FINAL DRAFT ECAO-CIN-D008 United States Environmenta' Protection SetMmber. '993 Aeency &EPA Research and Development DRINKING WATER CRITERIA DOCUMENT FOR MANGANESE Prepared for Office of Water Prepared by Environmental Criteria and Assessment Office Office of Health and Environmental Assessment U.S. Environmental Protection Agency Cincinnati, OH 45268 DISCLAIMER This report is an external draft tor review purposes onlY and does not constitute Agency policy. Mention of trade names or commercial prcducts does not constitute endorsement or recommendation for use. FOREWORD Section 1412 (b) (3) (A) of the Safe Drinking Water Act, as amended in 1986, requires the Administrator of the Environmental Protection Agency to publish maximum contaminant level goals (MCLGs) and promulgate National Primary Drinking Water Regulations for each contaminant, which, in the judgement of the Administrator, may have an adverse eHect on public health and which is known or anticipated to occur in public water systems. The MCLG is nonenforceable and is set at a level at which no known or anticipated adverse health eHects in humans occur and which allows for an adequate margin of safety. Factors considered in setting the MCLG include health eHects data and sources of exposure other than drinking water. This document provides the health eHects basis to be considered in establishing the MCLG. To achieve this Objective, data on pharmacokinetics, human exposure, acute and chronic toxicity to animals and humans, epidemiology and mechanisms of toxicity are evaluated. SpeCific emphasis is placed on literature "data providing dose-response Information. Thus, while the literature search and evaluation performed in support of this document has been comprehensive, only the reports considered most pertinent in the denvation of the MCLG are cited in the document. The comprehansive literature data base in support of this document includes information published up to 1992; however, more recent data ma;ly have been added during the review process. When adequate health eHects data exist, Health Advisory values for less than lifetime exposures (1-day, 10-day and longer-term, -10% of an individual's lifetime) are Included in this document. These values are not used in setting the MCLG, but serve as informal guidance to municipalities and other organizations when emergency spills or contamination situations occur. This document was prepared for the Office of Water by the Office of Health and Environmental Assessment (Environmental Criteria and Assessment Office, Cincinnati, 01~IO) to provide the scientific support for the human health-based risk assessment used In the determination of the drinking water MCLG. For more Information, contact the HUllian Risk Assessment Branch of the Office of Water at (202)260-7571. O~;c:e of SCience and Techrciogy James R E:c:er Dlrect:x OHlce cfGrcurdWaterand Drinking \Vater III DOCUMENT DEVELOPMENT Susan Velazquez. Document Manager Environmental Criteria and Assessment Office. Cincimati U.S. Environmental Protection Agency SCientific Reviewers Editorial Reviewer Julie T. Du, Ph.D. Enna Durden, B.A. Office of Water Environmental Criteria and Assessment Washington, DC Office U.S. Environmental Protection Agency Bemald Weiss, Ph.D. Cincinnati, OH Division of Toxicology University of Rochester Medical Center Rochester, NY Ellen Silbergeld, Ph. D Environmental Defense Fund Washington, DC Sheila Rosenthal, Ph. D Vincent J. Cogliano, Ph.D Human Health Assessment Group Washington, DC Richard Walentowicz, Ph.D Exposure Assessment Group Washington, DC Zottan Annau. Ph.D Reproductive Effects Assessment Group Washington, DC Chon Shoaf, Ph.D Environmental Criteria and Assessment Office Research Triangle Park, NC Document Preparation Technical Support Services Staff. Environmental Criteria and Assessment Office, Cincinnati iv TABLE OF CONTENTS Page I. SUMMARY ............................................. .. 1-1 II. PHYSICAL AND CHEMICAL PROPTERTIES ... .................. .. 11-1 INTRODUCTION ....................................... .. 11-1 MANGANESE (I) COMPOUND. ............................ .. 11-3 Methylcyclopentadienyl Manganese Tricarbonyl 11-3 Manganese (II) Compounds .......................... .. /1-3 Manganous Carbonate .............................. .. 11-3 Manganous Chloride '" ............................ .. 11-3 Manganese Ethylenebisdithiocarbamate 11-6 Manganous Acetate ................................ .. 11-6 Manganous Oxide ................................. .. 11-6 Manganous Phosphate 1/-6 Manganous Sulfate 11-7 Manganous Soaps. ................................ .. 11-7 MANGANESE (IV) COMPOUNDS ........................... .. 11-8 Manganese Dioxide " 11-8 MANGANESE (VII) COMPOUNDS 11-8 Potassium Permanganate ............................ .. 11-8 SUMMARY ........................................... .. 11-9 III. TOXICOKINETICS 111-1 ABSORPTION . I11-1 Gastrointestinal . 111-1 Respiratory . 111-6 DISTRIBUTION 111·6 METABOLISM. ...................... .. 111-12 EXCRETION ..................... .. .. ...... .. 111-13 HOMEOSTASIS. ...................................... .. 111-17 SUMMARY .......................................... .. "'-17 v TABLE OF CONTENTS (cont.) IV. HUMAN EXPOSURE .. .................................. .. IV-1 (To be provided by the Office of Water) V HEALTH EFFECTS IN ANIMALS. ........................... .. V-1 GENERAL TOXICITY V-1 Acute Toxicity .... ................................ .. V-1 Subchronic and Chronic Toxicity. ...................... .. V-3 Oral Exposure. ................................... .. V-6 Parenteral Exposure V-24 Inhalation Exposure ................................ .. V-27 OTHER EFFECTS .. V-28 Carcinogenicity ......................... .. V-28 Mutagenicity '., V-34 Reproductive Effects V-3 7 TeratogenicIty .................................... .. V-38 SUMMARY " V-41 VI. HEALTH EFFECTS IN HUMANS VI-1 INTRODUCTION VI-1 CLINICAL CASE STUDIES ........................... .. VI-1 EPIDEMIOLOGIC STUDIES VI-? Carcinogenicity ... VI·~E MutageniCity and Te;atoge:;ic.:y VI. ~ "7 SlJ r.' ~.'ARY '.' I. < -. r.iECHAN1SMS OF NEUROTOXICITY \,1'\ .• r,'ECHANISfI.1S OF OTHER EFFECTS SUr-.1MARY V!I ..t Vi TABLE OF CONTENTS (cant.) VIII. QUANTIFICATION OF TOXICOLOGIC EFFECTS VIII-1 INTRODUCTION ' VIII-1 NONCARCINOGENIC EFFECTS OF MANGANESE IN THE DIET ..... VIII-? QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR MANGANESE IN DRINKING WATER , VIII-19 Derivation of 1-Day and 10-Day HAs , VIII-19 Derivation of Longer-term HA ........................ .. VIII-20 Assessment of Lifetime Exposure and Derivation of a DWEL VIII-21 WEIGHT-OF-EVIDENCE FOR CARCINOGENIC EFFECTS VI/I-21 EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS , VIII-24 SPECIAL GROUPS AT RISK , VIII-25 IX. REFERENCES.......................................... IX-1 VII LIST OF TABLES No. Title Page 11-1 Estimated U.S. Production, Capacity and Use of Selected Manganese Compounds 11-2 11-2 Physical Properties of Some Manganese Compounds .. ....... .. 11-4 V-1 Oral LO so Values for Manganese Compounds. .............. .. V-2 V-2 Parental LD so Values for Manganese Compounds ..... ....... .. V-4 V-3 Neurotoxic Effects of Manganese in Experimental Animals: Oral and Inhalation Studies V-16 V-4 Neurotoxic Effects of Manganese in Experimental Animals: Parenteral Studies ................................... .. V-1 7 V-5 liver Effects of Manganese Exposure in Animals .. _.... _.... _.. V-20 V-6 Summary of Carcinogenicity Studies Reporting Positive Findings for Selected Manganese Compounds _.... .. V-31 V-7 Pulmonary Tumors in Strain A Mice Treated with Manganese Sulfate , V-33 V-8 Carcinogenicity of Manganese Powder. Manganese Dioxide, and Manganese Acetylacetonate in F344 Rats and Swiss Albino Mice V-35 V-g Reproductive Effects of Exposure to Manganese . V-39 '11- 1 Studies of Manganism In HL.;mans ard E\pos'~re-Re?~cr,se Relat,onsr:p '/1-2 )1,,:: Fer~oailo/ Workers ,',1:th Neuro;~gIC Slgrs 2/ Le'.-e! cf Ex~osure ~o ~.1anga;"ese 'il- ..; VIII-'1 Oral Studies on Manganese Neurotoxlcity for Quantification of Toxicologic Effects .. VIII- ~ 5 VIII LIST OF ABBREVIATIONS CNS Central nervous system DWEL Drinking water equivalent level GI Gastrointestinal HA Health Advisory i.m. Intramuscular i. t. Intratracheal i.V. Intravenous LC so Concentration lethal to 50% of recipients LD50 Dose lethal to 50% of recipients LOAEL Lowest-observed-adverse-effect-level MAO Monoamine oxidase NOAEL No-observed-adverse-effect level RfD Reference dose RSC Relative source contribution s.c. Subcutaneous ix !. SU~"'!MARY Manganese is a gray-pink metal that is too brittle to be used unless a1royed. It 4 7 eXists in 11 oxidation states with the compounds containing Mn2 +. Mn + and Mn + being the most economically and environmentally important. r...~anganese is absorbed from the G! tract after ingestion and is distributed primariiy to the jiver, kidney, endocrine glands and brain. The absorption of manganese is low, averaging 3-9% in adults. Bile is the main route of excretion of manganese and represents the principal regulatory mechanism. The metabolism of manganese is controlled by homeostatic mechanisms at the level of excretion as well as absorption, which respond very efficiently to increases in manganese concentration. However, prolonged exposure to excess manganese lessens the efficiency of the homeostatic mechanism. The bioiogic haif-iife ranges from 2-5 weeks and depends upon body stores of manganese. In both humans and animals, the biologic half-life decreases with Increased exposure. Retention in the