United States Environmental Protection Agency March, 1988 Research and Development HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT FOR THALLIUM AND COMPOUNDS Prepared for OFFICE OF SOLID HASTE AND ENERGENCY RESPONSE Prepared by Environmental Criteria and Assessment Office Office of Health and Environmental Assessment U.S. Environmental Protection Agency Cincinnati, OH 45268 DRAFT: DO NOT CITE OR QUOTE NOTICE This document Is a preliminary draft. It has not been formally released by the U.S. Environmental Protection Agency and should not at this stage be construed to represent Agency policy. It Is belna circulated for comments on Us technical accuracy and policy Implications. ------- DISCLAIMER This report 1s an external draft for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. 11 ------- PREFACE Health and Environmental Effects Documents (HEEOs) are prepared for the Office of Solid Waste and Emergency Response (OSWER). This document series Is Intended to support listings under the Resource Conservation and Recovery Act (RCRA) as well as to provide health-related limits and goals for emer- gency and remedial actions under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Both published literature and Information obtained for Agency Program Office files are evaluated as they pertain to potential human health, aquatic life and environmental effects of hazardous waste constituents. The literature searched for 1n this document and the dates searched are Included 1n "Appendix: Literature Searched." Literature search material 1s current up to 8 months previous to the final draft date listed on the front cover. Final draft document dates (front cover) reflect the date the document 1s sent to the Program Officer (OSWER). Several quantitative estimates are presented provided sufficient data are available. For systemic toxicants, these Include Reference doses (RfOs) for chronic and subchronlc exposures for both the Inhalation and oral exposures. The subchronlc or partial lifetime RfO, 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval I.e., for an Interval that does not constitute a significant portion of the Hfespan. This type of exposure estimate has not been extensively used, or rigorously defined as previous risk assessment efforts hrave focused primarily on lifetime exposure scenarios. Animal data used for subchronlc estimates generally reflect exposure durations of 30-90 days. The general methodology for estimating subchronlc RfDs 1s the same as traditionally employed for chronic estimates. except that subchronlc data are utilized when available. - . . _ > In the case of suspected carcinogens, RfDs are not estimated. Instead, a carcinogenic potency factor, or q-|* (U.S. EPA, 1980a) Is provided. These potency estimates are derived for both oral and Inhalation exposures where possible. In addition, unit risk estimates for air and drinking water are presented based on Inhalation and oral data, respectively. Reportable quantities (RQs) based on both chronic toxlclty and carcino- gen 1 city are derived. The RQ Is used to determine the quantity of a hazardous substance for which notification Is required 1n the event of a release as specified under the Comprehensive Environmental Response, Compen- sation and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclnogenldty) represent two of six scores developed (the remaining four reflect 1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty). Chemical-specific RQs reflect the lowest of these six primary criteria. The methodology for chronic toxlclty and cancer based RQs are defined 1n U.S. EPA, 1984 and 1986a, respectively. 111 ------- EXECUTIVE SUMMARY Thallium exists 1n both stable unlvalent and trlvalent states. Prop- erties of thallium compounds In the (I) valence state are similar to those of both alkali metals and silver salts. The hydroxide, carbonate, oxide and cyanide salts of thallium are water soluble like the corresponding alkali metal salts, and Us hallde salts, with the exception of fluoride salts, are Insoluble 1n water like the corresponding silver salts (Hul, 1983). Most thallium (III) salts, particularly the salts of weak adds (e.g., sulflde, carbonate, cyanide, acetate) are not stable 1n water and hydrolyze exten- sively (Cotton and Wilkinson, 1980). Three chemical companies are currently the principal domestic producers of thallium and compounds (Hu1, 1983; SRI, 1987). The U.S. demand for thallium was 2500 pounds In 1984 (USDI. 1986). Thallium has limited commercial use because of Us toxldty. According to USDI (1986), the U.S. consumption pattern for thallium In 1984 was agricul- ture, OX; electrical, 70%; pharmaceutical, 4X; other, 26X. Available Information regarding the fate and transport of thallium In environmental media Is extremely limited. The principal sources of thallium In the environment are cement factories, coal burning power plants and metal smelters (Sharma et al., 1986; Brockhaus et al., 1980, 1981). In the atmo- sphere, thallium may be present as elemental Tl, oxides of Tl, Tl.S and T12S04. T12S 1s likely to be speclated to T12S04. and T120 will be rapidly hydrolyzed to T10H by the moisture In the atmosphere. Because of their water solubilities, both these compounds are likely to be removed from the atmosphere by wet deposition; however, because It Is Insoluble In water, T1203 may persist for a longer period In the atmosphere. T1o°3 1s likely to be removed from the atmosphere by dry deposition. No estimate of 1v ------- the half-life of thallium In the atmosphere was located In the available literature cited In Appendix A. In water, most of thallium that enters the medium 1n the Insoluble form may be found In the sediment (Mathls and Kevern, 1975). Some thallium may be removed from the water by sorptlon onto suspended solids 1n water (Kempton et al., 1987a,b). Host of the thallium that enters natural waters In the soluble state will remain In the soluble form because of the formation of soluble complexes with Inorganic and organic Ugands, and these complexes will be more stable at higher pHs (Stephenson and Lester, 1987a,b; O'Shea and Mancy, 1978). Thallium 1n water may be transported to fish and vegetation (Wallwork-Barber et al., 1985). The BCF of thallium In whole aquatic organisms ranges from 12-34 (ZUko and Carson, 1975; Barrows et al., 1980). Based on Its transport In water, leaching of thallium from soil, particularly from sandy soil, appears to be likely. Up to 10X of thallium absorbed In plant roots from soil may .be transported from the root to the shoot of the plant (Cataldo and Mlldung, 1983). . ^. ^. ... . . v .. '. ..,;....', Inhalation of contaminated air and consumption of vegetables and fruits grown near thallium emission sources are the major routes of human thallium Intake (Sharma et al., 1986; Brockhaus et al., 1980, 1981). From the limited air monitoring data available, U.S. EPA (1980b) estimated a dally Inhalation absorption of 3.4 yg of thallium per day by an Individual 1n the United States; however, the dally absorption may be higher for Individ- uals who live 1n the vicinity of emission sources (Brockhaus et al., 1980, 1981). Thallium has been detected 1n surface waters that receive waste- waters from certain mining and smelting operations (U.S. EPA, 1980b; Mathls and Kevern, 1975; ZUko et al., 1975). Thallium was not detected 1n >99% of tap waters sampled In the United States at a minimum detection limit of 0.3 ------- vg/l. U.S. EPA (1980b) estimated that >99% of U.S. adults would consume <1 tig of thallium per day by Ingestlon of drinking water. From the limited monitoring data on foods, U.S. EPA (1980b) estimated a maximum dietary Intake of thallium by a U.S. adult as 3.8 yg/day. According to Sharma et al. (1986), the average dietary Intake of thallium by an adult 1s -2 jig/day. There appeared to be considerable differences 1n the sensitivity of different aquatic species to the toxlclty of thallium salts; however, there did not appear to be marked differences 1n toxlclty between different salts of thallium. The lowest concentration of thallium associated with acute toxlclty was 1.142 mg/l, an LC5Q for Dabhnla maqna (Brlngmann and Kuehn, 1977). In a chronic study, a concentration of <0.04 mg/l was an MATC determined 1n an embryo-larval test In the fathead minnow, Plmephales promelas (U.S. EPA, 1978). A concentration of 0.008 mg/i was associated with 50% plant damage to duckweed, Lemna minor (BroWn and Rattlgan, 1979). Absorption or uptake of soluble thallium salts Is rapid and virtually complete by any route of exposure (Smith and Carson, 1977; Venugopal and Luckey. 1978; U.S. EPA, 19805; MoeschUn. 1980; Stoklnger, 1981; Hanzo et al., 1983a). Distribution from the blood Is rapid and widespread, with highest levels located 1n the kidney, heart and liver and lowest levels In the nervous system and body fat (Manzo et al., 1983a,b; Rauws, 1974; Barclay et al.. 1953, Lie et al.. 1960; Sabblonl et al.. 1980). The relative concentrations In different tissues appear to be Independent of route of administration (Lie et al., 1960), the valence of thallium administered (Sabblonl et al., 1980). the time after administration (Lie et al.. 1960) or the dosage (Gregus and Klaassen, 1986). Thallium translocates to the placenta and fetus, but levels In the fetus are substantially lower than v1 ------- those 1n maternal tissues (Gibson and Becker, 1970; Rade et al., 1982; Zlskoven et al., 1983). The metabolism of thallium 1s not well understood, but It Is hypothesized that thallium .In. vivo Is transformed to one oxidation state (Sabblonl et al., 1980). The excretion of thallium appears to be species-dependent, with fecal excretion predominating In the rat (Lie et al., 1960; Rauws, 1974; Barclay et al., 1953; Gregus and Klaassen, 1986) and urinary excretion predominating In humans (Barclay et al., 1953; Rlchelml et al., 1980). Estimates of excretion half-lives In humans range from 2.15 days for tracer doses In ambulatory heart patients (Talas et al., 1983) to 21.7 days In a terminal cancer patient (Barclay et al., 1953; U.S. EPA, 1980b). Thallium salts are potent poisons that cause acute toxlclty In humans. Human poisoning has resulted from accidental Ingestlon of thallium salts used as rodentlddes and Insecticides, from Internal and topical use as a depilatory agent, and from cases of homicide and suicide (Gettler and Weiss, 1943; Mpeschlln, 1980). Symptoms In humans Include neurological and gastro- intestinal effects. Death 1s usually due to respiratory failure (Gettler and Weiss. 1943; Stoklnger, 1981). A threshold for acute toxlclty In children appears to be -6 mg Tl/kg/day (Bedford, 1928). An average lethal dose for adults Is -8-12 mg Tl/kg (Moeschlln, 1980). Acute oral LD™ values In rats and mice range from 16-35 mg Tl/kg, apparently Independent of species or the Identity of the thallium salt. Chronic oral exposure of humans appears to Increase the Incidence of neurological and subjective symptoms, as observed In a population living In the vicinity of a cement factory that discharged large quantities of thallium Into the atmosphere (Brockhaus et al., 1980, 1981; Dolgner et al., a 1983). Exposure was primarily through Ingestlon of thallium from home-grown ------- fruits and vegetables. Subchronlc oral exposure of laboratory animals Is associated with hair loss, elevated kidney weights (Downs et al., 1960), neurological and skeletal muscle effects (Manzo et al., 1983b; Deshlmaru et al., 1977} and mortality (Downs et al., 1960). A NOAEL of 0.25 mg thallium (I) sulfate/kg/day (0.20 mg Tl/kg/day) for these effects was Identified 1n a 90-day gavage study using rats (U.S. EPA, 1986b; MRI, 1986). Inhalation animal toxlclty data consist of an unfinished rat study 1n which Intermittent exposure to thallium (III) oxide at 0.5-2 mg/m3 was associated with deteriorating health and Increased mortality (U.S. EPA, 1979). Adverse health effects were not reported In humans occupationally exposed to thallium 1n a magnesium seawater battery plant (Marcus, 1985) or In cement production (SenaHer et al., 1980; Ludolph et al., 1986). Thallium salts have not been tested for cardnogenlclty In animals and the NTP (1987) has not scheduled cancer and toxlclty testing. Cancer data In humans are limited. Mixed results have been observed In genotoxlclty testing. Negative results were obtained 1n reverse mutation tests (Kanematsu et al., 1980; Singh, 1983) and 1n tests for effects on cell division (Loveless et al., 1954). Positive results were obtained In a rec assay (Kanematsu et al., 1980) and In several mammalian test systems Includ- ing a dominant lethal test In male rats (Zasukhlna et al., 1983). Thallium results In achondroplastlc malformations when Injected Into developing chicken eggs (Karnofsky et al., 1950; Landauer, 1960; Ford et al., 1968; Hall, 1972b; Skrovlna et al., 1973) or tested 1n mammalian whole embryo cultures (Anschuetz et al.. 1981) or 11mb bud cultures (Neubert and Bluth, 1985; Barrach and Neubert, 1985). Parenteral administration to pregnant rats at high doses (>2 mg Tl/kg/day) resulted In reduced fetal body weights, hydronephrosls and the absence of vertebral bodies (Gibson and V111 ------- Becker, 1970). Oral administration to rats (>2 mg Tl/kg/day) and mice (>4 mg Tl/kg/day) during organogenesls resulted only In a slight Increase 1n fetal loss 1n both species (Roll and Matthlaschk, 1981). Malformations of the skeleton and Internal organs were not observed. In offspring of rats and mice allowed to deliver, reduced survival at weaning (both species) and reduced growth rate (mice) were observed. Adult offspring of dams treated with thallium during gestation had significant learning deficits In a lever-pressing behavior conditioning test (Bornhausen and Hagen, 1984). Recent studies Indicate that thallium may have an adverse effect on male reproduction. Adult male rats exposed to thallium In the drinking water at 0.74 mg/kg/day for 60 days had decreased sperm motllUy and hlstopatho- loglcal alteration of the testes (Form1gl1 et al., 1986). Thallium and Its salts were classified In EPA Group D, unable to be classified as to cardnogenlclty In humans, because cancer data 1n animals and humans are lacking. Lack of adequate data also precluded derivation of RfDs for Inhalation exposure. Subchronlc. and chronic oral RfOs for thallium and selected salts were derived from a NOAEL of 0.25 mg thallium (I) sulfate (0.20 mg Tl/kg/day) In a 90-day gavage study using rats (U.S. EPA, 1986b; MRI, 1986). The subchronlc RfD for thallium 1s 0.1 mg/day and the RfD for selected salts Is 0.2 mg/day. The chronic oral RfD for thallium Is 0.01 mg/day and for thallium salts Is 0.02 mg/day. An RQ of 10 for thallium and salts was based on Increased mortality In an Inhalation experiment 1n rats (U.S. EPA, 1979). 1x ------- TABLE OF CONTENTS Page 1. INTRODUCTION 1 1.1. STRUCTURE AND CAS NUMBER 1 1.2. PHYSICAL AND CHEMICAL PROPERTIES 4 1.3. PRODUCTION DATA 4 1.4. USE DATA 5 1.5. SUMMARY 6 2. ENVIRONMENTAL FATE AND TRANSPORT 7 2.1. AIR 7 2.2. WATER 7 2.3. SOIL 9 2.4. SUMMARY 9 3. EXPOSURE 11 3.1. WATER 11 3.2. FOOD 11 3.3. INHALATION 12 3.4. DERMAL 13 3.5. SUMMARY 13 4. AQUATIC TOXICITY 14 4.1. ACUTE TOXICITY 14 4.2.-, CHRONIC EFFECTS. ..,..., 14 4.3. PLANT EFFECTS. 14 • 4.4. 'SUMMARY. ..:....;: ; . . /....... 19 5. PHARMACOKINETCS 20 5.1. ABSORPTION 20 5.2. DISTRIBUTION 22 5.3. METABOLISM 26 5.4. EXCRETION 27 5.5. SUMMARY 28 6. EFFECTS 30 6.1. SYSTEMIC TOXICITY 30 6.1.1. Inhalation Exposures 30 6.1.2. Oral Exposures 33 6.1.3. Other Relevant Information 38 ------- TABLE OF CONTENTS (cont.) Page 6.2. CARCINOGENICITY 43 6.2.1. Inhalation 43 6.2.2. Oral 44 6.2.3. Other Relevant Information 44 6.3. MUTAGENICITY 45 6.4. TERATOGENICITY 48 6.5. OTHER REPRODUCTIVE EFFECTS 51 6.6. SUMMARY 51 7. EXISTING GUIDELINES AND STANDARDS 54 7.1. HUMAN 54 7.2. AQUATIC 56 8. RISK ASSESSMENT 57 8.1. CARCINOGENICITY 57 8.1.1. Inhalation 57 8.1.2. Oral 57 8.1.3. Other Routes 57 8.1.4. Height of Evidence 57 8.1.5. Quantitative Risk Estimates 58 '8.2. SYSTEMIC TOXICITY. ;.".-. 58 8.2.1. Inhalation Exposure 58 8.2.2. Oral Exposure 59 9. REPORTABLE QUANTITIES 65 9.1. BASED ON SYSTEMIC TOXICITY 65 9.2. BASED ON CARCINOGENICITY 77 10. REFERENCES 79 APPENDIX A: LITERATURE SEARCHED 104 APPENDIX B: SUMMARY TABLES FOR THALLIUM AND COMPOUNDS 107 x1 ------- LIST OF TABLES No. Title Page 1-1 Chemical Identity and Physical Properties of Thallium and a Few Compounds 2 4-1 Acute Toxlclty of Thallium Salts to Aquatic Organisms .... 15 4-2 Chronic Toxlclty of Thallium Salts to Aquatic Organisms ... 16 4-3 Toxlclty of Thallium Salts to Aquatic Plants 17 5-1 Concentration of Thallium201 In tissues of Rats Following Intraperltoneal Administration of Tl201 Salts 24 6-1 Experimental Protocol of Inhalation Study with Thallium (III) Oxide 1n Groups of Male and Female 8-month-old Wlstar Rats 31 6-2 Acute Oral 1059 Data for Thallium Salts 39 6-3 GenotoxIcHy Testing of Thallium Salts 46 7-1 Oral RfDs for Thallium Salts 55 8-1 Subchronlc Oral RfDs for Selected Thallium Salts 62 8-2 Chronic Oral RfDs for Selected Thallium-Salts 64 9-1 Systemic Toxlclty Summary for Thallium Salts Using the Rat. . 66 9-2 Composite Scores for Thallium Using the Rat '68 9-3 Thallium (and salts): Minimum Effective Dose (MED) and Reportable Quantity (RQ) 70 9-4 ThaiI1um(III)ox1de: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 71 9-5 Thall1um(I)acetate: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 72 9-6 Thall1um(I)carbonate: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 73 9-7 Thall1um(I)chlor1de: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 74 9-8 Thall1um(I)n1trate: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 75 ------- LIST OF TABLES (cont.) No., Title Page 9-9 Thal11um(I)su1fate: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 76 9-10 Thall1um(I)se]en1de (Tl2Se): Minimum Effective Dose (MED) and Reportable Quantity (RQ) 78 ------- LIST OF ABBREVIATIONS ATP Adenoslne tr1phosphate BCF Bloconcentratlon factor bw Body weight CAS Chemical Abstract Service CNS Central nervous system CS Composite score DNA DeoxyMbonuclelc add EC5Q Concentration effective to 50% of recipients EEG Electroencephalogram LC5Q Concentration lethal to 50% of recipients LOso Dose lethal to 50% of recipients (and all other subscripted dose levels) LDH Lactate dehydrogenase MATC Maximum acceptable toxicant concentration MED Minimum effective dose NOAEL No-observed-adverse-effect level NOEL No-observed-effect level PEL Permissible exposure limit ppb Parts per billion ppm . , Parts per million RfO Reference dose RQ Reportable quantity RV. Dose-rating value RV Effect-rating value SGOT Serum glutamlc oxaloacetlc transamlnase STEL Short-term exposure level TLV Threshold limit value TWA Time-weighted average x1v ------- 1. INTRODUCTION 1.1. STRUCTURE AND CAS NUMBER Thallium (Tl), with an abundance of -0.3 ppm 1n the earth's crust. Is not considered to be a rare metal (Hu1, 1983). There are numerous thallium compounds, but only 18 of the most commonly used compounds have been Included In this document. The synonyms, molecular formulas, molecular weights and the CAS Registry numbers for thallium and these compounds are given In Table 1-1. There 1s much confusion 1n the literature regarding the correct chemical formula and the CAS registry number of thallium selenlde. CAS (1983) lists the following four CAS numbers for thallium selenlde: Tl (I) selenlde (Tl2Se), 15572-25-5; thallium (III) selenlde (Tl2Se3), 12039-58-6; a mixed thallium selenlde. 37189-37-0; and thallium selenlde with a molecular formula of TISe and an ambiguous valence state (perhaps a valence state of 2 1n which the compound 1s usually not stable), 12039-52-0. In addition, both Sax (1984) and HSDB (1987) Incorrectly assigned the CAS number1for thallium selenlde .(TTSe) (12039-52-0). to thallium (I) selenlte; thallium selenlte, with a correct molecular formula of Tl-SeO^, 1s a different compound than thallium selenlde (TISe) and should have a different CAS number. In U.S. EPA (1985f), It Is not clear whether the risk assess- ment was conducted for thallium selenlde or thallium selenlte because the compound names and the CAS numbers were assigned Incorrectly. Since thallium selenlte (Tl.SeO-) Is not a common chemical and of the three thallium selenldes (Tl-S, Tl2Se3, TISe), T12S Is commonly used In semiconductor and electrical switching devices (CAS, 1983). 1t 1s likely that U.S. EPA (1985a) Intended to perform a risk assessment on this compound, which has a CAS number of 15572-25-5. 0083d -1- 01/11/88 ------- TABLE 1-1 Chemical Identity and Physical Properties of Thai HUM and a Few Compounds* § en Element/ Compound Thallium Thallium! I) acetate Thalllua(IIl) acetate Thalllua(I) broalde i !' Thall lua( III) i , bromide Tballlua(l) carbonate Thallium! I) chloride Thai llua( 111) chloride Thallium! I) ethoxlde o Thalllua(III) ^ fluoride ^ co Thalllua(I) 00 formate Synonyas thalllua acetic acid; thall tua(l) salt; thallous acetate acetic acid; thalllua! Ill) salt; thai lie acid thallous broalde; thai HUB aonobro- alde thai lie broalde; thalllua trlbro- alde dlthalllua carbo- nate; carbonic acid; dlthalltua salt; thallous carbonate thallous chloride; thalllua mono- chloride thai lie chloride; thalllua tri- chloride thallous ethoxlde thalllc fluoride thalllua trl- fluorlde thallous formate Atomic/ Molecular Formula Tl T1C2H302 T1(C2H302)3 TIBr T1Br3 T12C03 T1C1 T1C13 (T10C2H5)4 T1F3 T1HC02 Atoalc/ Molecular Height 204.37 263.43 381.51 284.29 444.10 468.78 239.64 310.74 997.78 261.38 249.40 CAS . Registry Number 7440-28-0 563-68-8 2570-63-0 7789-40-4 13701-90-1 6533-73-9 7791-12-0 13453-32-2 20398-06-5 7783-57-5 992-98-3 Physical Fora : bluish-white aetal silky-white deliquescent solid 'solid - .yellow-white solid yellow deliquescent ' solid "colorless solid - • white solid discolors In air white, hygro- scopic solid colorless liquid colorless solid colorless. hygroscopic Melting Point CC) 303.5 131 decomposes at 182«C» 480 decoaposes 273 430 25 -3 327 101 Boiling Point Density <*C) (g/caVsp. gr.) 1457 11.85 NA 3.765 NA NA 815 7.557 at 17.3»C NA NA NA 7.11 720 7.004 decomposes NA decoaposes 3.522 at 80*C 655 8.23 at 4*C NA 4.967 Hater Solubility Insoluble very soluble • NA 500 ag/t at 2S*C soluble 40,300 ag/t at 15.5«C 2900 ag/t at 15.6-C very soluble soluble but decomposes 78.69/100 at at 15-C 500.0 g/100 at at 10*C Vapor Pressure 10 am 1000'C NA NA 10 am 517«C NA NA 10 am 531 'C NA NA NA NA at • at at solid ------- TABLE 1-1 (cont.) o o CO s CJ 1 Eleaent/ Coopound Thalllua(I) hydroxide Thalltua(l) Iodide ThallliM(III) nitrate ThallliM(l) nitrate Thalllua(l) oxide ThallliMlIlI) oxide Thalllui(I) sulfate Thalllua(l) selentde Synonym thallous hydroxide thallous Iodide thallous nitrate; thalllui aono- nltrate; nitric acid. thalltua(I) salt thai lie nitrate; thalllua trt- nltrate; nitric acid; thallliM(IIl) salt thallous oxide thalllc oxide; thalllui peroxide; thai HIM sesquloxlde; thai HUB oxide |T1203) thallous sulfate; sulfurtc acid; thalllua(l) salt thallous selentde Atoaic/ Molecular Foraula T10H Til T1N03 T1|M03>3 T120 T1203 T12S04 T12Se AtOMtC/ Molecular Height 221.39 331.29 266.39 390.40 424.77 456.76 504.82 487.74 CAS Registry Nuaber 12026-06-1 7790-30-9 10102-45-1 13746-98-0 1314-12-1 1314-32-5 7446-18-6 15572-25-5 Physical Fora pale yellow solid yellow solid <-) red solid (B) white solid exists In a. 0 and T crys- • talllne fora colorless solid black . deliquescent solid colorless solid colorless solid gray solid Malting Point rc> deconposes at 139'C transform to B-fora at 170*C 440 206C NA 300 717 632 340 Soiling Point (•C) NA NA 823 430C NA loses oxygen at 1080'C loses two oxygen at 875*C deconposes NA Density (g/caVsp. gr.) NA 7.29 7.098 at 14.7*C NA NA 9.52 at 16*C 9.65-10.19 at 21 »C 6.77 9.05 at 25/4*C Water Vapor Solubility Pressure 25.9 g/100 NA •t at 0*C 6 «g/t at NA 20«C Insoluble 1.0 MI at 440*C 9.55 g/100 NA M at 20*C soluble NA very soluble NA but decomposes Insoluble NA 48.700 ag/t NA at 20*C Insoluble NA •Source: Ueast. 1985; HSDB. 1987; Hut. 1983; Ulndholz. 1983 °The aeltlng point Is for thalltiw(lll) acetate sesqulhydrate [T1(CH3COO)3>3/2H20] as given In Aldrtch (1986) cThe physical properties are for the a-fora. ------- 1.2. PHYSICAL AND CHEMICAL PROPERTIES Thallium exists In both stable unlvalent (I) and tMvalent (III) states. Thallium compounds 1n the unlvalent states are called thallous salts and In the trlvalent states thalUc salts. The physical properties of thallium and Us selected compounds are given In Table 1-1. Properties of thallium compounds 1n the (I) valence state are similar to those properties of both alkali metal and silver salts. Like alkali metal salts, the hydroxide, carbonate, oxide and cyanide of thallium (I) salts are water soluble. The fluoride of thallium (I) Is very water soluble, but the other halldes are Insoluble 1n water like the corresponding silver salts. Thallium (III) salts' are easily reduced to the thallium (I) salts by common reducing agents (Hu1, 1983). Most thallium (III) salts, particularly the salts of weak adds (e.g., sulfldes, carbonates, cynldes, acetates) are subject to extensive hydrolysis and do not exist In contact with water (Cotton and Wilkinson, 1980). Both thallium (I) carbonate and oxide also hydro!yze In water with the formation of T10H (Ueast, 1985; Hul, 1983). 1.3. PRODUCTION DATA Noah Industrial Corp., Farmlngdale, NY. Harshaw/Flltrol Partnership, Solon, OH, and Morton Thlokol, Inc., Danvers. MA, are currently the princi- pal domestic producers of thallium and compounds since American Smelting and Refining Co. discontinued Us operation In February of 1981 (Hu1, 1983; SRI, 1987). The current suppliers of thallium and Us salts In the United States are as follows (OPD. 1986): AldMch Chemical Co., Inc., Milwaukee, WI; Alfa Products, Morton Thlokol Inc., Toronto, Ont.; Atomerglc Chemicals Corp. and Noah Industrial Corp., Farmlngdale, NY; R.P. Cargllle Laboratories. Inc.. Cedar Grove, NJ; Davos Chemical Corp., Fort Lee, NO; GFS Chemical, Columbus, 0083d -4- 01/20/88 ------- OH; Rhone-Poulenc Inc., Monmouth Juctlon, NJ; Sharpe Chemical Co., Burbank, CA; and United Mineral and Chemical Corp., New York, NY. According to the latest figure available from the USOI (1986). the U.S. demand for thallium and compounds was 2500 pounds In 1984. In the same year, 1000 pounds was produced 1n U.S. mines and 2535 pounds of thallium and compounds was Imported Into the United States. The difference between the U.S. supply and demand was used for export and Industry stock, but no data were available regarding these uses (USOI, 1986). Thallium Is obtained commercially from flue dusts of pyrlte (FeS_) burners, lead and zinc smelters and refiners and as a by-product of cadmium production. If the thallium content of flue dust Is water soluble, direct leaching with water or dilute add separates thallium from other Insoluble compounds. For water Insoluble thallium compounds In the dust or by-product, the material Is solublUzed by oxidizing roasts, by sulfatlzatlon or by alkali treatment. Thallium metal may be obtained either by electrolysis of carbonates, sulfates or perchlorates; by precipitation- with Zn; or by reduction of - " v .'.•.- ' • ' ' •'-••»• * ' thallium (I) oxalate or chloride (Stoklnger. 1981; Hu1. 1983). 1.4. USE DATA Thallium has limited commercial applications because of Us toxldty. Thallium Is used In alloy manufacture 1n bearings, contact points, anodes, and switches and seals for equipment designed for use In polar regions or In the stratosphere; manufacture of certain kinds of glass; In electronic devices; In agriculture; and In medicine (Uallwork-Barber et al., 1985; Hu1, 1983). Because of Us toxlclty, the use of thallium compounds as a rodent1- clde 1n agriculture was stopped 1n 1972 (Stoklnger, 1981). According to USDI (1986), the U.S. consumption pattern for thallium In 1984 was agricul- ture, OX; electrical. 70X; pharmaceutical, 4%; other, 26X. 0083d -5- 01/20/88 ------- 1.5. SUMMARY Thallium exists In both stable unlvalent and trlvalent states. Prop- erties of thallium compounds 1n the (I) valence state are similar to those of both alkali metals and silver salts. The hydroxide, carbonate, oxide and cyanide salts of thallium are water soluble like the corresponding alkali metal salts, and Us hallde salts, with the exception of fluoride salts, are Insoluble 1n water like the corresponding silver salts (Hu1, 1983). Most thallium (III) salts, particularly the salts of weak acids (e.g., sulflde, carbonate, cyanide, acetate) are not stable In water and hydrolyze exten- sively (Cotton and Wilkinson, 1980). Three chemical companies are currently the principal domestic producers of thallium and compounds (Hul, 1983; SRI. 1987). The U.S. demand for thallium was 2500 pounds In 1984 (USDI, 1986). Thallium has limited commercial use because of Its toxldty. According to USOI (1986). the U.S. consumption pattern for thallium In 1984 was agricul- ture, OX; electrical, 70%; pharmaceutical. 4%; other, 26%. 0083d -6- 01/20/88 ------- 2. ENVIRONMENTAL FATE AND TRANSPORT 2.1.. AIR The primary sources of anthropogenic thallium In the atmosphere are likely to be emissions from cement factories, coal burning power plants and metal smelters (Sharma et al., 1986; Brockhaus et al., I960, 1981). Infor- mation regarding the fate and transport of thallium In the atmosphere 1s extremely limited. Since thallium 1s collected In the form of oxide and sulfate In the flue dust from metal smelters (Hu1, 1983), It Is likely that the chemical form of atmospheric thallium originating from metal smelters, coal burning power plants and cement plants will be elemental thallium, oxides of thallium, Tl.SO. and T1~S (Smith and Carson, 1977). Like other metals In the atmosphere chemical and photochemical Interaction of thallium may change thallium from one species to another, but these processes will not remove the metal species from the atmosphere. As Is the case with lead, atmospheric Tl.S may be partially spedated to Tl-SO. and any T1J) will be rapidly hydrolyzed to T10H. Both of these processes will enhance the removal of atmospheric thallium by wet deposition because of the higher water solubilities of the spedated products; however, 1f T1?0 or elemental thallium 1s spedated 1n the atmosphere to Tl^O,, It may persist 1n the atmosphere for a long time because of Its high chemical stability and low water solubility. Dry deposition will be the likely route of removal of the compound. No estimate of the atmospheric half-life of thallium was found In the available literature cited 1n Appendix A. 2.2. HATER Data regarding the fate and transport of thallium In water are avail- able. Little Is known about the transformation of thallium In water by either abiotic or blotlc processes. For example, thallium may undergo 0083d -7- 01/20/88 ------- methylatlon similar to Hg, Se, Pb and As, and this process may cause mobili- zation of thallium from sediment Into the water column or from the water column Into air (Helt and Klusek, 1985); however, there are no data In the literature to confirm this process. The photolysis of the thallium (III) salts of carboxyllc adds (e.g., acetic add, n-butyrlc acid, n-valerlc add) In benzene solution at 254 and 350 nm was studied by Kochl and Bethea (1968). At the higher wavelength, which 1s more relevant to environmental conditions (cutoff wavelength of solar radiation Is "290 nm), Tl (I) carboxylate, CO, and the corresponding alkanes were formed. Similar photolytlc homolysls of other Tl (III) salts may be possible, but 1n aquatic media the water soluble Tl (III) salts are likely to undergo more rapid hydrolysis than photolysis. Pertinent data regarding the photolysis or hydrolysis of environmentally relevant thallium salts (e.g.. sulfate, oxide, sulflde) 1n water were not located In the available literature cited 1n Appendix A. Stephenson and Lester (1987a,b) reported that the removal of thallium from water 1s due primarily to precipitation of Insoluble salts and not to adsorption of the soluble metal compound onto water partlculates containing high organic carbon such as sludge. In natural waters, both Inorganic llgands (hydroxo- and carbonato-llgands) and organic llgands (humlc materials) present 1n water will have a tendency to form complexes with thallium and keep thallium 1n the water phase. The complexatlon with humlc materials will be more Intense than with Inorganic llgands and the stability of these complexes will be higher with Increase 1n pH (O'Shea and Mancy, 1978). Removal of thallium from the aquatic phase by adsorption onto non- complexlng suspended solids Is likely to remove some thallium from solution (Kempton et al., 1987a,b). In a study of the transport of thallium 1n 0083d -8- 01/20/88 ------- aquatic media, Uallwork-Barber et al. (1985) found that the concentration of thallium 1n water decreased slowly and thallium was transported to vegeta- tion, and fish but not to sand. This study also pointed out that most thallium that enters water In the soluble form will not be found In the sediment but 1n the aquatic phase. A mean concentration of 13.1 mg/kg of thallium detected 1n the sediment of Lake Wlntergreen, MI, was attributed to fallout of (Insoluble) airborne partlculate matter (Hathls and Kevern, 1975). The bloconcentratlon of thallium 1n aquatic organisms 1s much less than other heavy metals (Zltko and Carson, 1975). BCFs of 18.2 1n clams, Mya aremaroa. and 11.7 In mussels. HytHus edulls have been reported (ZHko and Carson, 1975). The BCF 1n muscle tissue of juvenile Atlantic salmon. Salmo salar. was 130 (ZHko et al., 1975). In blueglll sunflsh, Lepomls macro- chlrus. the maximum BCF was 34 (Barrows et al., 1980). 2.3. SOIL Pertinent data regarding the fate and transport of thallium In soil were not located In the available literature cited In Appendix A. with the excep- tion of a study by Cataldo and Ulldung (1983). In this study, the authors estimated that up to a maximum of 10% of thallium absorbed In the plant roots from soil may be transported from root to shoot. Based on Its trans- port characteristics 1n water (see Section 2.2.), leaching of thallium from solil, particularly from sandy soil Is likely to occur. 2.4. SUMMARY Available Information regarding the fate and transport of thallium 1n environmental media 1s extremely limited. The principal sources of thallium In the environment are cement factories, coal burning power plants and metal smelters (Sharma et al., 1986; Brockhaus et al., 1980, 1981). In the atmosphere, thallium may be present as elemental T1. oxides of Tl, T1.S 0083d -9- 01/11/88 ------- and T12S04. T12S Is likely to be spedated to T12S04. and T120 will be rapidly hydrolyzed to T10H by the moisture In the atmosphere. Because of their water solubilities, both these compounds are likely to be removed from the atmosphere by wet deposition; however, because It 1s Insoluble In water, Tl-Og may persist for a longer period 1n the atmo- sphere. Tl-O- 1s likely to be removed from the atmosphere by dry deposition. No estimate of the half-life of thallium In the atmosphere was located 1n the available literature cited In Appendix A. In water, most of thallium that enters the medium In the Insoluble form may be found In the sediment (Hathls and Kevern, 1975). Some thallium may be removed from the water by sorptlon onto suspended- solids 1n water (Kempton et al.. 1987a,b). Most of the thallium that enters natural waters In the soluble state will remain In the soluble form because of the formation of soluble complexes with Inorganic and organic Ugands, and these complexes will be more stable at higher pHs (Stephenson and Lester, 1987a,b; O'Shea and Mancy, 1978). Thallium In water may be transported to fish and vegetation (Wallwork-Barber et al., 1985). The BCF of thallium In whole aquatic organisms ranges from 12-34 (Zltko and Carson, 1975; Barrows et al., 1980). Based on Us trans- port In water, leaching of thallium from soil, particularly from sandy soil, appears to be likely. Up to 10% of thallium absorbed In plant roots from soil may be transported from the root to the shoot of the plant (Cataldo and Ulldung, 1983). 0083d -10- 01/20/88 ------- 3. EXPOSURE 3.1,. AIR The concentration range of thallium In the air of six major U.S. cities was reported to range from 0.02-0.1 ng/m3, with a typical concentration of 0.04 ng/m3 (U.S. EPA, 1980b). In another study, the concentration range of thallium In Chadron, NB, was reported as 0.04-0.48 ng/m3 (U.S. EPA, 1980b). Given this value and the assumption that an Individual Inhales 20 m3 of air/day and that 35% of the Inhaled amount 1s retained. U.S. EPA (1980b) estimated a maximum dally average absorption of 3.4 ng of thallium per day by an Individual In the United States; however, the dally absorption may be higher for Individuals who live 1n the vicinity of cement plants, smelters and coal burning power plants, as Indicated by higher hair and urinary thallium levels among a population living In the vicinity of a cement plant In Germany (Brockhaus et al., 1980, 1981). The estimated concentration of atmospheric thallium near a coal burning plant .was 0.7 yg/m3 (Smith and Carson, 1977). Assuming an Inhalation rate of 20 ma/day and and an absorption of 35X of the Inhaled amount, this air level will amount to an absorption of 4.9 ^g/day by an Individual — an amount more than twice the dally average dietary Intake (Section 3.3.) of thallium. 3.2. HATER In a study that monitored metal runoffs to surface waters from several mining and smelting operations 1n the United States, the highest concentra- tions reported were 30 pg/l In a slag runoff near Kellog, ID, and 21 vg/l In water from the Colorado River just below the Big Williams River which drained the Planet Nine (U.S. EPA, 1980b). Thallium was qualitatively detected In samples of sediment/solI/water mixtures obtained from the Love Canal, Niagara Falls, NY (Hauser and bromberg, 1982). Zltko et al. (1975) 0083d -11- 01/20/88 ------- detected thallium concentrations of 0.7-88.3 yg/8. In water from three rivers that served as drains for mining operations 1n New Brunswick, Canada. Hathis and Kevern (1975) reported concentrations of thallium 1n sediments of Lake Wlntergreen, Kalamazoo, HI, In the range 2.1-23.1 mg/kg, with a mean value of 13.1 mg/kg. The authors reported that fallout from airborne participate matter was the source of this thallium. In their survey of pollutant emission levels 1n wastewaters from the refining Industry, Snider and Harming (1982) detected no thallium at minimum detection levels ranging from 1-15 vg/l. In a survey of tap waters from 3834 homes throughout the United States, thallium was detected 1n only 0.68X of the samples at an average thallium concentration of 0.89 »g/i (detection limit 0.3 yg/l) (U.S. EPA, 1980b). Based on the minimum detection limit and the assumption that an Individual consumes 2 4 of water per day, U.S. EPA (1980b) estimated that >99% of adults In the United States would consume <1 pg thallium/day. 3.3. FOOD The levels of thallium In vegetables (lettuce, red and green cabbage, leak and endive) and bread were reported to be 10 yg/kg wet weight and 0.75 yg/kg dry weight, respectively (U.S. EPA, 1980b). Given this value for the level of thallium In vegetables and assuming that human thallium Intake 1s primarily due to Ingestlon of vegetables and that the consumption of vegetables per day by an Individual In the United States Is 0.38 kg, U.S. EPA (1980b) estimated a maximum thallium Ingestlon of 3.8 yg/day by an Individual 1n the United States. According to Sharma et al. (1986), Inhala- tion of contaminated air and consumption of vegetables and fruits grown near thallium emission sources are the major routes of human thallium Intakes. The average dietary Intake of thallium by an adult Is estimated to be -2 pg/day (Smith and Carson, 1977; Sharma et al., 1986). 0083d -12- 01/20/88 ------- 3.4. DERMAL Dermal absorption of thallium may possibly occur as a result of bathing with thallium-containing water, although no estimate of thallium Intake from dermal absorption from this or any other source can be made. 3.5. SUMMARY Inhalation of contaminated air and consumption of vegetables and fruits grown near thallium emission sources are the major routes of human thallium Intake (Sharma et al., 1986; Brockhaus et al., 1980, 1981). From the limited air monitoring data available, U.S. EPA (1980b) estimated a dally Inhalation 'absorption of 3.4 yg of thallium per day by an Individual 1n the United States; however, the dally absorption may be higher for Individ- uals who live 1n the vicinity of emission sources (Brockhaus et al., 1980, 1981). Thallium has been detected In surface waters that receive waste- waters from certain mining and smelting operations (U.S. EPA, 1980b; Mathls and Kevern. 1975; Zltko et al., 1975). Thallium was not detected In >99% of tap waters sampled In the United States at a minimum detection limit of 0.3 vg/t. U.S. EPA (1980b) estimated that >99% of U.S. adults would consume <1 yg of thallium per day by 1ngest1on of drinking water. From the limited monitoring data on foods, U.S. EPA (1980b) estimated a maximum dietary Intake of thallium by a U.S. adult as 3.8 ng/day. According to Sharma et al. (1986), the average dietary Intake of thallium by an adult Is -2 yg/day. 0083d -13- 03/08/88 ------- 4. AQUATIC TOXICITY 4.1. ACUTE TOXICITY Data regarding the acute tox1c1ty of several thallium salts to fresh- water and saltwater aquatic species are presented In Table 4-1. Acute LC5Q values for two species of freshwater fish ranged from 110-600 mg/kg (Buccafusco et al., 1981; Oawson et al.t 1977; Juhnke and Luedemann, 1978); a concentration of 0.030 mg/i was estimated as an Incipient lethal level for the Atlantic salmon. Salmo salar (Zltko et al., 1975). An acute LC5Q of 31 mg/l was estimated for the saltwater Inland sllverslde, Henldla bervlllna (Oawson et al., 1977). LC5Q values In the water flea, Daphnla roagna. ranged from 1.1-3.6 mg/l (Brlngmann and Kuehn, 1977; Leblanc, 1980); a concentration of 0.11 mg/l was an EC™ for Immobility 1n this species (Brlngmann and Kuehn, 1982). The lowest concentration associated with acute toxldty was 0.11 mg/l, the EC.Q for Immobility In Daphnla roaqna (Brlngmann and Kuehn, 1977). Although the data were limited, It appeared that the thallium salts tested had similar toxic potencies. 4.2. CHRONIC EFFECTS The limited data available regarding the chronic toxldty of thallium salts to aquatic organisms are presented In Table 4-2. The lowest concen- tration associated with chronic toxldty 1n fish was <0.04 mg/l, an MATC In the fathead minnow, Plmephales promelas. In an embryo-larval test (U.S. EPA, 1978; LeBlanc and Dean. 1984). A 7-day LC5Q of 0.11 mg/i was reported In the narrow-mouthed frog, Hlcrohyla carollnensis (B1rge, 1978). 4.3. PLANT EFFECTS The limited data available on the toxldty of thallium salts to plants are presented In Table 4-3. Considerable species variation was observed 1n the toxic potency of thallium. A concentration of 1.43 mg/l depressed oxygen output In the waterweed, Elodea canadensls (Brown and Rattlgan, 1979). 0083d -14- 01/11/88 ------- 8 TABLE 4-1 Acute Toxlclty of Thai HIM Salts to Aquatic Organism Species Thai HIM Salt Concentration of ThallliM (•g/t) Effect Coment Reference FISH Blueglll, Lepoals aacrochlrus Blueglll. lepoals aacrochlrus Blueglll. lepoiils Mcrochlrus Golden orfe, leuclscus Idus Atlantic saloon. Salao salar INVERTEBRATES Uaterflea. Daphnla aaana Uaterflea. Oaphnla aaana Uaterflea. Oaphnla aaana Uaterflea, Daphnla aaana thai 1liM(l)sul fate thall1iM(I)acetate thalllwi(I)sulfate tha111w(I)n1trate NR thalllM(I)n1trate tha!1lui(I)sulfate thall1ua(l)sulfate tha11liM(I)nltrate FISH Inland stlverslde. Henldla bervlllna thall1u»(I)acetate Sheepshead Minnow, CypMnodon varleaatus NR INVERTEBRATES FRESHWATER SPECIES 600 170 120 110 0.030 1.142 3.6 2.2 0.11 24-hour LCjQ 96-hour LC§o 96 -hour ICso acute LCso Incipient lethal level 24-hour LCsQ 24-hour LCso 48-hour LCso ECcn for 1 Mobility S.U. Juvenile S.U. 33-75 m S.U. Juvenile S.U. other details NR Juvenile, other test conditions NR S.U S.U. <24 hours old S.U. <24 hours old; no Mortality at 1.7 ag/ft S.U ^ Nysld shrimp. Hvsldopsls bahIa NR SALTWATER SPECIES 31 96-hour LC50 S.U. 40-100 m 20.9 acute level. NOS S.U 2.130 acute level. NOS S.U Buccafusco et al., 1981 Dawson et al.. 1977 Buccafusco et al., 1981 Juhnke and Luedeoann. 1978 Zltko et al.. 1975 Brtngnann and Kuehn. 1977 LeBlanc. 1980 LeBlanc. 1980 Brlngaann and Kuehn. 1982 Oawson et al.. 1977 U.S. EPA. 1978 U.S. EPA. 1978 oo S • Static test conditions; U - unoeasured concentration; NR - not reported; NOS » not otherwise specified ------- § 00 TABLE 4-2 Chronic Toxtclty of Thallium Salts to Aquattc OrganlSMS Species Thai HIM Salt Concentration of Thallium (•g/t) Effect Connent Reference FISH Goldfish. Carasslus auratus Rainbow trout. SalMO galrdnerl FRESHWATER SPECIES tha111uM(III(chloride 7 thall luMjUsulf ate 1.5 thallluB(III(chloride . 0.17 Rainbow trout. SalMO galrdnerl AMPHIBIAN Narrow-Mouthed frog. Hlcrohyla carolInensls thallIUM( 111(chloride 0.11 Fathead Minnow. Plaeohales oroaelas SALTWATER SPECIES thallium sulfate 0.04 Sheepshead Minnow. Cyprlnodon varleaatus NR 7-day LC§o S.N.A. eggs 10-day LCjo S.N. Juvenile MATC NR E-L E-L Blrge. 1978 Craig and Beggs. 1979 28-day LC5o S.N.A. eggs Blrge. 1978 7-day LCgo S.N.A. eggs Blrge. 1978 U.S. EPA. 1978; LeBlanc and Dean. 1964 U.S. EPA. 1978 S • Static test conditions; N - Measured concentration; A - aerated tanks; E-L - embryo-larval test; NR - not reported ------- TABU 4-3 Toxlclty of ThallliM Salts to Aquatic Plants I*? a. Species Thai HUM Salt Concentration of Thalllua. (•g/t) Effect Content Reference FRESHWATER SPECIES i -4 i Uaterweed. thai 11ua(l)sulf ate ilodea canadensls Duckweed, Leona Minor, tha111ui(l)su1fate Green algae. thal1lui(I)su1fate Chlorelli vulgarls Algae. NR Chlaavdoaonas relnhardl Algae. NR Selenastrua caprlcornutm Algae. NR Selenastrua caprlcornutua "1.43 0.008 0.016 40.8 0.110 0.100 Op production reduced 90X SOX plant damage •axlmui concentra- tion tolerated for population growth 40X Inhibition of oxygen evolution 96-hour ECsp for chlorophyll a Inhibition 96-hour EC5Q for cell number S.U. 24 hours; SOX plant damage occurred at 2 *g/ft S.U. 28 days S.U, 3-4 Months exposure; 0.032 ag/t Inhibited growth NC NC NC Brown and Rattlgan. 1979 Brown and Rattlgan. 1979 OeJong, 1965 Overnell. 1975a U.S. EPA. 1978 U.S. EPA. 1978 SALTWATER SPECIES 88/1 I/ 10 Marine dlatoa. Bltylim brlghtwelll Algae. Ounallella tertlolecta Algae. Dunallella tertlolecta Algae. Ounallella tertlolecta thal11ui(l)ch1orlde NR tha111uMlH)salt unspecified thallliM(I)salt unspecified 0.75 4.080 -1.0 nH (-0.2 ng/l) -0.5 i* (-0.1 «g/l) S-day alglstatlc S.U SOX Inhibition of NC photosynthesis reduction In NC culture growth 'reduction In NC culture growth Canter ford and Canter ford. I960 Overnell. 1975b Puddu et al.. 1985 Puddu et al.. 1985 ------- TABU 4-3 (cont.) o 1 a. i CO 1 Species Algae. PhaeodactifltM trlcornutiM Algae. PhaeodactifliM trtcornutu» Algae. Phaeodact»ltM trtcornutua S - Static test conditions; ThalltiM Salt NR thal11u»(lll)salt unspecified thal1ti»|I)sa1t unspecified Concentration of Thai HIM SALTWATER 51.2 -1 .0 |M (-0.2 •g/l) -0.5 i* (-0.1 ag/t) U • unmeasured concentration; NC « no con Effect Coment SPECIES (cont.) SOX Inhibition of NC photosynthesis reduction In NC culture growth reduction In NC culture growth Bent; NR « not reported Reference Overnell. 19756 Puddu et al.. 1965 Puddu et al.. 1985 ------- Concentrations of thallium (I) salts of -0.1 mg/i and thallium (III) salts of -0.2 mg/i depressed culture growth 1n two species of marine algae, Dunallella tertlolecta and Phaeodactylum trlcornutum (Puddu et al., 1985). The duckweed, Lemna minor, appeared to be the most sensitive; 50% plant damage was reported after 28 days of exposure to 0.008 mg/8. (Brown and Rattlgan, 1979). 4.4. SUMMARY There appeared to be considerable species differences In toxlclty to thallium salts. Although the data were limited, there did not appear to be marked differences 1n toxldty between different salts of thallium. The lowest concentration of thallium associated with acute toxldty was 1.142 mg/l, an LC5Q for Daphnla maqna (Brlngmann and Kuehn, 1977). In a chronic study, a concentration of <0.04 mg/l was an MATC determined 1n an embryo-larval test In the fathead minnow, Plmephales promelas (U.S. EPA, 1978). In plants, a concentration of 0.008 mg/i was associated with 50X damage to duckweed, Lemna minor (Brown and Rattlgan, 1979). 0083d -19- 01/20/88 ------- 5. PHARMACOKINETICS 5.1. ABSORPTION The conclusion of several studies regarding the pharmacoklnetlcs of thallium Is that absorption of soluble salts occurs readily from any route of exposure (Smith and Carson, 1977; Venugopal and Luckey, 1978; U.S. EPA, 1980b; Moeschlln, 1980; Stoklnger, 1981; Manzo et al.. 1983a). The best documentation Is an experiment In which rats were administered thallium204 (I) nitrate by several routes (Figure 5-1). Body burden of radioactivity expressed as a percent of the administered dose over time was nearly Identical for all routes of administration Including the Intravenous route, suggesting virtually complete and rapid uptake from all sites of adminis- tration. Manzo et al. (1983a) observed rapid and virtually complete uptake from the gastrointestinal tract of rats. The uptake of single doses of 2 yg to 2 mg Tl* was measured In rats using an jri situ Intestinal loop clamped method. By.l hour after administration, 50% of the dose was absorbed; by 3 hours 90X was absorbed. No evidence of saturation of the absorption mecha- nism was observed within the dose range tested. Data regarding gastrointestinal absorption In humans are limited to a study 1n which a middle-aged woman with terminal osteogenlc carcinoma was given a single oral dose of thallium204 (Barclay et al., 1953). A dramatic rise In urinary radioactivity was noted, but fecal excretion over a 72-hour collection period accounted for only 0.5X of the dose, suggesting virtually complete absorption. Although data regarding absorption following Inhalation exposure were not located, data following Intratracheal administration (Figure 5-1) suggested that uptake through respiratory epithelium was rapid and complete 0083d -20- 01/20/88 ------- FIGURE 5-1 Body Burden of Thallium204 In Adult Hale Wlstar Rats Source: Lie et al.. 1960 IV « Intravenous: 0.01 mg Tlao«/rat; IP • Intraperltoneal: 0.0375 mg Tlao«/rat; SO - subcutaneous: 0.025 mg T1»°Vrat; IM > Intramuscular: 0.025 mg Tl«Vrat; IT • Intratracheal: 0.0315 mg Tl««/rat; 0 « oral: 0.20 mg Tl«Vrat 0083d -21- 01/11/88 ------- (Lie et al., 1960). According to U.S. EPA (1980b), the deposition pattern of Inhaled thallium salts would depend primarily on the aerodynamic size of the particles and rate of clearance would depend primarily on solubility. U.S. EPA (1980b) predicted that all salts of thallium except the oxide and halldes would be cleared rapidly. Quantitative data were not located regarding dermal absorption, but the toxic signs observed In humans following application of a depilatory containing thallium (Section 6.1.3.) suggest that dermal absorption may be substantial, at least from a cosmetic preparation. U.S. EPA (1980b), however, noted that dermal absorption 1s not likely to be significant under ordinary exposure conditions to low concentrations 1n environmental media. 5.2. DISTRIBUTION Distribution of thallium from the bloodstream appears to be rapid and widespread (U.S. EPA, 1980b; Hanzo et al., 1983a; Rauws, 1974). Lameljer and van Zwleten (1977a) described the disappearance of thallium204 (I) sulfate from the blood of Intravenously treated rats by a two-compartment model, with half-lives of 5 and 196 minutes, respectively. Using a small (<2 tig) dose of thallium"" (I) chloride, Talas and Wellhoener (1983) observed that plasma disappearance of radioactivity conformed to a three- compartment model 1n rabbits, with half-lives of 2.1. 89 and 2758 minutes. respectively. Higher doses (5.5 pinol/kg bw of thallium acetate) had little Impact on the half-lives of disappearance from the plasma. In humans, plasma disappearance of Tl * seemed to conform to a two-compart- ment model, with half-lives of 3.9 and 3108 minutes, respectively (Talas et al., 1983). Estimations of distribution volumes during the first and second phases suggested that thallium translocated rapidly from extracellular fluids to Intracellular space, and that large amounts of thallium were concentrated In tissues. 0083d -22- 01/20/88 ------- The tissue distribution of thallium In rats has been studied by a number of Investigators using different salts and different routes of administra- tion. Highest levels were located 1n the kidney, somewhat lower levels were located In the other parenchymatous organs and lowest levels were located 1n the central and peripheral nervous system and body fat (Barclay et al.t 1953; Lund, 1956a; Lie et al., 1960; Schwetz et al., 1967; Kamerbeek et al., 1971; Sabblonl et al., 1980; Rade et al., 1982; Ducket et al., 1983; Manzo et al., 1983b; Gregus and Klaassen, 1986). Typical data from a distribution experiment 1n rats are presented 1n Table 5-1. The relative concentrations of thallium In different tissues appeared to be Independent of the route of administration (Lie et al., 1960), the valence state of thallium administered (Sabblonl et al., 1980), the length of time after administration from 2 hours (Sabblonl et al., 1980; Gregus and Klaassen. 1986) to 7 days (Lie et al., 1960; Schwetz et al., 1967) or after thronlc administration (280 days) (Manzo et al., 1983b), or the dose admin- istered (Gregus and Klaassen, 1986),. Expressed as a percent of total body burden, greatest amounts of thallium were located In muscle, because this tissue accounts for -30% of the body mass of rats (Lie et al., 1960). Experiments using rabbits (Talas and Wellhoener, 1983) and mice (Andre et al., 1960; Achenbach et al., 1980) suggested that tissue distribution In these species was similar to that In rats, with highest concentrations located 1n the kidney, particularly 1n the renal medula (Andre et al., 1960). Gibson et al. (1967) noted that patterns of distribution 1n 1- and 7-day-old rats and mice were similar to patterns In adults; distribution was widespread with highest concentrations In the kidneys. In dogs and goats, highest tissue levels were located In heart, liver and kidney (Bradley-Moore et al., 1975; Emara and Sollman, 1950). 0083d -23- 01/20/88 ------- TABLE 5-1 Concentration of Thallium201 1n Tissues of Rats Following IntraperUoneal Administration of Tl201 Saltsa»b Tissue Concentration 2 Hours Post-Treatment (ng/g fresh tissue)0 Concentration 40 Hours Post-Treatment (ng/g fresh tissue)0 Kidney Liver Small Intestine Testls Stomach Pancreas Salivary glands LUng .Heart .. .... Thymus Spleen Brain Cerebellum Blood 97.2*17.3 14.8+1.7 21.6+5.3 6.4+0.9 22+2 32+16 30.1+5 15.5+1.4 25+6 . 14.4+6 16.3+1.2 0.4+0.1 4.7+0.6 1+0.2 167.7+16.5 6.5+0.65 NR 22+.S.9 14+0.98 21.2+4.8 28.1+12.9 12.7+1.3 14.5+1.5 14.3+5.1 9.2+1 4.1+0.5 7.4+2.2 1.6+1 aSource: Sabb1on1 et al.t 1980 bAdult male Sprague-Dawley rats were Injected with 2 jig thallium (I) sulfate labeled with Tl20i (50 WC1). cConcentrat1on as expressed 1s equivalent to parts per billion (ppb). NR o Not reported 0083d -24- 01/11/88 ------- Generally, administration of a single dose of thallium to rats resulted In peak tissue concentrations within 24 hours (Rauws, 1974; Ducket et al., 1983; Rade et al., 1982). Half-lives for depletion from several tissues In rats were estimated at 2.7 days for the brain to 6.0 days for the spleen (Ducket et al., 1983). Lie et al. (1960) estimated that total body clear- ance In rats occurred exponentially In rats with a half-life of 3.3 days (see Figure 5-1). No parenchymatous organ or tissue appeared to retain thallium more than any other, although Rade et al. (1982) reported slower decline from the brain and muscle than from other tissues of pregnant rats treated with a single IntraperUoneal Injection, and Lie et al. (1960) noted that the concentration 1n hair Increased with time. Thallium has been shown to cross the placenta and locate In the fetus, but, at concentrations substantially lower than those 1n maternal blood or tissues. Gibson and Becker (1970) Intravenously Infused rats on day 20 of pregnancy with thallium (I) sulfate and monitored the concentration of thal- lium In 'maternal blood and 1n the whole fetus at several time points during the 32-mlnute Infusion period. The concentration of thallium 1n maternal blood and the fetus Increased with Increasing time and dose, but fetal concentrations were -7% of those of maternal blood. Rade et al. (1982) administered a single Intraperltoneal dose of thallium201 to rats on day 13 of gestation and monitored radioactivity In several maternal tissues, placental tissue and the whole fetus for up to 192 hours (8 days). Levels of radioactivity In maternal tissues (except blood) and the placenta always exceeded those In the whole fetus. The decrease 1n concentration of thallium In the whole fetus paralleled that In maternal tissues, with a half-life for the terminal phase (of a two-phase model) of 64.2 hours. 0083d -25- 01/11/88 ------- Zlskoven et al. (1983) treated pregnant rats (gestation day 10) and mice (gestation day 9) with single oral doses of thallium (I) sulfate and measured levels of thallium In the maternal kidney and fetal tissues (presumably whole fetus) at various times up . to 50 hours after treatment. Concentrations In maternal kidney exceeded those In fetal tissues by a factor of -10 throughout the study. There were no significant differences between rats and mice. Using thallium204 (I) sulfate and a radlographlc technique, Olsen and Jonsen (1982) showed that T1* crossed the placenta of mice within 15 minutes of an Intraperltoneal Injection. Levels of radio- activity In the placenta exceeded those 1n the fetus. Olsen and Jonsen (1982) also administered single Intraperltoneal Injections of thallium204 (I) sulfate to mice on days 5-16 of gestation to measure uptake of radio- activity by the embryo, fetus and placenta! membranes at different stages of development. High concentrations of radioactivity were detected In the embryo and fetus on or after day 8 and 1n the surrounding declduae on or after day.5, Indicating early placental uptake of thallium. 5.3. METABOLISM Little Information Is available regarding the metabolism of thallium. Sabblonl et al. (1980) noted that the tissue distribution and retention of radioactivity In rats following oral and Intraperltoneal administration of 201-thai 11 urn was quite similar for thallium (I) and thallium (III) sulfate. These Investigators hypothesized that the different oxidation states were transformed jjn vivo to a single valence. As supportive evidence they cited similarities In the acute LD5Qs of thallium (I) and thallium (III) salts (Section 6.1.3.), but concluded that data were Insufficient to determine which oxidation state predominates In vivo. 0083d -26- 01/11/88 ------- 5.4. EXCRETION The route of excretion of thallium, which 1s strongly species-dependent, has been studied most extensively 1n the rat. Lie et al. (1960) adminis- tered thallium204 (I) nitrate to male Ulstar rats by a few natural or parenteral routes and observed an exponential removal of thallium from the body with an estimated half-life of 3.3 days, regardless of the route of administration (see Figure 5-1). In female Wlstar rats treated Intraven- ously with thallium204 (not otherwise specified), the estimated half-life of 204-thallium 1n blood at steady-state was -4 days (Rauws, 1974). At the end of a 72-hour collection period, fecal excretion accounted for 28.3% and urinary excretion for 14.2% of the administered dose of thallium204. Other experiments In rats Indicated that fecal excretion predominates over urinary excretion (Barclay et al., 1953; Lund, 1956a; Schaefer and Forth, 1980; Lehmann and FavaM, 1985; Gregus and Klaassen, 1986), and that excretion half-lives vary from 3.3 (Schwetz et al., 1967) to >4 days (Gregus and Klaassen, 1986). Gregus and Klaassen (1986) recovered only 0.150-0.160% of an Intravenous 1-30 mg/kg dose of 204-T1* within 2 hours of treatment In the bile of bile duct-cannulated rats, and concluded that biliary excre- tion was not significant In this species. Lund (1956a) reached the same conclusion using rats with 11 gated and sectioned bile ducts, and also determined that thallium administered subcutaneously Is excreted Into all sections of the gastrointestinal tract. Schaefer and Forth (1980) determined that excretion Into the bowel occurred against a concentration gradient. Truhaut (1959) observed a fecal to urine excretion ratio of 0.75 In rabbits In a 23-day collection period following treatment. Talas and Uellhoener (1983) studied the excretion of T120U 1n rabbits treated 0083d -27- 01/11/88 ------- Intravenously. Generally, fecal excretion predominated over urinary excre- tion; biliary excretion appeared to be Insignificant. Total body clearance averaged 11 mi/ra1nute and appeared to be Inversely correlated with dose. Available data Indicate that humans excrete thallium predominantly through the urine. Barclay et al. (1953) studied the excretion of thallium In a middle-aged woman with terminal cancer who was treated orally with 2.3 mg thallium204 followed by 5 doses of 45 mg thallium (I) sulfate every 3 days. Over a 5.5-day collection period, fecal excretion was described as Inconsequential and urinary excretion accounted for -15.4% of the admin- istered dose of thallium204. An excretion half-life of 21.7 days was estimated from these data (U.S. EPA, 1980b). More recently. Talas et al. (1983) estimated an average excretion half-life of 2.15 days In a group of nine ambulatory patients treated with <10 yg thallium201 (I) chloride Intravenously for myocardlal sdntlgraphy. These Investigators estimated total body clearance at 80 ml/minute, -66% of the glomerular filtration' rate. ..... .-.....-•'-. Other routes of excretion may play a role In the elimination of thallium from the body. Rlchelml et al. (1980) studied the concentration of thallium In saliva and urine of a woman who attempted suicide by Ingesting thallium sulfate. Levels 1n saliva were 5-15 times those In urine, but forced diuresis Induced by Intravenous administration of glucose probably Increased output of a less concentrated urine. Prick et al. (1955) Indicated that thallium Is excreted 1n tears, respiratory secretion and milk as well as the media discussed above. 5.5. SUMMARY Absorption or uptake of soluble thallium salts 1s rapid and virtually complete by any route of exposure (Smith and Carson, 1977; Venugopal and 0083d -28- 01/20/88 ------- Luckey, 1978; U.S. EPA, 1980b; Moeschlln, T980; Stoklnger, 1981; Hanzo et a!., 1983a), although dermal absorption Is not likely to be significant In environmental exposure. Distribution from the blood Is rapid and wide- spread, with highest levels located 1n the kidney, heart and liver and lowest levels In the nervous system and body fat (Hanzo et a!., 1983a,b; Rauws, 1974; Barclay et al., 1953; Lie et al., 1960; Sabblonl et al., 1980). The relative concentrations In different tissues appear to be Independent of route of administration (Lie et al., 1960), the valence of thallium admin- istered (Sabblonl et al., 1980), the time after administration (Lie et al.. 1960) or the dosage (Gregus and Klaassen, 1986). Thallium translocates to the placenta and fetus, but levels 1n the fetus are substantially lower than those In maternal tissues (Gibson and Becker, 1970; Rade et al., 1982; Zlskoven et al., 1983). The metabolism of thallium 1s not well understood, but H Is hypothesized that thallium 1_n vivo 1s transformed to one oxidation state (Sabblonl et al., 1980). The excretion of thallium appears to be species-dependent, with fecal excretion predominating In the rat (Lie et al., 1960; Rauws, 1974; Barclay et al., 1953; Gregus and Klaassen, 1986) and urinary excretion predominating In humans (Barclay et al., 1953; R1chelm1 et al., 1980). Estimates of excretion half-lives In humans range from 2.15 days for tracer doses 1n ambulatory heart patients (Talas et al., 1983) to 21.7 days 1n a terminal cancer patient (Barclay et al., 1953; U.S. EPA, 1980b). 0083d -29- 01/20/88 ------- 6. EFFECTS 6.1. SYSTEMIC TOXICITY 6.1.1. Inhalation Exposures. 6.1.1.1. SUBCHRONIC — Pertinent data regarding the subchronlc Inha- lation toxlclty of thallium salts were not located 1n the available litera- ture cited 1n Appendix A. 6.1.1.2. CHRONIC — U.S. EPA (1979) described the protocol of an Inhalation study with thallium (III) oxide In groups of 90 male and 90 female 8-month-old Wlstar rats. Rats were exposed In a stainless steel chamber to concentrations of thallium (III) oxide dust adjusted from 0.5-2 mg/m3 according to clinical signs as shown In Table 6-1. Controls were exposed to filtered air. Rats were exposed 7 hours/day, 5 days/week for 12 months, followed by a 4-month observation period, terminal sacrifice and hlstopathologlcal examination. Interim sacrifices of 5 rats/sex/group were scheduled for 6, 9 and 12 months. Rats that died or were sacrificed 1n a moribund condition were necropsled. In addition to the clinical signs noted In Table 6-1, alopecia was observed 1n exposed rats within 2 months. There were no effects on body weights of males, but exposed females had slightly reduced body weights at >26 weeks. Necropsy of dead rats and rats at Interim sacrifices revealed pale or dark livers, granular appearance of the kidneys and white or grey spots 1n the lungs of exposed rats. Hlstopatho- loglcal evaluation of rats 1n this study has not been performed (Groth, 1987). Human Inhalation data are limited. Marcus (1985) reported urinary thallium levels up to 236 yg/l (median value 28.0 »g/l) In 1976 In a group of 39 workers exposed to thallium In a magnesium seawater battery 0083d -30- 01/20/88 ------- TABLE 6-1 Experimental Protocol of Inhalation Study with Thallium (III) Oxide In Groups of Hale and Female 8-month-old Ulstar Rats* Concentration (mg/ma) Exposure Period Clinical Signs 1 2 0 1 0.5 first 5 weeks of exposure exposure weeks 6-18 week 19 weeks 20-30 weeks 31-52 no clinical signs high mortality NC deteriorating health NC 'Source: U.S. EPA. 1979 NC = No comment 00133d -31- 01/11/88 ------- plant since 1970. These urinary concentrations suggested to the Investi- gator that exposure levels exceeded the ACGIH TLV of 0.1 mg/m3, although exposures were not quantified. The Institution of stringent Industrial hygiene measures 1n 1977 led to a rapid decline In median urine thallium concentrations to <0.6 wg/t by the end of 1978. Based on available medical records, Marcus (1985) reported that there were no differences 1n 23 criteria of health (Including digestive, circulatory, CMS and mental health problems) In a cohort of 86 exposed workers, compared with 79 unexposed controls 1n the same factory. It Is unclear, however, whether the health effects phase of the study Included workers exposed before Institution of Improved hygiene. Furthermore, the length of employment of the exposed cohort was not reported. SenaHer et al. (1980) Investigated the effects of exposure to thallium on the health of 128 male workers aged 16-62 years and exposed for 1-42 years (mean: 19.5 years) In three cement plants. Health evaluation consisted of medical history and .a physical examination for symptoms of thallium toxldty. Urinary levels of thallium ranged from <0.3-6.3 jig/4, compared with a normal upper limit of 1 jjg/l for unexposed persons, suggesting that exposure to thallium above background levels had occurred. The health evaluation revealed no evidence of an effect from occupational exposure to thallium. Ludolph et al. (1986) Investigated the effects of thallium exposure on neurological health In 36 workers In cement production. The mean age of the subjects was 47.6 years (range 26-62) and the mean duration of employment was 22.9 years (range 5-44). The criteria for evaluating the neurological health of workers Included subjective symptoms, neurological examination and electrophyslcal parameters of nerve conduction, evoked potential and EEG. 0083d -32- 01/20/88 ------- Thallium levels were measured In blood, hair and urine. Although there was no unexposed control group, the Investigators reported a high Incidence of Impairment of the central and peripheral nervous system accompanied by a high level of concurrent disease. Graphic presentation of levels of thallium In blood, urine and hair Indicated that some Individuals had values above a "critical border value." There was no correlation, however, between levels 1n these biological media and the occurrence of clinical or electro- physical evidence of neurological Impairment. 6.1.2. Oral Exposures. 6.1.2.1. SUBCHRONIC — Downs et al. (1960) Investigated the sub- chronic toxldty of thallium (I) acetate and thallium (III) oxide In weanling Wlstar rats. In the first experiment, groups of five male and five female rats were fed diets containing 0, 0.0005, 0.0015 or 0.0050% thallium (I) acetate for 15 weeks. After several weeks, additional groups of rats were started on diets containing 0 or 0.003X thallium (I) acetate. These groups were maintained on their respective diets for 63 days. Host rats on the 0.005% diet died within 14 days; mortality rates of 80% for males and 60X for females occurred at 0.003X within 4-8 weeks. High mortality In the control groups precluded meaningful Interpretation of mortality data at the lower doses. Depression of growth rate occurred only In males at 0.003X. Rats on the 0.005X diet probably died before an Impact on growth rate became evident. The Investigators reported that relative weights of selected organs from rats that survived to termination were within normal limits except for a slight Increase 1n kidney weights; however, the significance of the slightly Increased kidney weights 1s doubtful since small numbers of rats were examined (3-5/group), and the authors did not specify which groups were Involved. The only significant gross observation was moderate to 0083d -33- 01/11/88 ------- marked alopecia In rats on the 0.0015 and 0.003% diets that became notice- able after 2 weeks of exposure and progressed to near halrlessness at termi- nation. Hlstopathologlcal examination of 12 major organs and tissues revealed no treatment-related lesions. The skin was not examined micro- scopically. In a second study, groups of five male and five female rats were fed for 15 weeks diets containing 0, 0.002, 0.0035, 0.005, 0.01 or 0.05% thallium (III) oxide (Downs et al., 1960). All rats died at >0.005%, 4/5 males and 2/5 females died at 0.0035%, 2/5 females died at 0.002% and 1/5 males died 1n the control group. The authors did not attribute the death of 2/5 females at 0.0035% -to thallium (III) oxide, because the same number of females died at 0.002%. Marked depression In growth rate, more evident In males than In females, occurred at >0.0035%. Moderate depression In growth rate occurred 1n males, but not females, at 0.002%. Progressive hair loss. more apparent In the males-than 1n the females, occurred at >0.002%. Elevated absolute (p<0.05) and relative kidney weights were observed at >0.002% 1n rats that survived to termination. Apparently, statistical analysis of relative kidney weights was not performed. Hlstopathologlcal examination of the lung, liver, kidney and brain revealed no thallium (III) oxide-associated lesions. Microscopic examination of the skin showed atrophy of the hair follicles and degenerative changes In the sebaceous glands. The most adequate study of thallium toxlclty was a 90-day gavage experi- ment In which groups of 20 male and 20 female Sprague-Oawley rats were treated with thallium (I) sulfate at 0, 0.01, 0.05 or 0.25 mg/kg/day (U.S. EPA, 19865; MRI, 1986). Parameters of toxlclty evaluated Included general observation, mortality, body and organ weights, food consumption, hematology 0083d -34- 01/20/88 ------- and clinical chemistry, neurotoxlcology, ophthamology, gross and hlstopatho- loglcal and neuropathologlcal examination. Effects possibly attributed to thallium (I) sulfate Included alopecia, lacrlmatlon and exophthalmos, although the Incidences and severity varied and did not clearly represent an adverse effect of treatment with thallium (I) sulfate. Some moderate and dose-related changes were observed In clinical chemistry parameters Includ- ing elevated SGOT, LOH and blood sodium concentrations, and other subtle changes In blood electrolyte concentrations were noted. The Investigators suggested that these changes reflected a "possible" compromise of cardiac and renal function, but that definitive Interpretation of the blood chemistry changes required completion of the hlstopathologlcal examination, which was not available for the Interim report of this experiment (U.S. EPA, 1986b). According to U.S. EPA (1987a) (presumably based on the final report after hlstopathologlcal examination), there were no effects on mortality, growth, organ weights, hlstopathologlcal .or neuropathologlcal morphology (HRI. 1986), and the highest dose, 0.25 mg thallium (I) sulfate/kg/day, was * ^ " . i ' judged to be a NOAEL. A recent drinking water study using rats Indicates that the testls may be an early sensitive target organ for the toxlclty of thallium salts. Form1gl1 et al. (1986) provided drinking water containing 0 or 10 ppm thallium from thallium (I) sulfate to groups of 10 mature male HI star rats for 30 or 60 days. Food and water consumption were monitored, and thallium Intake was estimated at 270 yg/rat/day. Using the starting average body weight of 365 g, the only body weight data provided by the Investigators, a dally dose of 740 ug/kg/day can be estimated. Treatment with thallium had no effect on food or water consumption or body weight gain. There was no •prominent" hair loss or clinical signs of neuropathy. Treatment for 30 0083d -35- 01/20/88 ------- days had no effect on biochemical parameters of the testls, apparently the only parameters evaluated In rats exposed for 30 days. Exposure for 60 days was associated with significantly decreased sperm motlllty, significantly Increased testlcular content of thallium, significantly decreased testlcular B-glucuronldase activity, the presence of Immature sperm cells In the tubular lumen, altered microscopic appearance of the tubular epithelium and altered ultrastructural appearance of the Sertoll cells. There were no effects on relative testlcular weights, diameter of the seminiferous tubules, plasma testosterone concentration or nonproteln thlol content of the testls. In an abstract from the Russian literature (Tlkhova, 1964, 1967). rabbits dosed orally with thallium (I) sulfate at 0.35 mg/kg/day or with thallium (I) carbonate at 0.25 mg/kg/day for 5-6 months exhibited behavioral changes (aggressiveness, retardation, rear 11mb paralysis) and altered blood protein profiles. Further data were not available. In a report on neurological effects at higher dosages, 80 female Sprague-Dawley rats Initially weighing 180-200 g were provided with drinking water containing 10 mg Tl/l from thallium sulfate for up to 36 weeks (Manzo et al., 1983b). A control group was maintained, but Us size and handling were not reported. Effects were reported after 40 and 240-280 days of treatment. The Investigators estimated dally Intake of thallium at 258.10 tig/rat at 40 days and 303.10 yg/rat at 240 days. Based on an Initial average body weight of 190 g, the 40-day dosage may be expressed as 1.36 mg/kg/day. Based on a reference body weight for rats of 350 g (U.S. EPA, 1985b), the dose at ,240 days may be expressed as 0.87 mg/kg/day. Hair loss appeared as early as 32 days and affected -20% of the rats within a few days. At termination, some rats were nearly hairless but some had no 0083d -36- 01/11/88 ------- evidence of hair loss. Cumulative mortality 1n treated rats was 15 and 21% after 40 and 240-280 days, respectively, but control data were not presented. Reduced motor action potential and sensory action potential were observed In the caudal nerves of treated rats compared with controls after 240 days, but not after 40 days. Hlstopathologlcal and ultrastructural examination of the sciatic nerves from six treated and three control rats after 240 days revealed WalleHan degeneration and other changes 1n the treated rats. Deshlmaru et al. (1977) administered thallium (I) acetate at 2 mg/rat/ day (5.7 mg/kg/day, assuming a reference body weight of 350 g) for 6 months and observed alopecia, but no neurological signs. Ultrastructural examina- tion revealed degenerative changes, however, 1n muscle tissue and 1n the cerebrum, thalamus and hypothalamus. 6.1.2.2. CHRONIC — Data were not located regarding the chronic oral toxlclty of thallium 1n animals. Human data are limited to a series of studies of health effects 1n persons living 1n the vicinity of a cement factory In West Germany that discharged thallium Into the atmosphere (Brockhaus et al., 1980, 1981; Dolgner et al.. 1983). Damage to plants and domestic animals 1n the vicinity of the factory was observed and attributed to exposure to thallium. Urine thallium concentrations of 1265 volunteers living In the contaminated region ranged from <0.1-76.5 yg/t (mean = 5.2 tig/l), compared with mean values In two control populations of 0.4 vg/l (31 persons, rural area) and 0.3 yg/l (10 persons, urban area). Concentrations In hair ranged from 0.6-565 ng/g (mean = 20.3 ng/g) In 1163 volunteers compared with a normal value of 10 ng/g. The Investigators determined that thallium Intake by exposed persons was due largely to Inges- tlon of fruits and vegetables grown near thallium emission sources, and was not due to 1ngest1on through drinking water or Inhalation of ambient air. 0083d -37- 01/11/88 ------- WUhln the subgroup of exposed persons who consumed substantial amounts of these fruits and vegetables, a positive correlation existed between proximity to the factory and thallium levels 1n urine and hair. Health effects, evaluated by questionnaire, were divided Into three broad cate- gories: alteration of skin, hair or nails (Including alopecia); effects on the oral cavity and gastrointestinal function; and neurological and subjec- tive symptoms. There was no association between urine or hair levels of thallium and effects In either of the first two categories. An effect on neurological and subjective symptoms was observed; however, the Incidence correlated positively with Increasing levels of thallium In hair or urine. This category Included visual disturbances, hyperesthesla of the lower extremities, tachycardia and extrasystoles, disturbed sleep and other Indications of polyneuropathy, psychasthenla and psychic alteration. 6.1.3. Other Relevant Information. Acute oral LO~Q values for various thallium salts In rats and mice expressed as mg Tl/kg bw are presented In Table 6-2. Stoklnger (1981) evaluated the acute toxldty of several salts of thallium administered orally and by various parenteral routes to five different species and observed that toxlclty appeared to be Independent of the anlon Involved, the species of animal and the route of administration. Death In rats from acute exposure to thallium has been attributed to respiratory failure (Hunch, 1928). Rats acutely poisoned with single high (20-50 mg/kg) IntraperHoneal doses exhibited marked weight loss, anorexia, diarrhea and lethargy (Herman and Bensch, 1967). Single Intraperltoneal doses of 50-200 mg/kg were associated with ultrastructural and biochemical changes 1n the liver consistent with Injury to the membranes of subcellular organelles In the hepatocytes (Moods and Fowler, 1986). Lower Intraperl- toneal doses (5-8 mg/kg/day) for up to 7 consecutive days resulted 1n 0083d -38- 01/20/88 ------- TABLE 6-2 Acute Oral 1059 Values for Thallium Salts Species Mouse Mouse Rat Mouse Mouse Mouse Mouse Mouse Rat Thallium Salt thallium (I) acetate thallium (I) acetate thallium (I) sulfate thallium (I) sulfate thallium (I) nitrate thallium (I) nitrate thallium (I) chloride thallium (I) carbonate thallium (III) oxide LD50 (mg Tl/kg) 27.6 35 16 29 15 33 24 21 22 Reference Jones et al., 1979 Sax, 1984 NIOSH, 1987a NIOSH, 1987a NIOSH, 1987b Sax. 1984 Sax. 1984 Sax. 1984 Sax. 1984 0083d -39- 01/11/88 ------- behavioral changes and ultrastructural and biochemical changes In the CNS (Brown et al.t 1985; Hasan et al., 1977). There are many reports of humans acutely poisoned with thallium com- pounds. It Is beyond the scope or purpose of this document to review them all. A brief overview of the subject taken largely from reviews 1s presented here. Acute toxlclty In humans has resulted from the accidental 1ngest1on of thallium salts used as rodentlddes or Insecticides, from use as a depilatory, both as an externally applied cream for cosmetic purposes and Internally as an aid In the treatment of ringworm of the scalp In children, and from cases of homicide and suicide (Gettler and Weiss, 1943; Moeschlln, 1980). The most commonly reported signs and symptoms of acute toxldty 1n humans Involve the central and peripheral nervous systems and Include paresthesla, particularly of the legs, other evidence of peripheral neuro- pathy such as ptosls and Impaired vision from retrobulbar neuritis, ataxla, tremors, delirium, hallucinations, convulsions and coma 1n severe cases, '..-•••• ;...•..•;. •-..•-,..-_...•. . -' . -, - • -.-..- culminating In death from respiratory failure (Stoklnger, 1981; Ginsberg and Nixon, 1932; Chamberlain et al., 1958; L1111e and Parker. 1932; Munch et al., 1933; Gettler and Weiss, 1943). Neurological signs were generally the first to appear when relatively low doses were Ingested, and usually occurred within 2-5 days (Stoklnger, 1981). When high doses were Ingested, gastrointestinal signs and symptoms of toxlclty Including gastroenteritis, diarrhea or constipation, vomiting and abdominal pain occurred within 12-14 hours (Stoklnger, 1981). Gastrointes- tinal symptoms were reported 1n a lesser number of cases Involving smaller doses (Chamberlain et al., 1958). Alopecia occurred as a fairly constant and often first symptom of toxlclty after prolonged exposure to lower doses (Gettler and Weiss, 1943; Moeschlln, 1980). 0083d -40- 01/20/88 ------- When used as a depilatory to treat ringworm In children, dally oral doses of 8 mg/kg/day (-6.2 mg Tl/kg/day) thallium acetate resulted In the beginning of hair loss In -12 days; depllatlon was complete In -3 weeks (Bedford, 1928). Toxic effects were observed In 3 of the 17 children treated, and Included loss of appetite and pain and swelling 1n the legs. Get.tier and Weiss (1943) estimated that 1.0 g of thallium (-14-15 mg/kg) represented the minimal lethal dose for an average adult, based on acute toxlclty data and organ concentrations of the metal In experimental dogs. MoeschUn (1980) estimated that the average lethal dose for thallium sulfate 1s 1 g or 10-15 mg/kg for an adult (-810 mg Tl, or -8-12 mg Tl/kg), although mortality occurred from a dose of thallium sulfate as low as 8 mg/kg/day (-6.5 mg Tl/kg). Thallium has been shown to Interact with potassium 1n biological systems (U.S. EPA, 1980b), probably because of similarities In the chemical behavior of Tlf and K* resulting from having nearly equivalent 1on1c radii (Hughes et al., 1976). Nulllns and Moore (1960) observed similarities In the Influx and efflux of thallium and potassium In frog muscle preparations. Hughes et al. (1976) reported that Tl* and K* had qualitatively similar effects when Injected Into In vitro rat heart preparations. Potassium has been shown to Increase renal excretion of thallium (Lund, 1956b; Gehrlng and Hammond, 1967), decrease the degenerative effects of thallium on eplphyseal cartilage 1n mouse limb bud cultures (Neubert and Bluth, 1985; Barrach and Neubert, 1985) (Section 6.4.), decrease placental transport of thallium (Sabblonl et al., 1982) and Increase the LD.- of thallium 1n animals (Gehrlng and Hammond, 1967). Equivocal results were obtained when potassium was applied as an antidote 1n cases of human poisoning (U.S. EPA, 1980b). 0083d -41- 01/20/88 ------- Other attempts at treating thallium toxldty have centered around drugs that accelerate elimination. Potent diuretics such as furosemlde and ethacrynlc acid enhanced the urinary excretion of thallium In rats (Lehmann and Favarl. 1985; Lameljer and van Zwleten, 1977a,b, 1978). These diuretics accelerated excretion of water and electrolytes such as Na1", K* and Cl~. No Increase In thallium excretion was observed with the diuretics K-canrenoate or trlamterene, which Increased water excretion without Increasing K* excretion (Lameljer and van Zwleten, 1979). Oral administration of activated charcoal and Prussian blue accelerated the elimination of orally administered thallium In rats (Lehman and Favarl, 1985; Lund, 1956b). These agents adsorb thallium In the gastrointestinal tract and are themselves unabsorbed, thus reducing gastrointestinal absorp- tion of thallium. Treatment with Prussian blue has been shown to reduce both maternal and fetal tissue levels In rats poisoned with thallium (D1 Nucd et al., 1979). In a study of the relative efficacy of several agents to accelerate the -.-'•'' . ..-•-•'. • • ..•,.-.*..- ;. •--'.. elimination of thallium In rats, dlthlzone was reportedly the most efficient (Lehmann and Favarl, 1985). In control rats treated orally with thallium (I) sulfate at 10 mg Tl/kg and studied for 8 days, fecal excretion accounted for 32% and urinary excretion for 21%, or total excretion of 53% of the dose. Treatment with dlthlzone Increased total excretion to 99% of the dose by the end of 8 days. Schwetz et al. (1967) demonstrated that both dlphenylthlocarbazone (dlthlzone) and dlethyldlthlocarbamate (dlthlocarb) enhanced excretion of thallium In rats, dlthlzone primarily by Increasing fecal excretion and dlthlocarb by Increasing both fecal and urinary excre- tion. Dlthlocarb, however, did Increase distribution of thallium to the brains of treated rats (Rauws et al., 1969; Kamerbeek et al., 1971), 0083d -42- 01/20/88 ------- probably because the chelate formed 1s UpophlUc and readily crosses the blood-brain barrier (Kamerbeek et al.t 1971). Stavlnoha et al. (1959) Investigated the ability of a number of sulfur- containing compounds to protect mice treated with thallium sulfate at 44.5 mg/kg, the ID-, for 1ntraper1toneal Injection. Greatest efficacy was obtained with S-B-am1noethy11soth1uron1um*Br*HBr and S-f-amlnopropyl- 1soth1uron1um*Br*HBr. The Investigators theorized that these compounds formed reversible bonds with the active sites of proteins, shielding them from attack by thallium. In other reports of Interactions, Hall (1972a) noted that cortisone acetate exacerbated and vitamin C alleviated the achondroplastlc effect of thallium on developing chick embryos (Section 6.4.). Levander and Argrett (1969) observed that thallium (I) acetate Inhibited the pulmonary excretion of volatile selenium compounds In rats Injected subcutaneously with sodium selenlte. Thallium (I) acetate provided no protection against chronic selenosls In rats. 6.2. CARCINOGENICITY 6.2.1. Inhalation. U.S. EPA (1979) described the protocol of an Inhala- tion carclnogenlclty and toxlclty study In groups of 90 male and 90 female Mlstar rats exposed to control air or thallium (III) oxide for 12 months, followed by a 4-month observation period. Exposure concentrations ranged from 0.5-2 mg/m3 and were administered 7 hours/day, 5 days/week. At the termination of the exposure period, the Incidences of rats with nodules or masses were 10 and 9 In control and exposed males, and 9 and 13 In control and exposed females. The hlstopathologlcal evaluation of these rats has not been performed and there are no Immediate plans to do so (Groth, 1987). 0083d -43- 01/20/88 ------- Human Inhalation data are limited. According to Marcus (1985) there was no Increase In the Incidence of benign neoplasms (not otherwise specified) In a group of 40 workers exposed to thallium 1n the manufacture of magnesium seawater batteries, compared with controls. Health status evaluation was limited tV> examination of current medical records, and was not adequate to detect an oncogenlc response to thallium. Schaller et al. (1980) reported on the health effects of 128 male workers exposed to thallium In three cement factories (see Section 6.1.1.2.), but the health evaluation used would not be expected to detect an oncogenlc response. 6.2.2. Oral. Pertinent data regarding the oncogenlcHy of thallium 1n experimental animals were not located. NTP (1987) has not scheduled thallium for toxlclty or cancer testing. The only human data available are a series of Investigations of thallium levels and health effects 1n persons living near a cement factory (Brockhaus et al., 1980, 1981; Dolgner et al., 1983) (see Section 6.1.2.2.). These studies were not designed to detect an oncogenlc response. 6.2.3. Other Relevant Information. Casto et al. (1979) demonstrated that 0.1 mM solutions of thallium (I) acetate and thallium (I) chloride signifi- cantly enhanced Simian SA7 viral transformation of hamster embryo cells 1n culture. Both thallium salts Increased the percentage of cells In the cultures that were transformed as well as the number of transformed foci In the affected cells. Solutions of thallium salts have been tested for their abilities to suppress tumor growth In experimental animals. Engman (1932) observed that 1ntraper1tonea1 Injection of an aqueous solution of thallium acetate 1n single or repeated doses had no effect on the growth of Flexner-Jobllng 0083d -44- 01/20/88 ------- tumors subcutaneously Implanted Into young albino rats. Total doses ranged from 12-44 mg/kg and often caused death from thallium toxlclty. More recently, Intraperltoneal Injection with thallium (III) chloride at 2-5 mg/kg Increased the median survival time and number of long-term survivors 1n rats carrying the ascltlc form of Walker 256 cardnosarcoma (Hart and Adamson, 1971). No effect was observed on the survival of mice carrying the asdtlc form of leukemia L1210. Intraperltoneal administration had no effect on the outcome of cancer 1n rats carrying the solid (subcutaneous) form of Walker 256 cardnosarcoma, nor did subcutaneous Injection affect the outcome 1n rats carrying the ascltlc form. Hart and Adamson (1971) suggested that Intraperltoneal administration resulted In concentrations of thallium too low at the subcutaneous tumor site to affect regression. 6.3. HUTAGENICITY Data regarding the genotoxlclty testing, of thallium (I) salts are presented In Table 6-3. Tl* was negative In reverse mutation tests In prokaryotes (Kanematsu et al.,. 1980) and the reverse mutation and mltotlc gene conversion tests In Saccharomyces cerevlslae (Singh, 1983). Tl* was positive In the rec assay (Kanematsu et al., 1980; Kada et al., 1980), but negative for effects on cell division 1n Escher1ch1a coll and S^ cerevlslae (Loveless et al., 1954). Positive results were reported for a number of tests 1n mammalian systems. Depressed DNA synthesis was observed In Chinese hamster ovary cell cultures (Garrett and Lewtas, 1983). Thallium (I) carbonate Induced mutation of vaccinia virus and single strand DNA breaks In rat and mouse embryo flbroblast cultures, and caused dominant lethal mutations In orally- treated male white rats (Zasukhlna et al., 1983). 0083d -45- 01/20/88 ------- TABLE 6-3 Genotoxtclty Testing of Thai HUM Salts o 00 G» O. o» i 88/lL/LO Assay Reverse •utatlon Reverse mutation Reverse mutation Nilotic gene conversion Rec assay Effects on cell division Effects on cell division Depressed DMA synthesis Vaccinia virus •utatlon Vaccinia virus •utatton Indicator Organise Salmonella typhlmurlua TA9B. TA100. TA1535. TA1537. TA1538 Escherlcnla coll B/r WP2 try and UP2 her try Saccharoayces cerevlslae. 07 Saccharoavces cerevlslae. D7 Bacillus subtllls H17 and N45 I- coll strain B S. cerevlslae Chinese hamster ovary cells vaccinia virus vaccinia virus Thallium Salt thalllu* (1) nitrate thalllu* (1) nitrate thai HIM (I) nitrate thalllui (1) nitrate thalllui (I) nitrate thai Hun (I) nitrate thall liui (1) nitrate thallium (I) acetate thalllu* (1) carbonate thallium (IJ carbonate Application Concentration or Dose spot test NR spot test NR plate 0.1 N Incubation. central well plate . 0.1 N Incubation, central well plate 0.001 H Incubation liquid medium 250 yg/mfc Incubation liquid medium NR Incubation cell culture 1000 tig/ml mouse embryo 10~« H flbroblast cell culture rat embryo 10'« N flbroblast cell culture Response Convent NC NC NC NC » Stronger response In N45 Concentration tested decreased cell growth No effect on cell growth » Cell viability was reduced and ATP and protein synthesis were reduced «• Greater response In C57B1/6 than In C8A strain cells » NC Reference Kanematsu et al., I960 Kanematsu et al.. 1980 Singh. 1983 Singh. 1983 Kanematsu et al.. 1980; Kada et al.. 1980 Loveless et al.. 1954 Loveless et al., 1954 Garrett and Lewtas. 1983 Zasukhlna et al.. 1983 Zasukhlna et al., 1963 ------- TABLE 6-3 icont.) o 8 Assay Q. Single strand DMA breaks Single strand DMA breaks Dominant lethal test Indicator Organise •ouse enbryo flbroblasts rat entry o flbroblasts •ale white rats Thai HUB Salt thai HIM (1) carbonate thai lira (I) carbonate thalltua (1) carbonate Application cell culture cell culture dally oral treatment for 8 aonths Concentration Response or Dose 10~» to 10'« N » 10"« to 10~« M » 5xlO~* to » 5xl(T« •g/kg/day Coonent Positive response In cells fro* C57B1/6. but not CBA strain •tee Magnitude of response was dose-related Magnitude of response was dose-related Reference Zasukhlna et al.. 1983 Zasukhlna et al.. 1983 Zasukhlna et al.. 1983 •C • No cooMent; MR • not reported ce CO ------- 6.4. TERAT06EMICITY A number of Investigations have demonstrated that thallium compounds Injected Into developing chicken eggs were associated with embryolethallty and the development of achondroplastlc dwarfs (Karnofsky et al.t 1950; Landauer, 1960; Ford et al.. 1968; Hall, 1972b; Skrovlna et al., 1973). These experiments and a more recent in vitro study with cultured chick tibiae (Hall, 1985) revealed that the chondrogenlc cells In the long bones underwent degeneration and necrosis when exposed to thallium. Recent experiments with whole embryo and organ cultures Indicated that chondrocytes 1n the long bones of mammals are also sensitive to thallium. Neubert and Bluth (1985) and Barrach and Neubert (1985) reported that thallium concentrations of 15 yM caused minimal effects and 50 yM caused clearly adverse effects on growth of the forellmb using 11-day-old 11mb buds from mice. Neubert and Bluth (1985) concluded that thallium concentrations >10-15 yM (2.0-3.1 yg/mi) 1n tissues of mammalian embryos may adversely affect fetal development, but that these levels are not likely to occur In environmentally exposed humans. In another study, thallium concen- trations of 3-100 yg/ml produced a dose-dependent retardation of growth In cultured whole rat embryos (Anschuetz et al., 1981). Hlstopathologlcal examination also revealed cytotoxlc effects 1n the CNS. Nogaml and Terashlma (1973) evaluated effects of thallium on the long bones of neonates and fetuses by hlstopathologlcal examination and by quantltatlng uptake of "SO. by mucopolysaccharldes as a measure of cartilage growth within the bone. When thallium (I) sulfate was adminis- tered by Intraperltoneal Injection to SO rats at 6 days of age (20 yg/kg) or at 9 days of age (40 yg/kg), the hlstopathologlcal appearance of 0083d -48- 01/11/88 ------- cartilage 1n the long bones Indicated retarded growth, and mucopolysac- charlde uptake of "SO. had decreased to 50% that of controls. Effects were less severe 1n fetuses and term offspring from rat dams treated with thallium (I) sulfate (doses and route of administration not reported). Hlstopathologlcal lesions were not observed 1n the cartilage of the long bones of the fetuses; however, cartilaginous uptake of "SO. was reduced 50% In term offspring from the treated rats. Gibson and Becker (1970) administered thallium (I) sulfate by IntrapeM- toneal Injection to groups of 4-7 mated Sprague-Dawley rats maintained on standard laboratory animal diets at doses of 0 or 2.5 mg/kg on days 8, 9 and 10 or on days 12, 13 and 14 of gestation. Additional groups were treated on days 12, 13 and 14 of gestation at 10.0 mg/kg. All treatments resulted In significantly reduced fetal body weights but did not significantly alter the frequency of fetal resorptlon from that observed 1n controls. An Increased Incidence of hydronephrosls and the absence of vertebral bodies In fetuses was also observed. Both defects were produced by administration of thallium sulfate during gestation; the effects were also produced during early gestation, although the Increase was not statistically significant In every treated group. The authors concluded that the failure of thallium sulfate to produce the severe teratogenlc effects In rats compared with chickens 1s the result of placental restriction of thallium transfer. The only oral developmental toxldty Information located was an abstract of a study 1n VMstar rats and NHRI mice. Roll and Hatthlaschk (1981) admin- istered thallium chloride or thallium acetate to rats and mice by gavage on days 6-15 of gestation. Gravlda were examined on gestation days 18 (mice) or 21 (rats), and some dams were allowed to deliver. Offspring were killed and examined at 21 days of age to evaluate the occurrence of late developing abnormalities. The only effects reported In mice were a slight Increase 1n 0083d -49- 03/08/88 ------- postlmplantatlon fetal loss at 6 mg thallium chlor1de/kg/day and a slight effect on birth weights at upper (unspecified) dose levels. Effects In rats were limited to slightly Increased postlmplantatlon loss at 3 mg/kg/day thallium acetate. Higher doses could not be tested because of acute maternal toxlclty. Malformations of the skeleton and Internal organs were not observed. Bornhausen and Hagen (1984) treated Wlstar rats with thallium sulfate by gavage on days 6-9 of gestation at doses of 0, 0.1, 0.5 or 2.0 mg Tl/kg to Investigate the effect of prenatal exposure to thallium on learning ability of the adult female offspring. The test was described as a conditioning program 1n which lever pressing was rewarded with a food pellet. Pre- natal ly-exposed offspring were apparently tested at 3 months of age. Prenatal exposure to thallium resulted In significant Impairment of learning at all doses. H1s.topatholog1cal examination of brain, liver and kidney revealed no lesions. Dolgner et .al. (1983) Investigated the Incidence of birth defects In children born between January 1, 1978 and August 31. 1979 to 297 mothers living in the vicinity of a cement factory that emitted large quantities of thallium Into the atmosphere. Data were obtained from questionnaires and urine samples. The study revealed that 19 children had possible congenital malformations; pedlatrlc and anemnestlc evaluation eliminated all but 5 from consideration. Based on the expected rate of birth defects 1n a population of 297 births (0.8), an observed:expected ratio of 6.25 was calculated. Generally, thallium levels In the urine of mothers of children with birth defects were near the lower limits of the general population, and the Inves- tigators concluded that exposure to thallium was not likely to have caused the malformations. 0083d -50- 03/08/88 ------- 6.5. OTHER REPRODUCTIVE EFFECTS Roll and Hatthlaschk (1981) reported a slight Increase 1n overall mortality up to weaning, and slightly decreased growth rate In offspring of mice treated by gavage with thallium chloride at 6 mg/kg/day for an unspecified period of time 1n breeding experiments. These effects were not observed with thallium chloride at 3 mg/kg/day. When similarly administered to rats, thallium chloride and thallium acetate at 3 mg/kg/day resulted 1n a slight Increase 1n overall mortality of the offspring. Since changes 1n testlcular biochemistry may precede other signs of toxic damage, for example hair loss and peripheral nervous system disorders (Manzo, et al., 1983b), Investigations were extended to selected testlcular enzyme (0-g1ucoron1dase) activities considered as Indicators of testlculae function 1n the rat. In a 30- to 60-day drinking water study using rats (Form1gl1 et al., 1986), rats treated with thallium [from thallium (I) sulfate] at 10 ppm thallium (270 yg/rat/day) for 60 days had significantly decreased sperm motnity, significantly Increased testlcular content of thallium, signifi- cantly decreased testlcular B-glucuron1dase activity, the presence of Immature sperm cells 1n the tubular lumen, altered microscopic appearance of the tubular epithelium and altered ultrastructural appearance of the Sertoll cells (see Section 6.1.2.1.). There were no effects on relative testlcular weights, diameter of the seminiferous tubules, plasma testosterone concen- tration or nonproteln thlol content of the testls. No abnormalities In testlcular morphology or biochemistry were seen 1n 30-day treated rats. In contrast, both the ubiquitous add phosphatase and sorbUol dehydrogenase, which are normally associated with postmelotlc spermatogenlc cells (Mills and Means, 1972) 'did not differ from controls. Degenerative changes In 0083d -51- 03/11/88 ------- Sertoll cells are associated with disarrangement of the seminiferous epithelium and premature release of 2 developing germ cells. In this study both the biochemical and morphological findings are consistent with thallium-Induced teslcular damage. 6.6. SUMMARY Thallium salts are potent poisons that cause acute toxldty 1n humans. Human poisoning has resulted from accidental 1ngest1on of thallium salts used as rodentlcldes and Insecticides, from Internal and topical use as a depilatory agent, and from cases of homicide and suicide (Gettler and Weiss, 1943; MoeschUn, 1980). Signs of toxldty 1n humans Include neurological and gastrointestinal effects. Death Is usually due to respiratory failure (Gettler and Weiss, 1943; Stoklnger, 1981). A threshold for acute toxldty In children appears to be ~6 mg Tl/kg/day (Bedford, 1928). An average lethal dose for adults 1s -8-12 mg Tl/kg (Hoeschlln, 1980). Acute oral LD50 values 1rt rats and mice range from 16-35 mg Tl/kg, apparently Independent of species or the Identity of the thallium salt. Chronic oral exposure of humans appears to Increase the Incidence of neurological and subjective symptoms, as observed In a population living In the vicinity of a cement factory that discharged large quantities of thallium Into the atmosphere (Brockhaus et al., 1980, 1981; Dolgner et al., 1983). Exposure was primarily through Ingestlon of thallium from fruits and vegetables grown near thallium emission sources. Subchronlc oral exposure of laboratory animals Is associated with hair loss, elevated kidney weights (Downs et al., 1960), neurological and skeletal muscle effects (Manzo et al.. 1983b; Deshlmaru et al., 1977), body weight loss and mortality (Downs et al., 1960). According to U.S. EPA (1986b) the highest dose (0.25 mg/kg/day) did not produce any effects on mortality, growth and target organ 0083d -52- 03/11/88 ------- toxlclty; therefore this dose (0.25 mg/kg/day thallium sulfate or 0.20 mg/kg/day thallium) was Identified as the NOAEL 1n the 90-day gavage study 1n rats. Inhalation animal toxldty data consist of a study 1n which rats were exposed Intermittently to thallium (III) oxide at 0.5-2 mg/m3 was associated with deteriorating health and Increased mortality (U.S. EPA, 1979). Adverse health effects were not reported 1n humans occupationally exposed to thallium 1n a magnesium seawater battery plant (Marcus, 1985) or In cement production (Schaller et a!., 1980; Ludolph et al., 1986). Thallium salts have not been tested for cardnogenlclty 1n animals, and the NTP (1987) has not scheduled 1t for cardnogenlclty testing. Cancer data 1n humans Is very limited. Mixed results have been observed In geno- toxldty testing. Negative results were obtained In reverse mutation tests (Kanematsu et al., 1980; Singh, 1983) and In tests for effects on cell division (Loveless et al., 1954). Positive results were obtained 1n a rec assay '(Kanematsu et al., 1980) and 1n several mammalian test systems. Including a dominant lethal test in male rats (Zasukhlna et al., 1983). Thallium results 1n achondroplastlc malformations when Injected Into developing chicken eggs (Karnofsky et al., 1950; Landauer, 1960; Ford et al., 1968; Hall, 1972b; Skrovlna et al., 1973) or tested In mammalian whole embryo cultures (Anschuetz et al., 1981) or 11mb bud cultures (Neubert and Bluth, 1985; Barrach and Neubert, 1985). Parenteral administration to pregnant rats at high doses (>2 mg Tl/kg/day) resulted 1n reduced fetal body weights, hydronephrosls and the absence of vertebral bodies (Gibson and Becker, 1970). Oral administration to rats (>2 mg Tl/kg/day) and mice (>4 mg Tl/kg/day) during organogenesls resulted only 1n a slight Increase 1n fetal loss In both species (Roll and Matthlaschk, 1981). Malformations of 0083d -53- 03/11/88 ------- the skeleton and Internal organs were not observed. In offspring of rats and mice allowed to deliver, reduced survival at weaning 1n both species and reduced growth rate 1n mice were observed. Adult offspring of dams treated with thallium during gestation had significant learning deficits In a lever-pressing behavior conditioning test (Bornhausen and Hagen, 1984). Recent studies Indicate that thallium may have an adverse effect on male reproduction. Adult male rats exposed to thallium In the drinking water at 0.74 mg/kg/day for 60 days had decreased sperm motHUy, Inhibition of 8-glucoron1dase activity and hlstopathologlcal alteration of the testes. These changes were not observed 1n animals sacrificed at the end of the 30-day thallium exposure. These findings therefore suggest that the male reproductive system Is a susceptible target site to toxic effects of thallium under chronic exposure. 0083d -54- 03/11/88 ------- 7. EXISTING GUIDELINES AND STANDARDS 7.1. HUNAN ACGIH (1987) adopted a TWA-TLV of 0.1 mg Tl/m3 for soluble compounds of thallium based predominantly on analogy to other toxic heavy metals, because data on thallium and Us salts were not sufficient for derivation of a TLV (ACGIH, 1986). No STEL was recommended. OSHA (1985) adopted 0.1 mg Tl/m3 as the occupational standard PEL for soluble compounds of thallium. U.S. EPA (1980b) recommended an ambient water quality criterion of 13 yg Tl/l for protection of human health, assuming consumption of 2 I water and 6.5 g of fish and shellfish/day. A concentration of 48 yg/l was calculated for consumption of edible aquatic products alone. These recommendations were based on an RfO of 37.3 yg Tl/day for a 70 kg man, calculated from the NOEL of 0.0005% (5 ppm) thallium (I) acetate (equivalent to 4 ppm Tl) 1n the subchronlc study by Downs et al. (1960), and a BCF of 119. Details of the derivation of this RfD are presented 1n Section 8.2.2.2. In an update of quality criteria for water, U.S. EPA (1987a) presented an RfD for thallium of 3.9xlO~4 mg/kg/day, which would be equivalent to 27.3 yg/day for a 70 kg human. Using an RfD of 27.3 yg/day, ambient water quality criteria of 9.8 yg/l for consumption of drinking water and aquatic products and 35 yg/l for consumption of aquatic products alone can be calculated. Verified oral RfDs for a number of thallium salts are listed 1n Table 7-1. The values listed 1n Table 7-1 were derived by analogy to thallium based on a NOEL of 0.39 mg Tl/kg/day 1n a 15-week study by Downs et al. (1960) In which rats were fed diets containing 0-500 ppm thallium acetate. A more recent oral RfD for thallium (I) sulfate of 0.25 yg/kg/day was derived and verified by the U.S. EPA (1987b) based on the 90-day gavage 0083d -55- 03/11/88 ------- TABLE 7-1 Oral RfDs for Thallium Salts Thallium Salt Thalllc oxide Thallium Thallium Thallium Thallium Thallium Thallium (I) (I) (I) (I) acetate carbonate chloride nitrate selenlte (I) sulfate Oral RfD (yg/kg/day) 0. 0. 0. 0. 0, 0. 0. 4 5 4 4 5 5' ' 5 U. U. U. U. U. U. U. Reference S. S. S. S. S. S. S. EPA, EPA, EPA, EPA, EPA, EPA. EPA, 1985c 1985d 1985e 1985f 1985g 1985a 1985h 0083d -56- 03/11/88 ------- study exposing rats to thallium (I) sulfate (MRI, 1986} 1n which the highest dose tested (0.25 mg/kg/day) was a NOAEL. Details of the derivations of these RfDs are discussed 1n Section 8.2.2.2. The U.S. EPA (1987c) listed thallium as a chemical requiring regulation under the Safe Drinking Mater Act amendments of 1986, but regulations are not currently available. 7.2. AQUATIC U.S. EPA (1986c) reported that data were Insufficient for derivation of ambient water quality criteria for protection of aquatic life. The follow- ing discussion was taken from that document: The available data for thallium Indicate that acute and chronic toxldty to freshwater aquatic life occurs at concentrations as low as 1400 and 40 yg/l, respectively, and would occur at lower concentrations among species that are more sensitive than those tested. Toxldty to one species of fish occurs at concentrations as low as 20 yg/t after 2600 hours of exposure. The available data for thallium Indicate that acute toxldty to saltwater aquatic life occurs at concentrations as low as 2130 vg/a and would occur at lower concentrations among species that are more sensitive than those tested. No data are available " concerning = the. chronic toxUHy of thaUtum -to...sensitive saltwater . aquatic life. 0083d -57- 03/11/88 ------- 8. RISK ASSESSMENT 8.1. CARCINOGENICITY 8.1.1. Inhalation. Inhalation cancer data In animals are limited to an unfinished study with thallium (III) oxide 1n which rats were exposed Inter- mittently for 12 months and the number of rats with masses and nodules was reported but hlstopathologlcal examinations were not performed (U.S. EPA, 1979). Human data consist of occupational studies of workers exposed to thallium 1n magnesium seawater battery manufacture (Marcus, 1985) and cement manufacture (Schaller et al.t 1980); these studies were Inadequately con- ducted to discern an oncogenlc effect. Marcus (1985) reported no Increased Incidence of benign neoplasms 1n workers 1n a magnesium seawater battery factory. 8.1.2. Oral. The oncogenlclty of thallium has not been tested In animals and NTP (1987) has not scheduled any thallium salts for testing. A series of health Investigations of persons living 1n proximity to a* cement factory that contaminated the area, with thallium (Brockhaus et al.. 1980, 1981; Dolgner et al., 1983) were not designed to detect an oncogenlc effect. In these studies 1t was determined that exposure was predominantly oral. resulting from Ingestlon of thallium-contaminated home-grown fruits and vegetables. 8.1.3. Other Routes. Pertinent data regarding the oncogenlclty of thallium administered by other routes were not located In the available literature cited 1n Appendix A. 8.1.4. Weight of Evidence. The studies reviewed 1n Sections 8.1.1. to 8.1.3 above constitute "no data" In both animals and humans that are useful for evaluating the overall weight of evidence for the carclnogenldty of 0083d -58- 03/11/88 ------- thallium 1n humans. Applying- the U.S. EPA (1986c) guidelines, thallium and Us salts are designated EPA Class D substances: unable to be classified as to human carclnogenlclty. 8.1.5. Quantitative Risk Estimates. The lack of adequate data precludes derivation of quantitative risk estimates for thallium salts for either Inhalation or oral exposure. 8.2. SYSTEMIC TOXICITY 8.2.1. Inhalation Exposure. 8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Pertinent data regarding the toxlclty of subchronlc Inhalation exposure were not located 1n the available literature cited 1n Appendix A, hence derivation of subchronlc Inhalation RfDs for thallium salts 1s precluded. 8.2.1.2. CHRONIC EXPOSURES — Animal data are limited to an unfin- ished study In which rats were exposed to thallium (III) oxide at levels of 0.5-2 mg/m3, 7 hours/day, 5 days/week for 12 months. Reported effects were limited to clinical signs, mortality, effects on body weight and necropsy observations of dead rats and rats subjected to Interim sacrifice. Hlstopathologlcal examination has not been performed. Human data are restricted to occupational Investigations of workers 1n a magnesium seawater battery manufacturing plant (Marcus, 1985) and 1n cement manufacture (Schaller et al., 1980; Ludolph et al., 1986) that associated no effects with exposure to thallium. Although Marcus (1985) concluded that the ACGIH (1987) TLV of 0.1 mg/m3 was adequately protective, exposures were not quantified and these data are Inadequate for estimation of Inhalation RfDs for thallium or Us salts. 0083d -59- 03/11/88 ------- 8.2.2. Oral Exposures. 8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Downs et al. (1960) fed weanling rats diets containing 0, 0.0005, 0.0015, 0.003 or 0.0050% thallium (I) acetate for 63 days to 15 weeks. The lowest dietary concentration tested, 0.0005X (5 ppm) was a NOEL; hair loss, depressed body weight gain, elevated kidney weights and mortality occurred at higher dietary concentrations. Downs et al. (I960) fed weanling rats diets containing thallium (III) oxide at 0, 0.002, 0.0035, 0.005, 0.01 or 0.05% for 15 weeks. Hair loss and elevated kidney weights were observed at all dietary levels. Increased mortality was reported at >0.0035%. The NOEL of 5 ppm dietary thallium (I) acetate 1s equivalent to 0.5 mg/kg/day, assuming weanling rats consume food equivalent to 10X of their body weight/day. The equivalent dose of thallium 1s 0.39 mg/kg/day. In a more recent study, rats were treated by gavage with thallium (I) sulfate at 0, 0.01, 0.05 or 0.25 mg/kg/day for 90 days In a comprehensive and well controlled subchronlc toxlctty test (U.S. EPA, 1986b; MRI. 1986). Effects possibly attributed to exposure to thallium Included alopecia, 1acr1mat1on, exophthalmos and some moderate changes In clinical chemistry parameters. There were no histopathologlcal alterations, however, and the highest dose. 0.25 mg/kg/day was considered a NOAEL (U.S. EPA, 1987a). A brief abstract from the Russian .literature reported behavioral changes 1n rabbits treated orally with thallium (I) carbonate at 0.25 mg/kg/day or with thallium (I) sulfate at 0.25 mg/kg/day for 5-6 months (Tlkhova, 1964, 1967). Because a full report of the conduct and results of this study were not available for evaluation, these data are not adequate for consideration 1n risk assessment. Neurophyslologlcal effects and degeneration of periph- eral nerves were reported In rats provided with drinking water containing 0083d -60- 03/11/88 ------- thallium sulfate at 10 mg Tl/l for °40 days (Manzo et al., 1983b). The dose of Tl was estimated at 0.87 mg/kg/day (see Section 6.1.2.1.). Degen- erative changes 1n skeletal muscle and different regions of the brain were reported 1n rats treated with thallium (I) acetate at 5.7 mg/kg/day for 6 months. Oral administration of thallium acetate at 3 mg/kg/day (2.3 mg Tl/kg/day) to rats during organogenesls resulted In slightly Increased post- Implantation loss and reduced survival of offspring at weaning (Roll and Matthlaschk, 1981). Rats treated with thallium (I) sulfate at 0.74 mg Tl/kg/day In drinking water for 60 days had reduced sperm motllUy and hlstopathologlcal alteration of the testes (Form1gl1 et al., 1986). Benchmarks of toxlclty available for consideration for derivation of a subchronlc RfD for oral exposure to thallium and Us salts Include the NOEL of 0.39 mg Tl/kg/day 1n the Downs et al. (1960) dietary experiment with thallium (I) acetate In rats and the NOAEL of 0.25 mg thallium (I) sulfate/ kg/day 1n the 90-day gavage experiment reported by U.S. EPA (1986b) and MRI (1986). Because tha>l1um (I)- sulfate contains 80.97% thallium (Wlndholz, 1983), this NOAEL corresponds to a dose of thallium of 0.20 mg/kg/day. The NOAEL of 0.20 mg Tl/kg/day Is chosen as the basis for subchronlc RfDs for thallium and Us salts, primarily because of the higher quality of the 90-day gavage study (U.S. EPA, 1986b; MRI, 1986); this study used larger numbers of rats/group than the Downs et al. (1960) study. Furthermore, 1n the Downs et al. (1960) study there was high mortality In all groups Includ- ing controls, rendering questionable the Interpretation of the results. The dose of 0.20 mg Tl/kg/day 1s substantially below doses associated with fetotoxlclty (Roll and Matthlaschk, 1981) and effects on male reproduction (Formlgll et al., 1986). 0083d -61- 03/11/88 ------- Application of an uncertainty factor of 100, 10 each for Inter- and Intraspecles variation, results In an RfD of 0.002 mg/kg/day, or 0.1 mg/day for a 70 kg human for subchronlc oral exposure to thallium 1n thallium salts. Subchronlc oral RfDs can be calculated for specific thallium salts, assuming their toxlclty depends entirely on the thallium moiety, by correct- Ing for the proportion of thallium 1n each salt. This approach 1s 1n keeping with an earlier Agency analysis, as explained In Section 8.2.2.2. Subchronlc oral RfDs for thallium and selected salts are presented In Table 8-1. Confidence 1n the critical study 1s rated medium because Interpreta- tion of the biological significance of some of the reported effects was unclear. Confidence In the data base and RfDs are also rated medium. 8.2.2.2. CHRONIC EXPOSURES — Chronic exposure data are limited to a series of Investigations of health effects 1n persons living In the vicinity of a cement factory that discharged thallium Into the atmosphere (Brockhaus et al., 1980, 1981; Dolgner .et al., 1983). An Increase In the Incidence of neurological and subjective symptoms was reported that correlated positively with distance from the factory. Exposure was shown to result from con- sumption of home-grown fruits and vegetables that were contaminated with thallium. Exposures were not quantified, however, and these data are Inadequate for use In risk assessment. U.S. EPA (1980b) derived an RfD for thallium based on the NOAEL of 5 ppm thallium (I) acetate, equivalent to 4 ppm thallium, 1n the subchronlc dietary study 1n weanling rats by Downs et al. (1960). U.S. EPA (1980b) assumed that the rats consumed 10 g of food/day, and estimated body weight at 0.075 kg to calculate an equivalent dose of 533 yg Tl/kg/day. Applica- tion of an uncertainty factor of 1000 and multiplication by the reference human body weight of 70 kg resulted In an RfD of 37.3 yg/day. In more 0083d -62- 03/11/88 ------- TABLE 8-1 Subchronlc Oral RfDs for Selected Thallium Salts3 Thallium Salt Thallium Thallium (III) oxide Thallium (I) acetate Thallium (I) carbonate Thallium (I) chloride Thallium (I) nitrate Thallium selenlde (TISe) Thallium (I) selenlde (Tl2Se)f Thallium (I) sulfate Thallium Content (*) 100 89.49b 77.59e 87.206 85.22e 76.72e 72.13& 83.816 80.976 Subchronlc (mg/kg/day) 0.002 0.002C 0.003C 0.002C 0.002C 0.003C 0.003C 0.002C 0.002C Oral RfD (mg/day) 0.1 0.2d 0.2d 0.2d 0.2d 0.2d 0.2d 0.2d 0.2d aSubchron1c oral RfDs were calculated for those thallium salts for which the Agency has calculated chronic oral RfOs. Calculated from molecular formula and atomic weights cCalculated by dividing the subchronlc oral RfD for thallium of 0.002 mg/kg/day by the fraction of the salt that Is thallium, and rounding to one significant figure. Calculated by dividing the subchronlc oral RfD for thallium of 0.002 mg/kg/day by the fraction of the salt that 1s thallium, multiplying the result by 70 kg and rounding to one significant figure. eW1ndholz, 1983 flt 1s likely that U.S. EPA (1985a) Intended to derive an oral RfD for this compound rather than for TISe (see Section 1.1.). 0083d -63- 03/11/88 ------- recent analyses the U.S. EPA (1985a,c,d,e,f,g,h) derived oral RfDs for a number of thallium salts (see Section 7.1.) from the NOEL of 5 ppm thallium (I) acetate In the Downs et al. (1960) study, by assuming that weanling rats consume food equivalent 1n amount to 10% of their body weight, resulting In a transformed dose of 0.5 mg/kg/day for thallium (I) acetate. Oral RfDs for the other thallium salts were calculated by correcting for differences 1n molecular weights and molarUy of thallium, 1f necessary. U.S. EPA (1987b) derived a new oral RfD for thallium (I) sulfate of 0.25 vg/kg/day or 17.5 yg/day (verified by the Agency-wide RfD Work Group on 07/16/87) for a 70 kg human by applying an uncertainty factor of 1000 to the NOAEL'of 0.25 mg/kg/day In the 90-day gavage study by U.S. EPA (1986b) and MRI (1986). As discussed 1n Section 8.2.2.1., this gavage study Is a more sound basis for risk assessment than the dietary study by Downs et al. (1960). Therefore, new oral RfDs for thallium salts are calculated from the NOAEL of 0.25 nig thallium (I) sulfate/kg/day, equivalent'to 0.20 mg Tl/kg/ day. Application.of an uncertainty factor of 1000, 10 for estimation of a chronic NOAEL from a subchronlc NOAEL, and 10 each for Inter- and 1ntra- specles variation, results In an oral RfD for thallium of 0.2 yg/kg/day or 14 yg/day for a 70 kg human. Oral RfDs for selected thallium salts are calculated In Table 8-2. Confidence levels In the critical study, data base and RfDs are all rated medium, as discussed 1n Section 8.2.2.1. 0083d -64- 03/11/88 ------- TABLE 8-2 Chronic Oral RfDs for Selected Thallium Salts3 Thallium Salt Thallium Thallium (III) oxide Thallium (I) acetate Thallium (I) carbonate Thallium (I) chloride Thallium (I) nitrate Thallium selenlde (TISe) Thallium (I) selenlde (Tl2Se)f Thallium (I) sulfate Thallium Content (%) 100 89.49b 77.59e 87.20s 85.22e 76.72e 72.13b 83.816 80.97 Subchronlc (yg/kg/day) 0.2 0.2C 0.3C 0.2C 0.2C 0.3C 0.3C 0.2° 0.3« Oral RfD (mg/day) 0.01 0.02d 0.02d 0.02d 0.02d 0.02d 0.02d 0.02d 0.029 .aQral RfDs were .calculated, for those thallium, salts for which the Agency had previously'calculated oral RfOs. ^Calculated from molecular formula and atomic weights cCalculated by dividing the oral RfO for thallium of 0.2 yg/kg/day by the fraction of the salt that 1s thallium and rounding to one significant figure. Calculated by dividing the oral RfD for thallium of 0.2 yg/kg/day by the fraction of the salt that 1s thallium, multiplying the result by 70 kg and rounding to one significant figure. eW1ndholz, 1983 flt 1s likely that U.S. EPA (1985a) Intended to derive an oral RfD for this compound rather than for TISe (see Section 1.1). QCalculated by rounding the U.S. EPA (1987a) estimate to one significant figure. 0083d -65- 03/11/88 ------- 9. REPORTABLE QUANTITIES 9.1. BASED ON SYSTEMIC TOXICITY Data relevant to the derivation of an RQ based on the systemic toxlclty of thallium salts Include an uncompleted subchronlc Inhalation toxldty study and a number of subchronlc oral studies (see Chapter 6). Pertinent data from these studies are summarized 1n Table 9-1. Although the effects reported by U.S. EPA (1979), Downs et al. (1960), and U.S. EPA (1986b) and MRI (1986) were observed In both male and female rats, the smaller body weights of the females resulted In the lower equivalent human doses, and therefore only data for the females are tabulated. All doses were expressed In terms of mg Tl/kg/day, because thallium 1s the toxic moiety In the thallium salts and toxic potency appears to be Independent of the salt selected (see Section 8.2.2.). Except for the developmental toxlclty study, an uncertainty factor of 10 was applied to estimate a chronic effect level from a subchronlc effect level. Effects attributed to subchrontc exposure to thallium Include mortality after 5 months of exposure In an Inhalation study (U.S. EPA, 1979), de- creased rate of body weight gain (Downs et al., 1960). alopecia, lacrlma- tlon, exophthalmos and biochemical changes (U.S. EPA, 1986b; MRI, 1986), Increased fetal loss (Roll and Matthlaschk, 1981) and hlstopathologlcal alteration of the testes (Form1gl1 et al., 1986). Downs et al. (1960) also reported mortality In their dietary studies, but Interpretation of the data and Identification of the MED was precluded by high mortality 1n the control or low dose groups. Mortality also appeared to be high In the drinking water study by Manzo et al. (1983b), but control data were not reported. CSs for these effects are calculated 1n Table 9-2. 0083d -66- 03/11/88 ------- TABLE 9-1 Systenlc Toxic I ty Suouary for Thai HUM Salts § CD g Route Thalllua Salt Inhalation thalllua (III) oxide Oral thalllua (1) acetate Oral thalllua (III) oxide e» Oral thalllua (I) •J-* sulfate Oral thalllua (I) sulfate Oral thalllua (I) acetate Species/ Strain rat/Ulstar rat/Ulstar rat/Ulstar rat/Sprague- Oawley rat/Sprague- Dawley rat/Ulstar Average Nuaber at Body Start/Sex Uelght (kg) 90/F 0.35 S/F 0.15* 5/N 0.20* 20/F 0.22b 80/F 0.350J NR/F 0.3501 ; Vehicle or Physical State/Purity dust/<15 ppa lapurltles dlet/>90X d1et/>90X water/>99X drinking water/NR • NR/NR Exposure 1 ag/a» for 5 weeks. 2 ag/a* for 13 weeks (TWU1.7 ag/a») 7 hours/day, 5 days/week 0.0015X diet (IS ppa) for 15 weeks 0.002X diet (20 ppa) for 15 weeks 0.01 og Tl2$04/ kg/day for 90 days 10 ag Tl/l (10 ppa Tl) for up to 36 weeks 3 ag/kg/day by gavage on days 6-15 of gestatlo Trans foraed Anlaal Dose (ag Tl/kg/day) 0.020c«d 0.058d.'.fl 0.089d«M 0.0008d-' 0.087d>k 2.39 n Equivalent Hunan Dosea Response (ag Tl/kg/day) 0.003 Mortality 0.007 Alopecia ele- vated kidney weight 0.013 Decreased rate of body weight gain 0.0001 Alopecia. exophthalaos. lacrlaatlon. at Id blocheal- cal changes 0.015 Neurophyslo- logtcal and neuropatho- loglcal changes 0.39 Increased fetal loss Reference U.S. EPA. 1979 Downs et al.. 1960 Downs et al.. 1960 U.S. EPA. 1986b; NR1. 1986 Hanzo et al.. 19835 Roll and Natthlaschk. .1981 00 oo ------- TABLE 9-1 (cont.) Average Vehicle or Transformed Route Thai ltu« Salt Species/ Nwber at Body Physical Exposure Animal Dose Strain Start/Sex Weight State/Purity (ng T1/kg/day) (kg) : Oral thai Hum (I) rat/ 10/N 0.365^ drinking 10 ppm Tl for 0.074d»k sulfate Ulstar water/NR up to 60 days "• Equivalent Human Dosea Response (mg Tl/kg/day) 0.013 Hlstopatho- loglcal alteration of testes Reference Formlgll et al.. 1986 . 'Calculated by multiplying the transformed animal dose by the cube root of the ratio of the animal body weight to the human reference body weight (70 kg). ^Estimated from tabular data provided by Investigators. • Calculated by multiplying 1.7 mg/m* by 7 hours/24 hours and 5 days/7 days to expand to continuous exposure, and by 0.223 m*/day respiratory rate for 0.35 kg rats (U.S. EPA. 19856). and by 1/0.35 kg and by O.B949. the fraction of Tl In T1203. to express the result In terms of mg Tl/kg/day. dAn uncertainty factor of 10 was applied to estimate a chronic effect level from a subchrontc effect level. 'Estimated from graphic data provided by Investigators. 'Reference food factor for rats of 0.05 (U.S. EPA. 1985b). {(Factor of 0.1759 (the fraction of Tl In T^H^) was applied to express, the dosage as mg Tl/kg/day. "Factor of 0.8949 (the fraction of Tl In TlpOa) was applied to express the dosage as mg Tl/kg/day. 'Factor of 0.8097 (the fraction of Tl In T12504) was applied to express the dosage as mg Tl/kg/day. ^Reference rat body weight (U.S. EPA. 1985b) kSee estimation of dosage In Section 6.1.2.1. 'Body weight estimate provided by Investigators. ------- TASli 9-2 Compos lie Scores for Thai1 tun Using the Rata Chronic Route Animal Dose Human NED' RVd ' Effect RVe (mg Tl/kg/day) (mg Tl/kg) Inhalation 0.020 0.21 6.5 Mortality 10 Oral O.OS8 0.49 6.0 .Alopecia, elevated 4 kidney weight Oral 0.089 0.91 5.6 Decreased rate of body 4 weight gain Oral 0.0008 0.007 8.7 Alopecia, exophthalmos. 3 lacrlmat ton.' minor bio- chemical zchanges i * Oral 0.087 1.05 5.5 tfeurophystologlcal and 7 neuropathologlcal change Oral 2.3 27.3 3.3 Increased fetal loss 8 Oral 0.074 0.91 5.6 Hlstopathologlcal alter- 7 atton of testls CSC RQ Reference 65 10 U.S. EPA. 1979 24 100 Downs et al.. 1960 22.4 100 Downs et al.. 1960 26.1 100 U.S. EPA. 1986b; HRI. 1986 38.5 100 Nanzo et al.. 19835 26.4 100 Roll and Hatthlaschk. 1981 39.2 100 formtgll et al.. 1986 'Individual salts of thallium are not listed because It Is assumed that toxlclty Is due to the thallium moiety Calculated by multiplying the equivalent human dose (ag Tl/kg/day) by 70 kg to express the MED In term of ag/day for a 70 kg human 'Calculated as the product of RVd and RVe ------- CSs for all effects ranged from 22.4-39.2, which correspond to an RQ of 100, with the exception of a CS of 65 and an RQ of 10 for mortality 1n sub- chronic Inhalation exposure (U.S. EPA, 1979). The larger CS and smaller RQ associated with Inhalation exposure may reflect greater toxlclty of thallium by this route. The CS of 65 and the RQ of 10 are selected as most appro- priately representing the toxlclty of thallium In thallium salts and are presented In Table 9-3. CSs for several salts of thallium can be calculated from the data In Table 9-3 by correcting for molecular weight differences (I.e., by dividing the MED by the decimal fraction of thallium In each of the salts, recalcu- lating the RV. and multiplying the new RV. by the RV of 10 to calcu- late a new CS). These data are presented 1n Tables 9-4 through 9-9. In a series of earlier analyses the Agency derived RQs for several salts of thallium. An RQ of 100 was derived for thallium (III) oxide based on the dietary study by Downs et al. (1960) with that compound (U.S. EPA, 1983a). An RQ of 100 was derived for thallium and compounds (U.S. EPA. 1983b) and for 'thallium '(I) acetate (U.S. EPA, 1983c) based on the Downs et al. (1960) study with thallium (I) acetate. An RQ of 100 was also derived for thallium (I) carbonate (U.S. EPA, 1983d), thallium (I) chloride (U.S. EPA, 1983e), thallium (I) nitrate (U.S. EPA, 1983f) and thallium (I) sulfate (U.S. EPA. 1983g) by analogy to thallium (I) acetate. The only toxlclty data available 1n these earlier analyses were the dietary studies by Downs et al. (I960). The present analysis 1s larger 1n scope and Includes data that suggest greater toxic potency by Inhalation compared with oral exposure. Therefore, an RQ of 10 Is currently recommended for thallium and for the Individual salts of thallium Included 1n Tables 9-4 through 9-9. 0083d -70- 03/11/88 ------- TABLE 9-3 Thallium (and Salts) Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dose*:"^ 0.21 mg Tl/day Effect: mortality Reference: U.S. EPA, 1979 RVd: 6.5 RVe: 10 Composite Score: 65 RQ: 10 'Equivalent human dose 0083d -71- 03/11/88 ------- TABLE 9-4 Thallium (III) oxide Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dose*: 0.23 rug/day Effect: mortality Reference: U.S. EPA, 1979 RVd: 6.5 RVe: 10 Composite Score: 65 RQ: 10 ^Equivalent human dose 0083d -72- 03/11/88 ------- TABLE 9-5 Thallium (I) acetate Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dose3: 0.27 mg/dayb Effect: mortality Reference: U.S. EPA, 1979 RV(j: . 6.4 RVe: 10 Composite Score: 64 RQ: 10 Equivalent human dose bBy analogy to thallium (III) oxide with which the experiment was performed. 0083d -73- 03/11/88 ------- TABLE 9-6 Thallium (I) carbonate Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dose3: 0.24 mg/dayb Effect: mortality Reference: U.S. EPA, 1979 RVd: 6.4 RVe: 10 Composite Score: 64 RQ: 10 Equivalent human dose bBy analogy to thallium (III) oxide with which the experiment was performed. 0083d -74- 03/11/88 ------- TABLE 9-7 Thallium (I) chloride Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dosea: 0.25 mg/dayb Effect: mortality Reference: U.S. EPA, 1979 RVd: 6.4 RVe: 10 Composite Score: 64 RQ: 10 Equivalent human dose bBy analogy to thallium (III) oxide with which the experiment was performed. 0083d -75- 03/11/88 ------- TABLE 9-8 Thallium (I) nitrate Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dosea: 0.27 mg/dayb Effect: mortality Reference: U.S. EPA, 1979 RVd: • 6.4 RVe: 10 Composite Score: 64 RQ: 10 Equivalent human dose bBy analogy to thallium (III) oxide with which the experiment was performed. 0083d -76- 03/11/88 ------- TABLE 9-9 Thallium (I) sulfate Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Inhalation Dosea: 0.26 mg/dayb Effect: mortality Reference: U.S. EPA. 1979 RVd: 6.4 RVe: .10 Composite Score: 64 RQ: 10 Equivalent human dose bBy analogy to thallium (III) oxide with which the experiment was performed. 0083d -77- 03/11/88 ------- U.S. EPA (1983h) did not derive an RQ for thallium (I) selenlde by analogy, because both the thallium and selenium moieties are toxic and because deriving an RQ by analogy does not account for the additive or potentiating effects of toxic substltuents. In agreement with this analy- sis, data are considered Insufficient for derivation of an RQ for thallium (I) selenlde (Table 9-10). 9.2. BASED ON CARCINOGENICITY As discussed 1n Section 6.2., cardnogenlclty data for thallium consist of an unfinished Inhalation study and a few human health effects studies that are Inadequate for Identifying a carcinogenic response to thallium. NTP (1987) has not scheduled any thallium compounds for cardnogenlclty testing. Because of the lack of animal or human data, thallium and Us salts are classified In EPA Group D and hazard ranking based on cardno- genlclty Is not possible. 0083d -78- 03/11/88 ------- TABLE 9-10 Thallium (I) selenlde (Tl2Se) Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Dose: Effect: Reference: RVd: RVe: Composite Score: RQ: Data are not sufficient for deriving an RQ 0083d -79- 03/11/88 ------- 10. REFERENCES ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. p. 569. ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1987. Documentation of the Threshold Limit Values and Biological Exposure Indices for 1987-1988. Cincinnati, OH. p. 34. Achenbach, C., 0. Hauswlrth, C. He1ndr1chs, et al. 1980. Quantitative measurement of time-dependent thallium distribution In organs of mice by field desorptlon mass spectrometry. J. Toxlcol. Environ. Health. 6(3): 519-528. Aldrlch. 1986. Catalog Handbook of Fine Chemicals. Aldrlch Chemical Co., Inc., Milwaukee. HI. p. 1256-1257. Andre, T., S. Yllberg and G. Wlnqvlst. 1960. The accumulation of thallium In tissues of the mouse. Acta Pharmacol. Toxlcol. 16(3): 229-234. Anschuetz, H., R. Herken and D. Neubert. 1981. Studies on embryotoxlc effects of thallium using the whole-embryo culture technique. Iri: 5th Symp. Prenatal Oev., Cult. Tech. p. 57-66. (CA 097:209842Y) AQUIRE (Aquatic Information Retrieval System). 1987a. On-line: Oct. 16. 1987a. CAS Registry No. 13453-32-2. Chemical Information Systems, Baltimore, NO. 0083d -80- 03/11/88 ------- AQUIRE (Aquatic Information Retrieval System). 1987b. On-line: Oct. 16, 1987. CAS Registry No. 7446-18-6. Chemical Information Systems, Baltimore, MO. AQUIRE (Aquatic Information Retrieval System). 1987c. On-line: Oct. 16. 1987. CAS Registry No. 7791-12-0. Chemical Information Systems, Baltimore, MO. Barclay, R.K., H.C. Peacock and D.A. Karnorsky. 1953. Distribution and excretion of radioactive thallium In the chick embryo, rat and man. 0. Pharmacol. Exp. Ther. 107: 178-187. Barrach, H. and 0. Neubert. 1985. The moderating Influence of potassium on the thallium effect 1n tissue differentiation |ri vitro. Teratology. 31(3): 42A. Barrows, M.E., S.R. PetrocelH, K.J. Hacek and J.J. Carroll. 1980. Bio- concentration and elimination of selected water pollutants by blue gill sunflsh (Lepomls macrochlrus). IJK Symp. Dyn. Exposure Hazard Assess. Toxic Chem., 1978. Ann Arbor Science, Ann Arbor, MI. p. 379-392. Bedford, G.V. 1928. Oep1lat1on with thallium acetate In the treatment of ringworm of the scalp 1n children. Can. Med. Assoc. J. 19: 660-662. (Taken from NIOSH Abstr. 00131135) Blrge, M.J. 1978. Aquatic toxicology of trace elements of coal and fly ash. In: Energy and Environmental Stress on Aquatic Systems, J.H. Thorp and J.W. Gibbons, Ed. DOE Symp. Ser. 48: 219-240. 0083d -81- 03/11/88 ------- Bornhausen, M. and U. Hagen. 1984. Operant behavior performance changes 1n rats after prenatal and postnatal exposure to heavy metals. IRCS Ned Sc1. 12: 805-806. Bradley-Moore, P.R., E. Lebowltz, J.W. Greene, H.L. Atkins and A.M. Ansarl. 1975. Thalllum-201 for medical use. II: Biologic behavior. J. Nucl. Hed. 16(2): 156-160. Brlngmann, G. and R. Kuehn. 1977. The toxldty of waterborn contaminants towards Daphnla magna. Z. Nasser Abwasser Forsch. 10(5): 161-166. (In German with English abstract) Brlngmann, G. and R. Kuehn. 1982. Results of toxic action of water pollu- tants on Daphnla magna Straus tested by an Improved standardized procedure. Z. Manser Abwasser Forsch. 15(1); 1-16. (In German with English transla- tion). . • . ... Brockhaus, A., R. Dolgner. U. Ewers, et al. 1980. Excessive thallium absorption among a population living near a thallium emitting cement plant. in: Mechanisms of Toxlclty and Hazard Evaluation, B. Holmstedt, R. Lauwerys, M. Herder and M. Roberfrold, Ed. Elsevler/North-Holland B1omed1cal Press, The Netherlands, p. 565-568. Brockhaus, A., R. Dolgner, U. Ewers. U. Kramer, H. Soddemann and H. Ulegand. 1981. Intake and health effects of thallium among a population living In the vicinity of a cement plant emitting thallium containing dust. Int. Arch Occup. Environ. Health. 48: 375-389. 0083d -82- 03/11/88 ------- Brown, B.T. and B.M. Rattlgan. 1979. ToxIcUy of soluble copper and other metal Ions to Elodea canadensls. Environ. Pollut. 20(4): 303-314. Brown, O.R., B.G. Callahan, M.A. Cleaves and R.A. Schatz. 1985. Thallium Induced changes In behavioral patterns: Correlation with altered Upld peroxldatlon and lysosomal enzyme activity 1n brain regions of male rats. Toxlcol. Ind. Health. 1(1): 81-98. (Taken from NIOSH 00157670) Buccafusco, R.J., S.J. Ells and G.A. LeBlanc. 1981. Acute toxlclty of priority pollutants to blueglll (Lepomls macrochlrus). Bull. Environ. Contam. Toxlcol. 26(4): 446-452. Canterford, G.S. and O.R. Canterford. 1980. Toxlclty of heavy metals to the marine diatom Dltylum brlghtwelU (West) grunow: Correlation between toxlclty and metal spedatlon. J. Mar. B1ol. Assoc. U.K. 60(1): 227-242. .(Cited- In AQUIRE, 1987c) . . . CAS (Chemical Abstract Service). 1983. Chemical Substance Index. 99:6679CS; 131769z; 97346x. Casto, B.C., J. Neyera and J.A. Olpaolo. 1979. Enhancement of viral trans- formation for evaluation of the carcinogenic or mutagenlc potential of Inorganic metal salts. Cancer Res. 39: 193-198. Cataldo, 0. and R. Ulldung. 1983. The role of soil and plant metabolic processes In controlling trace element behavior and bloavallabllUy to animals. Sd. Total Environ. 28: 159-168. 0083d -83- 03/11/88 ------- Chamberlain, P.H.. H.B. Stavlnoha, H. Davis, W.T. Knlket and T.C. Panos. 1958. Thallium poisoning. Pediatrics. 1958: 1170-1182. Cotton, F.A. and G. Wilkinson. 1980. Advanced Inorganic Chemistry. A Comprehensive Text, 4th ed. John Wiley and Sons, New York. p. 329-333, 348-351. Craig, G.R. and G.L. Beggs. 1979. Evaluation of fish loading rates In regulatory static bloassays. Tech. Rep. - Fish. Mar. Serv. (Can). 862: 146-160. (Cited In AQUIRE, 1987b) Dawson, G.W., A.L. Jennings, D. Orozdowskl and E. Rider. 1977. The acute toxldty of 47 Industrial chemicals to fresh and saltwater fishes. J. Hazard. Mater. 1(4): 303-318. DeJong, L.E. 1965. Tolerance of Chlorella vulqaMs for metallic and non- metallic Ions. J. Nlcroblol. Serol. 31: 301-313. (Cited 1n AQUIRE. 1987b) Deshlmaru, M., T. Mlyakawa, S. Sumlyoshl, F. Yasuoka and K. Kawano. 1977. Electron microscopic study of experimental thallotoxlcosls. Folia Psych. Neurol. Jpn. 31: 269-275. 01 Nucd, A., B. Ferr1n1, C. Gregottl, P. R1chelm1 and I. Manzo. 1979. Placenta! transfer of thallium and Its modification by Prussian blue. IRCS Med. Scl. Llbr. Compend. 7: 272. (CA 91:50749) 0083d -84- 03/11/88 ------- Dolgner, R., A. Brockhaus, U. Ewers, H. VMegand, F. Majewskl and H. Soddeman. 1983. Repeated surveillance of exposure to thallium 1n a population living 1n the vicinity of a cement plant emitting dust containing thallium. Int Arch. Occup. Environ. Health. 52: 79-94. Downs, VI.L., O.K. Scott, L.T. Steadman and E.A. Haynard. 1960. Acute and subacute toxldty studies of thallium compounds. Am. Ind. Hyg. Assoc. 21: 399-406. Ducket, S., D. Miller and S.K. Ballas. 1983. Quantltatlon and localization of 204-thall1um 1n the central and peripheral nervous system of adult and young rats. Neurotoxlcology. 4(2): 227-234. Emara, M. and N.A. Sollman. 1950. The distribution of Ingested thallium In the tissues of animals. J. Egyt. Hed. Assoc. 33:1-15. (Taken from NIOSH Abstr. 00131656) . Engman, M.F., Jr. 1932. A study of the effect of thallium acetate upon the growth of the Flexner-JobUng tumor In albino rats. Am. J. Cancer. 16: 847-853. Ford, O.K., E.J. Eyrlng and C.E. Anderson. 1968. Thallium chondrodystrophy In chick embryos. J. Bone Joint Surg. 50A: 687-700. Formlgll, L., R. Scelsl, P. Poggl et al. 1986. Thallium-Induced testlcular toxldty 1n the rat. Environ. Res. 40: 531-539. 0083d -85- 03/11/88 ------- Garrett, N.E. and J. Lewtas. 1983. Cellular toxlclty 1n Chinese Hamster ovary cell cultures. I. Analysis of cytotoxldty endpolnts for twenty-nine priority pollutants. Environ. Res. 32: 455-465. Gehrlng, P.O. and P.B. Hammond. 1967. The Interrelationship between thallium and potassium In animals. J. Pharmacol. Exp. Ther. 155: 187. (Cited In U.S. EPA. 1980b) Gettler, A.O. and L. Weiss. 1943. Thallium poisoning. III. Clinical toxicology of thallium. Am. 0. CUn. Pathol. 13: 422-429. Gibson, 3.E. and B.A. Becker. 1970. Placental transfer, embryotoxIcHy and teratogenldty of thallium sulfate In normal and potassium-deficient rats. Toxlcol. Appl. Pharmacol. 16: 120-132. G.1bsonr J;E., C.P.. Slides tad and B.A. Becker. 1967. Placental transport and distribution of thal11um-204 sulfate 1n newborn rats and mice. Toxlcol. Appl. Pharmacol. 10: 408. Glnsburg, H.M. and C.E. Nixon. 1932. Thallium poisoning. A preliminary report of eleven cases at the General Hospital of Fresno County, California. J. Am. Med. Assoc. 98: 1076-1077. Gregus, Z. and C.O. Klaassen. 1986. Disposition of metals In rats: A comparative study of fecal, urinary and biliary excretion and tissue distri- bution of eighteen metals. Toxlcol. Appl. Pharmacol. 85: 24-38. 0083d -86- 03/11/88 ------- Groth, D.H. 1987. Personal communication. Telephone conversation with P.F. Goetchlus. Syracuse Research Corporation, Syracuse, NY. 11/9/87. Hall, B.K. 1972a. Achondroplasla In the embryonic chick: Its potentlatlon by cortisone acetate and alleviation by vitamin C. Can. J. Zool. 50: 1527-1536. (CA 78:67828e) Hall, B.K. 1972b. Thallium Induced achondroplasla 1n the embryonic chick. Devel. B1ol. 28(1): 47-60. .. Hall, B.K. 1985. Critical periods during development as assessed by thallium-Induced Inhibition of growth of embryonic chick tibiae jjn vitro. Teratology. 31: 353-361. Hart, M.M. and R.H. Adamson. 1971. Ant Humor activity and toxldty of salts of Inorganic group 3a metals: Aluminum, gallium. Indium, and thallium. Proc. Natl. Acad. Scl. 68: 1623-1626. Hasan, N., V.K. Bajpal and A.C. Shlpstone. 1977. Electron microscope study of thallium Induced alterations la the ollgldendrocytes of the rat area postrema. Exp. Pathol. 13(6): 338-345. (Taken from TOXIBIB Abstr. 78:043460) Hauser, T.R. and S.H. Bromberg. 1982. EPA's monitoring program at Love Canal 1980. Environ. Monlt. Assess. 2: 249-272. 0083d -87- 03/11/88 ------- HeH, M. and C.S. Klusek. 1985. Trace element concentrations In the dorsal muscle of white suckers and brown bullheads from two acidic Adirondack lakes. Hater A1r Soil Pollut. 25: 87-96. Herman, M.M. and K.G. Bensch. 1967. Light and electron microscopic studies of acute and chronic thallium Intoxication 1n rats. Toxlcol. Appl. Pharmacol. 10(2): 199-222. HSDB (Hazardous Substances Data Bank). 1987. On-Hne: Oct. 16, 1987. CAS Nos. 563-68-8, 12039-52-06533-73-9, 7791-12-0, 10102-45-1, 1314-32-5, 6533-73-9. Hughes, M.N.. M.K. Man and B.C. Whaler. 1976. The effect of thallium on skeletal and cardiac muscle. 3. Physlol. 256(2): 126P-127P. % * Hu1, B;C. .1983.. Thallium and .thallium compounds. Irt: K1rk-0thmer Encyclo- pedia of Chemical Technology. Vol. 22, 3rd ed. John Wiley and Sons, New York. p. 835-845. Jones, N.M., J.E. Schoenhelt and A.O. Weaver. 1979. Pretreatment and heavy metal LD™ values. Toxlcol. Appl. Pharmacol. 49(1): 41-44. Juhnke, I. and D. Luedemann. 1978. Results of the Investigation of 200 chemical compounds for acute fish toxldty with the golden orfe test. Z.F. Wasser- und Abwasser Forschung. 11(5): 161-164. (Ger.) 0083d -88- 03/11/88 ------- Kada, T., K. Hlrano and Y. Shlrasu. 1980. Screening of environmental chemical mutagens by the Rec assay system with Bacillus subtnis. Chem. Mutagens. 6: 149-173. Karoerbeek, H.H., A.G. Rauws, H. ten Ham and A.M. P. van Heljst. 1971. Dangerous redistribution of thallium by treatment with sodium dlethyldUhlo- carbamate. Acta Med. Scand. 189: 149-154. Kanematsu. N., M. Hara and T. Kada. 1980. Rec assay and mutagenlclty studies on metal compounds. Mutat. Res. 77: 109-116. Karnofsky, D.A., L.P. Rldgway and P.A. Patterson. 1950. Production of achondroplasla 1n the chick embryo with thallium. Proc. Soc. Exp. B1ol. Hed. 73: 255-259. Kemp ton, „ S;-, R.M.,Sterrltt and J.H. Lester. T987a. Heavy metal removal 1n primary sedimentation. I. The Influence of metal solubility. Scl. Total Environ. 63: 247-258. Kempton, S., R.M. Sterrltt and J.N. Lester. 1987b. Heavy metal removal In primary sedimentation. II. The Influence of metal speclatlon and particle size distribution. Scl. Total Environ. 63: 231-246. Kochl, J.K. and T.M. Bethea, III. 1968. Photochemical decarboxylatlon of acids with thallium (III). J. Org. Chem. 33: 75-82. 0083d -89- 03/11/88 ------- Lameljer, H. and P.A. van Zwleten. 1977a. Kinetics of thallium elimination In the rat after acute and subacute Intoxication: Influence of diuretic treatment. Proc. Eur. Soc. Toxlcol. 18: 163-164. Lameljer, W. and P.A. van ZweHen. 1977b. Kinetic behavior of thallium In the rat. Accelerated elimination of thallium owing to treatment with potent diuretic agents. Arch. Toxlcol. 37(4): 365-373. (Taken from TOXBIB abstr. 78:019162) Lameljer, H. and P.A. van Zwelten. 1978. Accelerated elimination of thal- lium In the rat due to subchronlc treatment with furosemlde. Arch Toxlcol. 40(1): 7-16. Lameljer, U. and P.A. van Zwleten. 1979. The efficacy of a potassium-rich diet compared to diuretic treatment of the renal elimination of thallium'1n the rat. Arch. Toxlcol, 42(1): 33-41. Landauer, VI. 1960. Experiments concerning the teratogenlc nature of tha!11um:polyhydroxy compounds, hlstldlne and Imldazole as supplements. J. Exp. Zool. 143: 101-105. LeBlanc, G.A. 1980. Acute tox1c1ty of priority pollutants to water flea (Daphnla magna). Bull. Environ. Contain. Toxlcol. 24: 684-691. LeBlanc, G.A. and J.M. Dean. 1984. Antimony and thallium toxlclty to embryos and larvae of fathead minnows (Plmephales promelas). Bull. Environ. Contam. Toxlcol. 32: 565-569. 0083d -90- 03/11/88 ------- Lehman, P.P.A. and L. FavaM. 1985. Acute thallium Intoxication: Kinetic study of the relative efficacy of several antidotal treatments 1n rats. Arch. Toxlcol. 57: 56-60. Levander, O.A. and L.C. Argrett. 1969. Effects of arsenic, mercury, thal- lium and lead on selenium metabolism 1n rats. Toxlcol. Appl. Pharmacol. 14(2): 308-314. Lie, R., R.G. Thomas and J.K. Scott. 1960. The distribution and excretion of thal11um-204 In the rat with suggested MFC's and a bloassay procedure. Health Phys. 2: 334-340. LllUe, W.I. and H.L. Parker. 1932. Retrolobular neuritis due to thallium poisoning. J. Am. Hed. Assoc. 98: 1347-1349. Loveless* L.E<, E. Spoerl.and T.H. Helsman. 1954. Survey of effects of .* ' •*.*"* chemical on division and growth of yeast and Escher1ch1a coll. J. BacteMol. 68: 637-644. Ludolph, A., C.E. Elger, R. Sennhenn and H.P. Bertram. 1986. Chronic thallium exposure In cement plant workers: Clinical and electrophyslologlcal data. Trace Elem. Ned. 3(3): 121-125. Lund, A. 1956a. Distribution of thallium In the organism and Its elimina- tion. Acta Pharm. Toxlcol. 12: 251-259. 0083d -91- 03/11/88 ------- Lund, A. 19565. The effect of various substances on the excretion and the toxldty of thallium In the rat. Acta Pharm. Toxlcol. 12: 260-268. Hanzo, L., 0. Rade-Edel and E. Sabb1on1. 1983a. Environmental toxicology research on thallium: Metabolic and lexicological studies In the rat as carried out by nuclear and radloanalytlcal methods. NTIS PB 83-133249. Manzo, L., R. Ecelsl, A. Hog la et al. 1983b. Long-term toxldty of thal- lium In the rat. In; Chemical Toxicology and Clinical Chemistry of Metals, S.S. Brown and J. Savory, Ed. Academic Press, London, p. 401-405. Marcus, R.L. 1985. Investigation of a working population exposed to thallium. J. Soc. Occup. Med. 35(1): 4-9. Mathls, B.J. and N.R. Kevern. 1975. Distribution of mercury, cadmium, lead* and thallium 1n a eutrophlc lake. Hydroblologla. 46(2-3): 207-222. Mills, N.C. and A.R. Means. 1972. Serbltol dehydrogenase of rat testls: changes of activity during development, after hypophysectomy and following gonadotrophlc hormone admlnstratlon. Endocrinology. 91: 147-156. Moeschlln, S. 1980. Thallium poisoning. Cl1n. Toxlcol. 17: 133-146. MRI (Midwest Research Institute). 1986. Subchronlc (90-day) toxldty study of thallium sulfate In Sprague-Oawley rats. Office of Solid Waste, U.S. EPA, Washington. DC. (Cited 1n U.S. EPA. 1987a) 0083d -92- 03/11/88 ------- MulUns, D.J. and R.O. Moore. 1960. The movement of thallium Ions In muscle. 3. Gen. Physlol. 43: 759. (Cited 1n U.S. EPA. 1980b) Munch, J.C. 1928. The toxlclty of thallium sulfate. J. Am. Pharm. Assoc. 17(11): 1086-1093. Munch, J.C., H.M. Glnsburg and C.E. Nixon. 1933. The 1932 thallotoxlcosls outbreak 1n California. J. Am. Med. Assoc. 100: 1315-1319. Neubert, 0. and U. Bluth. 1985. Effect of thallium on 11mb development 1n organ culture. Teratology. 32:29A. NIOSH (National Institute for Occupational Safety and Health). 1987a. RTECS (Registry of Toxic Effects of Chemical Substances). Online: Oct., 1987. CAS No. 7446-18-6. NIOSH (National Institute for Occupational Safety and Health). 1987b. RTECS (Registry of Toxic Effects of Chemical Substances). Online: Oct.. 1987. CAS No. 10102-45-1. Nogaml, H. and Y. Terashlma. 1973. Thallium-Induced achondroplasla In the rat. Teratology. 8: 101-102. NTP (National Toxicology Program). 1987. Management Status Report. 10/09/87. Olsen, I. and J. Jonsen. 1982. Whole-body radiography of 204-T1 1n embryos, fetuses and placentas of mice. Toxicology. 23(4): 353-358. 0083d -93- 03/11/88 ------- OPD. 1986. OPO Chemical Buyers Directory. 1987, 74th ed. Schnell Publish- ing Co., Inc., New York. p. 690. OSHA (Occupational Safety and Health Administration). 1985. Occupational Standards Permissible Exposure Limits. 29 CFR 1910.1000. O'Shea, T.A. and K.H. Mancy. 1978. The effect of pH and hardness of metal Ions on the competitive Interaction between trace metal Ions and Inorganic and organic complexlng agents found 1n natural waters. Water Res. 12(9): 703-711. Overnell, J. 1975a. Effect of some heavy metal Ions on photosynthesis 1n a freshwater alga. Pest. Blochem. Physlol. 5: 19. (Cited 1n U.S. EPA, 1980b) 'Overnell, 0. 1975b. The effect of heavy metals on photosynthesis and a loss of cell potassium In two species of marine algae,. Dunallella tertlo- lecta and Phaeodactyluro trlcornatum. Mar. Blol. 29: 99-103. Prick, J.J., M.G. Smltt and L. Nuller, Eds. 1955. Thallium Poisoning. Elsevler, Amsterdam. (Cited In Smith and Carson, 1977) Puddu, A.. M. Pettlne, F. Bacdu, T. La Noce and R. Pagnotta. 1985. Thallium and chromium toxldty In phytoplankton cultures. In: Fifth Int. Conf. Heavy Metals Environ.. Vol. 2. CEP Consultants, Edinburgh, UK. p. 304-306. (CA 106:62621a) 0083d -94- 03/11/88 ------- Rade, J.E., E. Marafante, E. Sablonl, C. Gregottl, A. Nucd and L. Hanzo. 1982. Placenta! transfer and retention of 201T1-Thai11 urn 1n the rat. Toxlcol. Lett. 11(3-4): 275-280. Rauws, A.G. 1974. Thallium pharmacoklnetlcs and Us modification by Prussian blue. Naunyn-Schmled. Arch. Pharmacol. 284: 295-306. Rauws, A.G., N. ten Ham and H.H. Kamerbeek. 1969. Influence of the antidote dUhlocarb on distribution and toxiclty of thallium In the rat. Arch. Int. Pharmacodyn. Ther. 182: 425-426. (CA 12:000027M) R1che1m1t P., F. Bono, L. Guardla, B. Ferrlnl and L. Manzo. 1980. Salivary levels of thallium In acute human poisoning. Arch. Toxlcol. 43: 321-325. Roll, R. and G. Matthlaschk. 1981. Investigations on embryotoxic effects of thallium chloride and thalUm acetate 1n mice and rats. Teratology. 24(2): 46A-47A. Sabb1on1 E., L. Loetz, E., Maravante, C. Gregottl and L. Manzo. 1980. Metabolic fate of different Inorganic and organic species of thallium In the rat. Sd. Total Environ. 15(2): 123-135. Sabblonl, E., C. Gregottl, J. Edel, E. Marafante, A. 01 Nucd and L. Manzo. 1982. Organ/tissue disposition of thallium 1n pregnant rats. Arch. Toxlcol. 5: 225-230. (Taken from TOXBIB 82:255944) 0083d -95- 03/11/88 ------- Sax. N.I., Ed. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van Nostrand Relnhold Co.. New York. p. 2555-2558. Schaefer, S.G. and M. Forth. 1980. Excretion of metals Into the Intestine; a comparative study In rats. Dev. Toxlcol. Environ. Scl. 8: 547-550. Schaller, K.H., G. Manke, H.J. RaHhel, G. Buhlmeyer, H. Schmidt and H. Valentin. 1980. Investigations of thallium-exposed workers In cement factories. Int. Arch. Occup. Environ. Health. 47(3): 223-231. Schwetz, B.A.. P.V. O'Nell, F.A. Voelker and D.W. Jacobs. 1967. Effects of dlphenylthlocarbazone and d1ethy1d1th1ocarbamate on the excretion of thallium by rats. Toxlcol. Appl. Pharmacol. 10(1): 79-88. Sharma, J.. R.L. Sharma, H.B. Singh and N. Satake. 1986. Hazards and analysis of thallium — A review. Toxlcol. Environ. Chem. 11: 93-116. ', • *...*.», t ^ « . , Singh, I. 1983. Induction of reverse mutation and mltotlc gene conversion by some metal compounds In Saccharomyces cerevlslae. Hutat. Res. 117: 149-152. Skrovlna, B., J. N1cek, J. Hronska and L. Splssak. 1973. Experimental and human achondroplasla. Teratology. 8: 237. Smith, I.C. and B.L. Carson. 1977. Environmental thallium losses and associated health hazards to humans and other life forms. In: Trace Metals In the Environment, Vol. 1. Ann Arbor Science Publishers, Inc., Ann Arbor, HI. p. 185-307. 309-322. 0083d -96- 03/11/88 ------- Snider, E.H. and F.S. Manning. 1982. A survey of pollutant emission levels 1n waste waters and residuals from the petroleum refining Industry. Environ. Int. 7: 237-258. SRI (Stanford Research Institute). 1987. Directory of Chemical Producers. United States of America. SRI International, Menlo Park, CA. p. 1044. Stavlnoha, U.B., G.A. Emerson and J.B. Nash. 1959. The effects of some sulfur compounds on thallotoxicosis In mice. Toxlcol. Appl. Pharmacol. 1(6): 638-646. Stephenson, T. and J.N. Lester. 1987a. Heavy metal behaviour during the activated sludge process. I. Extent of soluble and Insoluble metal removal. ScJ. Total Environ. 63: 199-214. Stephenson., T. and J.N. Lester.. .1.987b, Heavy .metal behaviour during the activated sludge process. II. Insoluble metal removal mechanisms. Sc1. Total Environ. 63: 215-231. Stoklnger. H.E. 1981. The metals: 32 thallium, TI. 14: Patty's Industrial Hygiene and Toxicology, Vol. 2A, 3rd ed., G.C. Clayton and F.E. Clayton, Ed. John Wiley and Sons, Inc.. New York. p. 1914-1931. Talas, A. and H.H. Wellhoener. 1983. Dose-dependency of thalHum(U) kinetics as studied 1n rabbits. Arch. Toxlcol. 53(1): 9-16. 0083d -97- 03/11/88 ------- Talas, A., O.P. Pretschner and H.H. Wellhoner. 1983. Pharmacok1net1c parameters for thallium (I)-1ons 1n man. Arch. Toxlcol. 53(1): 1-7. Tlkhova, T.S. 1964. Industrial hygiene 1n the manufacture of metallic thallium and Us salts. Gig. 1 SanH. 29(2): 23-27. (CA 60:13786c) Tlkhova, T.S. 1967. Thallium and Us compounds. Iri: Novye Dannye po Toks1kolog11 Redkldh Hetallov 1 Ikh Soed1nen11, Z. Izrael'son, Ed. Medltslna. Moscow, USSR. p. 24-34. (Cited In Smith and Carson, 1977) Truhart, R. 1959. Recherches sur la Toxlcologle du Thallium. Instltut National SecurU} pour la Prevention des Accidents du Travail, Paris. (Cited 1n Stoklnger, 1981) USDI (U.S. Department of the Interior). 1986. Mineral Industry Surveys. Prepared ,1n the Division .of Nonf.errous Metals, Apr.1l 7, 1986. Bureau of Mines, USDI, Washington, DC. p. 3, 52-53. U.S. EPA. 1978. In-depth Studies on Health and Environmental Impacts of Selected Water Pollutants. Prepared by E.G. and G. Bionomics. Contract No. 68-01-6464. U.S. EPA. 1979. Study of Carc1nogen1c1ty and Tox1c1ty of Inhaled Antimony Trloxlde, Antimony Ore Concentration and Thalllc Oxide In Rats. MRI Project No. 4466-B. Contract No. 210-77-0156. OTS F1che No. 0511065. 0083d -98- 03/11/88 ------- U.S. EPA. 1980a. Guidelines and Methodology Used In the Preparation of Health Effect Assessment Chapters of the Consent Decree Hater Criteria Documents. Federal Register. 45:(231): 49347-49357. U.S. EPA. 1980b. Ambient Water Quality Criteria Document for Thallium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu- lations and Standards, Washington, DC. EPA 440/5-80-074. NTIS PB81-117848. U.S. EPA. 1983a. Reportable Quantity Document for Thalllc Oxide [Thallium (III) Oxide]. Prepared by the Office of Health and Environmental Assess- ment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1983b. Reportable Quantity Document for Thallium (and Compounds). Prepared, by the Office of Health.and,Environmental Assessment, Environmental t ' * # •** * Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1983c. Reportable Quantity Document for Acetic Acid, Thallium (I) Salt [Thallium (I) Acetate]. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Wash- ington, DC. 0083d -99- 03/11/88 ------- U.S. EPA. 1983d. Reportable Quantity Document for Carbonic Acid, 01 thal- lium (I) Salt [Thallium (I) Carbonate]. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Wash- ington, DC. U.S. EPA. 1983e. Reportable Quantity Document for Thallium (I) Chloride. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1983f. Reportable Quantity Document for Thallium (I) Nitrate. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1983g. Reportable Quantity Document for Sulfurlc Acid, Thallium (I) Salt (Thallium Sulfate). Prepared by the Office of Health and Environ- mental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1983h. Reportable Quantity Document for Thallium (I) Selenlde. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. 0083d -100- 03/11/88 ------- U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Determinations Based on Chronic Toxlclty Data. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1985a. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thallium (I) Selenlte. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1985b. Reference Values for Risk Assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC.' (Table 2). • ',.•..:... .-.'•,...< * .'.. ••.,.-'... ., ...-• •-.. • ..... - • . . • U.S. EPA. 1985c. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thalllc Oxide. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environ- mental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1985d. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thallium (I) Acetate. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. Cincinnati, OH. 0083d -101- 03/11/88 ------- U.S. EPA. 1985e. Integrated Risk Information System (IRIS): Reference Dose (RfO) for Oral Exposure for Thallium (I) Carbonate. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1985f. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thallium (I) Chloride. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1985g. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thallium (I) Nitrate. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. . 1985h. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thallium (I) Sulfate. Online. (Revised; Verification date 08/05/85.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1986a. Methodology for Evaluating Potential Carclnogenlclty In Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102. Prepared by the Office of Health and Environmental Assessment, Carcinogen Assessment Group, for the Office of Solid Haste and Emergency Response, Washington, DC. 0083d -102- 03/11/88 ------- U.S. EPA. 1986b. Subchronlc (90-day) Toxlclty of Thallium (I) Sulfate (CAS No. 7446-18-6) In Spr ague-Daw "ley Rats. Final Report. Prepared for the Office of SOlId Waste, U.S. EPA, Washington, DC. Project No. 8702-L (18). U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. U.S. EPA. 1987a. Quality Criteria Water - 1986. Office of Water Regula- tions and Standards, Washington, DC. EPA 440/5-86-001. U.S. EPA. 1987b. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Thallium (I) Sulfate. Online: Input pending. (Revised; Verification date 06/17/87.) Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S;, EPA.. ;.1987c. 40 CF.R . 14-1. Drinking Water;,. Proposed Substitution . of Contaminants and Proposed List of Additional Substances Which Hay Require Regulation Under the Safe Drinking Water Act. Federal Register. 52(130): 25734. Venugopal, B. and T.D. Luckey. 1978. Chapter 3. Toxlclty of group III metals. In.: Metal Toxlclty In Mammals. 2. Chemical Toxlclty of Metals and Metalloids. Plenum Press, New York. p. 122-127, 353-402. Wallwork-Barber, M.K., K. Lyall and R.W. Ferenbaugh. 1985. Thallium movement 1n a simple aquatic ecosystem. J. Environ. Sd. Health, Part A. 20: 689-700. 0083d -103- 03/11/88 ------- Ueast. R.C., Ed. 1985. CRC Handbook of Chemistry and Physics, 66th ed. CRC Press, Boca Raton, FL. p. B150-B151, 0195, D215. Wlndholz, M., Ed. 1983. The Merck Index. An Encyclopedia of Chemicals, Drugs, and Blologlcals, 10th ed. Merck and Co., Inc., Rahway, NJ. p. 1324-1325. Woods, J.S. and B.A. Fowler. 1986. Alteration of hepatocellular structure and function by thallium chloride: Ultrastructural, morphometrlc, and biochemical studies. Toxlcol. Appl. Pharmacol. 83(2): 218-229. Zasukhlna, G.D., I.M. Vasllyeva, N.I. Sdlrkova, et al. 1983. Mutagenlc effect of thallium and mercury salts on rodent cells with different repair activities. Mutat. Res. 124(2): 163-173. Zlskpveru, R.,. C. Achenbach, H.R« . Schulten and R. Roll. 1983. Thallium determinations In fetal tissues and maternal brain and kidney. Toxlcol. Lett. 19: 225-231. ZHko, V. and W.V. Carson. 1975. Accumulation of thallium In clams and mussels. Bull. Environ. Contam. Toxlcol. 14(5): 530-533. ZHko, V., W.V. Carson and W.G. Carson. 1975. Thallium: Occurrence In the environment and toxldty to fish. Bull. Environ. Contam. Toxlcol. 13: 23-30. 0083d -104- 03/11/88 ------- APPENDIX A LITERATURE SEARCHED This HEED 1s based on data Identified by computerized literature searches of the following: CHEMLINE TSCATS CASR online (U.S. EPA Chemical Activities Status Report) TOXLINE TOXLIT TOXLIT 65 RTECS OHM TADS STORET SRC Environmental Fate Data Bases SANSS AQUIRE TSCAPP NTIS Federal Register CAS ONLINE (Chemistry and Aquatic) HSDB These searches were conducted In October 1987. and the following secondary sources were reviewed: - ' ' ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1987. TLVs: Threshold Limit Values for Chemical Substances In the Work Environment adopted by ACGIH with Intended Changes for 1987-1988. Cincinnati. OH. 114 p. Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and Sons. NY. 2878 p. Clayton, G.D. and F.E. Clayton. Ed. 1981. Patty's Industrial Hygiene and Toxicology. 3rd rev. ed., Vol. 2B. John Wiley and Sons. NY. p. 2879-3816. Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and Sons, NY. p. 3817-5112. 0083d -105- 03/11/88 ------- Grayson, H. and D. Eckroth. Ed. 1978-1984. Klrk-Othmer Encyclo- pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23 Volumes. Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed. Publishing Sciences Group, Inc., Littleton, MA. 575 p. IARC (International Agency for Research on Cancer). IARC Mono- graphs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC, MHO, Lyons, France. Jaber, H.M., H.R. Mabey, A.T. Lieu, T.M. Chou and H.L. Johnson. 1984. Data acquisition for environmental transport and fate screening for compounds of Interest to the Office of Solid Waste. EPA 600/6-84-010. NTIS PB84-243906. SRI International. Henlo Park, CA. NTP (National Toxicology Program). 1987. Toxicology Research and Testing Program. Chemicals on Standard Protocol. Management Status. Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide Register. McGraw-Hill Book Co., NY. Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van Nostrand Relnhold Co., NY. SRI (Stanford Research Institute). 1987. Directory of Chemical Producers. Menlo Park, CA. U.S. EPA. 1986. Report on Status Report In the Special Review '' 'Program, Registration Standards' Program and the Data Call In Programs. Registration Standards and the Data Call 1n Programs. Office of Pesticide Programs, Washington, DC. USITC (U.S. International Trade Commission). 1986. Synthetic Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ. 1892, Washington, DC. Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY. Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual. British Crop Protection Council. 695 p. Wlndholz. M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.. Inc., Rahway, NJ. 0083d -106- 03/11/88 ------- In addition, approximately 30 compendia of aquatic toxlclty data were reviewed. Including the following: Battelle's Columbus Laboratories. 1971. Water Quality Criteria Data Book. Volume 3. Effects of Chemicals on Aquatic Life. Selected Data from the Literature through 1968. Prepared for the U.S. EPA under Contract No. 68-01-0007. Washington, DC. Johnson, W.W. and H.T. Flnley. 1980. Handbook of Acute Toxlclty of Chemicals to F1sh and Aquatic Invertebrates. Summaries of Toxlclty Tests Conducted at Columbia National Fisheries Research Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife Serv. Res. Publ. 137, Washington, DC. McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed. Prepared for the Resources Agency of California, State Water Quality Control Board! Publ. No. 3-A. Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target Species. Prepared for the U.S. EPA, Washington, DC. PB-269605. Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S. EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876. 0083d -107- 03/11/88 ------- APPENDIX B-l Summary Table for Thallium and Salts Inhalation Exposure Subchronlc Chronic Carclnogenlclty Oral Exposure Subchronlc Chronic Carclnogenlclty REPORTABLE QUANTITIES Based on chronic toxlclty: Based on Carclnogenlclty: Species ID ID ID rat rat ID 10 ID Exposure Effect RfD or qj* Reference ID ID ID ID ID ID ID ID ID ID ID ID 0.25 mg thallium (I) NOAEL 0.002 rag/kg/day U.S. EPA, 1986b; sul fate/kg/day for or 0.1 rag /day HRI, 1986 90 days 0.25 mg thallium (I) NOAEL 0.2 yg/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.01 mg/day HRI, 1986 90 days ID ID ID ID U.S. EPA. 1979 ID = Insufficient data ------- APPENDIX B-2 g GO C3 a. i Inhalation Exposure Subchronlc Chronic Carcinogenic Ity Oral Exposure g Subchronlc Chronic CarctnogenlcUy REPORTABLE QUANTITIES Based on chronic toxlclty: o S£ Based on cancer: Species ID ID ID rat rat ID 10 ID Summary Table for Thallium (III) oxide Exposure Effect RfD or q-\* Reference • ID ID ID ID ID ID ID ID ID • ID HI 10 ... 0.25 mg thallium (I) NOAEL 0.002 mg/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.2 rug/day NRI, 1986 90 days 0.25 mg thallium (I) NOAEL 0.2 pg/kg/day U.S H'A. I'lOOh; sulfate/kg/day for or 0.02 mg/day NRI, 1986 90 days ID ID ID ID • U.S. EPA. 1979 CO 00 ID = Insufficient data ------- APPENDIX B-3 1 o o CO Inhalation Exposure Subchronlc Chronic Carclnogentclty Species ID ID ID Summary ID ID ID Table for Thallium (I) acetate Exposure Effect RfD or q-\* Reference • • ID ID ID ID ID ID ID ID ID Oral Exposure i =J Subchrontc Chronic Carclnogenlclty rat 0.25 mg thallium (I) NOAEL sulfate/kg/day for 90 days rat 0.25 mg thallium (I) NOAEL sulfate/kg/day for 90 days ID ID ID 0.003 mg/kg/day or 0.2 rag/day 0.3 ng/kg/day or 0.02 mg/day ID U.S. EPA. 1986b; HRI. 1986 U.S. EPA. 1986b; NRI. 1986 ID REPORTABLE QUANTITIES Based on chronic toxlclty: 10 Based on cancer: ID U.S. EPA. 1979 ID = Insufficient data ------- as APPENDIX B-4 Summary Table for Thallium (I) carbonate 1 o § Inhalation Exposure Subchronlc Chronic Carclnogenlclty Oral Exposure Subchronlc Chronic Carclnogenlclty REPORTABLE QUANTITIES Based on chronic toxlclty: Based on cancer: Species ID ID ID rat rat ID 10 ID Exposure Effect RfD or q^* Reference ID ID ID ID ID ID ID ID ID ID ID ID • • 0.25 rag thallium (I) NOAEL 0.002 mg/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.2 mg/day HRI. 1986 90 days 0.25 mg thallium (I) NOAEL 0.2 yg/kg/day U.S. EPA. 1986b; sulfate/kg/day for or 0.02 mg/day HRI. 1986 90 days ID ID ID ID • U.S. EPA. 1979 00 00 ID = Insufficient data ------- APPENDIX B-5 f * Summary Table for Thallium (I) chloride ro O «s, s^ Species Inhalation Exposure Subchronlc ID Chronic ID Carclnogenlclty ID Oral Exposure Subchronlc rat Chronic rat Carclnogenlclty ID REPORTABLE QUANTITIES Based on chronic toxlclty: 10 Based on cancer: ID Exposure Effect RfD or qj* Reference - ID ID ID ID ID ID ID ID ID ID ID ID « 0.25 rag thallium (I) NOAEL 0.002 rog/kg/day U.S. EPA, 19865; sul fate/kg/day for or 0.2 rag /day NRI. 1986 90 days 0.25 rag thallium (I) NOAEL 0.2 yg/kg/day U.S. EPA. 19865; sul fate/kg/day for or 0.02 mg/day NRI. 1986 90 days ID ID ID ID U.S. EPA. 1979 00 00 ID = Insufficient data ------- g APPENDIX B-6 Summary Table for Thallium (I) nitrate Species Inhalation Exposure Subchronlc ID Chronic ID Carclnogenlclty ID Oral Exposure i £ Subchronlc rat i Chronic rat Carclnogenlclty ID REPORTABLE QUANTITIES Based on chronic toxlctty: 10 o ££ Based on cancer: ID i Exposure Effect RfD or qj* Reference •• ID ID ID ID ID ID ID ID ID ' . ID ID ID 0.25 nig thallium (I) NOAEL 0.003 rag/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.2 nig/day HRI. 1986 90 days 0.25 mg thallium (I) NOAEL 0.3 yg/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.02 nig /day HRI. 1986 90 days ID ID ID ID U.S. EPA. 1979 ID = Insufficient data ------- 00 CO APPENDIX B-7 Summary Table for Thallium selenlde (TISe) Inhalation Exposure Subchrontc Chronic Carctnogenlclty Oral Exposure Subchronlc Chronic Carclnogenlclty RE PORT ABLE QUANTITIES Based on chronic toxIcHy: Based on cancer: Species 10 ID ID rat rat ID ID ID Exposure Effect RfD or qj* Reference ;.• ID ... • ID ID ID ID ; ID ID ID ID ID ID ID 0.25 mg thallium (I) NOAEL 0.003 mg/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.2 rag /day NRI, 1986 90 days 0.2S mg thallium (I) NOAEL 0.3 ng/kg/day U.S. EPA. 1986b; sul fate/kg/day for or 0.02 rag/day HRI. 1986 90 days ID ID ID ID • ID - Insufficient data ------- APPENDIX B-8 Summary Table for Thallium (I)sulfate Inhalation Exposure Subchronlc Chronic Carclnoyenlclty Oral Exposure i £ Subchronlc Species ID ID ID rat Exposure. Effect RfD or qi* Reference '•: ID . ID ID ID ID . ID ID ID ID ID ID ID :- • 0.25 rag thallium (I) NOAEL 0.002 rag/kg/day U.S. EPA. 1986b; r..1ftl*. /I,*. /A**, £.» «... A 1 mr./A*t. UD1 1OOC. Chronic Carclnogenlclty 90 days rat 0.25 mg thallium (I) NOAEL sulfate/kg/day for 90 days ID ID ID 0.3 yg/kg/day or 0.02 mg/day ID U.S. EPA. 1986b; HRI. 1986 ID REPORTABLE QUANTITIES Based on chronic toxlctty: 10 Based on cancer: ID U.S. EPA. 1979 ID = Insufficient data ------- |