement Health and Education Act of 1994, 7 1-3 Animal Dietary Supplement, 8 4-1 Nutrients and Xenobiotics Are Managed Differently by the Body, 42 5-1 An Outline for Safety Assessment of Animal Dietary Supplements, 64