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VER/AR INC.
                                   INDIUM
                             TABLE OF CONTENTS
                                                                    Page
                                                                    •W^^^KV
           FOREWORD	    II-l
      I.    INDIUM INDUSTRY IN THE UNITED STATES .	    II-2
           A.  Producers and Sites	    II-2
           B.  Costs	    II-4
           C.  Physical Properties of Important Commercial Indium
                 Compounds	    II-4
      II.   PRODUCTION	    II-6
           A.  Domestic Production  	 ......    II-6
           B.  Imports of Indium	    II-6
           C.  Production Process	    II-7
      III.  USES
           A.  Indium Metal	    .11-8
           B.  Uses of Indium and its Compounds	    II-8
           C.  Forecast and Future Use for Indium	    II-8
      IV.   CURRENT PRACTICES	    11-12
      V.    ENVIRONMENTAL CONTAMINATION	  .    11-13
           A.  From Production	    11-13
           B.  From Use and Disposal	    11-13
           C.  Inadvertent Sources  . •.	    11-13
      VI.   ANALYSIS  	  .......    11-15
           A.  Detection  	  .....    11-15
               1.  Physical Techniques	    11-15
               2.  Chemical Techniques	    11-15
           B.  Quantitative Analysis	    11-15
      VTI.  CHEMICAL REACTIVITY	    11-16
           A.  Environmental and Use Associated Reactions  ....    11-16
      VTII. BIOLOGY
           A.  Distribution and Transport	    11-17
           B.  Absorption and Excretion	    11-20
           C.  Metabolic Effects and Biochemistry  ........    11-20
           D.  Pharmacology	    11-21
                                     i.

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VER/AR  INC.
                                   INDIUM
                             TABLE OF CONTENTS
                                  (Con't)
                                                                   Page
     IX.    ENVTODNjyENTAL EFFECTS: BIOACOJMULATION	11-23
                                      \
     X.     TOXICm	  .  11-24
            A.  Humans	11-24
                1.  Occupational Exposures	  11-24
                2.  Other Exposures	11-24
            B.  Mammals	  11-24
                1.  Acute and Subacute Toxicity	11-24
                2.  Chronic Toxicity	11-26
                3.  Teratology	11-26
            C.  Plants 	  .....  11-26
            D.  Microorganisms	11-27
            E.  Results of Personal Contacts with Madical
                  Personnel	  11-27
     XI.    CURRENT REGULATIONS	11-28
     XII.   STANDARDS.	  11-29
     XIII.  SUMMARY AND CONCLUSIONS	11-30
            A.  Suntnary	  H-30
            B.  Conclusions	11-31
            C.  RecomnEndations	11-31
                                     11.

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                          LIST OF TABLES
1.  Indium Products and Producers	   II-2
2.  Physical Properties  . . .	   II-5
3.  Uses of Indium	   11-10
                         LIST OF FIGURES

1.  International use of Indium	   II-9
                               111.

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VER/AR  INC.
                                    11-2
I.   INDIUM INDUSTRY IN THE UNITED STATES
     A.  Producers and Sites
         Table I lists commercially significant chemical products  and the
companies involved.  lor this study significant is defined as production
exceeding approximately $1,000 value.  Other materials may also be included
in the discussion because of their unusual properties, such as toxicity, or
their anticipated future significance.

                                  Table 1(1)
                       Indium Products and Producers
                                             Producer
Chemical
Indium  (metal)
Indium acetylacetonate
Indium antimonide


Indium arsenide


Indium carbonate
Indium cyanide
Company, subordination
Anerican Smelting and Rsfining Co.
Atomergic Chemetals Co.
  Gallard-Schesinger
Electronic Space Products, Inc.
Fairmount Chemical Co., Inc.
Goldsmith, D. F.
 Chem. & Metal Corp.
Indium Corp. of America
Kawecki Beryloo Ind., Inc.
Rocky Mountain Research, Inc.
United Mineral & Chem. Corp.
Var-Lac-Oid Chem. Co.
MacKenzie Chem. Works, Inc.
Monsanto Co.
  Monsanto Commercial Products Co.
    Electronic Products
Monsanto Co.
  Monsanto Conmercial Products Co.
    Electronic Products
City Chem. Corp.
The Indium Corp. of America
Location
Denver, Colo.

Carle Place, N.Y.
Los Angeles, Calif.
Newark, N.J.

Evanston, 111.
Utica, N.Y.
New York, N.Y.
Golden, Col.
New York, N.Y.
Elizabeth, N.J.
Central Islip, N.Y.


St. Peters, Mo.


St. Peters, Mo.
Jersey City, N.J.
Utica, N.Y.

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YER/A
IAR INC.
                              Table 1  (Con't)
                          Indium Products and Producers
11-3
                                             Producer
 Chemical
 Indium fluoborate
 Indium hydroxide
 Indium iodide,
   anhydrous
 Indium nitrate
 Indium oxide
 (Indium sesquioxide)
 (Indium trioxide)
 Indium phosphide
 Indium sulfamate
 Indium sulfate

 Indium sulfide
 Indium tribromide
 Indium trichloride
 (Indium chloride)
                     Company, subordination
                     Allied Chem. Corp.
                       Specialty Chems. Div.
                     Harstan Chem. Corp.
                     The Indium Corp. of America
                     American Smelting and Refining Co.
                     The Indium Corp. of America
                     Ventron Corp.
                       Alfa Products Div.
                     The Indium Corp. of America
                     American Smelting and Refining Co.
                     Apache Chems., Inc.
                     Fairmount Chem. Co., Inc.
                     The Indium Corp. of America
                     Apache Chems., Inc.
                     The Indium Corp. of America
                     Fairmount Chem. Co., Inc.
                     The Indium Corp. of America
                     The Indium Corp. of America
                     The Indium Corp. of America
                     American Smelting and Refining Co.
                     Fairmount Chem. Co., Inc.
                     The Indium Corp. of America
                     Ventron Corp.
                       Alfa Products Div.
   Location

   Marcus Hook,  Pa.:
   Brooklyn,  N.Y.
   Utica, N.Y.
   Denver, Colo.
   Utica, N.Y.

   Beverly, Mass.
   Utica, N.Y.
   Denver, Colo.
   Rockford,  111.
   Newark, N.J.
   Utica, N.Y.
   Rockford,  111.
   Utica, N.Y.
   Newark, N.Y.
   Utica, N.Y.
   Utica, N.Y.
   Utica, N.Y.
   Denver, Colo.
   Newark, N.J.
   Utica, N.Y.

   Beverly, Mass.

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                                                                1-4
                              Table 1 (Can't)
                         Indium Products and Producers

                                             Producer
Cheinical                   Company, subordination                 Location
Ihdiun trifluoride         The Indium Corp. of America            Utica, N.Y.
                           Ozark-Mahoning Co.                     Tulsa, Ckla.
Indium triiodide           The Indium Corp. of America            Utica, N.Y.

     B.  Costs
         The price of indium has declined steadily since 1940, when it first
became available commercially in the United States.  The first quoted price in
September,1930 was $15.00 per gram.  This dropped to $0.072 per gram by
December, 1945, as demand developed and supplies became available.  Since then
the price has fluctuated within a relatively narrow range and stabilized at
$0.056 per gram in September, 1968.  Imported material was available at substantial
discounts from 1971 through 1972, as low as $0.030 to 0.032 per gram.  Prices are
                    (2)
now back to normal.     The producer  prices of indium during 1972 were unchanged
at $0.080 per gram for sticks in lots of less than 3.1 kg; 3.1 kg ingots were
$0.066 per gram and lots of 320 sticks were priced at $0.056 per gram.
         The price of indium cannot be discussed without considering the
association of indium with zinc since their resources and production are inter-
related.  As a consequence of this association, the output of indium does not
readily respond to indium price advances.  The amount of reserves of indium
                                                           (4)
at recovery facilities is another factor to be considered.
     C.  Physical Properties of Important CoititErcial Indium Goitpounds
         The three most iitportant indium compounds are the metal, the oxide
and the sulfate.  Physical properties of these are presented in Table 2.

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                                                                (4,5)
                                                 Physical Propertdes
 Chemical


 Indium

 Indium
 sesquioxide

 Indium
 sulfate
Specific
Gravity


7.3020


7.179
7.179
Melting
 Point
  °C
156.61
                  3.438
Boiling
 Point
  °C
2000 ± 10

volat.
850
Solubility
  Water
g/lOOcc °C
Comments
i  (hot & cold)* Malleable, ductile;
                Softer than lead
i cold
                                s cold
                                vs hot
*Finely divided indium forms hydroxide on contact with water.

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                                                                1-6
II.  PRODUCTION
     A.  Domestic Production

         Company                            Location
         American Smelting &                Denver, Colo.
           Refining Company (ASARCO)

         The above firm was the only reported domestic producer of indium for
1972.  They recovered indium from flue dusts and residues in which indium's
source materials were concentrated during the processing of zinc ores and con-
centrates.  Other firms sent them flue dusts and zinc processing residues for
recovery of the indium.  Production figures are not available.  U.S. zinc smelter
production of 15,000 grams of indium was reported for 1968 only after considering
the number of years which had elapsed.  The firm considers production figures
proprietary information.
         Despite the limited domestic extraction of indium, it is not a rare
element.  As late as 1924, indium was still a laboratory curiosity.  Today
indium is available in considerable quantities, in niany sections of the
*ria.(6>
         ASARCO provides a commercial grade indium of 99.97 per cent purity
and a refined product of unspecified purity.  Indium of 99.9999 per cent purity
is refined by the Indium Corporation of America.
         Based on the meager knowledge of the indium content of zinc reserves,
the domestic reserves of indium are estimated at 400,000 grams.  The reserves of
indium for the rest of the world are estimated at 2 million grams of recoverable
.  ^-    (4)
indium.
         Indium is not on the list of strategic and critical materials and there
are no Government programs for stockpiling or production assistance for indium.
                                                                                  (4)
The demand for indium is fulfilled by domestic production and substantial imports.
U.S.  producers maintain reserve supplies of recovered indium.  Details of the
amount stockpiled are not available.

     B.  Imports of Indium
         The imports of indium metal in 1972 increased 62 per cent over 1971 imports.

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VER/AR INC.
1-7
 •Hie increase is attributed to the lower price.  Dealers could trade foreign
 itetal for more than 3 cents per gram less than the domestic producer price.
 The total 1972 ijtports were 20,200 grams with the suppliers as follows:
 Canada,  33%; U.S.S.R, 27%; Peru, 15%; United Kingdom, 14% and others 11%.(3)

      C.   Production Process
          Indium recovery in the U.S. is a byproduct of primary zinc production.
 The details  of the  process used by ASARDO are not available.  Two independent
 processes are known to have been developed by the company.  In one, indium-
 containing residues are leached with strong acid and indium precipitated as a
 phosphate.  This is then treated with hot sodium hydroxide to obtain indium
 hydroxide.  The hydroxide is reduced to the metal and further refined electro-
 litically.  In the  other method, a chloride slag obtained from zinc-lead bullion
 is leached with dilute sulfuric acid and an indium-zinc sponge produced by the
 addition of  zinc dust.  The sponge is further purified by chlorination followed
 by electrolysis.

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                                                               11-8
III. USES

     A.  Indium Metal
         Indium was first used oamercially over 30 years ago as a dental
alloy.  The only available breakdown on the uses of indium is on an internat-
ional, rather than domestic basis. (See Figure 1)  This information was
published in 1973.(2)

     B.  Uses of Indium and its Compounds
         The solder and alloy industries offer the best opportunity for growth
for the indium market.  This is because indium increases hardness and fatigue
resistance and improves corrosion resistance, producing generally high quality .
solders and braze-bonded connections.
         The use of indium in semi-conductor devices is closely tied to silicon and
germanium device production where indium is used to form the alloy junction.
The use of germanium devices is declining.  They are being replaced by silicon
devices.  The use of indium-containing solders in silicon device fabrication,
therefore, is on the increase.
         Substitutes are available for most uses of indium.  Continuing re-
search in the transistor field could lead to replacement of the germanium-
indium type of transistor.  Gallium can be used instead of indium in dental
alloys and glass joint seals; however, gallium is more expensive than indium.
Since the cost of materials is a relatively small part of the end product cost
in most of the uses, adequacy of supply and desirable properties (or fewer
                                                                            (4)
undesirable properties) are more likely to determine which element is used.N
A detailed summary of current indium usage is presented in Table 3.

     C.  Forecast and Future Use for Indium
         The U.S. Bureau of Mines prepared a forecast of the requirements for
indium by the year 2000.  1968 was used as the base year and the annual growth
rate projected for total population was 1.6 per cent for 1968 to 2000.  Pro-
jecting from an estimated consumption of 18,000 grams of indium in 1968, the

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                                                          1-9
                             15%
                           OTHER
    '/o
RESEARCH
   10%
ELECTRIC LAMPS
                                       25%
                               SOLDERS AND ALLOYS
       20%
   SEMICONDUCTORS
                           20%
                          BEARINGS
                     Figure  I
         International use of Indium

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                                                     Table 3.
                                                           (2,8)
                                                  Uses of Indium
Conpound

Indium
Indium
Oxide
Indium
Sulfate

Radioisotopes
of Indium &
Indium Compounds
Use

Dental alloy

Solder and alloy
industries

Automotive
bearings

Low pressure
sodium lanps

Other
Glass



Electroplating


Medical
Purpose
                                        Produces high quality solders and
                                        braze-bonded connectors
Comments
                                                                                  Strictly European use
                                                                                  Strictly European use
Nuclear reactor control rod alloys
Catalysts
Indium oxide fuel cells
Cryogenic gasket material

Used for coloring.  A light to
dark brown can be obtained, de-
pending on the amount used

Used to prepare sulfate electrolytes
Treatment of cancer and diagnostic
organ scanning
                                                                                                                   i
                                                                                                                   o

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VER/A
>AR IMC.                                              II-M
 demand in year 2000 will be in the range of 21,000 to 37,000 grams, or a
 median of 29,000.  This estimate was postulated on normal technological
                                                               (4\
 development, growth in existing uses, and no new breakthroughs.
          A  new use developed by Western Electric and now being implemented
 by the Bell System is indium-plated components.  Splicing connectors which
 employ indium-plated contacts are used with both aluminum and copper cables.
 One type connector is for splicing, bridging and butt splicing.   Special
 tools  have  been designed for installing the connectors.  Coating of the
 contacts with  indium may present a chance for indium to spill over into  the
                                                                      (9)
 environment.   The Bell System will use about a billion of these  units.
 In terms of the quantity of indium involved, tiiis could amount to as much
 as three per cent of the total consumed in the United States. A supply
 problem is  not anticipated.  One company supplies indium sulfate plating
 solution to a  number of contractors.  They provide the indium-plated components
                      /Q\
 in a "sealed system".

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VER/A
(AR INC.                                              11-12
 IV.   CURRENT PRACTICES

      Indium and most of its compounds are considered to be locally a moderately
 toxic irritant.  Indium ingested or inhaled into the system is  considered
 severely toxic.
      Indium in the form of dust may pose a moderate fire hazard in the pre-
 sence of heat or flame.      Heated indium bums with a nonluminous blue-red
 flame to form indium sesquicxide.  Approved respiratory equipment should be
 worn when burning indium.  Carbon dioxide, dry chemicals, or foam can be used
 to extinguish an indium or an indium sesquioxide fire.
      Indium metal requires careful packing in bars, stick, foil,  or shot for
 shipment to prevent pieces from sticking and to avoid cutting or  denting of
 the  shapes.  Indium wire, in continuous lengths of 0.081 cm. minimum diameter
                                               (12)
 is available in 0.5, 2.5 or 10 kilogram spools.
      Indium sulfate is available as a dry powder or in solution and is packed
 in bottles  in units of one gram.  Indium sesquioxide is available as dry powder
 packed in bottles in 900 gram units.

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      JAR  INC.
V.   ENVIRONMENTAL CONTAMINATION
   /
     A.  Fran Production
         Fairly routine procedures are used to recover indium as a byproduct
of primary zinc production.   (See IIIB)  Operational data are not available;
however, indium contamination of the environment should not pose a problem.
This is because special procedures are required to take care of wastes (lead
for instance) and contaminants  (such as sulfur dioxide) present or developed
during tiie production of primary zinc.

     B.  From Use and Disposal
         The environmental hazard from indiun appears to result from the use
and disposal of radioactive isotopes and not chemical toxicity.  In a study in
Cape Town, South Africa, for example, indium-113 was still detectable as a bolus
with an average radioactivity on the order of 10   microcuries per ml, even
after travelling a considerable distance after being dumped into the city
sewage system by a hospital.
         The use of carrier-free radioactive isotopes of indiun in medical
applications essentially eliminates the hazard from chemical toxicity.  The
use of indium as a lubricant and the use of indium antimonide for semi-conductor
purposes appear to pose no direct environmental threat.
         Indium and its compounds are rated moderately toxic.  Recovered indium
has a recycled value so a minimum quantity is discarded.  Closed containers are
required for the disposal of indium and its compounds.      In view of the
practices indicated above and the limited applications and small amounts in-
volved, indium and its compounds do not seem to pose environmental contamination
problems either in production or use.
     C.  Inadvertent Sources
         Indium is recovered comtercially as a byproduct in processing zinc-
bearing ores.  Over and above that obtained by design in the procedures for
recovering zinc (as well as other nonferrous materials), there is seme con-
centration of indium in the residuals.  |Cn this manner indium may get into

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     'AR  INC.                                              n-14
the environment from flue  and Cottrell precipitator dusts, residues from zinc
retorts, residues from cadmium recovery, lead blast furnace slags and crude
zinc and lead.  The amounts of indium involved in these inadvertent sources
should not cause problems  unless trace amounts of indium should prove harmful.
Furtiiermore, should the supply of indium become tight, some of these could
                                       (4)
become valuable for recovery  of indium.

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                                                              11-16
VII.  CHEMICAL BEflCTIVnY
      A.  Environmental and Use Associated Reactions
          Indian metal is unaffected by air at ordinary temperatures, but at
red heat it bums with a blue flame to form the oxide, In2^3*  The metal
reacts with sulfur and the hat ides when heated.

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      IAR  INC.
VIII.    BIQLOOf
         A.   Distribution and Transport
              Different chemical compounds of the various radionuclides of
indium are organ specific, hence radioactive indium compounds are used in
diagnostic organ scanning.   '     The mode of administration of the indium
compound also affects its biological behavior.  Regardless of the mode of
administration, the predominant accumulation of radioindium several hours
after administration occurs within the organs of the reticuloendothelial
system  (RES): the liver, spleen, and bone marrow.      In pregnant rats,
an initial placental retention of radioindium is followed by a gradual release
of the indium.   '      Two times the indium found in the blood was found in
the mammary glands of lactating rats, but very little was found in the milk.
                                       (18)
The indium does not cross to the fetus.      Subcutaneously injected radiocolloid
indium-111 in dogs was primarily distributed in the injection site, the regional
                                                   (19)
lymph nodes, and the liver, via the systemic veins.      The largest concentr-
ations of radioindium after intravenous injection of white mice occurred in the
liver and spleen, with little activity recovered from the blood, kidneys, or
      /ig\
lungs.      In humans, the distribution of injected indium colloid made with
gelatin and phosphate buffer appears to be 80 per cent in liver, 3 per cent
in spleen, and 10 per cent in the red bone marrow.      Indium distribution was
studied 2 to 48 hours after an oral dose of 0.5 microcuries of indium-114 in a
basic solution.  Maximum activity was noted in the kidneys, liver and spleen;
minimum activity, in the heart and epididymis.  After iritratracheal administration,
                                                                             (21)
the lungs had the highest activity.  Most of the excretion was via the feces.
              The distribution of injected radioindium can be controlled by con-
trolling the pH of the preparation.  The indium activity in the blood was high
with a pH of 3.5 ± 1.0.  With a pH of 10.5 ± 0.5, approximately 80 per cent of
                                      (22)
the indium was localized in the liver.    •
              Indium-113M, with a half-life of 100 minutes, can easily be
generated from tin-113, and if it is carrier free, toxicity effects are re-
                                     (23)
duced since less indium is utilized.      Intravenously injected ionic indium-
                                                       (24)
113M becomes bound to the plasma protein, transferrin.      Transferrin was

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                                                               11-18
saturated with a plasma indium concentration of four micrograms per ml. of
normal plasma.  Excess indium above this level was bound mainly to alpha-2-
           t*\ A \                                                        /OC \
globulins.      Indium injected in this form or as indium transferrin     or
                           (26)
indium human serum albumin     conpleseas is useful for blood volume studies,
cardiac blood pool and placental scanning.  Ninety-five per cent of indium-113M
human serum albumin microaggregates, ranging in size from 10 to 150 microns,
were retained in the lungs thirty minutes after an intravenous injection into
                     (27)
experimental animals.      Indium is removed from the blood by the liver,
spleen, and the kidneys.  The kidney uptake of ionic indium injected into
mice is the greatest of all organs on a per gram basis.  The liver and spleen
                                          (28)
rapidly accumulate hydrated indium oxide.
         Colloidal indium-Ill and indium-Ill transferrin distribute evenly
                                               (29)
throughout the cerebrospinal fluid compartment.      Indium phosphate colloid,
however, tends to accumulate in the basal cisterns and is, therefore, not useful
for cerebrospinal scanning.      Indium phosphate colloids injected intravenously
are accumulated by the reticuloendothelial system and are useful for liver,
                                (25)
spleen and bone marrow scanning.
         Eighty per cent of the colloidal indium-113M injected intravenously with
mannitol or gelatin is found in the liver.  Without these additives, only 60 per
cent of the indium appears in the liver, while 15 per cent is located in the
lungs.      Eighty-five per cent of injected indium-113M hydroxide colloids
                                     (32)
was localized in the liver of humans.      Gallium hydroxide, which blocks the
                                                    (33)
RES, decreased the liver uptake of indium hydroxide„      The liver uptake of
                                                   (34)
colloidal indium-113M is greater than for gold-198;     however, the indium
uptake is diminished in the liver in favor of the spleen if the liver function
is impaired.  This occurs in patients with polycythemia vera, osteomyelofibrosis,
primary carcinoma of the liver, metastases in the liver and liver cirrhosis.
         Indium-113M chloride stabilized by gelatin becomes bound to the gamma-
globulins after intravenous injection into man and animals.  Five to ten minutes
after injection, the heart, large abdominal vessels, and cerebral circulation
become radiopaque.      Placental localization was correctly accomplished in
                                                                 (37)
38 of 41 patients after intravenous injection of indium chloride.      Colloidal
                                                                       /OQ
indium-113M chloride is accumulated by liver, spleen,  and bone marrow.   '

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                                                               11-19
         Indium-111 chloride is selectively accumulated by some types of


malignant tumors.      The subcellular soluble fraction frcm epidermoid


carcinoma in rats contained more indium radioactivity than the same fraction

                (41)
from the liver.



         Indium-iron hydroxide complex injected intravenously becomes localized


in the lung.         Fifteen minutes after injection, 90 per cent of the radio-


activity was found in the lung of the mouse.  About 45 per cent of the dose


remained in the lungs 42 days later.  The highest activity observed in the


liver, 13 per cent of the injected dose, occurred after two days.  The peak

                                                      (42)
activity in the carcass was 35 per cent after 14 days.      On the average,


83 per cent of injected indium-113M ferric hydroxide particles, 20 to 50 microns

                                           (43)
in size, were taken up by the lungs in rats;  '  Significant deposition of


indium also occurred in the liver and spleen if gelatin was included in the


injection.


         Indium-iron-ascorbic acid complex, pH 9.0, remains in the blood for at


least two hours after intravenous injection in man.  During this period, as much


as 81 per cent of the activity occurred in the blood, while only 0.9 per cent

                                               (43)
of the injected dose was excreted in the urine.      The disappearance of indium-


113M EDTA injected into the iliac bone marrow of the rabbit provides an appro-


priate estimation of bone marrow blood flow.  Drug-induced vasodilation decreased


the biological half-life of indium in the marrow; vasoconstriction had the

                (45)
opposite effect.      Indium-113M glutathione injected into the rabbit remained


mostly in the blood.  The half-life of this compound was three times that of


indium-EDTA.(46)



         Indium-113M diethylenetriaminepentacetic acid CDTPA) accumulates in


the brain, providing a useful brain scanning agent when indium DTPA is injected


intravenously.  In 87 patients, detection and characterization of intracranial

                                                          (47)
lesions was satisfactorily accomplished with indium DTPA.      Oral administration


of indium DTPA has been useful for the study of gastric emptying.      In rats

                                                                         (27)
with Yoshida sarcomas, the tumor to brain ratio of indium DTPA was 34:1.

                                (49 50)
Excretion occurs via the kidney   '   , making indiun>-DTPA useful for kidney


scanning.  An indium-iron DTPA-asoorbic acid complex was useful in distinguishing


between renal cysts and neoplasms.

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                                                               11-20
         Eighty-two per cent of indium-113M sulfur colloid was found in the
 liver and bone marrow, illustrating the specific accumulation by the reti-
 culcendothelial system.  Indium chondroitin sulfate colloid is also accumu-
                                                                      (52)
 lated by the reticuloendothelial system, specifically the bone narrow.

     B.  Absorption and Excretion
         Intestinal absorption of orally administered indium compounds is
 apparently not great.  The LD5Q for oral administration of indium sulfate is,
 for example, almost 200 times the ID5Q for intravenous administration.  The
 oral ID,-Q for indium oxide in mice is about lOg per kg, compared with the
 intravenous ID™ of about 0.5 mg per kg.  Most of the orally administered
 indium is excreted in the feces.
         The mode of injection, as well as the particular compound involved,
 influences the mode of excretion.  For example, intravenously injected indium
 chloride is mainly excreted in the urine; however, intraperitoneally injected
 indium chloride is mainly excreted in the feces, being accumulated by the liver
 and passed into the small intestine in the bile.  Indium chelates are excreted
 principally by the kidney, but the fecal excretion of high doses of indium
 sulfate injected intravenously into mice was seven to eight times the amount ex-
 creted in the urine.(53)
         It appears that the indium compounds which are most readily accumulated
 by the liver are most likely to appear in the feces, whereas compounds which
 remain in the vascular system are predominantly excreted by the kidneys.

     C.  Metabolic Effects and Biochemistry
         Indian (±3)  inhibited the enzyme-catalyzed conversion of isocitrate
                                                (54)
 to alpha ketoglutarate in the presence of NADPH.      Four injections of seven
mg of indium sulfate into rats markedly influenced the urea cycle.  The  transfer
 of glutamic acid to ornithine was blocked, while glutamic acid was transformed
 to proline.l  '  Trivalent metal cations inhibit ferrooxidase (ceruloplasmin EC
 1. 12. 3.1),  The metal ions studied in order of decreasing effectiveness of
                                                                  tec \
 inhibition were: indium>zirconium oxide>aluminum>scandium>gallium.      Indium
 is thought to influence a metalloenzyme necessary for limb bud development in
                                                              (57)
 hamster embryos of mothers injected intravenously with indium.

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                                                               11-21
         Subcutaneous injection of indium compounds produces local tissue cal-
cification.  This response is prevented by the systemic administration of an
                          (58)
iron-dextran preparation.
         Indium sulfate added to the liquid culture medium enhanced the rate
                                                                      (59)
of nitrification of Nitrobacter agilis up to an optimum concentration.
         Pretreatment of plasma proteins with EDT2V affects the in vitro
binding of indium-113M.  Ihe results of the experiments suggest that indium
binding to serum protein occurs in two stages: the first is through a multi-
valent anion, which is released during saturation binding.
         Studies comparing the in vitro deposition of transferrin-bound indium-Ill
(+3) and iron-59 (+3) demonstrated that the characteristics of their transport
                                                       (38)
into reticulocytes were very similar, if not identical.
         The interaction of indium (±3)  with a phospholipid monolayer was
studied at various concentrations of indium.  Indium decreased the surface
pressure of the mDnolayer, suggesting that indium and other heavy metal ions
may disrupt biomembranes to some extent.

     D.  Pharmacology
         Ihe biological half life of indium-114M injected into rabbits was 6.8 days
The highest concentration was found in the kidneys, the lowest in the heart.
Histological examination of different organs revealed extensive damage, especially
                          //-p\
to the kidneys and liver.      Blood clotting was studied in 79 patients
before and after administration of radioindium compounds.  The change in blood
clotting factors and coagulation process depended on the target organ of the
indium conpound used.  Although the blood clotting changes were significant,
no clinical manifestations were observed since the deficits in clotting factors
were only partial and compensated each other.
         Dogs were injected with 200 ml. of indium-iron hydroxide pellets  (138,000
particles per mL) in the main pulmonary artery.  After 100 ml»of particles, a
significant increase occurred in the blood pressure in the pulmonary artery.
However no changes occurred in the pulmonary diffusion capacity or venous
oxygen capacity.

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                                                               11-22
         Calcium deposits occurred at the site of subcutaneous injection
of indium chloride (0.2 mg) six days after injection in young, but not in
adult, rats.(65)

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                                                               11-23
IX.  ENVIRONMENTAL EFFECTS:  BIQAOCUMULATION
     The transport of radioactive indium through the food chain poses a
possible hazard to man.  Bioaccumulation of indium-114M by the Atlantic
croaker, Micropogon undulatus, was studied.  The biological half life of
indium in this food fish was 224 days.  The radioactivity half life of
indium-ll4M is 40.2 days.  The conclusion drawn was that fish retaining
large amounts of indium-114M could pose a hazard to public health.

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                                                                \-M
x.   TOXICITY
     A.  Humans
         1.   Occupaticnal Exposures
              Individuals exposed to Indium oaipounds during the production of
indium complained of tooth decay, pains in joints and bones, nervous and
                                                              (67)
gastrointestinal disorders, heart pains, and general debility.
         2.   Other Exposures
              Out of 770 patients injected with indium-llSM radiopharmaceuticals
for liver scanning, three developed anaphylaetoid reactions.  These three patients
had cancer and an altered general condition.  Vascular shock set in immediately
or within 20 minutes after intravenous injection and lasted from 10 minutes to
an hour.
              In a parallel study of coagulation in patients receiving labelled or
unlabelled indium compounds, changes in intravascular coagulation were observed.
During the first two hours after injection, hyper-coagulation with increased
platelet adhesiveness occurred.  After twenty-four hours, and five  days later,
lengthened coagulation time were observed with decreases in platelet ad-
                                        tCQ\
hesiveness and fibrlnogen concentration.   '
              The toxic effects of indium can be reduced by the use of carrier-
free radioactive isotopes.
     B.  Mammals
         1.   Acute and Subacute Toxicity
              In mice, hydrated indium oxide injected intravenously is forty
times more toxic than ionic indium on a weight basis.  The ID5Q for hydrated
indium oxide was 0.323 ± 0.063 mg per kg body weight.  For ionic indium, the
DD_0 was 12.5 ± 0.6 mg per kg.  Lethal amounts of ionic indium produced in-
activity of the animals and hind leg paralysis one day after injection; rapid
and spasmodic respiration, weight loss and abnormal pelt after two  days; at
three days the mice became totally inactive and died by day four.  In addition
to the above symptoms, lethal doses of hydrated indium oxide produced muscle
tremors and clonic convulsions after two to three days; the mice bled from the
                                                                (28)
mouth, nose, ears, and intestines before they died on day three.

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     50 after seven days for a single intraperitoneal injection of indium chloride
to the albino rat was 1.8 mg per kg; the intravenous eight day ID5Q was 4.1 ntj
per kg.  The principle site of injury following intraperitoneal injection was
the liver.  The proximal convoluted tubule of the kidney was the principal site
of injury with intravenous injection.  An increase in neutrophil count and de-
crease in lymphocytes occurred in rats injected intravenously with indium chloride
over a four month period.
              The U350's for the rat for indium sulfate, expressed in ing-atoms
indium per kg body weight are: 20.5 for oral dose, 2.76 for intraperitoneal
injection, and 0.11 for intravenous.  Massive congestion of all organs,
particularly the liver and kidneys, peaked at about four days after injection.
                                                              (53)
Survivors show complete recovery 30 to 90 days after exposure.
                                                                              \
              Intraperitoneal injection of indium nitrate to mice has an ID,-.
of 0.1 g per kg.  The ID..Q was 0.5 g per kg.  The ID™ for indium nitrite
was 4.2 g per kg with intragastric administration.  The oral administration of
indium oxide to mice had an ID_Q of about 10 g per kg.
              The H>50 of indium antimonide following oral administration was
3.7 g per kg.  The greatest toxicity occurred after intratracheal administration,
with alterations in the pulmonary tissue and dystrophic changes in parenchymatous
tissue.(70)

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              The intratracheal administration of a dust containing 0.1 per
 cent indium in  25 and 50 mg doses resulted in 100 per cent lethality in guinea
 Pigs."1'
         2.   Chronic Toxicity
              Rabbits given 0.16 g indium nitrate per kg daily for 4.5 nonths
                                                                      (72)
 had decreased serum albumin and increased alpha-2-and gamma-globulins.
 Aqueous indium  sulfate  (0.1 to 1.0 mg indium per kg per day)  injected into mice
 for 15 days  produced marked anemia and damage to the lungs, liver and spleen.
 Pulmonary lesions were quite evident.      In male rats killed 2 to 49 days
 after subcutaneous injection of indium triacetate (80 mg per kg), adrenal hyper-
 trophy at the expense of both the cortical and medullary layers was observed,
                                           (74)
 and enlarged nuclei were seen in the cells.
              Topical application of 0.1 per cent indium nitrate to intact
 tooth enamel at pH 1.7 to 3.2 produced partial dissolution.  This finding
 supports the clinical evidence that topical indium nitrate increases caries
 incidence.(75)
              The physicochemical properties of metal cations could be related
 to  their acute  doses on rabbit, rat and mouse.  The log of the lethal dose of
 metal ions decreases linearly with the increase in the log of the stability
 constant of  the metal EDTA complex, which is the product of the electro negativity
 and the ionic charge.
         3.   Teratology
              Indium nitrate injected into the hamster on the eighth day of
 gestation caused a high incidence of malformation of the digits of the offspring,
 including fusion, stunting and polydactyly.  Doses above one mg per kg were
 completely embryopathic.
      C.  Plants
 the roots.
         Indium was toxic to cucumber seedlings, producing disorientation of
           (77)

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                                                               11-28
XI.  CURRENT REGULATIONS
     No specific regulations for shipment of indium or its compound were
found.  In view of the recommended "threshold limiting value" assigned to
this group, they must be treated as class B poisons.  This requires a
"Poison" label on all containers for shipments.

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                                                               11-29
XII.   STANDARDS



       The Threshold Limit Value for indium and its compounds is  0.1 mg/m .

This value is recommended in view of the character and severity of injury

from indium salts, especially the pulmonary effects.   Indium and  its compounds
                                                                (?)
may decompose to form the hazardous product uidiuirr sesquioxide.

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                                                                     11-31
     
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                                                                     1-32
                                References
  (1)  Stanford Research Institute.  U.S.A.  Chemical Information Series.  1974 Directory
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  (2)  White, C.E.T.  Indium. Article for American Metal Markers, (April 25, 1973).

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  (4)  Mineral Facts and Problems,  1970, Indium Chpt. Bureau of Mines, U.S.  Department
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  (8)  Encyclopedia of Chemical Technology III,  3rd ed.  R. Kirk and D. F. Othmer,  eds.
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  (9)  Contact with Western Electric, April - June 1974.

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(11)   Workplace Standards Administration, Bureau of Labor Standards.  Material Safety
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                                                                    11-33
                               References
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                                                                      1-34
                              References
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(32)   Ogiso, Akira,  Rie Yoshida, Kazuo Umeno, Toshiharo Akutsu and Kozo Matsumoto.
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(35)   Franke, Wolf-Gunter, Beate A. Johannsen and Konrad Henning.
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(37)   Huddelstun,  James  E., Fred S.  Mishkin,  Mames E. Carter,  Phillip D. Dubois, and
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(38)   Lilien, David L., Howard G. Berger, Donald P. Anderson,  and Leslie R. Bennett.
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(39)   Miskin, FredS., Isacc C. Reese, Gonzalo T. Chua, and James E. Huddlestun.
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(40)   Ando, Atsushi, and Kin-lchi Hisada. Studies on affinity of  the element in group
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                                                                          11-36
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