Item D Number 04950 D NotScannflI| Author Hood> Ronald D. Veterans Administration Central Office, Department of M Report/Article TltlB Cacodylic Acid: Agricultural Uses, Biologic Effects, and Environmental Fate Journal/Book Title Year 1985 Month/Day December Color D Number of Images ° Descriptor Notes Friday, February 22, 2002 Page 4950 of 5115 Cacodylic Acid: Agricultural Uses, Biologic Effects, and Environmental Fate Ronald D. Hood, Ph.D. Department of Biology The University of Alabama Tuscaloosa, Alabama and R. D. Hood and Associates Consulting Toxicologists Northport, Alabama December 1985 Veterans Administration Central Office Department of Medicine and Surgery Agent Orange Projects Office Washington, D.C. 20420 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 Preface The intent of this monograph is to provide a single source of information on cacodylic acid (CA) and its sodium salt (NaCA). These two compounds were the active ingredients in Agent Blue, one of the group of herbicides used in Vietnam to defoliate hiding places, supply lines, and staging areas held by the opposing forces. Along with the phenoxy herbicides such as Agent Orange, Agent Blue was used experimentally in the early to mid-1960's and more extensively from 1965 to 1970. As with the phenoxy herbicides, these organic arsenicals had been widely used in agriculture and forestry for many years with no known risk to human health. But as with Agent Orange, albeit to a somewhat lesser extent, there has been an expression of concern on the part of some veterans of the Vietnam conflict that exposure to these chemicals might have a potential for adverse health effects. It is for this reason that the Veterans Administration has undertaken the preparation of this monograph. It is hoped that in addition to providing detailed in- formation to Veterans Administration health care and research professionals, it will be of use to the general scientific community as a reference guide to virtually all of the available literature on CA and some material on related methylated arsenicals. The first five chapters address in great detail the very complex and highly technical aspects of the chemical and physical properties as well as the production, agricultural uses, and en- vironmental considerations of these compounds. It is, therefore, recommended that the reader whose primary interests are with biological aspects such as pharmacology, metabolism and tox- icology start with chapters 6, 7, or 8. Chapter 9 provides a summary overview and discusses areas where additional research is needed to fill the gaps in our knowledge of these interesting compounds. Virtually all the literature available through 1984 covering the many aspects of the methylated arsenicals has been included in this monograph. The chapters on agricultural uses and environmental sources and fate put into perspective the various ecologic and economic con- sequences of the use of these herbicides. The inclusion of an extensive review of the analytic methodology for methylated arsenicals should be of considerable benefit to future researchers interested in these compounds. Such information will also facilitate assessment of the accuracy of previous studies that relied on the analysis of these compounds in biologic or environmental samples. Related material on other methylated arsenicals is included to give a broader perspec- tive of the role and likely effects of cacodylate. The very extensive body of literature dealing with these organic arsenicals is widely scattered among traditional journals as well as variety of other sources not commonly indexed. For this reason, many documents were more difficult to locate or to obtain than were the more tradi- tional journal articles. With the exception of one 1975 review done by the Midwest Research Institute for the U.S. Environmental Protection Agency, which itself is not widely available, there appears to have been no previous attempts to assemble all the literature on CA in one source document. Some of the more recent literature on CA has also been included in a review series done for the Veterans Administration, but the major emphasis of this effort has been on the phenoxy herbicides and dioxins. It is hoped that this monograph will serve as a valuable reference source to a broad range of interested users, including health care providers, research scientists, and science writers and editors dedicated to the important role of interpreting highly complex and technical literature to the less scientifically oriented public. Acknowledgements I wish to acknowledge the assistance of those who helped me in preparing this monograph. I am particularly indebted to Lt. Col. Alvin L. Young, Ph.D., Senior Policy Analyst for Life Sciences, Office of Science and Technology, Executive Office of the President. Lt. Colonel Young sparked my interest in the project and provided both encouragement and logistic support while he was associated with the Agent Orange Projects Office of the Veterans Administration. I am also grateful for assistance by Lt. Colonel Young's staff, especially Mr. Larry Stockmoe and Ms. Michel Bright, of the Agent Orange Projects Office. Invaluable aid was also provided by Edwin A. Woolson, Ph.D., of the U.S. Department of Agriculture's Pesticide Degradation Laboratory, Beltsville, Maryland. Dr. Woolson made available his extensive files of references on methylated arsenicals and was kind enough to criticize the chapter on analytic methods. Walter W. Melvin, M.D., Sc.D., of Colorado State University reviewed the entire manuscript. Once Lt. Colonel Young left the project, final publication was facilitated by Barclay M. Shepard, M.D., Director, Agent Orange Projects Office, and by his staff, Mr. Layne A. Drash, Mrs. Elaine M. Morrow, Publications Coordinator, and Mrs. Laverne L. Cooper. I also express my special gratitude to my wife, Barbara, and to my daughter, Rebecca Ann, for their encouragement, patience, and understanding while I was preparing the manuscript. iii CONTENTS Page Preface i Acknowledgements iii Chapter 1. Chemical and Physical Properties of Cacodylic Acid 1 Physical properties 1 Synthesis and production methods 2 Chemical properties 3 Reactions 4 Chapter 2. Analysis of Methylated Arsenicals 7 Original methodology 7 Colorimetric procedures 7 Ion-exchange chromatography 8 Gas-liquid chromatography (GLC) 10 High-pressure liquid chromatography (HPLC) 12 Atomic absorption spectrophotometry (AAS) and glow-discharge detection 13 Elimination of methylarsenic in total arsenic determination 19 Miscellaneous analytic methods 20 Chapter 3. Production and Uses 21 Commercial formulations 21 Federally approved uses 22 Production volume 23 Estimated use by user and function 23 Chapter 4. Agricultural and Related Uses 25 Effects on plants 25 Grass and weed control 25 Use of cacodylic acid in cotton defoliation 27 Silvicidal effects 28 Effects on plants from cacodylate residues in soil 29 Miscellaneous effects on plants 30 Effects on insects 31 Use as a pesticide 31 Effects on beneficial insects 33 Chapter 5. Environmental Sources and Fate 35 Microbial methylation and demethylation of arsenic, and arsenic cycling 35 Methylated arsenicals in fresh and sea waters and in sediments 43 Methylated arsenicals in aquatic organisms 45 Methylated arsenicals in soils 47 Methylated arsenicals in terrestrial organisms 49 Page Chapter 6. Pharmacology of Methylated Arsenicals 57 Cacodylate absorption and distribution 57 Metabolism and excretion of inorganic arsenicals 60 Chapter 7. Animal Toxicology 67 Acute toxicity 68 Oral exposure 68 Inhalation exposure 69 Other exposure routes 72 Effects in lower organisms 74 Subacute and chronic toxicity 74 Effects on laboratory and domestic animals 74 Effects on wildlife 80 Teratogenicity and reproductive toxicity 81 Mutagenicity 85 Carcinogenicity 89 Toxicity to micro-organisms 90 Mechanisms of cacodylate toxicity 92 Chapter 8. Human Exposure and Toxicology 95 Sources of human exposure 95 Dietary exposure 95 Dermal and respiratory exposure 96 Health-related effects of human exposure 101 Early clinical trials with cacodylic acid 104 Margin of safety estimates for fetotoxicity 106 Chapter 9. Overview - Summary, Conclusions, and Research Needs 109 Chemical and physical properties 109 Analytical methods 109 Production and uses 109 Agricultural and related uses 110 Environmental sources and fate 110 Pharmacology Ill Animal toxicology 112 Human exposure and toxicology 114 References 117 Glossary 147 Index 1-1 vi Chapter 1 Chemical and Physical Properties of Cacodylic Acid Physical properties Cacodylic acid, (CH3)2As(O)OH, was perhaps first described by Bunsen (1843), who referred to it as "alkargene." It is an organic arsenical with a molecular weight of 137.99 and the empirical formula C2H7AsO2 (MRI, 1975). It is also referred to as hydroxydimethylarsine oxide, dimethylarsinic acid, or CA. Sodium cacodylate or NaCA, C2H6AsO2Na, has a molecular weight of 159.98 and is also known as sodium dimethylarsinate. The structural formulas of the acid and sodium salt are: cacodylic acid sodium cacodylate CH3 N. o,/\~ "./ X The prefix "caco" was derived from the Greek kakos or "bad," and the Greek kakodes refers to an offensive odor (MRI, 1975). Although CA and its sodium salt are odorless, the radical As(CH3) or two such radicals united as (CH3)2AsAs(CH3)2 are known for their garlic-like scent. CA and NaCA are both colorless solids, and CA forms triclinic crystals whose unit-cell dimensions have been described as: a = 6.53 nm, b = 6.82 nm, c = 6.61 nm,a = 77° 30', (3 = 98° 45', 7= 55° 9' (Trotter and Zobel, 1965). The crystal was said to resemble that of carboxylic acids, with centrosymmetrical hydrogen-bonded dimers, rather than the more complex hydrogen bonding associated with arsonic acids, i.e., RAsO(OH)2. Smith et al. (1970b), however, list the dimensions as a = 8.34 nm, b = 6.82 nm, c = 10.16 nm, a = 59.5°, 0 = 89.3°, 7= 106.0°. According to Trotter and Zobel (1965), the configuration around the arsenic atom is tetrahedral, and the bond angles range from 106° to 115°.