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                  DRAFT: DO NOT CITE OR QUOTE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.

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                                  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

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                                   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

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                               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

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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

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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

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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

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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

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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

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                             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

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                           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

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                               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

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                           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

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                             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

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                               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

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                                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

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                                                                      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.

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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

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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

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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

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                     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

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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

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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

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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

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                                 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

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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

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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

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                             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

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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.
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    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.
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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

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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


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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).
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                                  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
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                                  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
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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.

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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


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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


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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


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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


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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

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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

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                                   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

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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

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    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

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    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

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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

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    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

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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

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              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

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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

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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.
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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

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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

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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


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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.
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                    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


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                                   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

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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.
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                              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

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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.
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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


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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).
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    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

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                                  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

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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

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                                   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

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                           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

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                                                                                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

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                                                                      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

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                                  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

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                                   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

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                                  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

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                                  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

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                                  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

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                                  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

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                                  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

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    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

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                                  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

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                                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

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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
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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

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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

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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

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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

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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

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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

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 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

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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

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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

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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

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                                  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

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    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

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    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

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                                               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

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                                                     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

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                                               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

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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

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                                                     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

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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

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                                                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

-------