"vft
            /•
                                                                               January 1992
                                                 FINAL
                                   DRINKING WATER CRITERIA DOCUMENT
                                                  FOR
                                               ANTIMONY
                               Health  and  Ecological  Criteria Division
                                   Office of Science and Technology
                                           Office  of  Water
                                 U.S. Environmental Protection Agency
                                        Washington, DC   20460
                                           HEADQUARTERS LIBRARY
                                           ENVIRONMENTAL PROTECTION AGENCY
                                           WASHINGTON, D.C. 20460

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TABLE OF CONTENTS
                                            Paoe



I.
II.
III.






IV.
V.










VI.




Lidi ur rjyuKta 	 	
LIST OF TABLES 	
FOREWORD 	
SUMMARY 	
PHYSICAL AND CHEMICAL PROPERTIES 	
TOXICOKINETICS 	 .....
A. Absorption 	
B. Distribution . 	
C. Metabolism 	
D. Excretion 	
E. Bioaccumulation and Retention 	
F. Summary 	
HUMAN EXPOSURE 	
HEALTH EFFECTS IN ANIMALS 	
A. Short-term Exposure 	
1. Lethality 	
2. Other Effects 	
B. Long-term Exposure ' 	
1. Subacute/Subchronic Toxicity 	
2. Chronic Toxicity 	
C. Reproductive/Teratogenic Effects 	
D. Mutagenicity 	 • 	
E. Carcinogenicity 	
F. Summary 	 	 	
HEALTH EFFECTS IN HUMANS 	
A. Clinical Case Studies 	 - 	
B. Epidemiological Studies 	 , 	
C. High-Risk Populations 	
D. Summary 	 * 	
... v
... VI
... vi 11
... 1-1
... II-l
. . . III-l
. . . III-l
. . . III-2
. . . III-7
. . . III-9
. . . 111-12
. . . 111-18
. . . IV- 1
... V-l
. . . V-I
. . . V-l
. . . V-5
. . . V-7
. . . V-7
. . . V-9
. . . V-ll
. . . V-12
. . . V-13
. . . V-16
. . . VI-1
. . . VI-1
. . . VI-3
. . . VI-6
. . . VI-6
      iii

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                         TABLE  OF  CONTENTS  (continued)

                                                                          Paoe

 VII.    MECHANISMS OF TOXICITY	      VIM

         A.   Enzyme Inhibition	      VIM
         B.   Enzyme Activation 	      VII-1
         C.   Interactions	      VII-2
         D.   Summary	      VII-6

VIII.    QUANTIFICATION OF TOXICOLOGICAL EFFECTS  	     VIII-1

         A.   Procedures for Quantification of Toxicological
              Effects	 .     VIII-1
                      >
              1.   Noncarcinogenic Effects   	     VIII-I
              2.   Carcinogenic Effects 	     VIII-3

         B.   Quantification of Noncarcinogenic Effects for
              Antimony	     VIII-6

              1.   One-day Health Advisory   	     VIII-6
              2.   Ten-day Health Advisory   	 .  	     VIII-6
              3.   Longer-term Health Advisory  .....'	     VIII-6
              4.   Reference Dose and Drinking Water Equivalent
                   Level  	     VIII-9

         C.   Quantification of Carcinogenic Effects for Antimony .    VIII-12
         D.   Summary	    VIII-12

  IX.    REFERENCES	       IX-1
                                      iv

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                                LIST OF  FIGURES
Figure No.

   III-l


   III-2


   III-3


     V-l



   VII-1


   VII-2


   VII-3
Mathematical Model for the Distribution of Antimony
in Humans 	

Excretion of Trivalent and Pentavalent Antimony by
Several Species 	

Whole-body Radioactivity of Mice Following a Single
Intraperitoneal Injection of '"SbCl,   	
Dose-Response (Chromosomal Aberrations) of Single or
Multiple,Doses of Potassium Antimony Tartrate or
Piperazine Antimony Tartrate in Rats  	
Effect of Cysteine on the LD50 of Potassium Antimony
Tartrate (PAT) in Mice  	
Effect of Cysteine on Serum Enzymes in Rabbits
Treated With Potassium Antimony Tartrate  . . .
Average Body Weights of Rats Treated With Dietary
Antimony, With and Without Parenteral Thyroxin  .
  Page


 III-6


III-10


111-14



  V-14


 VII-4


 VII-5


 VII-7

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                                LIST OF TABLES


Table No.                                                                 Page

   II-l       Physical Properties of Antimony and Some Antimony
              Compounds	       II-2

   III-l      Antimony Levels In Tissue or Organs of Mice
              Administered 52 mg Sb/kg Body Weight as RL-712  ...      III-4

   III-2      Antimony Levels in Tissue or Organs of Mice
              Administered 50.3 mg Sb/kg Body Weight as
              Glucantime	      III-8

   III-3      Average Antimony Levels 1n Red Blood Cells and
              Plasma  (ps/g) at Various Intervals After im
              Injection of Trivalent Antimony (Anthiomaline and
              M.A.T.) or iv Injection of Pentavalent Antimony
              (Solustibosan and Neostibosan)  	      III-8

   111-4      Excretion of Antimony in Humans Following Repeated
              Administration of Antimony   	      111-13

   III-5      Mean Antimony Levels in Tissues of Mice Following
              Lifetime Exposure to Potassium Antimony Tartrate
              in Water   	      111-17

     V-l      Acute Toxicity of Antimony   	        V-2

     V-2      Emetic  Dose of Antimony Compounds in Dogs	        V-4

     V-3      Incidence  of Lung Tumors in  Female Rats Examined at
              Specified  Intervals  	       V-17

     VI-1     Mortality  of Males Employed  in a Factory
              Manufacturing Antimony Oxide and Followed Through
              December 1981	       VI-5

    VII-1     Effect  of  Potassium Antimony Tartrate and
              Dehydration on Mortality in  Rats and Mice 	      VII-8

    VII-2     Effect  of  Potassium Antimony Tartrate and
              Environmental Temperature on Mortality in Rats
              and Mice	  .      VII-9

   VIII-1     Summary of Candidate Studies for Derivation of the
              Ten-day Health Advisory for Antimony  	      VII1-7

   VIII-2     Summary of Candidate Studies for Derivation of the
              Longer-term Health Advisory  for Antimony  	      VIII-8

   VIII-3     Summary of Candidate Studies for Derivation of the
              Drinking Water Equivalent Level for Antimony  ....    VIII-10

                                      vi

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Table No.

   VIII-4


   VIII-5
                          LIST OF TABLES (continued)
Summary of Candidate Studies for Calculation of
Carcinogenic Risk Estimates 	
Summary of Quantification of Toxicological  Effects
for Antimony  	
   Page


VIII-13


VIII-14
                                     vii

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                                   FOREWORD


     Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986,
requires  the  Administrator of the Environmental  Protection  Agency to publish
Maximum Contaminant Level  Goals (MCLGs) and promulgate National Primary Drinking
Water  Regulations  for  each  contaminant,   which,   in  the  judgment  of  the
Administrator, may have an adverse effect on public health  and which is known or
anticipated to occur in public water systems.  The MCLG  is  nonenforceable and is
set at a level  at which no  known or anticipated adverse  health effects in humans
occur and which allows for an adequate margin of safety.   Factors considered in
setting the MCLG include health effects data  and sources of exposure other than
drinking water.

     This  document provides  the  health  effects  basis   to  be  considered  in
establishing the MCLG.  To achieve this  objective,  data  on pharmacokinetics,
human exposure, acute and chronic toxicity to animals and  humans, epidemiology,
and mechanisms of  toxicity  were evaluated.   Specific emphasis is  placed  on
literature data providing dose-response information.  Thus, while the literature
search and evaluation  performed  in support of this document was comprehensive,
only the  reports  considered most pertinent  in the derivation of the MCLG are
.cited in the document.  The comprehensive literature data base in  support of this
document  includes  information published up to April 1987; however, more recent
data  have' been  added during  the review process and  in response  to  public
comments.

     When adequate health  effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime)  are-included  in this document.  These values are not
used in setting the MCLG,  but serve as  informal guidance  to municipalities and
other organizations when emergency spills or contamination situations occur.

                                                                James R. Elder
                                                                      Director
                                      Office  of Ground Water  and Drinking Water

                                                               Tudor T. Davies
                                                                      Director
                                               Office of  Science of Technology
                                     viii

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                                  I.  SUMMARY

     Antimony  (Sb) is a semimetal element of Group V, sharing some chemical
properties with lead, arsenic, and bismuth.  The most stable valence states  of
antimony are Sb3+ and Sb5+.  Numerous inorganic and organic compounds of anti-
mony are known.  Most of the common antimony compounds are slightly to readily
soluble in water.

     About 7 to 15% of an oral  dose of trivalent antimony is absorbed by
rodents.  No estimate of gastrointestinal absorption in humans was located  in
                         /
the available  literature.  Absorbed antimony usually distributes to most
tissues of the body, with some preferential accumulation in bone, thyroid,
and adrenal.   In mice injected intramuscularly with either antimony dextran
glucoside or N-methyl-glucamine antimonate, the compounds were absorbed from
the site of injection and deposited in the liver and spleen.  Trivalent antimony
is readily taken up by red blood cells, but pentavalent antimony does not enter
red blood cells.

     Claims have been made that Sb(V)  is reduced to Sb(III)  in the body, but no
strong evidence exists to support this idea.  Pentavalent antimony is excreted
primarily in the urine of most species, including humans.  In the mouse, white rat,
hamster, guinea pig, rabbit, dog, and human, trivalent antimony is excreted  in
both the urine and feces, the ratio depending upon the species.  In cows,
82% of the total dose was excreted in the feces, 1.1% in the urine, and 0.008%
in the milk when 124$bCl3 was administered orally.  When 124sbd3 was  given
intravenously to cows, 2.4% of the total dose was excreted in the feces, 51% in
the urine, and 0.08% in the milk.
                                      1-1

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     Antimony shows little tendency to accumulate in the body.  Levels of
antimony have been reported in human milk and tissue.  A mean of 3 ng Sb/g of
milk was reported in Italian women.  A mean concentration of 17.51 x 10-8 g/g
dry weight of 90 pineal glands was reported in humans for both sexes.  A median
concentration of 0.015 ppm was found in the bone tissue of industrially exposed
workers, whereas only 0.007 ppm was found in the control group.  .In mice fed
125$bCl3 in the diet, a steady-state whole-body level was reached after 4 days.
Following intraperitoneal injection in mice, antimony was cleared from the body
biphasically, with a rapid phase  (tjyg * 6 hours) accounting for about 95% of
the dose and a slow phase (tj/2 =2.4 days) accounting for 5% of the dose.  In
mice fed antimony in the diet during pregnancy and 15 days postpartum, antimony
was cleared biphasically, with half-times of 1.8 and 96 days when exposure was
discontinued.  In mice exposed to 0.8 mg Sb/kg/day for life -{mean +^ SE was 786
i 3.7 days for males and 843 +_ 47.8 days for females), tissue levels of anti-
mony at time of natural death were only 6 to 14 ug Sb/g tissue.  Similar
results were obtained in rats exposed to 0.4 mg Sb/kg/day for life (mean +_ SE
was 999 +_ 78 days for males and 1,092 +_ 30.0 days for females), although levels
tended to increase somewhat with  age at time of natural death (p <0.05).

     Estimates of acute oral LD5Q values in mice and rats range from 115 to 600
mg Sb/kg.  An oral 1050 of 15 mg/kg has been reported in rabbits.  Intravenous
and intraperitoneal 1050 values range from 11 to 329 mg Sb/kg.
     Early acute oral toxicity studies showed that considerable variation in
sensitivity to antimony exists among species; mice and rats are less sensitive
than dogs and cats.  In addition, considerable variation in toxicity exists
between different chemical forms  of antimony; the soluble compounds, especially
potassium antimony tart rate, are  more toxic than the less soluble oxides.
                                       1-2

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     The most  prominent  signs  of  acute oral antimony toxicity are nausea and
 vomiting,  often  with  diarrhea.  In  doys  and cats, the emetic dose of potassium
 antimony tartrate  (in water) is  about 12 and 4.2 mg Sb/kg, respectively.  In
 one  study  (Flury,  1927), exposure of. rats and mice to high doses of insoluble
 antimony compounds  {e.g.,  Sb^,  Sb205) was without effect.  However, in
 another study  (Potkonjak and Vishnjick,  1983), intraperitoneal or endotracheal
 administration of  80203  and Sb20§ suspension (50 mg of dust) caused pneumo-
 coniosis in  rats.   In yet  another study  {Pribyl, 1927), lower doses of potassium
 antimony tartrate  (5.6 mg  Sb/kg/day, given in milk for 1 to 3 weeks) caused
                          /
 only minor changes  in blood and  urine nitrogen levels in rabbits but produced
 histological changes  in  the intestine, liver, and kidney.

     Parenteral  administration of antimony (as potassium antimony tartrate) at
 doses of 1.5 to  15 mg Sb/kg results in various signs of myocardial  injury.  One
 report of injury to the  inner  ear of guinea pigs has been reported following
 repeated injections .with sodium antimony bis(pyrocatechol-2,4-disulfate) and
 piperazine-di-antimonyl tartrate.

     Lifetime oral  exposure to potassium antimony tartrate (about 0.8  mg
Sb/kg/day)  in drinking water was without effect  in mice,  but  0.4  mg  Sb/kg/day
 in drinking water caused decreased longevity and altered blood levels  of
 cholesterol and  glucose  in rats.  Doses  of 8 to  100 mg Sb/kg/day  administered
 in water or feed (as  potassium,antimony tartrate) for 4 months to 1  year
 did  not cause decreased growth in rats  or rabbits, but histological  changes
 were observed in tissues.

     Parenterally administered antimony  (about 2.2 mg  Sb/kg)  led  to  decreased
 fertility in rabbits.  No  abnormalities  were found in  rat fetuses whose  mothers
                                      1-3

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were exposed to the pentavalent antimony drug RL-712.  No adverse effects were
found in ewes whose mothers were fed potassium antimony tartrate for 45  days  or
throughout gestation.
     Sodium antimony tartrate has been found to be mutagenic in bacteria, rat
bone marrow cells, and human lymphocytes.  Lifetime exposure of rats and mice
to potassium antimony tartrate (in water) at doses of 0.4 to 0.8. mg Sb/kg/day
did not result in any increase in tumor frequency..
     Few studies were found of antimony toxicity following oral exposure in
humans.  Most cases involved ingestion of food, or liquid stored in antimony-
containing enamel vessels, and the symptoms that followed were characteristic
of gastrointestinal distress (nausea, vomiting).  In one case, administration
of 132 to 198 mg antimony led to severe vomiting, diarrhea, and finally  death.
     Inhalation of antimony under industrial settings is more common, and
abnormal electrocardiograms (EKGs) and increased ulcer frequency have been
related to antimony exposure.  Parenteral administration of antimony compounds-
is used in the treatment of various parasitic diseases.  Adverse effects of
such treatment have included vomiting, diarrhea, liver dysfunction, and  skin
abnormalities.
     Dose-related increases in EKG abnormalities were found in 59 Kenyan
patients following 65 courses  of antimony treatment.  An increase in lung
tissue  concentration of  antimony (280 ppb ug/kg compared with 32 and 19  ppb  in
controls) was  found in 76  copper smelter workers at  autopsy.  Suggestive
evidence of  adverse effects (spontaneous abortions,  premature births, etc.)  of
antimony was  presented in  female workers employed in an antimony plant.
                                       1-4

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     Antimony is thought to exert its toxic effects by interacting with  intra-
cellular enzymes or cofactors.  A number of suIfhydryl-containing compounds
reduce the toxic effects of antimony, suggesting that it may bind to cellular
suIfhydryl groups.  Antimony has been reported to increase the activity  of heme
oxygenase, to increase the action of thyroid hormone, and to decrease the  toxi-
city of selenium, but the mechanisms of these effects are not known.

   There were no suitable studies to calculate the one-day or ten-day health
advisories for a 10-kg child.  It was, therefore, recommended that the
Drinking Water Equivalent Level (DWEL) of 15 ug/L be used as a conservative
estimate for the one-day and ten-day health advisories.  Similarly, a suitable
study for the calculation of a Longer-term HA was not available.  Therefore,  it
is recommended that the Drinking Water Equivalent Level (DWEL) of 15 ug/L  be
taken as an appropriate estimate of the Longer-term HA value.  A LOAEL of  0.43
mg/kg/day, based on decreased longevity in a lifetime study in rats supplied
potassium antimony tartrate in water, was used to calculate a Reference  Dose
(HfD) of 0,4 ug/kg/day and a DWEL of 15 ug/L (15 ug/L).  A limit of 50 ug/L  is
recommended in the U.S.S.R.

     Antimony has been found to be mutagenic in several test systems, and
various types of tumors, including lung neoplasms, have been induced in  rats
upon inhalation exposure; however, no evidence has been found that orally
ingested antimony is carcinogenic.  No subpopulation has been identified that
is more sensitive to the effects of antimony.than is the general population.
                                      1-5

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                     II.  PHYSICAL AND CHEMICAL PROPERTIES

     Antimony is a semimetal element with atomic number 51 and an atomic  weight
of 121.75.  It occurs in four valence states {0, 3-, 3+, and 5+) and forms  a
large number of organic and inorganic compounds.  Table II-l lists the important
properties of antimony and some common antimony compounds.

     Antimony has been used by man since early times.  Ancient Chinese litera-
ture suggests that its use was known some 5,000 years ago (Dyson, 1928).
                     f
Antimony  (or stibium, as designated by the ancient Latins) is not an abundant
mineral but is a component of many ores, of which antimony trisulfide (stib-
nite) is the most abundant  (Weast et al.ğ 1986).  Antimony is used in modern
industry as an alloy in semiconductor technology, batteries, antifriction
compounds, ammunition, cable sheathing, flame-proofing compounds, ceramics,
glass, and pottery.  In 1979, U.S. production of antimony was reported to be
approximately 35,000 metric tons per year (CEH, 1985).  The most widely known
and earliest pharmaceutical antimony compound is tartar emetic (potassium
antimony  tartrate).  A  number of organic antimony compounds have been developed
in recent times that are safer and more effective than tartar emetic.
                                       II-l

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Table II-l
. Physical Properties of Antimony
L
and Some Antimony Compounds II
r
il


Chemical
Antimony

Potassium
antimony
tartrate

Sodium
antimony
tartrate
Antimony
sulfate

Antimony
trichloride
Antimony
tri fluoride
Antimony
tri oxide
Antimony
pentoxide
Antimony
tartrate
Sodium
antimony
bis(pyro-
catechol-2,4-
di sulfate)


Synonyms Formula
Stibium ' Sb

Tartar KSbOC4H4Og
emetic


Stibunal, NaSbOC4H4Og
Emeto-Na

Sb2(S04)3

SbCU
ij
SbF3
*>
Sb203
tmf If
S5205
Sb2(C4H4Og)3-6H20

Stibophen NF C12H18Na5023S4Sb



(i
Solubility!*
Molecular Valence in water ,
weight state (g/100 g} !|
;i
121.75 0 vss ;
•t
324.92 +3 8.3
!
|)
.t
308.83 +3 66.7

'i
531.72 +3 i .
i]
i(
228.12 +3 601
i
178.76 +3 387.4 !
|
291.52 +3 ss

323.52 +5 ss
795.81 +3 s

895.21 +5 s



-
Abbreviations used:
   vss = very slightly soluble.
   i = insoluble.
   ss = slightly soluble.
   s = soluble.
SOURCE:  Adapted from Weast et al.  (1986)  and Windholz et al.  (1983}.
                                      II-2

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                              III.  TOXICOKINETICS

A.  ABSORPTION

     Moskalev (1959) dosed white rats (mean body weight 165  g,  strain not
specified) with potassium antimony tartrate (4.4 nig/kg) via  gastric  gavage or
intravenous (iv) injection.  The dose included 7 ug of 125$b.  The animals were
sacrificed at definite intervals after antimony administration.  Organ  samples,
including urine, feces, and blood, were assayed for 125Sb activity.  Results
were reported as a percentage of the administered radioactivity per  gram wet
                        /
weight of tissue and entire organ.  Roughly 15% of the radioactive dose was
absorbed from the intestine.
     Gerber et al. (1982) studied the absorption of tracer levels of 125Sb
(given as 125sbCl3.in food) in pregnant BALB/c mice following repeated  dosing.
Total-body radioactivity reached an equilibrium level  (1.7%  of  the daily intake)
within 4 days.  Assuming a half-life of 6 hours (see Section III.E,  Bioaccumu-
lation and Retention), the authors calculated that 7%  of the ingested SbCl3 was
absorbed.
     Combined elimination data from cows administered  single oral or intrave-
nous doses of 124$bCl3 (see Section III.D, Excretion)  indicated that very
little (<5%) of the orally administered dose was absorbed via the
gastrointestinal tract of  ruminants.  Most of the administered  radiolabel was
excreted in the feces  (Van Bruwaene et al., 1982).
     Felicetti et al.  (1974) studied the retention of oral doses of  trivalent
or pentavalent 124Sb-tartrate (specific activities not reported) in  Syrian  ham-
sters.   An oral  dose  of 2  uCi/mL was given via gastric gavage.  Two  hamsters
were given 2 ml, two  were  given  1 ml of trivalent 124Sb-tartrate, and  four

                                     III-l

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were  given  1 ml of pentavalent  124Sb-tartrate.  Very little of either the tri-
valent  or pentavalent antimony  was absorbed (no data given).  For both valence
states, antimony was retained  {in the body) with a half-life of less than 1
day.  The two animals that  received 2 ml of the trivalent compound retained 9
and 15% of  the dose by day  4, most of which (88 to 90%) was found-in the gastro-
intestinal  tract.  In the other four animals, 1.6 to 2% of the dose was
retained on day 4; of this, 61  to 64% was in the gastrointestinal  tract.
B.  DISTRIBUTION
                         t
      Gerber et al. (1982) studied distribution of tracer levels of 125SbCl3
given in food to pregnant BALB/c mice.  The diet containing 125$b  was started
on the  day  the vaginal plug was observed.  After 6 days, animals were sacri-
ficed, and tissue levels of 125sb were measured.  Concentrations (expressed as
percent daily dose per gram tissue) in lung, bone, ovary,  and uterus ranged
from 0.085  to 0.2%, although the results were judged by the authors to be
somewhat unreliable (due to low levels of radioactivity).   From 30 to 36% of
the daily dose (assuming 3 g of food was ingested daily) was found in the
intestinal  tract.

     Westrick (1953)  studied antimony distribution in rats.   Groups of five
male Sprague-Dawley rats {average weight about 120 g) were fed diets containing
0 or 2% Sb203 for 7 weeks.   Using a mean body weight of 0.18 kg (the mean of
reported initial  and  final  weights)  and  assuming average food consumption of 12
g/day (Arrington,  1972),  this corresponds to an  average daily dose of about
1,100 mg Sb/kg/day.  After  49 days,  animals  were sacrificed, and tissue levels
of antimony were measured.   Average concentrations in the  liver, kidney,  heart,
spleen, lung, adrenal,  and  thyroid were  8.9, 6.7,  7.6,  18.9, 14, 67.8,  and 88.9
ug Sb/g tissue,  respectively.  A wide variation  was observed within the sample
                                     III-2

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values of some tissues; for example, 125Sb  concentrations  in the thyroid ranged
from 10.7 to 280 ug/g tissue.  A similar pattern  of  antimony distribution was
found in tissues of two adult male rabbits  dosed  by  capsule with 13 mg SbgOs/
kg/day (10.9 mg Sb/kg/day) for 20 days.

     Gerber et al. (1982) also measured tissue  distribution In  pregnant BALB/c
mice following intraperitoneal (ip) injection of  125sbCl3  at day 12 of preg-
nancy.  Peak concentrations in tissues (percent dose per gram tissue) were
observed at 2 to 6 hours after injection.  Highest levels  (approximately 50%)
were seen in the intestine and bone surfaces.  Levels in other  tissues observed
at 2 hours were 1 to 5% in the uterus and ovary,  and 0.01  to 1.0%  in the kidney,
liver, spleen, lung, thyroid, blood, muscle,  skin, and brain.   Low levels
(about 0.1%) were measured in the placenta  and  fetus.

     Casals (1972) investigated the absorption  and tissue  distribution of anti-
mony in NMRI mice.  Female mice were injected intramuscularly (im) either with
antimony dextran glucoside (RL-712) (52 mg  Sb/kg) or with  N-methyl-glucamine-
antimonate (glucantime) (50.3 mg Sb/kg), and  sacrificed at various intervals
between 6 hours and 6 weeks after the injection.  RL-712 was absorbed from the
site of injection and deposited mainly in the liver  and spleen  (Table III-l).
Glucantime was also deposited in liver and  spleen but in smaller amounts (Table
III-2).
     Rowland (1971) studied distribution of antimony in humans  given a single
iv injection of 124sb-labeled potassium antimony  tartrate. Four main compart-
ments were determined via surface scanning:  blood,  liver, skeletal tissue, and
urine.  A detailed model  of the distribution in humans is  shown in Figure III-l.
                                     111-3

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           Table III-l.
Antimony Levels in Tissue or Organs of Mice
Administered 52 mg Sb/kg Body Weight as RL-712

Time after
injection
6 hours
24 hours
48 hours
72 hours
1 week
2 weeks
3 weeks
4 weeks
5 weeks
6 weeks
Skeletal
muscle
1.3
17.6
33.8
__
._
*•
__
•ğ<ğ
__
— —

Kidneys
15.3
14.3
11.7
13.6
12.7
9.1
4.4
0.5
1.0
1.4

Heart
24.4
26.0
23.5
22.2
21.1
8.8
6.8
1.3
2.0
1.5

Spleen
65.1
67.6
39.7
—
32.7
7.4
7.5
6.6
5.0
4.6

Liver
156.8
ğ*•>
124.0
105.0
80.6
68.0
66.7
33.6
34.0
20.7
Q
 Expressed in ug of antimony per g wet tissue (organ),


SOURCE:  Adapted from Casals (1972).
                                     III-4

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           Table III-2.   Antimony  Levels  in Tissue  or  Organs  of Mice
                         Administered  50.3 mg  Sb/kg Body  Weight as Glucantime

Time after
•-injection
24 hours
1 week
4 weeks
Skeletal
muscle Kidneys
1.0 3.5
2.5
<0.5

Heart
4.5
2.0
<0.5

Spleen
4.5
2.5
<0.5

Liver
7.5
7.5
3.0

 Expressed in ug of antimony per g wet tissue (organ).
                      /
SOURCE:  Adapted from Casals (1972).
                                      III-5

-------
                  I—
   B
   Y
   V
   w
   z
   BX
   YX
   VX
   WX
   2X
   X,     Concentration of:
   V '
Definition of the Variables

  free exchangeable antimony  in blood
  free exchangeable antimony  in liver
  antimony in "fast bound" blood compartment
  free exchangeable antimony  in skeletal A
  antimony in urine
  antimony in "slow bound" blood compartment
  free exchangeable antimony  in kidney tissue
  free exchangeable antimony  in "other" tissue
  free exchangeable antimony  in skeletal B
  binding substance in liver
  binding substance in skeletal A
  binding substance in skeletal B
  binding substance in "other"  tissue
  binding substance in kidney tissue
  bound complex in liver
  bound complex in skeletal A
  bound complex in skeletal B
  bound complex in "other" tissue
  bound complex in kidney tissue
Figure III-i.   Mathematical model  for the distribution of  antimony in humans

SOURCE:  Adapted from Rowland  (1971).
                                       III-6

-------
     Leffler and Nordstroem (1983)  demonstrated the transfer  of  Sb  from maternal
to fetal blood in three Syrian golden hamsters intratracheally exposed to
antimony on days 13 and lb after fecundation.  Experimental  details were  not
given.

     Molokhia and Smith (1969) incubated antimony (trivalent or pentavalent)
compounds with equine whole blood in vitro and found that the erythrocyte mem-
brane was permeable to trivalent antimony and impermeable to pentavalent  anti-
mony.  Trivalent antimony bound to plasma proteins but not to erythrocytes.

     Otto et al. (1947) studied antimony distribution between blood cells and
plasma in humans.  Fourteen adult black males with filiaria were treated for 5
aays by daily im injection:  six were administered lithium antimony thiomalate
(anthiomaline)  (up, to 21 daily doses of U.5 my Sb(III)/kg-}; three were adminis-
tered monosodium antimony thioglycollate  (M.A.T.)  (up to 11 daily doses of 0.5
mg Sb(III)/kg); two were administered iv  injection twice daily of neostibosan
(2 to 4 mg  Sb(V)/ky/dose); and three were administered iv injection twice daily
of stibanose  (solustibosan) to 6 mg Sb(V)/kg/dose).  Antimony concentrations in
red  blood cells and plasma were measured  colorimetrically (Table III-3).  For
both trivalent  and pentavalent antimony,.plasma  concentrations were sustained
for  only a  short time  (well under 24 hours).   For  both trivalent compounds,
antimony was  found largely  inside the red blood  cells, with very little in
plasma,  ana the converse was  observed for both  pentavalent compounds.  The
authors  concluded  that  trivalent antimony readily  enters red  blood cells, but
that pentavalent antimony  does not.

C.   METABULISM
      There  are  recurrent  suggestions  in the  literature that  pentavalent  anti-
mony is  reduced to the  trivalent  form  in the mammalian body.   For  example,  Otto
                                      III-7

-------
Table III-3.
Average Antimony Levels In Red Blood Cells  and Plasma  (ug/g)
at Various Intervals After 1m Injection of  Tn'valent Antimony
(Anthlomaline and M.A.T) or iv Injection of Pentavalent
Antimony (Solustibosan and Neostibosan)


Chemical
Anthiomaline

M.A.T.

Solustibosan

Neostibosan

Dose
mg Sb/kg
0.5

0.5
/
3.0

2.0
,
Cells/
Plasma
Cells
Plasma
Cells
Plasma
Cells
Plasma
Cells
Plasma
Time (hours)
0.25
.26
.13
..*
—
3.9
11.8
1.3
10.9
1
.78
.18
1.1
.12
1.1
6.3
.8
5.0
3
.68
.13
.79
—
.3
2.4
.7
3.3
6
.36
.11
.44
.08
.4
1.1
.6
2.1
12
.19
.11
.35
.05
0
.3
.3
1.1
24
.15
.03
.35
.07
.2
.3
.3
.8

*— Not  reported.

SOURCE:  Adapted from Otto et al. (1947).
                                      111-8

-------
and Maren (1950) found large amounts of antimony in erythrocytes  following  im
injection of stibanose (6 mg Sb(V)/kg)  in dogs.   Previous results from  this
group (Otto et al., 1947) and others (Molokhia and Smith, 1969) had shown that
Sb(V) does not enter erythrocytes but that Sb(III) does, suggesting that, in
this case, the Sb(V) had been reduced to Sb(III).  Otto and Maren (1950) did
not detect antimony accumulation in erythrocytes following an im  dose of 0.5 mg
Sb(V)/kg or entry into red cells following iv injection of either 0.5 or 5  mg
Sb(V)/kg.  The authors stated that the available data were not sufficient to
support a conclusion regarding possible reduction of Sb(V) to Sb(III).
                          i
     Goodwin and Page (1943) used polarography to analyze the valence state of
antimony in the blood and urine of humans injected iv with Sb(V).  During the
first 12 hours  after the administration of pentavalent antimony (sodium antimony
gluconate equivalent to 50 ug/Sb), 83.5% (average of three subjects) of the
administered dose was excreted in the  urine as  pentavalent antimony.  Only  2.5%
of the administered dose was excreted  as trivalent antimony during the same
period, indicating that reduction of Sb(V) to Sb(III) was slight.  Otto and
Maren (1950) pointed out that some of  the Sb(III) found in urine may have  been
formed during  sample preparation in hydrochloric  acid for polarographic exam-
ination.

D.   EXCRETION
      Otto  and  Maren  (1950)  reviewed the  routes  of excretion of parenterally
administered antimony in the mouse, white rat,  hamster,  guinea pig, rabbit, dog,
and  human.  Trivalent antimony was excreted via the feces and urine.  With  the
exception  of the mouse,  pentavalent antimony  was  excreted primarily in the
urine (Figure  III-2).  While the percent  of the dose excreted in the feces was
'less than  5%  for all  species tested, the percent  excreted in the urine was
approximately  80,  60, 65,  70,  10, and  43% in  the  white  rat, hamster, guinea pig,
                                     III-9

-------
  90
  60
e
III

I"   M
ff   0
o
x
HI  '



O  90

i

x


*  60
  30
            J
                                         J
            MOUSE  WHTCERAT  M*M5TW  QUTCAPC  FUflBTT     DOG
                           PENTAVAIENT ANTIMONY
               n
           fl
                                0    .a
n
n	TL
MOUSE
                            HAMSTER OJTCA HG  AAB8TT


                           TRIVALENT ANTIMONY
                                                       DOG     MAN
         feces


         urine
Figure III-2.  Excretion of trivalent  and pentavalent antimony by several species.



SOURCE:  Adapted from Otto and Maren (1950).
                                     111-10

-------
rabbit, dog, and human, respectively.  Casals  (1972)  investigated the excretion
of antimony in female mice and rats.  Female mice were injected im  either with
antimony dextran glucoside (RL-712) (52 mg Sb/kg) or  with N-methyl-glucamine-
antimonate (glucantime) (50.3 mg Sb/kg).  Female albino rats were injected  im
with RL-712 (50 mg Sb/kg).  The urine was collected for 48 hours.   Excretion of
antimony in urine was low.  In 48 hours, only 12 and 10% of the doses adminis-
tered were excreted in the urine of mice and rats, respectively.

     Van Bruwaene et al.  (1982) studied the excretion and tissue distribution
of antimony in lactating  cows.  Three cows (weight 423, 420, and 402 kg) were
given a single oral dose  of 124SbCl3 (2.84, 2.72, and 2.00 mCi, respectively).
Since the compound had a  specific activity of 3.5 x 10-2 mCi/mmol,  the  average
dose corresponds to 21.1 mg Sb/kg.  Total excretion of antimony in  feces was
tri phasic and amounted to about 82% of the dose.  Most of the radioactivity in
the feces appeared shortly after dosing (t1/2 * 0.91 day).  About 5% was
excreted more slowly  (t^/2 =3-3 days), and a small amount, 0.002%  of the  dose,
was excreted with a half-life of 29.1 days.  Excretion into urine was biphasic
and amounted to a total of 1.1% of the dose.  Most of the urinary radioactivity
appeared in the initial phase (t^ * 0.97 day), and about 0.003% of the dose
appeared in the second phase  (^1/2 s 4'6 days).  Excretion of antimony  in  milk
was also biphasic and amounted to a total of 0.008% of the dose. Radioactivity
in tissues, at 102 days after dosing, amounted to a total of 0.024% of  the oral
dose.   Highest values of  radioactivity were found in the spleen, liver, bone,
and skin.   In a.parallel  study, one cow  (533 kg) received an iv injection
of 124SbCl3 (0.234 mCi),  which corresponds to a dose of 1.5 mg Sb/kg.   Excretion
of antimony in feces was  triphasic and amounted to a total of 2.4%  of the
injected dose.  Excretion of  antimony accounted for 51% of the dose in  urine
                                      III-ll

-------
and for 0.08% in milk.  At 70 days after dosing, almost 16% of the dose  was
still In the body.  Of the retained dose, 60.8% was found at the site of injec-
tion  (heart) and 25.2% in the liver.  The combined data suggest that  very
little of the administered dose is absorbed via the gastrointestinal  tract of
ruminants (see Section III.A, Absorption).

  .    Lippincott et al. (1947) administered potassium antimony, tartrate (0.566
to .0.576 g of antimony over 25 days) or fuadin (0.566 to 0.576 g of anti-
mony  over 29 days) parenterally to humans as treatment for infection  with
Schistosoma japonicumi  The average 24-hour urinary antimony excretion in
the potassium antimony tartrate group ranged from approximately 12% of the
administered dose at the beginning of treatment to 25% at the end of  treatment.
In the fuadin group, the 24-hour excretions ranged from 17% at the beginning
of treatment to 42% toward the end of treatment.  Toward the end of the
treatment, the combined excretion of antimony in urine and feces in 48 hours
was roughly 55% of the administered dose.  Monkeys administered iv doses of
piperazine diantimonyl tartrate or potassium antimony tartrate had maximum
excretion of antimony 24 hours postdosing (Abdel-Wahab et al., 1974).

     Otto et al. (1947) studied excretion of antimony in humans (see  Section
III.B, Distribution).  Fourteen black adult males with filiaria were  treated
for 5 days by daily im injection: six were administered lithium antimony thio-
malate (up to 21 daily doses of 0.5 mg Sb(III)/kg); three were administered
monosodium antimony thioglycollate (up to 11 daily doses of 0.5 mg Sb(III)/kg);
two were administered iv injections twice daily of neostibosan (2 to  4 mg
Sb(V)/kg/dose); and three were administered iv injections twice daily  of
stibanose (3 to 6 mg Sb(V)/kg/dose).  The amount of antimony excreted  in 24
hours in urine and feces was measured colorimetrically after the first dose and
                                     111-12

-------
at the end of the treatment.  In all cases, most of the excreted antimony
appeared in urine, with only low levels appearing in feces (Table II1-4).   The
pentavalent forms of antimony were excreted in urine more rapidly than  the
trivalent forms.  The authors speculated that these differences reflected the
differences in plasma concentration (Sb(V)>Sb(III)) known to occur (see Section
III.B, Distribution).

E.  BIOACCUMULATION AND RETENTION

     Gerber et al. (1982) measured whole-body (except intestinal tract) levels
of 125$b in pregnant mice (BALB/c strain) fed tracer levels of 125$bCl3 in  the
diet.  The diet was started from the day of the vaginal plug.  The values
obtained (expressed as percent of daily dose) on days 2, 4, and 6 were  0.26 +_
0.07%, 1.92 +_ 0.51%, and 1.53^0.93%, respectively.  The authors concluded
that a steady-state level of 1.7% was reached by day 4.  The authors  also
studied the kinetics, of 125Sb loss from pregnant mice injected ip with  125SbCl3
on day 12 of pregnancy.  The label was lost in a biphasic fashion {Figure
III-3), with the two components having half-times of about 6 hours (represen-
ting about 95% of the dose) and 2.4 +_ 0.3 days  (representing about 5% of the
dose).  A similar biphasic clearance of label from a number of tissues  was
observed following ip injection of !25SbCl3, but half-lives were not estimated.
In another test, mice were fed 125SbCl3  (tracer levels) during pregnancy and
for 15 days after delivery.  When exposure ceased, antimony was cleared biphasi-
cally, with half-lives of 1.84 ħ0.22 days and 96 +_ 48 days  (the latter repre-
senting 3,1% 1 0.7% of the total).  The half-life of antimony in the newborns
was estimated to be about 10 days.
      Bradley and Fredrick (1941) studied antimony levels in  albino rats and
rabbits following chronic exposure.  Several series of tests 'were performed in

                                     111-13

-------
            Table III-4.  Excretion of Antimony in Humans Following
                          Repeated Administration of Antimonya
                                       After
                                 first treatment^
End of treatment
Chemical
Lithium antimony
thiomalate
Monosodium antimony
thioglycollate
Stibanose
Neostibosan
Valence
+3
+3
+5
+5
Urine
11.4
8.1
43.0
16.7
Feces
0.2
1.3
0.02b
0.12b
Urine Feces
21. Gib 2.2b.
70b
67 0.8
55 8.4

^Excretion is expressed as percentage of daily dose excreted in 24 hours.
DSingle value.
SOURCE:  Adapted from Otto et al. (1947).
                                     111-14

-------
                           PAYt  P09T-DOSE
Figure III-3.  Whole-body  radioactivity of mice following a  single  intraperitoneal
               injection of  125SbCl3.


SOURCE:  Adapted from Gerber et  al.  (1982).
                                     111-15

-------
which rats were fed potassium antimony tartrate (8 mg Sb/kg/day}  or antimony
metal (8 or 40 mg Sb/kg/day) in the diet for 6 or 12 months.   In  another test,
rats were fed potassium antimony tartrate (8 mg Sb/kg/day)  or antimony metal
(40 mg Sb/kg/day} for 7-1/2 months ad libitum.  In a third  test,  potassium
antimony tartrate was fed to rats for 6 months in doses increasing to 100 mg
Sb/kg/day and then maintained at that level  for an additional 6 months.  Anti-
mony metal was fed similarly to another group of rats by increasing the dose to
1 g Sb/kg/day.  Rabbits were fed potassium antimony tartrate  or antimony metal
at a dose of 8 mg Sb/kg/day or 40 mg Sb/kg/day, respectively, for 4 months.
                       /
Antimony content of body tissues was measured semiquantitatively  by chemical
and spectrographic methods.  An average of 1 mg of Sb was found in the car-
casses of antimony -exposed rats, regardless of the daily dose, while control
animals contained an average of 0.1 mg Sb.  The authors concluded that antimony
does not accumulate to any extent in the animals.
     Bomhard et al. (1982) studied accumulation of antimony in rats (SPF-derived
Wistar TNO W74) following subchronic oral exposure to two antimony-containing
pigments.  The pigments were nickel rutile yellow [(Tio.88Sb0.05Ni0.075^2^
and chrome rutile yellow [{Tig^SbQ^Crg^^].  On a weight basis, these
pigments contain 7.2 and 4.4% antimony, respectively.  Groups of  15 male and 15
female Wistar TNO W74 rats {4 to 5 weeks old) were fed diets  containing 0,  10,
100, 1,000 or 10,000 ppm of these pigments for 3 months.  Assuming a mean body
weight of 0.3 kg and food consumption of 15 g/day (Arrington, 1972), this
corresponds to average daily doses of about 0, 0.036, 0.36, 3.6,  or 36 mg
Sb/kg/day from nickel rutile yellow and of 0, 0.022, 0.22,  2.2, or 22 mg Sb/kg/
day from chrome rutile yellow.  No measurable accumulation  (<5 ppb) of antimony
in liver or kidney was observed in animals receiving doses  up to  1,000 ppm  of
either pigment for 3 months.
                                     111-16

-------
     Schroeder et al. (1968) studied antimony accumulation  in mice following
chronic exposure.  Groups of about 54 male and 54 female Charles  River CD
strain mice were supplied with water containing 0 or  5  ppm  Sb {as potassium
antimony tartrate) from the time of weaning until death.  This  corresponds to
an average daily dose of about 0.83 mg Sb/kg/day, assuming  mean body weights of
0.03 kg and water consumption of 5 ml/day (Arrington, 1972).  When death
occurred, samples of heart, lung, kidney, and spleen  were removed and pooled in
groups of 5 to 15 as a function of age.  Samples were ashed at  low temperature
and analyzed by atomic absorption spectrophotometry.  The results are shown in
Table III-5.  Antimony was measurable in 17 to 60% of the tissue  samples at
concentrations of 6 to 14 ug Sb/g wet weight.

     Schroeder et al. (1970) also studied antimony accumulation in rats follow-
ing chronic exposure.  Groups of 100 or more Long-Evans rats  (at  least 50 of
each sex) were supplied with drinking water containing  0 or 5 mg  Sb/L (as potas-
sium antimony tartrate) from the time of weaning until  death.   This corresponds
to an average daily dose of about 0.43 mg Sb/kg/day,  assuming mean body weight
of 0.35 kg and water consumption of 30 ml/day (Arrington, 1972).  When death
occurred, samples of tissues were removed, pooled in  lots of two  to eight,
ashed at low temperature, extracted in 2% ammonium pyrrolidine  dithiocarbamate,
and analyzed for antimony content by atomic absorption  spectrophotometry.  The
extraction procedure improved the sensitivity of the  analysis over the previous
study.  Mean antimony levels in tissues from treated  animals  of all ages were
found to range from about 10 to 18 ug Sb/g dry weight.   Antimony  levels were
found to increase with  age  over the interval of 9 to  35 months  of age  (correla-
tion coefficient - 0.525, p <0.05).
                                     111-17

-------
        Table III-5.  Mean Antimony Levels  in  Tissues  of  Mice  Following
                      Lifetime Exposure to  Potassium Antimony  Tartrate
                      in Water

Control mice
Tissue
Kidney
Liver
Heart
Lung
Spleen
No.
19
38
I9
19
19
ug/gb
NDd
ND
ND
ND
ND
Antimony-exposed micea
No.
60
48
88
61
78
% foundc
25
51
17
60
19
ug/gb
13
6
9
11
H

aAnimals were supplied with water containing 5 ppm Sb
bfrom weaning until death.
cug Sb/g wet weight of tissue; these values are approximately
d% found is percent of samples with measurable Sb levels.
 not detected.

SOURCE:  Adapted from Schroeder et al.  (1968).
                                     111-18

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     Swanson and Truesdale (1971) measured antimony  concentration  in normal and
cataractous human lens tissue.  Low or undetectable  levels were found in the
younger age groups (0 to 5 and 10 to 20 years).   Some accumulation was noted in
older age groups (50 to 60 and 70 to 85 years).   Antimony concentration levels
in cataractous tissue (age groups 40 to 55,  60 to 75, and 80 years and over)
were somewhat higher than in age-matched normal  tissue.   The authors suggest
that antimony accumulation in the lens might be  age-dependent.

     The levels of antimony in human milk and tissues have also been determined
in several studies.  Clemente et'al. (1982)  studied  the  concentrations of
antimony and other elements in human milk obtained from  subjects in  Italy.
More than 130 samples were obtained from 21  women for about 2 to 3 months
starting 15 days after childbirth.  A mean +_ SO  of 3.0 +.0.4 ng Sb/g of milk
(wet basis) was reported for 49 samples-of milk  obtained from 16 women with
antimony levels above the detection limit of O.U5 ng Sb/g.  Antimony values
ranged from less than 0.05 to 12.9 ng/g among the 21 subjects.

     Demmel et al. (1982) reported a mean antimony concentration of 17.51 x
10-8 g/g dry weight in 90 pineal glands obtained from humans of both sexes.

     Lindh et al. (1980) studied antimony levels in  bone tissue of industrially
exposed workers.  Specimens of femur were collected during autopsy of seven
workers employed more than 10 years at a smelting and refining  plant in Sweden.
The ages ranged from 45 to 75 years, and the time between retirement and death
ranged from 0 to 21 years.  Antimony levels in bone ranged from less than 0.02
to 0.58 ppm, with a median of 0.015 ppm.  Control values, obtained from five
individuals, ranged from 0.007 ppm to 0.1 ppm, with a median of 0.007 ppm.
                                    111-19

-------
F.  SUMMARY

     About 7 to 15% of an oral  dose of trivalent antimony is absorbed  in
rodents and about 2% in ruminants (cows).  Very little trivalent or pentavalent
antimony was absorbed when introduced into the gastrointestinal  tract  of  Syrian
hamsters.  No estimate of gastrointestinal absorption was found  in humans.
Absorbed antimony usually distributes to most tissues of the body, with some
preferential accumulation in bone, thyroid, and adrenal.  In mice injected  im
with either antimony dextran glucoside or N-methyl-glucamine antimonate,  the
compounds were absorbed from the site of injection and deposited in the liver
and spleen.  Trivalent antimony is readily taken up by red blood cells, but
pentavalent antimony does not enter the red blood cells.
     Claims have been made that Sb(V) is reduced to Sb(III) -in the body,  but
no strong evidence exists to support this hypothesis.  Pentavalent antimony is
excreted primarily in the urine in most species (including humans).  In the
mouse, white rat, hamster, guinea pig, rabbit, dog, and human, trivalent
antimony is excreted both in urine and in feces, the ratio depending upon the
species.  In cows, 82% of the total dose was excreted in the feces, 1.1%  in
the urine, and 0.008% in the milk when 124sbCl3 was administered orally.  When
l24SbCl3 was given intravenously to cows, 2.4% of the total dose was excreted
in feces, 51% in the urine, and 0.08% in the milk.
     There appears to be minimal accumulation of antimony in the body, although
antimony has been reported in human milk and tissues.  A mean +_  SO of  3.0 ^ 0.4
ng Sb/g of milk (range <0.05 to 12.9 ng/g) was reported in Italian women.  A
mean concentration of 17.51 x 10-8 g/g dry weight of 90 pineal glands  was reported
in humans of both sexes.  A median concentration of 0.015 ppm was found in  the
bone tissue of industrially exposed workers, compared to 0.007 ppm in  the
                                     111-20

-------
nonindustrial  control  group.   In mice fed  125sbCl3 in the diet, a steady-state
whole-body level was reached after 4 days.  Following  ip  injection in mice,
antimony was cleared from the body biphasically,  with  a rapid phase  (t]/2 = 6
hours) accounting for about 95% of the dose, and  a slow phase  (t1/2  =2.4 days)
accounting for 5% of the dose.  In mice fed antimony in the diet  during  pregnancy
and 15 days postpartum, antimony was cleared biphasically,  with half-times  of
1.8 and 96 days when exposure was discontinued.  In mice  exposed  to  0.8  mg
Sb/kg/day for life, tissue levels of antimony were only 6 to 14 ug Sb/g  tissue.
Similar results were obtained in  rats exposed to 0.4 mg  Sb/kg/day for life,
although  levels tended to'increase  somewhat with age (p <0.05).
                                       111-21

-------
                              IV.  HUMAN EXPOSURE
     This chapter will be supplied by the Science and Technology Branch,
Criteria and Standards Division, Office of Drinking Water.
                                      IV-1

-------
                         V.  HEALTH EFFECTS IN ANIMALS

A.  SHORT-TERM EXPOSURE

!•  Lethality

     A summary of acute lethality data for antimony and several  antimony  com-
pounds Is shown 1n Table V-l.  Estimates of oral LD50 values range from 15 mg
Sb/kg In the rabbit to 600 mg Sb/kg 1n the mouse.  The LD50 value of  a  single
intraperitoneal (ip) implantation of elemental antimony is 100 mg/kg  in the
                       t
albino rat and 150 mg/kg in the guinea pig (Bradley and Fredrick, 1941).   Large
multiple doses (>55 mg) of the element are lethal when fed to rabbits (Carozzi,
1930).  Rats survived oral doses of 700 mg elemental antimony but failed  to
gain weight (Bradley and Fredrick, 1941).  Potassium antimony tartrate  is
roughly 10 times more toxic than the elemental form, while other salts  of
antimony are less toxic.

     Girgis et al. (1965) found that mice developed tolerance to ip doses of
potassium antimony tartrate.  The ip LD5t) of potassium antimony  tartrate  was
49 _+ 1 mg/kg in untreated male white mice.  This corresponds to  a dose  of 18 mg
Sb/kg.  After an initial nonlethal ip dose of 35 mg/kg potassium antimony
tartrate, there was an increase of about 50% in the LD50 (to approximately 75
mg/kg potassium antimony tartrate).
     Ghaleb et al. (1979) investigated the acute toxicity of five organic
trivalent antimonials in mice and compared it to that of tartar  emetic  (potas-
sium antimony! tartrate, 36.47% Sb).  Estimates of the ip LD50 values of  these
compounds ranged from 13 to 329 mg Sb/kg and are listed on page  V-3.
                                      V-l

-------


^••^^^•^M^^^B
Table V-l.

i
'i
Acute Toxicity of Antimony j,
ii



Dose
Compound
Sodium antimony
tartrate
Potassium
antimony tartrate
(tartar emetic)














Antimony


Antimony
trifluoride
Sb (OH) (COONa)
(Na Acr.) Naphth.b
Sb (OH)2(OH) Me Pyr.b
Sb (OH) (COONa) Naphth.b
Sb (OH)2 Pyr.b
Sb Form (OH) QS.&

Species Routea
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
Mouse
'Mouse

Rat
Rat
Rat ,
Rat
Guinea pig
Guinea pig
Rabbit
Rabbit
Mouse
Rat
Guinea pig
Mouse

Mouse

Mouse
Mouse
Mouse
Mouse

ip
sc
po
ip
sc
ip
IP
iv
iv
sc

po
PO
ip
im
ip
im
po
iv
ip
ip
ip
sc

ip

ip
iP
iP
ip

(mg Sb/kg)
LDSO
LDso
LDso
I>DSQ
LDso
LD50
LDso
L050

LD50

LD50
LD50
LD50
LD60
LD50
LDLO
LDSO
LD50
LDSO
LD50
LD50
LDSO

LD50

LD50
LD50
LD50
LD50

* 24
* 19
* 600
= 50
- 20
= 49
- 18
= 24
= 45
= 55

= 300
= 115
= 11
= 33
* 15
= 55
* 15
= 15
= 90
= 100
= 150
= 22.9

= 329

= 305
= 61
= 147
= 13

|[

Reference
i

Ercoli (1968)
Ercoli (1968)
HSDB (1987)
HSDB (1987)



Ercoli (1968)
Girgis et al . (1965)
Ghaleb et al . (1979) it '
Ercoli (1968)
HSDB (1987)


HS08 (1987)
i
Bradley and Fredrick (1941))
HSDB (1987)
Bradley and Fredrick (1941)
HSDB (1987)
Bradley and Fredrick (1941)
HSDB (1987)




HSDB (1987) m
HSDB (1987) ^
HSDB (1987) j
Bradley and Fredrick (1941):
Bradley and Fredrick (1941)!
Levina and Chekunova (1965)
i

Ghaleb et al . (1979)

Ghaleb et al . (1979)

Ghaleb et al . (1979)
Ghaleb et al . (1979) ;'
Ghaleb et al . (1979)


a
 Abbreviations used:  ip ğ intraperitoneal,  iv
bpo ğ peroral, im = intramuscular.
 Defined in text on following page.
intravenous,  sc *  subcutaneous,
                                       V-2

-------
    o   Antimony!  2-hydroxy,3-carboxy,l-sodium  acrylate naphthalein "Sb (OH)
        (COONa)  (Na  Acr.)  Naphth."   17.40%  Sb;  1050 * 1,750 mg/kg (329 mg Sb/kg).
    o   Antimony!-2,4-dihydroxy-5-hydroxymethyl  pyrimidine "Sb  (OH)2(OH) Me
        Pyr."  46.27% Sb;  LD50 • 660 mg/kg  (305 mg Sb/kg).
    o   Antimony!-2-hydroxy-l,3-dicarboxy sodium naphthalein  "Sb  (OH)  (COONa)
        Naphth.11  18.80% Sb;  LD50 - 350 mg/kg (61 mg Sb/kg).
    o   Antimony!-2,4-dihydroxy pyrimidine  "Sb  (OH)2 Pyr."  48.993% Sb;
        LD50 * 300 mg/kg (147 mg Sb/kg).
    o   Antimony!-7-formy1-8-hydroxyquinoline-5-sulfonate "Sb Form  (OH) QS."
        17.72% Sb; LD50 = 75 mg/kg (13 mg Sb/kg).
      The emetic dose of six antimony compounds in  6.5- to 7.5-kg dogs was
determined by Flury  (1927).   In each case,  antimony trioxide  (one dog), anti-
mony pentoxide  (one  dog), sodium antimonate (one dog),  potassium antimonate
(three dogs), and sodium meta-antimonate (two dogs) were suspended  with gum
arabic in water; potassium antimony tartrate (three dogs) was dissolved in 50 g
of water and was administered via  stomach  tube.  Table V-2 presents the results
of the experiments.   Potassium antimony tartrate was the most effective compound
causing emesis  at 33 mg/kg  (about  12 mg Sb/kg).  A dose of 16 mg/kg (about 6 mg
Sb/kg)  produced no  apparent  effect.  Flury added that when very concentrated
solutions  were  administered  (concentrations  not given) to fasting dogs, the
emetic  dose  was as  low  as  4  mg/kg  (about 1.5 mg Sb/kg).
     Cats  appear  to be  more sensitive  than dogs to the emetic  effect  of potas-
 sium antimony tartrate.  Flury (1927)  observed emesis in three cats given  11.5
or 14.3 mg/kg (4.3  or 5.4 mg Sb/kg) in 50  ml of water via stomach tube.  In  one
 cat that  received a dose of 7.2 mg/kg  potassium antimony tartrate  (2.7 mg
 Sb/kg), vomiting did not occur but marked  salivation  (a  common precursor of
 emesis) was observed.  One cat dosed with  6.9  mg/kg  (2.6 mg  Sb/kg) showed  no
 apparent  response.
                                       V-3

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    Table V-2.  Emetic Dose of Antimony Compounds in Dogs

Compound
Antimony tri oxide
Antimony pentoxide
Sodium antimonate
Potassium antimonate
Potassium antimonate
Sodium meta-antimonate
Sodium meta-antimonate
Potassium antimony tartrate
Potassium antimony tartrate
Potassium antimony tartrate
Dose
(mg/kg)
430
400
460
440
440
400
530
49
33
16
Remarks
No effects
No effects
Nausea
Nausea
Ernes is
No effects
Nausea
Ernes is
Ernes is
No effects

SOURCE:  Adapted from Flury (1927).
                             V-4

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     Bradley and Fredrick (1941) observed the toxic response in albino  rats
following a single ip injection of antimony (metal) or five of its  compounds
(potassium antimony tartrate, antimony trisulfide,  antimony pentasulfide,
antimony trioxide, antimony pentoxide) at dose levels up to the minimum lethal
dose (100, 11, 1,000, 1,500, 3,350, 4,000 mg Sb/kg, respectively).   Animals
dying within a few days showed dyspnea, loss of weight, general weakness,  loss
of hair, and myocardial insufficiency.  In surviving animals, prominent signs
included immediate weight loss'(slowly regained after 5 to 10 days), marked
loss of hair; dry, sca\y skin; and eosinophilia.  At necropsy, gross examina-
tion revealed myocardial congestion with engorgement of coronary vessels and
dilation of the right heart.  Death was attributed to myocardial failure.
Other signs included congestion and occasional necrosis in spleen,  liver,  and
kidney, and hemorrhages in the small intestine.

     Bromberger-Barnea and Stephens (1956) studied the in vivo and  in vitro
acute effects of antimony on canine hearts.  Isolated canine hearts were
injected with 30 mg potassium  (or sodium) antimony tartrate/kg tissue weight
(11.2 mg Sb/kg).  There was bradycardia and a progressive fall in myocardial
contractile force, which was nonreversible.  The authors suggested  that some
antimony became bound to. the heart tissue and continued to exert its toxic
effects.  Single-cell transmembrane potential was unchanged.  In intact animals,
a single iv injection of 30 mg potassium antimony tartrate/kg (11.2 mg Sb/kg)
was lethal within 2 hours postdosing.  There was a progressive decrease in
contractile force and a fall in systemic blood pressure as well as  changes in
the S-T segment of the electrocardiogram.  Death was preceded by myocardial  .
insufficiency and ventricular fibrillation.
                                      V-5

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     Girgls et al. (1970) studied the effect of antimony injection on  electro-
cardiograms (standard limb leads I, II, and III and augmented leads AVR,  AVL,
and AVF) in mongrel dogs.  The dogs were given 5 mg sodium antimony tartrate/kg
(2.0 mg Sb/kg) by iv injection for 4 successive days.  Electrocardiographic
changes occurred immediately after treatment.  There was a decrease in the
P-wave amplitude, a decrease in the QRS complex amplitude with no prolongation
of QRS interval, a flattened or depressed S-T segment, and a decrease  in  ampli-
tude and inversion of the T-wave.
                      /
2.  Other Effects

     Flury (1927) fed high doses of five antimony compounds to rats (one  per
chemical) for 9 days.  Each rat received daily doses increasing from 100  mg to
2 or 3 g.  Doses up to 2 g/day of antimony trioxide or antimony pentoxide or up
to 3 g/day of sodium meta-antimonate caused no adverse effects.  Potassium
antimony tartrate was found to be toxic, however, causing death after the daily
dase was increased to 500 mg (about 1,100 mg/kg Sb/kg) on day 7.  Potassium
antimonate produced adverse effects at dose levels of 2 g/day, but recovery was
rapid when dosing ceased.

     Pribyl (1927) investigated the effect of repeated exposure to 15 mg  potas-
sium antimony tartrate/kg/day (given in a milk plus sugar solution) over  a 7- to
22-day period on nitrogen metabolism and toxicity in four rabbits.  This  cor-
responds to a dose of 5.6 mg Sb/kg/day.  Nonprotein nitrogen, urea nitrogen,.
and ammonia nitrogen were measured in the blood and urine of each animal  before
and after exposure.  A small rise (10 to 13%) in nonprotein nitrogen in blood
and urine was observed  (no p value given); this was partly due to an increase
in urea nitrogen.  Mean  urine ammonia nitrogen was also slightly increased (7%,
                                      V-6

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no p value given).  The author interpreted these increased nitrogen  levels  in
blood and urine as evidence of increased protein catabolism in tissues.   Gross
and microscopic examination showed nemorrhagic lesions in the stomach  and small
intestine, liver atrophy with fat accumulation and congestion, and hemorrhage
in the kidney cortex, with some tubular necrosis.

     Hashash et al. (1981) induced inner ear pathology in adult guinea pigs
with two antimonial  antibilharzial drugs (eight animals/drug).  In each  group,
half of the animals were injected intramuscularly (im) for 15 days with  the
therapeutic dose, and half were injected im for 15 days with the experimental
                         f
dose (twice the therapeutic dose).  The therapeutic doses were 1 mg/kg of
Stibophen NF (sodium antimony bis(pyrocatechol-2,4-disulfate)) and 0.7 mg/kg of
Bilharcid EP (piperazine-di-antimonyl  tartrate).  The test doses were  2  mg/kg
and 1.4 mg/kg for Stibophen NF and Bilharcid EP., respectively.  Tissue changes
occurred after the 15-day treatments.  Atrophy of the organ of Corti and
replacement by granular, vacuolated epithelioid cells were seen in the animals
receiving experimental doses of either drug.  The spiral  ganglion was  not
affected.  The therapeutic dose caused patchy hydropic degeneration  of the  hair
and supporting cells of the organ of Corti.  The therapeutic dose of piperazine-
di-antimonyl tartrate caused generalized degeneration of the same tissues.

B.  LONG-TERM EXPOSURE
1.  Subacute/Subchronic Toxicity
     Westrick (1953) studied the effects of feeding antimony for 7 weeks on
thyroid function in rats.  Four groups of five male Sprague-Dawley rats  (ini-
tial mean body weight about 120 g) were fed diets containing 0 or 2% Sb203  for
7 weeks.  In addition, one group each of the 0 and the 2% Sb203 diet received
                                      V-7

-------
thyroxin injections.  Using a mean body weight of 0.18 kg (the mean  of  reported
initial  and final weights) and assuming average food consumption  of  12  g/day
(Arrington, 1972), this corresponds to an average daily dose of 1,114 mg
Sb/kg/day.  Animals were weighed periodically, and oxygen consumption (an index
of thyroid activity) was measured after 1, 2, 3, 4, and 6 weeks.   Growth was
not affected in the antimony-treated rats, but there was a drastic weight loss
at 4 weeks in the antimony-thyroxin-treated rats.

     After 2 weeks, there was a significant (p <0.01) increase in oxygen con-
sumption in the antimony-thyroxin-treated group.  The author suggested  that
                         j
antimony enhances the action of thyroxin, causing hypermetabolism.  Since these
changes were not accompanied by changes in the thyroid histopathology,  the
action of antimony plus thyroxin was judged to be extrathyroidal. The  antimony-
treated group had some thyroid hyperplasia, suggesting a thyroid  block. Similar
results (hypermetabolism) were observed in two adult male rabbits dosed by
capsule with 13 mg SbgC^/kg/day (10.9 mg Sb/kg/day) for 20 days.

     Flury (1927) performed an extensive series of studies on the health
effects of orally ingested antimony in animals.  In the first study, rats (two
per test group) were exposed to potassium antimony tartrate or potassium anti-
monate (dissolved in water), or to antimony trioxide or antimony  pentoxide
(mixed with dextrose) in food.  Doses began at 0.1 mg/day and were increased
periodically over the course of 107 days to a final level of 4 mg/day.  For
most of the period, both animals received a low dose (0.1 mg/day  for the first
21 days and 0.2 my/day for the next 50 days); one of each pair of rats  then
received daily doses that were doubled each week to reach the final  level for
the last 5 days.  No toxic effects were observed, and growth was  unaffected
except for a stimulation of growth at low doses.
                                      V-8

-------
     In the second study, Flury (1927) tested  higher doses  of  potassium antimony
tartrate and antimony trioxide and sodium meta-antimonate in food  for  a slightly
longer period, 131 days.  Groups of two rats were exposed to doses of  the  first
two compounds beginning at 1  mg/day for 45 days, and then increasing over  the
course of 86 days to 200 mg/day, with the dose being doubled in an irregular
fashion.  The third compound was given in doses from 3 to 1,000 mg/day in  a
similar pattern.  No effects were seen,'even at the highest doses, for antimony
trioxide and sodium meta-antimonate, but potassium antimony tartrate caused  a
generalized deterioration and death at high doses {200 mg/day).  This  corre-
sponds to about 485 mg Sb/kg/day, assuming a mean body weight of 155 g (approx-
imately 130 to 180 g).

     Bomhard et al. (1982) studied the subchronic oral toxicity of two anti-
mony-containing pigments fed to rats  for 91 days.  The pigments were nickel
rutile yellow l(Tig.88Sb0.05N10.075)°2^ and chrome rutile yellow
t(T10.94Sb0.03Cr0.03^02^'  On a wei9ht basis, these pigments contain 7.2 and
4.4% antimony, respectively.  Groups  of 15 male and 15 female Wistar TNO W74
rats  (4 to  5 weeks old)  were  fed  diets containing  0,  10,  100,  1,000, or 10,000
ppm of these pigments  for 91  days.. Assuming  a mean body weight of 0.3 kg and
food consumption  of  15 g/day  (Arrington,  1972), this  corresponds to daily doses
of about 0,  O.U36, 0.36, 3.6, or  36 mg/kg/day from  nickel  rutile yellow or 0,
0.022, 0.22,  2.2, or 22 mg Sb/kg/day  from  chrome  rutile  yellow.  Appearance,
behavior,  food  consumption,  growth, mortality,  hematological  and  clinical
chemical data,  organ weights, and gross  and microscopic  appearance of organs
were  not affected in  any dose group.
                                            T
      Potkonjak  and  Vishnjich (1983)  injected  female "Wistar-type"  alhino  rats
with  0.5 ml of  Sb203 or Sb205 suspension (50  mg of  dust) ip in  one group  and
                                       V-9

-------
endotracheally in another group.  The animals were sacrificed after 2  months,
and the lungs and omentum were examined histologically.  Pneumocom'osis  of  a
noncollagenous nature was observed.

     Kazem et al. {1980} demonstrated that male albino rats repeatedly injected
with 99mTC-antimony-sulfide colloid (693 ug Sb, given in nine equivalent doses
at 1-week intervals) showed no macroscopic or microscopic evidence of  tissue  or
cellular damage in the liver, spleen, kidneys, or bone marrow.  The total dose
administered corresponds to 2 mg Sb/kg, assuming a mean body weight of 0.35 kg
(Arrington, 1972).

2.  Chronic Toxicity

     Bradley and Fredrick (1941) studied the chronic toxicity of antimony in
albino rats and rabbits.  Several series of tests were performed in which rats
were fed potassium antimony tartrate (8 mg Sb/kg/day) or antimony metal  (8  or
40 mg Sb/kg/day) in the diet for 6 or 12 months.  In another test, rats  were
fed potassium antimony tartrate (8 mg Sb/kg/day) or antimony metal (40 ing
Sb/kg/day) for 7-1/2 months ad libitum.  In a third test, potassium antimony
tartrate was fed to rats for 6 months in doses that were increased up  to 100  mg
Sb/kg/day and then maintained at that level for an additional  6 months.   Anti-
mony metal was fed similarly to another group of rats by increasing the  dose  to
1 9 Sb/kg/day.  Rabbits were fed potassium antimony tartrate or antimony metal
at a dose of 8 or 40 mg Sb/kg/day, respectively, for 4 months.  All  animals
maintained their normal growth rates.  Basophilic blood cell counts were normal
throughout the study period in both rats and rabbits, although rats showed
slight leukocytosis.  Gross and microscopic examination of tissues from  these
animals revealed changes similar to those observed in animals receiving  sub-
lethal doses of potassium ammonium tartrate by ip injection.  These changes

                                      V-10

-------
     included  congestion  and  altered fiber  appearance In the heart, congestion with
     degeneration and polymorphonuclear  leukocyte  infiltration  in the  liver, conges-
     tion with glomerulonephritis  and  tubular  necrosis  in the kidney,  softened and
     congested viscera with hemorrhages  in  the small intestine, and congestion of
     the spleen.
          Schroeder et al.  (1968)  studied the  effect of chronic exposure to antimony
     in mice.   Groups of  about 54  male and  54  female Charles River CD  strain mice
     were supplied with drinking water containing  0 or  5 ppm Sb (as potassium anti-
     mony tartrate) from  the time  of weaning until death.   This corresponds to an
     average daily dose of  about 0.83  mg Sb/kg/day, assuming a  mean body weight of
     0.03 kg and water consumption of  5  ml/day (Arrington,  1972).  Animals were
     weighed weekly for 8 weeks and then monthly.  Antimony did not significantly
     suppress growth in either males or  females during  the  first year,  but did
     result in weight loss  in males after 18 months (p  <0.025)  and decreased weight
     gain in females measured at 12 and  18  .months  (p <0.005).   Antimony did not
     significantly affect the mean or  medial lifespan or  lifetime until 75, 90, or
     100% deaths occurred in either males or females.   Upon necropsy,  histologic
     examination of the liver revealed no significant difference in the incidence or
     degree of fatty degeneration  between controls (22.2%)  and  antimony-exposed
     animals (16.4%).
          The effect of chronic exposure to antimony in rats was also  studied
     (Schroeder et al., 1970).  Groups of 100 or more Lony-Evans rats  (at  least 50
     males and 50 females)  were supplied with drinking  water containing 0  or.5 mg
     Sb/L (as potassium antimony tartrate)  from the time  of weaning until  death.
     This corresponds to  an average daily dose of  about 0.43 mg Sb/kg/day, assuming
^^~a mean body weiyht of  0.35 kg and water consumption  of 30  ml/day  (Arrington,

                                           V-ll

-------
1972).  Antimony was toxic to rats.  Mean longevity (in days) +_ SE was 1,160 +_
27.8 for control males, 1,304 ^ 36.0 for control females, 999+. 7.8 for treated
males, and 1,092^ 30.0 for treated females.  Antimony had a negligible effect
on body weight.  Serum cholesterol levels were increased in male rats (97.6_+
4.9 mg/100 ml in treated animals versus 77.5 ħ 2.1 mg/100 ml in controls)  and
decreased in female rats (97.0 ħ 5.6 mg/100 ml in treated animals versus 116.0
_+ 6.0 in controls).  Fasting blood glucose levels were not significantly different
in either males or females, but nonfasting blood glucose levels were lower in
both males (94.5 _+ 6.2 mg/100 ml in treated animals versus 134.4 +,5.1 mg/100
ml in controls) and females (82.5 ^7.0 mg/100 ml in treated animals versus
114.2 +_ 5.4 mg/100 ml in controls).  No significant effects of antimony on
glucosuria, proteinuria, heart weight, or heart/body weight ratio were observed.
Histopathology was not performed in this study.
C.  REPRODUCTIVE/TERATOGENIC EFFECTS
     Hodyson et al. (1927) studied the reproductive effects of antimony in
rabbits (strain not specified) and English white mice (2 males and 10 females
per breeding group).  The rabbits (four females/group, 1.8 kg) were injected iv
with seven to seventeen 10-mg doses of sodium antimony tartrate (2.2 mg Sb/kg)
or nine to sixteen 50-mg doses of an unknown organic antimony compound over
16 to 38 days.  Tne mice were injected hypodermical ly with 30 to 39 doses  of
10 mg of another unknown organic antimony salt over 60 to 77 days.  Injections
were given to only the males in one breeding group, only the females in two
breeding groups, and to both sexes in two breeding groups.  In general, in the
female rabbits and mice, contraception, abortion, and fetal damage (details not
specified) occurred; in males, the antimony salt did not cause sterility.
                                      V-12

-------
     James et al. (1966) fed antimony potassium tartrate to four yearling  ewes
at a dose level  of 2 mg/kg of body weight for 45 days or throughout gestation.
All ewes fed antimony gave birth to normal, full-term lambs.  No adverse effects
were found in ewes upon necropsy.

     Belyaeva (1967) investigated the reproductive effects of inhalation expo-
sure of antimony trioxide in rats.  Repeated exposure to 250 mg/m3 Sb03 dust
over a 2-month  period resulted in sterility and fewer offspring in dosed rats
than in the control group.
     Casals (1972) reported the  absence  of any abnormalities in rat fetuses
whose mothers were exposed to pentavalent antimonial drug RL-712 (antimony dex-
tran glycoside) during  gestation.  Wistar female  rats were administered five im
injections of 125 and 250 mg Sb/kg between days 8 and 14 of .gestation.  On day
20, the dams were sacrificed; the number of  fetuses, resorptions, and implanta-
tions were recorded, and fetuses were examined for external malformations.

0.  MUTAGENICITY
     Paton and  Allison  (1972) studied the effect  of  antimony on chromosome
damage  in human leukocytes  in vitro.  A  concentration of 1  uM sodium antimony
tartrate was toxic  to cells, and incubation  for 48 hours with 2.3 nM sodium
antimony tartrate caused  a  significant  (p  <0.05)  increase  in cells with chroma-
tid breaks.  Cytologic  examination  revealed  that  12% metaphases had chromatid
breaks  in treated eel Is,  and only  2%  had chromatid breaks  in control cells.
      Hashem and Shawki  (1976) studied human  peripheral  blood lymphocytes  (Pis)
cultured  with  or without  phytohemagglutinin  stimulation from patients treated
with potassium antimony tartrate (injected  dose  * 2  mg/kg,  twice each week  for
6 weeks).   In  Pis cultures  of treated patients,  4.0  i 0.59% of  Pis were

                                       V-13

-------
transformed  into  lymphoblasts.  Phytohemagglutinin-stimulated cultures had a
mitotic  index  significantly lower than that in cultures from nonantimony-treated
patients.  There  was also an increase in chromosome breaks and fragmentation in
the antimony-treated yroup.  Cultures without phytohemagglutinin stimulation did
not have a lower  mitotic index or increased chromosomal damage between groups.
     Kanematsu and Kada (1978) and Kanematsu et al. (1980) determined that
antimony trichloride, antimony pentachloride, and antimony trioxide were muta-
genic in the rec-assay.  An improved rec-assay procedure employing the insertion
of a cold intubation before incubation of plates at 37°C was used.  Two strains
of Bacillus  subtil is (H17 and M45) were used.  Filter paper disks soaked in
metal solution were dropped on streaked agar plates.  When the DNA damage is
produced by  a  chemical  and subjected to cellular recombination-repair function,
the growth of  recombination-deficient cells is inhibited much more than that of
the wild-type cells.  All three compounds (concentrations Ğ 0.005 to 0.5 M)
strongly inhibited the cellular growth of a recombination-deficient strain of
!• subtil is  (M45) as compared with the wild-type strain (H17).  The results
indicate the DNA-damaging capacities of the three antimony compounds.

     El Nahas et  al. (1982) studied the cytogenetic effects of potassium anti-
mony tartrate  (36.5% antimony)  and piperazine antimony tartrate (36.9% antimony)
in male rats (Rattus norvegicus).  Five rats were dosed within each treated
group.  Four untreated rats served as control for each dose.  Fifty metaphases
were studied per  rat.  The rats were administered ip injections of 2, 8.4, or
14.8 my potassium antimony tartrate/kg or 1, 10, or 19.1 mg piperazine antimony
tartrate/kg.  Each dose was given as a single dose or daily for 5 days.  Animals
were sacrificed at 6, 24, or 28 hours after a single dose or 6 hours after a
multiple dose.  Chromosomal aberrations in bone marrow cells were observed as
                                      V-14

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chromatid yaps, chromatid breaks, centric fusions,  and chromosomal  stickiness.
The dose-response of single and multiple treatments of both drugs suggests  a
maximal effect at the intermediate dose {Figure V-l).  The only exception was
the single treatment with potassium antimony tartrate, which had a linear
response.
     The transformation of hamster cells by SA7 virus was enhanced 'by tungsten
antimonate (ĞSb04) and Sb^HsOeJs (Casto et al., 1979).
£.  CARCINOGEN I CITY
                          t
     Schroeder et al . {1968} studied the effect of lifetime exposure to antimony
on tumor frequency in mice.  The experimental details of this study are reported
in Section B.2, Chronic Toxicity.  Groups of about 54 male and 54 female Charles
River CD strain mice were supplied with drinking water containing 0 or 5 ppm Sb
(as potassium antimony tartrate) from the time of weaning until death.  This
corresponds to an average daily dose of about 0.83 mg Sb/ kg/day, assuming a
mean body weight of 0.03 kg and water consumption of 5 ml/day (Arrington,
1972).  When death occurred, animals were dissected, gross tumors and other
lesions were noted, and abnormal tissues were prepared for histologic examina-
tion.  Tumors were found  in 34.8% of control animals and 18.8% of the antimony-
treated animals.  The authors concluded that antimony exposure had no effect on
the incidence or type of  spontaneous tumors, either benign or malignant.

     Schroeder et al . (1970) studied the effect of lifetime exposure to .anti-
mony on tumor frequency in  rats.  Groups of  100 or more Long-Evans rats (at
least 50 of each sex) were  supplied with drinking water containing 0 or 5 mg
Sb/L (as potassium antimony tartrate) from the time of weaning until death.
This corresponds to an average  daily dose of about 0.43 mg Sb/kg/day, assuming
a mean body weight of 0.35  kg and water consumption of 30 ml/day (Arrington,
                                      V-15

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   IK

   O
   •ğ
   O
   s
   O
   ff

   u
   III
   f>
        10
         8
                               6     1    12


                                   DOSE <*a/k0)
16
20
           O - Single treatment of  piperazine  antimony tartrate.


           A - Multiple treatment of piperazine antimony tartrate.


           • - Single treatment of  potassium antimony tartrate.


           A- Multiple treatment of potassium antimony tartrate.
Figure V-l.  Dose-response (chromosomal  aberrations) of single or  multiple doses
             of potassium antimony tartrate or piperazine antimony tartrate
             in rats.

SOURCE:  Adapted from El Nahas et al. (1982).
                                      V-16

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1972).  Ko significant effect of antimony exposure on tumor frequency  was
observed in either male or female animals.

     In contrast, recent studies indicate that antimony trioxide is carcino-
genic in rats following inhalation exposure.  Watt (1983), in a dissertation
abstract, reported that antimony trioxide is fibrotic and neoplastic to female
rats when inhaled at levels close to the threshold limit values (TLVs).  Female
CDF rats and S-l miniature swine were exposed by inhalation to antimony trioxide
dust at 1.6 +_ 1.5 nuj/mS (as Sb) or 4.2 +_ 3.2 mg/m3 (as Sb) for 6 hours/day, 5
                         /
days/week for approximately 1 year.  Some rats were held for one year  post-
exposure (actual data not provided).  The doses selected were close to the TLV.
The lungs of exposed animals (rats and swine) were mottled and heavier than the
lungs of unexposed animals.  Serum blood urea nitrogen (BUN) levels were consis-
tently higher though not statistically significant in treated animals.  Body
weights were significantly higher for exposed rats.  Primary lung neoplasms
were seen in rats but not in swine.  The incidence and/or severity of  the
response was related to the exposure time and the exposure level.  Most of the
neoplasms were seen in the higner dose group sacrificed 1 year after exposure
and were either  scirrhous carcinomas, squamous cell carcinomas, or bronchio-
alveolar adenomas.  Actual data on incidences of tumors was not provided in the
report.  The nonneoplastic responses observed in both high- and low-dose groups
of rats consisted of focal fibrosis, adenomatous hyperplasia, multinucleated
giant cells, cholesterol clefts, pneumonocyte hyperplasia, and pigmented
microphages.
     Groth et al. (1986) investigated the carcinogenic effects of antimony
trioxide and antimony ore concentrate in rats.  Three groups of 8-month-old
Wistar-derived albino rats (90 males, 90 females per group) were exposed by
                                      V-17

-------
 inhalation  in six Rochester-type stainless-steel exposure chambers (two cham-
 bers  for each group) to either Sb203,  Sb ore concentrate, or filtered air
 (control).  The mean daily time-weighted averages (TWAs) in SbgOs chambers were
 45.0  (range 0 to 18.5) and 46.0 (range 0 to 91.1) mg Sb203/m3.  The mean TWAs
 in Sb ore concentrate chambers were 36.0 {range 0 to 83.2) and 40.1 (range 0 to
 91.1) my Sb ore/m3.  The rats were exposed for 7 hours/day, 5 days/week, for up
 to 52 weeks.  Five rats/sex/group were serially sacrificed after 6, 9, and 12
 months of exposure.  All  remaining animals were sacrificed 20 weeks after
 termination of exposure.   Histopathological  examinations revealed the  presence
                          *
 of lung neoplasms in 27%  of the females in the $0303 group and 25% of  the
 females in the Sb ore concentrate group.  No tumors  were found in the  male rats
 or control  females.   The  incidence of lung tumors in females  at various  intervals
 is shown  in Table V-3.

 F.  SUMMARY

      Estimates of  acute oral 1059  values in mice  and  rats  range  from 115 to 600
mg Sb/kg, although an oral LD-so value of 15 mg Sb/kg  has been reported for
rabbits.  The iv and ip LDso values are generally somewhat lower, ranging from
11 to 329 mg Sb/kg.

     Early studies showed that there is considerable variation in sensitivity
to antimony among species; mice and rats are less sensitive than dogs and cats.
In addition, considerable variation in toxicity exists between different
chemical forms of antimony; the soluble compounds, especially potassiunv anti-
mony tartrate, are more toxic than the less soluble oxides.

     The most prominent signs of acute oral  antimony toxicity  are nausea  and
vomiting,  often with diarrhea.   In dogs  and cats,  the emetic dose of potassium
                                      V-18

-------
              Table V-3.  Incidence of Lung Tumors in Female Rats
                          Examined at Specified Intervals

Incidence of lung tumors
Interval (in weeks)
18-40 (died and serial sacrifice)
40 (serial sacrifice)
41-53 (died)
53 (serial sacrifice)
54-71 (died)
71-73 (serial sacrifice)
Total (18-73 wk)
41-72 wk
Controls
0/15
0/5
0/10
0/5
0/15
0/39
0/89
0/69
Sb203
0/14
0/5
0/11
2/5
5/23
12/31(39%)*
19/89(21%)*
19/70 (27%)*
Sb ore
0/14
0/5
1/9
2/5
3/21
11/33 (33%)*
17/87 (20%)*
17/68 (25%)*

*Significantly greater incidences of lung tumors than the controls,  p £ 0.001.

SOURCE:  Adapted from Groth et al. (1986).
                                      V-19

-------
antimony tartrate (in water) is about 12 and 4.2 mg Sb/kg, respectively.   In
one study  (Flury, 1927), exposure of rats and mice to high oral  doses of
insoluble  antimony compounds (e.g., Sb2l)3, Sb205) was without effect; however,
in another study (Potkonjak and Vishnjick, 1983), ip or endotracheal  administra-
tion of 50203 and $0305 suspension (50 mg of dust) caused pneumoconiosis  in
rats.  In  yet another study (Pribyl, 1927), lower doses of potassium antimony
tartrate (5.6 mg Sb/kg/day) administered in milk for 1 to 3 weeks caused  only
minor changes in blood and urine nitrogen levels, but produced histological
changes in the intestine, liver, and kidneys in rabbits.
                         >
     Parenteral administration of antimony (as potassium antimony tartrate) at
doses of 1.5 to 15 mg Sb/kg results in various signs of myocardial  injury.   In
addition,  injury to the inner ear following repeated im injection of antimony
bis(pyrocatechol-2,4-disulfate) or piperazine-di-antimonyl tartrate at 0.7  to 2
my/ky for  15 days to guinea pigs has been reported.

     Lifetime oral  exposure to potassium antimony tartrate (about 0.8 mg
Sb/kg/day) in drinking water was without effect in mice, but 0.4 mg Sb/kg/day
caused decreased longevity and altered blood levels of cholesterol  and glucose
in rats.   Oral doses of 8 to 100 mg Sb/kg/day (as potassium antimony  tartrate)
for 4 months to 1 year did not cause decreased growth in rats or rabbits;  how-
ever, histological  changes such as congestion and altered fiber  appearance  in
the heart, congestion with degeneration and polymorphonuclear leukocyte
infiltration in the liver, and congestion with glomerulonephritis and tubular
necrosis in the kidney were observed*

     Although antimony may cross the placental  barrier (see Section III.8),
orally ingested antimony at doses of 190 mg Sb/kg/day did not interfere with
pregnancy  in dogs.  Parenterally administered antimony (about 2.2 mg  Sb/kg)

                                      V-20

-------
   led  to decreased fertility  in  rabbits  and  mice.  No  abnormalities were found in
   rat  fetuses  whose mothers were  exposed  to  pentavalent antimonial drug RL-712.
   No adverse effects were  found in ewes whose mothers were fed potassium antimony
  tartrate for 45  days or throughout gestation.

       Various salts of antimony have been found to be mutagenic in various test
  systems.  Antimony trichloride, antimony pentachloride,  and antimony trioxide
  induced DNA damage in bacteria.   Potassium  antimony  tartrate and  sodium anti-
  mony  tartrate induced chromosomal  aberrations  in  human leukocytes.   Piperazine
  antimony tartrate and potassium  antimony tartrate induced chromosomal aberra-
  tions in  bone marrow  cells of rats.

      Evidence shows that carcinogenicity of antimony is directly associated
 with the route of  exposure.  Antimony dust and ore, when  inhaled, appears  to be
 carcinogenic in both animals  and humans.  Primary  lung tumors were observed
 with no  evidence for systemic neoplasia.  In contrast, no evidence of carcino-
   
-------
                          VI.   HEALTH  EFFECTS  IN HUMANS
A.  CLINICAL  CASE STUDIES

     Cases  of antimony toxicity resulting from oral ingestion are infrequent
in humans.  Kaplan and Korff  (1936) briefly reviewed several reports of "food
poisoning"  that were traced to antimony extracted from enamel-coated vessels by
acid contents (lemonade). Symptoms were not  detailed, but acute attacks of
vomiting occurred in at least  one case.  The amount of antimony ingested was
not reported. Tests performed by the authors indicated that 0.5 to 2.6 mg of
antimony could be extracted into 200 g of sauerkraut, an amount equal  to about
one-fourth  of an emetic dose.  It may be noted that antimony migrates  only in
traces from pottery into  drinks (Zawadzka and Brzozowska, 1979).  However,
intoxication  of antimony  with  contaminated drinks from vesse-ls or tartar emetic
is known (McCallum, 1977}.  The maximum contents of antimony in food tolerated
by the U.S. FDA is 2 ppm  (Spitz and Goudie, 1967).
     Miller (1982) reported a  case of antimony poisoning leading to the death
of a patient  (Oliver Goldsmith, a famous English author) suffering from head-
ache, kidney  trouble, and fever.  The patient was administered two or  three
doses of James powder (each dose containing 66 mg of antimony) and consequently
received a total  of 132 to 198 mg of antimony (1 to 1.5 mg/kg of body  weight).
The treatment resulted in severe vomiting and diarrhea lasting for 18  hours
and, finally, death.

     Antimony compounds are used in human medicine for the treatment of'various
parasitic diseases such as schistosomiasis.  These are generally organic  antimo-
nials and are administered parenterally, either intravenously or intramuscularly,
                                      VI-1

-------
     Jolliffe (1985)  reported  the  effect  of  sodium  stibogluconate  ("Pentostam")
given intravenously,  for 10 days,  in a standard  daily dose  of 600  mg Sb (V) to
16 British soldiers with cutaneous leishmaniasis.   The treatment did not adversely
affect either glomerular or renal  functions.  Stemmer (1976) noted that similar
to arsenic compounds, the trivalent compounds  of antimony are more toxic than
pentavalent compounds.

     Schroeder et al. (1946) studied the effect  of  trivalent and pentavaTent
antimony compounds on the,electrocardiograms of  human patients  being treated
for scnistosomiasis with potassium antimony  tartrate or sodium  antimony
bis(pyrocatechol-2,4-disulfonate)  (Stibophen NF  or  Fuadin). Fuadin was given
intramuscularly, and  potassium antimony tartrate was given  intravenously,  daily
or on alternate days, for about 1  month.  Assuming  an average  body weight  of 70
kg, average daily doses ranged from 0.24 to  0.89 mg Sb/kg/day.   Examination of
315 electrocardiograms (EKSs)  from 100 patients  revealed the following altera-
tions: increased P-wave amplitude  in 11% of  the  patients; fusion of S-T segment
and T-waves in 45% of the patients; decreased T-wave amplitude in  99%  of the
patients; and prolongation of the  Q-T interval in 27% of the patients. The
duration of the changes was variable but was noted up to 2  months  after treat-
ment ended in some cases.  The authors concluded that these effects were not
indicative of cardiac damage or serious impairment of cardiac  function.

     Rugemalila (1980) reported the .incidence of two deaths due to parenteral
antimony (astiban) intoxication.  The first case involved a 4-year-old girl
with a history of  periodic  fevers.  She was administered (route not  specified)
100 mg astiban  (stibocaptate) for active schistosomiasis.  This corresponds to
a  dose of  about 2  mg  Sb(III)/kg.  Two weeks elapsed before she returned for a
second dose,  after which  she  developed severe vomiting and diarrhea.   She  then
                                      VI-2

-------
become comatose, with dehydration and hepatosplenomegaly.  Shortly thereafter,
she developed fits and died.  Analysis of cerebrospinal fluid showed decreased
sugar levels, and postmortem examination showed marked hepatic microvacuolar
steatosis.  Death was attributed to hepatotoxicity.  The second case involved
a 7U-year-old woman who was put on weekly injections of 320 mg astiban (about
2 my Sb(III)/kg) to control hookworm.  A few hours after receiving her second
injection, she displayed breathlessness, coughing, and fainting.  She was
dyspneic and had low blood pressure, cardiomegaly, bilateral  basal pulmonary
                         t
crepitations, and hepatomegaly.  Her condition deteriorated rapidly, and death
ensued.  Death was attributed to heart failure.

      Christopherson (1921) described an 18-year-old male patient who devel-
oped skin complications during the course of treatment with intravenous injec-
tions of potassium antimony tartrate (87.5 g in 86 days).  After an accumulated
dose .of 3U g, the patient developed leukoderraa, a pigment disturbance that
gives- a piebald appearance to the skin.  In addition, the man's skin became
rough; dull, bumpy, and granular, resembling goose skin.  This condition con-
tinued to exist 1 to 2 months after the end of treatment.

B.  EPIDEMIULOGICAL STUDIES

     Several reports on health effects related to occupational  exposure to
antimony by inhalation have been reported.  Oliver (1933) examined the health
of six adult males who had worked in an antimony smelter for 2 to 13 years and
received considerable exposure to antimony as evidenced by the presence of
antimony in the feces (an average of 47.5 mg) but not in the urine.  No signs
of adverse effects were identified, including cardiac, kidney, or bladder
effects, general health, and hematology.
                                      VI-3

-------
    Brieger et al. (1954). examined workmen in a plant where antimony  trisulfide
was used in the manufacture of grinding wheels.  Antimony levels  were as  high
as 5.5 mg/m3 (equal  to approximately 0.4 mg/kg antimony trisulfide).
This study focused on cardiovascular status,  since prior to the study there  had
been six sudden deaths in a group of 125 workers exposed to antimony  for  8
months to 2 years.  The.deaths were suspected to be due to heart  disease.  In
the workers studied, 14 of 113 had blood pressures that were >150/90  mmHg,  and
37 of 75 showed significant changes in their EKGs, mostly the T-wave.  Ulcers
were detected in 7 of 111 exposed persons (63 per 1,000} as compared  with 15
per 1,000 in the total plant population.  No other disorders suspected of being
related to antimony exposure were observed.  Although use of SbgSs was discon-
tinued, EKG changes persisted in 12 of 65 workers subsequently reexarained.

     Chulay et al. (1985) studied EKG changes in 59 Kenyan patients treated
with pentavalent antimony (sodium stibogluconate) for leishmaniasis.   Dose-
related increases in EKG abnormalities were found following 65 courses of anti-
mony treatment.  The incidences of EKG abnormalities were 22% (2/9 patients)
at 10 mg Sb/kg/day;  52% (25/48 patients) at 20 to 30 mg Sb/kg/day; and 100%
(8/8 patients) at 40 to 60 mg Sb/kg/day.  Furthermore, the frequency  of EKG
abnormalities increased with the duration of the treatment.  The  abnormalities
occurred in 41% (18/49) of the patients after 7 days, 67% (26/39) of  the
patients after 30 days, and 92% (11/12) of the patients after 60  days.

     Belyaeva (1967) presented suggestive evidence of possible adverse effects
of  antimony in female workers employed in an antimony plant.  When compared to
female workers working under similar conditions but not exposed to antimony
dust, the  female workers in the antimony plant showed increased incidence of
spontaneous abortions, premature  births, and  other gynecological  problems.
                                      VI-4

-------
     Doll (1985) investigated the occupational  causes of cancer.   Mortality
due to lung cancer was compared with mortality due to other causes in a British
factory manufacturing antimony oxide.  The compound was manufactured  before
World War II, but no records were available before 1961 either for dust measure-
ments or for males who terminated employment.  Antimony oxide dust has  been
greatly reduced since the 1960s.  As shown in Table VI-1, an increase in lung
cancer (SMR = 186) was observed for men first employed prior to 1961.

     Potkonjak and Pavlov
-------
      Table VI-1.  Mortality of Males Employed in a Factory Manufacturing
                   Antimony Oxide and Followed Through December 1981
                                        No. of deaths
                                            Expected at local       Standardized
                                               conurbation*          mortality
Category of employees         Observed            rates                ratio
Men f i rst empl oyed
before 1961
Lung cancer
Other causes


31
101


16.7
107.7


186
94
Men first employed
 January 1961 through
 December 1981

   Lung cancer                   7               10.1                    69
   Other causes                 62               84.0      -              74
a
 i
 An aggregation of urban communities.

SOURCE:  Adapted from Doll (1985).
                                      VI-6

-------
D.  SUMMARY

     Only a few studies of antimony toxicity following oral  exposure  in  humans
were found.  Most cases involved ingestion of food or liquid stored in antimony-
containing enamel vessels, and the symptoms that followed were characteristic
of gastrointestinal distress (nausea, vomiting).  In one case, administration
of 132 to 198 mg antimony led to severe vomiting, diarrhea,  and finally  death.

     Inhalation of antimony due to occupational  exposure is  more common, and
abnormal EKGs and increased ulcer frequency have been reported.

     Parenteral administration of antimony compounds is used in the treatment
of various parasitic diseases.  Some cases of adverse response to such treat-
ments have been noted, and reported effects included vomiting, diarrhea, liver
dysfunction, and skin abnormalities.

 -    Dose-related increases in EKG abnormalities were found  in 59 Kenyan
patients following 65 courses of antimony treatment.  An increase in  lung  .
tissue concentration of antimony (280 ppb mg/kg  compared with 32 and  19  ppb in
controls) was found in 76 copper smelter workers at  autopsy.  Evidence sugges-
tive of adverse reproductive effects, including  spontaneous  abortions  and
premature births, was reported in female workers employed in an antimony plant.
                                                                                      L
                                      VI-7

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                          VII.  MECHANISMS OF TOXICITY

A.  ENZYME INHIBITION

   .  Antimony, like other metal cations, interacts with proteins;  therefore,
most studies of the mechanism of antimony toxicity focus on antimony-induced
inhibition of various enzyme activities.
     Barren and Kalnitsky (1947) reported that 2 x 10-3 M Sb(III)  {as sodium
antimony biscatechol disulfonate) produced half-maximal inhibition of succinate
oxidase {isolated from pigeon breast) in vitro, and that this could be reversed
by 4 x 10r-2 M glutathione.

     Amer et al. (1967, 1969) studied the effect of antimony drugs on trypto-
phan metabolism in homogenates of mouse liver.  The authors reported that
kynureninase and kynurenine transaminase were both inhibited by the drugs in
proportion to the amount  of antimony added.  Pyridoxal phosphate is a required
cofactor for both these enzymes, and it appeared that antimony interacted with
this cofactor in a way that inhibited enzyme activity.

     Kelada et al.  (1972) studied the effect of potassium antimony tartrate on
tryptophan metabolism  in  children being treated for schistosomiasis.  Eight
children  (5 to 12 years old,  21 to 35 kg) were given  an oral dose of 0.5 g
tryptophan, and the  pattern of urinary metabolites was measured 24 hours later
before and after treatment with potassium antimony tartrate.  Treatment with 6
to 12 intravenous  (iv) injections of potassium antimony tartrate (1 to 2 mg/kg)
resulted  in a  pattern  of  urinary metabolites that  indicated that tryptophan
metabolism was inhibited.  These in vivo  results support the in vitro results
of Amer et al.  (1967,  1969).
                                      VIM

-------
B.  ENZYME ACTIVATION

     Drummond and Kappas (1981) studied the enhancement of heme degradation in
rats treated with antimony compounds.  Subcutaneous administration of SbCl3
or SbCls as single doses in the range of 3 to 30 mg Sb/kg resulted in a dose-
dependent increase in the activity of heme oxygenase, the rate-limiting enzyme
in the oxidative metabolism of heme to bile pigment.  A maximum induction
effect of heme oxygenase activity, 10-fold in the liver and 11-fold in the
kidney, was observed w'ith SbCl3 at a dose of 15 mg Sb/kg.  On the other hand,
in animals dosed with SbCIs, maximal increase of heme oxygenase activity was
only 3-fold in the liver and 1.5-fold in the kidney at respective doses of 30
and 15 mg Sb/kg.  Associated with the increase in heme oxygenase activity,
renal and hepatic levels of cytochrome P-450, hepatic levels of microsomal
heme, and aniline hydroxylase activity were decreased in rats dosed with SbCls
at 30 mg Sb/kg.  These decreases were observed despite an increase in the
 -iĞ
activity of delta-aminolevulinate synthetase, the rate-limiting enzyme in the
synthesis of heme.  Subcutaneous administration of trivalent antimonium, as the
parasiticidal drugs antimony potassium tartrate and antimony sodium dimercapto-
succinate, at a dose of 10 mg Sb/kg, also resulted in a significant increase in
heme oxygenase activity in the liver.  No such increase in enzyme activity was
observed when sodium stibogluconate, containing pentavalent antimony,  was
administered at a dose of 10 mg Sb/kg.

 C.  INTERACTIONS

     A number of reports indicate that the effects of antimony are reduced fay
various sulfhydryl reagents.  For example, Girgis et al. (1970) reported that
treatment of dogs with penicillamine (3-mercaptovaline) reduced the changes in
the electrocardiogram caused by potassium antimony tartrate.  Both compounds

                                     VII-2

-------
were administered intravenously.  The authors suggested that the sulfhydryl
group of penicillamine competitively inhibits antimony binding to intracellular
sulfhydryl-containing enzymes.

     Antimony has an inhibitory effect on the tryptophan-niacin pathway, speci-
fically inhibiting kynureninase and kynurenine transaminase (Amer et al., 1967,
1969).  Kelada et al. (1972) studied the effects of potassium antimony tartrate
(given intravenously) and 2,3-dimercaptopropanol (given intramuscularly) on the
tryptophan-niacin pathway in 5- to 12-year-old children.  The authors found
that 2,3-dimercaptopropanol, a metal chelator, prevented antimony inhibition of
the tryptophan-niacin pathway.
     Saleh and Khayyal  (1976) used cysteine as an adjunct to potassium antimony
tartrate  (both given intraperitoneally) and found that this compound reduced
the acute toxicity of antimony  in albino mice (strain not indicated) (Figure
VII-1).  The LD50 of antimony was raised from 33 to 47 mg/kg.   Liver function
tests in rabbits were analyzed  after treatment with parenteral  potassium anti-
mony tartrate  (PAT) and  cysteine.  The tests included  (1) serum glutamic-oxalo-
acetic transaminase  (SCOT)  and  serum glutamic-pyruvic transaminase  (SGPT); (2)
alkaline phosphatase  (AP);  (3)  thymol turbidity and flocculation; (4) icterus
index; and  (5) serum lipoproteins.  Rabbits were injected with  PAT  at 4 mg/kg
daily  for  5 days  either alone  or  in addition to a separate  injection of 12
mg/kg  cysteine.   One group  of  rabbits received cysteine  (12 mg/kg)  alone and
another  group  of  untreated  rabbits was maintained as controls.  There was no
 significant difference  in icterus index and thymol turbidity test between PAT-
treated  rabbits with  or without cysteine,  but there was  significant reduction
 of SGOT,  SGPT,  and  AP with  cysteine + PAT  treatment  (p <0.05)  (Figure VII-2).
                                      VII-3

-------
                   50
                   40
                   30
                   20
                    10
                               <.
                                           ^-^v
                                           x-:':-:-:.V:..---v
                                           .V.'. .*-•.*. I- • • • •
::.:£*:;; :#:..

K^-y-l


*lll
mm&
SSS-S;-
:s:#;i#-
                               PAT        PAT-Cyit.      PAT-Cytt.    PAT-Cytl



                                             l:i .           1^          t:8 .
Figure  VII-1.  Effect of cysteine on the LDsn of  potassium antimony tartrate

                (PAT) in mice.
SOURCE:   Adapted from Sal eh  and Khayyal (1976).
                                       VII-4

-------
   u
   IV
   S
   iU
   u

   i
   *
             SCOT    SGPT
SCOT    SGPT
AP
            24 HOURS AFTER COURSE
   2 WEEKS AFTER COURSE
        •  m Potassium antimony tarcrate

        D  ğ Potassium antimony tartratc 4  cysteine
Figure VII-2.  Effect  of cysteine on serum enzymes in rabbits treated with
               potassium antimony tartrate.
SOURCE:  Adapted from Sal eh and  Khayyal (1976).
                                     VI1-5

-------
 The results suggest that the thiol  groups of cysteine  bind with  antimony and
 prevent its binding with intracellular enzymes.  However, because  both  cysteine
 and APT were administered via the same route (ip), there is  a  possibility of
 interaction of the two chemicals prior to absorption into the  blood  stream.
 This interaction could essentially  decrease the amount of antimony available
 for absorption from the peritoneal  cavity.
     Moxon et al. (1947) found that  antimony was partially effective  in  pre-
 venting selenium toxicity/  Groups  of young rats (two  males  and  three females,
 age and strain not given) were fed  diets  containing  neither  selenium nor anti-
 mony (control),  selenium alone (12  ppm),  or selenium (12 ppm)  plus antimony (12
 ppm Sb, as SbC^), and body weights were  measured for  90 days.   Selenium alone
 caused a marked  decrease in the rate of weight  gain, and this  was  partially
 reversed by inclusion of antimony in the  diet.   The  effect of  antimony  alone
 was not investigated.
      Westrick (1953) studied the interaction between antimony  and the thyroid
 hormone in Sprague-Dawley rats.  Animals  receiving subcutaneous  injections of
 thyroxin (1 mg/kg/day) showed decreased weight  gains relative  to controls after
.25 to 50 days of treatment.  Feeding of 2% Sb203 in  the diet did not have an
 effect on weight gain in animals not treated with thyroxin but caused dramatic
 weight loss in animals receiving thyroxin (Figure VII-3).  Using a mean body
 weight of 0.18 kg (the mean of reported initial and  final weights) and  assuming
 average food consumption of 12 g/day (Arrington, 1972), this corresponds to an
 average daily dose of 1,114 mg Sb/kg/day.  The  author  concluded  that antimony
 enhanced the action of thyroxin in  extrathyroidal tissues.

      Baetjer (1969) injected (iv or ip) 10 or 15 mg  potassium  antimony  tar-
 trate/kg into dehydrated or hyper-thermal  mice and rats (no species,  weight, or
                                      VII-6

-------
Figure VI1-3.  Average body weights of rats treated with dietary antimony, with
               and without parenteral thyroxin.
SOURCE:  Adapted from Westrick (1953).
                                     VI1-7

-------
age given).  Dehydration was created by water deprivation 24  to  72  hours before
dosing or by substitution of 2% saline for drinking water 1 to 3 weeks  prior .to
antimony dosing.  Hyperthermia was created by exposure to a temperature of
34.4°C for 1 week following antimony dosing.  Dehydration caused an increase in
mortality and decreased survival  time in both rats and mice {Table  VII-1).
Exposure of rats and mice to a high temperature increased antimony-induced
mortality and decreased survival  time (Table VII-2).  The effect of dehydration
or hyperthernia alone (no antimony exposure) was not reported. The  author
suggested that data support the theory that hyperthermia or dehydration may
contribute to sensitivity to antimony toxicity.

D.  SUMMARY

     Antimony is thought to exert its toxic effects by interacting  with intra-
cellular enzymes or cofactors.  A number of sulfhydryl-containing compounds
reduce the toxic effects of antimony, suggesting that it may  bind to cellular
sulfhydryl groups.  Antimony has been reported to increase the activity of heme
oxygenase, increase the action of the thyroid hormone, and to decrease  the
toxicity of selenium, but the mechanism of these effects is not  known.
                                     VI1-8

-------
            Table VIM.
Effect of Potassium Antimony Tartrate and
Dehydration on Mortality in Rats and Mice


Dose
Species (mg Sb/kg)
Rat 10
10
10
15
15
15
15
Mouse 15
15
15
15
15 -
15
15
15
Route
of
injection
iv
iv
iv
iv
' iv
iv
iv
iv
iv
iv
iv
iv
ip
ip
ip

Mortal
Sb Sb
11.1 (19)a
50.0 (10)
5.3 (19)
84.6 (39)
100.0 (12)
100.0 (9)
60.0 (20)
13.3 (30)
20.0 (15)
10.0 (20)
20.0 (15)
13.3 (15)
— c
20.0 (5)
**

ity
+ dehydration
100.0 (10)
100.0 (10)
36.8 (19)
100.0 (41)
100.0 (12)
100.0 (13)
100.0 (20)
73.3 (30)
22.2 (18)
80.0 (20)
66.7 (9)
21.4 (-14)
50.0 (10)
88.9 9)
0.0 (5)

Probability
(Pi)
0.003
0.032
0.21
0.012
NSb
NS
0.003
<0.001
NS
<0.001
0.021
NS
—
0.046
™ *

aValues in parentheses denote sample size.
bNS = Not significant.
CNo data were reported.

SOURCE:  Adapted from Baetjer (1969).
                                     VII-9

-------
     Table VI1-2.   Effect of Potassium Antimony Tartrate and Environmental
                   Temperature on Mortality in Rats and Mice

Mortality (%)
Speci es
Rat

Mouse
Sex
Ma lea
Femalec
Male*
Normothermia
35.7 (14)b
0.0 (6)
25.0 (24)
Hyperthermia
100.0 (14)
20.0 (5)
87.5 (24)
Probability
(PI)
0.01
NSd
0.01

aAdministered by intravenous injection.
byalue in parentheses is sample size.
^Administered by intraperitoneal injection.
dNS = Not significant.

SOURCE:  Adapted from Baetjer (1969).
                                      VII-10

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                 VIII.   QUANTIFICATION OF  TOXICOLOGICAL  EFFECTS

     The quantification of toxicoVogical  effects of a chemical  consists of an
assessment of noncarcinogenic and carcinogenic  effects.   Chemicals  that do not
produce carcinogenic effects are believed to have a threshold dose  below  which
no adverse, noncarcinogenic health effects occur, whereas carcinogens  are
assumed to act without a threshold.

A.  PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS
                       >
1.  Noncarcinogenic Effects

     In the quantification of noncarcinogenic effects, a Reference Dose (RfD),
formerly called the Acceptable Daily  Intake (ADI), is calculated.  The RfD is
an estimate of a daily exposure to the human population that is likely to be
without appreciable risk of  deleterious health effects, even if exposure occurs
over a lifetime.  The  RfD is derived  from a No-Observed-Adverse-Effect Level
(NOAEL) or Lowest-Observed-Adverse-Effect Level  (LOAEL), identified from a
subchronic or chronic  study, and  divided by an uncertainty factor (UF).  The
RfD is calculated as follows:

                 RfD m   (NOAEL  or LOAEL)    = 	 mg/kg bw/day
                         uncertainty  ractor
      Selection of the  uncertainty factor to be employed  in the calculation
 of the RfD is  based on professional  judgment while considering the entire
 data  base  of toxicological  effects for the chemical.  To ensure that uncertain-
                                                 4
 ty factors  are selected  and applied  in a  consistent  manner,  the Office of
 Drinking Water (ODW) employs a modification to the guidelines proposed by the
 National  Academy of Sciences (NAS, 1977,  1980),  as follows:
                                      VIII-1

-------
     o  An uncertainty factor of 10 is generally used when good chronic  or
        subchronic human exposure data identifying a NOAEL are available
        and are supported by good chronic or subchronic toxicity data in other
        species.

     o  An uncertainty factor of 100 is generally used when good chronic
        toxicity data identifying a NOAEL are available for one or more  animal
        species (and human data are not available), or when good chronic or
        subchronic tox'icity data identifying a LOAEL in humans are available.

     o  An uncertainty factor of 1,000 is generally used when limited or
        incomplete chronic or subchronic toxicity data are available, or when
        good chronic or subchronic toxicity data identifying a LOAEL, but not
        a NOAEL, for one or more animal species are available.

     The uncertainty factor used for a specific risk assessment is based prin-
cipally on scientific judgment, rather than scientific fact, and accounts for
possible intra- and interspecies differences.  Additional considerations not
incorporated in the NAS/ODW guidelines for selection of an uncertainty factor
include the use of a 1ess-than-1ifetime study for deriving an RfD, the signifi-
cance of the adverse health effect, and the counterbalancing of beneficial
effects.

     From the RfD, a Drinking Water Equivalent Level (DUEL) can be calculated.
The DWEL represents a medium-specific {i.e., drinking water) lifetime exposure
at which adverse, noncarcinogenic health effects are not expected to  occur.
The DWEL assumes 100% exposure from drinking water.  The DWEL provides the non-
carcinogenic health effects basis for establishing a drinking water standard.
For ingestion data, the DWEL is derived as follows:
                                     VIII-2

-------
RfD x (body weight in kg)    s _ mg/L
nking water volume In L/day
                      Drinking water volume In L/day
where:

     Body weight * assumed to be 70 kg for an adult.
     Drinking water volume • assumed to be 2 L per day for an adult.

     In addition to the RfD and the DWEL, Health Advisories (HAs)  for exposures
of shorter duration (One-day, Ten-day, and Longer-terra HAs) are determined.
The HA values are used 'as informal guidance to municipalities and  other organi-
zations when emergency spills or contamination situations occur.  The HAs are
calculated using a similar equation to the RfD and DWEL; however,  the NOAELs
or LOAELs are identified from acute or subchronic studies.  The HAs are derived
as follows:
                     HA = INOAEL or LOAEL) x (bw) s _ mg/L  ( _ Ug/L)
                              ( _ L/day) x (UF)

     Using the above equation, the following drinking water HAs are developed
for noncarcinogenic effects:
     1.   One-day  HA for a  10-kg child  ingesting  1 L water per day.
     2.   Ten-day  HA for a  10-kg child  ingesting  1 L water per day.
     3.   Longer-term HA for  a 10-kg child ingesting 1 L water per day.
     4.   Longer-term HA for  a 70-kg adult ingesting 2 L water per day.

     The One-day  HA, calculated for a  10-kg child, assumes a single acute expo-
sure to  the  chemical and is  generally  derived  from a study of less than 7 days'
duration. The Ten-day HA  assumes a limited exposure period of 1 to 2 weeks and
is  generally derived from  a  study of less than 30 days' duration.  The Longer-
term HA  is calculated  for  both a 10-kg child and a 70-kg adult and assumes an
                                      VIII-3

-------
exposure period of approximately 7 years (or 10% of an individual's lifetime)
The Longer-term HA is generally derived from a study of subchronic duration
(exposure for 10% of an animal's lifetime).

2.  Carcinogenic Effects

     The EPA categorizes the carcinogenic potential of a chemical, based on
the overall weight of evidence, according to the following scheme:

     o  Group A:  Known Human Carcinogen.  Sufficient evidence exists from
                  epidemiology studies to support a causal association
                  between exposure to the chemical and human cancer.

     o  Group B:  Probable Human Carcinogen.  Sufficient evidence of
                  carcinogenicity in animals with limited (Group Bl'}  or
                  inadequate (Group B2) evidence in humans.

     o  Group C:  Possible Human Carcinogen.  Limited evidence of
                  carcinogenicity in animals in the absence  of human  data.

     o  Group.D:  Not Classified as to Human Carcinogenicity.  Inadequate
                  human and animal evidence of carcinogenicity or for which
                  no data are available.

     o  Group E:  Evidence of Noncarcinogenicity for Humans.  No evidence of
                  carcinogenicity in at least two adequate animal  tests  in
                  different species or in both adequate epidemiologic and
                  animal studies.

     If toxicological evidence leads to the classification of the contaminant
as a known, probable, or possible human carcinogen, mathematical  models  are
                                     VIII-4

-------
used to calculate the estimate of excess cancer risk associated with  the  inges-
tion of the contaminant in drinking water.  The data used in these estimates
usually come from lifetime exposure studies in animals.   To predict the risk
for humans from animal data, animal doses must be converted to equivalent
human doses.  This conversion includes correction for noncontinuous exposure,
less-than-lifetime studies, and for differences in size.  The factor  that com-
pensates for the size difference is the cube root of the ratio of the animal
and human body weights.  It is assumed that the average adult human body  weight
is 70 kg and that the'average water consumption of an adult human is  2 liters
of water per day.

     For contaminants with a carcinogenic potential, chemical levels  are
correlated with a carcinogenic risk estimate by employing a cancer potency
(unit risk) value together with the.assumption for lifetime exposure  via
ingestion of water.  The cancer unit risk is usually derived from a linearized
multistage model, with a 95% upper confidence limit providing a low-dose
estimate; that is, the true risk to humans, while not identifiable, is not
likely to exceed the upper limit estimate and, in fact,  may be lower.  Excess
cancer risk estimates may also be calculated using other models such  as the
one-hit, Weibull, logit, and probit.  There is little basis in the current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than  any
others.  Because each model is based on differing assumptions, the estimates
that were derived for each model can differ by several orders of magnitude.

     The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement.   In most cases, only studies using
                                     VIII-5

-------
experimental animals have been performed.  Thus, there is uncertainty when the
data are  extrapolated  to humans.   When developing cancer risk rate levels,
several other areas of uncertainty exist, such as the incomplete knowledge
concerning the health  effects of contaminants in drinking water; the impact of
the experimental animal's age, sex, and species; the nature of the target organ
system(s) examined; and the actual rate of exposure of the internal targets in
experimental animals or humans.  Dose-response data usually are available only
for hign  levels of exposure, not for the lower levels of exposure closer to
where a standard may be set.  When there is exposure to more than one contami-
nant, additional uncertainty results from a lack of information about possible
synergistic  or antagonistic effects.

B.  QUANTIFICATION OF  NONCARCINOGENIC EFFECTS FOR ANTIMONY

1.  One-day  Health Advisory

     No appropriate studies were found to be suitable for calculation of a
One-day HA  for antimony.  The results from Flury {1927} were considered in
.developing  a One-day HA  for antimony.  Flury (1927) indicated that nausea and
vomiting  occurred  in cats and dogs at doses of 4 to 12 mg Sb/kg and that No-
Observed-Adverse-Effect  Levels  (NOAELs) occurred at 2.6 to 6.0 in cats and dogs.
However,  these studies were judged inappropriate due to lack of study details
and  small number  of  animals per test dose.  Therefore, in the absence of a more
suitable  study, it is  recommended  that the DWEL of 15 ug/L be used as a
conservative estimate  of the One-day HA for a 10-kg child.

•2.   Ten-day Health Advisory
     Table  VIII-1  summarizes the  studies considered for calculation of the
Ten-day HA for  antimony.  None  of these studies were found to be suitable
                                     VIII-6       .              .

-------
           Table VIII-1. . Summary of Candidate Studies for Derivation
                          of the Ten-day Health Advisory for Antimony
                                Exposure                 NOAEL (rag    LOAEL (mg
Reference   Species   Route     duration    Endpoint     Sb/kg/day)    Sb/kg/day)
Pribyl
(1927)



Westrick
(1953)
Rabbi t Oral
in milk



Rat Di et

7-22 days Histopath-
ology:
liver,
kidney,
intestine
7 weeks Body weight,
oxygen
5.6




10.9

Bomhard     Rat
et al.
(1982)

James et    Sheep
al. (1966)
Diet      3 months
Oral      45 days
consumption,
hypermetabo-
lism

Growth,
hematology,
organ weight

Hematology,
mineral
deposition
in tissues
>2
                                        VI11-7

-------
for calculation of the ten-day HA.  The study by Peribyl  (1927) was  not
selected because it appeared outdated and offered very little details
upon which a confident analysis could be made.  The study by Westrick (I9b3)
was not chosen, because the duration was excessive (7 weeks) and no
histopathological examination of tissues was performed.  In addition, the LOAEL
was higher than that found in the Pribyl (1927) study.  The study by Bomhard  et
al. (1982) was not selected, since the chemical given was an insoluble complex
of .several metals.  The study by James et al. (1966) was not selected because
                      f
the dose tested was not high enough to elicit a toxic response.  In  absence
of appropriate data, it is recommended that the DWEL of 15 ug/L be used as
a conservative estimate of the Ten-day HA,
3.  Longer-term HealthAdvisory
     Table VJII-2 summarizes the studies considered for calculation  of the
Longer-term HA values for antimony.  None of the studies was found suitable for
calculation of the Longer-term HA values because a good estimate of  the NOAEL
or LOAEL could not be obtained.  The study by Westrick (1953) was not chosen,
                                  4
because no histological examination of the tissues was performed, the only
selected dose (1,114 mg Sb/kg/day) was too high to permit calculation of a
LOAEL, and the period of exposure (7 weeks) was too short.  The studies by
Bomhard et al. (1982) and James et al. (1966) were not selected because the
doses studied were not high enough to elicit a toxic response.  Additionally,
in the Bomhard study the chemical administered was an insoluble complex of
                                     VIII-8

-------
           Table VIII-2.  Summary of Candidate Studies  for Derivation  of
                          the Longer-term Health Advisory for Antimony
Reference   Species
        Exposure
Route   duration-
Endpoint
NOAEL (mg   LOAEL (mg
Sb/kg/day)  Sb/kg/day)
Westrick Rat
(1953)




Bomhard Rat
et al.
(1982)
James Sheep
et al.
(1966)

Bradley Rat
and
Fredrick
(1941)
Flury Rat
(1927)
Diet 7 weeks Body weight, --' <1114
oxygen
consump-
tion, hyper-
metabolism,
organ weight
Diet 3 months Growth, >10
hematology,
organ weight
Oral 45 days Hematology, >2
mineral
deposition
in tissues
Oral 6, 7-1/2, Growth rate,
12 months blood count j
gross
pathology
Diet 107, 131 Growth >1.5
days

                                     VI1I-9

-------
 several metals.  The  studies  by Bradley and Fredrick  (1941) were not selected,
 because in  two studies  only  one dose  was used, and in the third study continually
 increasing  doses were used for the first 6 months.  Neither a NOAEL or LOAEL
 was identified in these  studies.  The studies by Flury  (1927) were not selected
 because ^very  few animals were used per dose group and because most of the
studies involved continually  increasing doses of chemical.  In the absence of a
 suitable study for calculation of the Longer-term HA, it is recommended that
 the DWEL for  antimony of 15 ug/L be taken as an appropriate estimate of the
 Longer-term HA value  for adults.  It can be assumed that the DWEL value will
more than adequately  protect  both adults and children over long-term exposures
 (6 to 12 months), since  the RfD and DWEL values were based on a lifetime study
 in rodents  and a large safety factor (1000) was incorporated into the
derivation.

4.  Reference Dose and Drinking Water Equivalent Level

     Table  VIII-3 summarizes the studies considered for derivation of the RfD
and DWEL for  antimony.

     The study by Schroeder et al. (1970)  has been selected to serve as the
basis for calculation of the RfD and DWEL because it involved lifetime  exposure
of rats to potassium antimony tartrate (the most toxic of the common antimony
compounds)  given in drinking water.  This study identified a LOAEL of 0.43
mg/kg/day on the basis of decreased longevity and altered blood levels  of
glucose and cholesterol.  The lifetime study in mice by Schroeder et al.  (1968)
has not been selected because the LOAEL identified (0.8 mg Sb/kg/day) is  based
on a single parameter - namely decreased body weight of females after 12  months
of antimony administration.  Moreover, only a single dose was used.  Antimony
did not significantly suppress the growth  of male mice except after 18  months
                                     VIII-1U

-------
           Table VIII-3.  Summary of Candidate Studies for Derivation  of  the
                          Drinking Water Equivalent Level for Antimony
References   Species   Route
                                  Exposure                  NOAEL (mg   LOAEL {mg
                                  duration      Endpoint    Sb/kg/day)   Sb/kg/day)
Schroeder
 et al.
 (1968)

Schroeder
 et al.
 (1970)
             Mouse     Drinking   Lifetime   Body weight,
                       water                 liver histology
             Rat       Drinking   Lifetime    Longevity,
                       water                 blood analysis
0.83
0.43
                                     VIII-11

-------
of antimony  administration.  No histopathological changes were observed in

either sex.

     Using this study, the DWEL is derived as follows:


Step 1:  Determination of Reference Dose (RfD)
     RfD
            (.43 mg/kq/day) • 0.00043 mg/kg/day (0.4 ug/kg/day)
                (1,000)                                      3>
where:
     0.43 mg/kg/day =
                       LOAEL,  based on decreased longevity  and  altered  blood
                       glucose and cholesterol  in rats  exposed  to potassium
                       antimony tartrate in  drinking  water  for  a lifetime
                       (Schroeder et al.,  1970).

               70 kg  = assumed weight of adult.

               1,000  = uncertainty factor.   This uncertainty  factor was chosen  in
                       accordance  with ODW/NAS guidelines"for use when a LOAEL  from
                       an  animal  study is  employed.


Step 2:   Determination of Drinking  Water Equivalent  Level  (DWEL)


     DWEL =  (0.00043  mg/kg/day)(70  kg)  = 0.015  mg/L  (15 ug/L)
                    2 L/day


where:


     0.00043 mg/kg/day * RfD.

                 70 kg - assumed weight of  adult.

               2 L/day = assumed water consumption by 70-kg adult.



C.  QUANTIFICATION OF CARCINOGENIC EFFECTS FOR ANTIMONY


     Table VIII-4 summarizes the studies considered for calculation  of

carcinogenic risk estimates.
                                       VIII.12

-------
         Table VIII-4..  Summary of Candidate Studies for Calculation of
                         Carcinogenic  Risk Estimates
   References
Species
Route
Exposure/study
   duration
Result
Schroeder et al.    Mouse
 (1968)
Schroeder et al.    Rat
 (1970)
Watt (1983)
Rat
Groth et al.
 (1986)
 Rat
Drinking      Lifetime     At .a daily dose of
water                      0.83 mg Sb/kg/day,
                           18.8% mice devel-
                           oped tumors (34.8%
                           control).

Drinking      Lifetime     At a daily dose of
water                      0.43 mg Sb/kg/day,
                           no significant
                           effect of antimony
                           on tumor frequency
                           was observed.

Inhalation    1 year/      At a daily dose of
              2 years      4.2 mg Sb/kg/day,
                           female rats devel-
                           oped scirrhous car-
                           cinomas, squamous
                           cell carcinomas, or
                           bronchiolar adenomas,

Inhalation    52 weeks/    At levels close to
              72 weeks     threshold limit
                           values, the rats
                           developed primary
                           lung neoplasms.
                                      VIII-13

-------
     The evidence regarding the potential  carcinogenicity  of antimony  when
ingested in drinking water is inconclusive.  This is based on the lack of
carcinogenicity in two studies in which antimony was administered in drinking
water to two strains of rats.  These studies, however, are judged inadequate in
design, since only one dose level was utilized and an MTD  level  may.not have
been achieved.  In contrast, studies in which antimony dusts were inhaled by
rats revealed primary lung neoplasia.  Since no systemic neoplasia was evident
and no absorption data were presented, these data cannot be utilized in asses-
                      >
sing the potential carcinogenicity of a soluble form of antimony in drinking
water.  It should be noted that some evidence exists to indicate that  workers
inhaling antimony dust may also be at increased risk for lung tumors.   The
evidence in humans, however, is inadequate.  On this basis, antimony in drinking
water is categorized in Group D, not classified as to human carcinogenicity;
thus, no quantification of carcinogenicity has been performed.

D.  SUMMARY
     Table VIII-5 summarizes HA and DWEL values (calculated on the basis of
noncarcinogenic endpoints).  Excess cancer risks were not  estimated because
there is no evidence that orally ingested antimony is carcinogenic in  animals.
                                     VIII-14

-------
„'Ğ
                   Table VIII-5,
Summary °f Quantification of Toxicological
Effects for Antimony
                  Value
           Drinking water
           Concentration
             (ug/L)
Reference
One-day HA for 10-kg child
Ten-day Ha for 10-kg child
Longer-term HA for 10-kg child
Longer-term HA for 70-kg adult
DWEL (70-kg adult)
Excess cancer risk (10-6)
..a
—a
—a
..a
15 Schroeder et al .
(1970)
"

         "It is recommended that the DWEL  value  be used  as  a  conservative  estimate  for
         the one-day, ten-day and  longer-term health advisory, values.
                                              VIII-15

-------
                                IX.  REFERENCES
Abdel-Wahab MF, Abdul la WA, Nasr A, El-Garhi MZ, Kamel S.  1974.  Comparative
study on two labelled antimonial drugs, Bilharcid and tartar emetic using
monkeys.  Egypt. J. Bilh. 1:101-106.

Amer MS, Abdel-Daim MH, Abdel-Tawab GA.  1967.  Studies with tryptophan meta-
bolites in vitro.  II. Effect of tartar emetic on kynurenine metabolism by
normal mouse liver.  Biochem. Pharmacol. 16:1227-1236.

Amer MS, Abdel-Daim MH, Abdel-Tawab GA.  1969.  Studies with tryptophan meta-
bolites in vitro.  III.  The effect of schistosomicidal drugs on kynureninase
and kynurenine transaminase of normal mouse liver.  Biochem. Pharmacol.
18:821-826.
                      >
Arrington LR.  1972.  The laboratory animals.  In:  Introductory Laboratory
Animal Science.  The Breeding, Care and Management of Experimental Animals.
Danville, IL:  Interstate Printers and Publishers, Inc., pp. 9-11.

Baetjer AM.  1969.  Effects of dehydration and environmental temperature on
antimony toxicity.  Arch. Environ. Health 19:784-792.

Barron ESG, Kalnitsky G.  1947.  The inhibition of succinoxidase by heavy
metals and its reactivation with dithiols.  Biochem. J. 41:346-351.

Belyaeva  AP.  1967.  The effect of antimony on reproductive function.  Gig.
Tr.  Prof.  Zabol.  11(1)32-37.

Bomhard E, Loser E, Dornemann A, Schilde B.  1982.  Subchronic oral toxicity
and analytical studies on nickel rutile yellow and chrome rutile yellow with
rats.  Toxicol. Lett. 14:189-194.

Bradley WR and Fredrick WG.  1941.  The toxicity of antimony.  Ind. Med., Ind.
Hyg. Sect. 2:15-22.

Brieger H, Semisch CW, Stasney J, Piatnek DA.  1954.  Industrial antimony
poisoning. Ind. Med. Surg. 23:521-523.

Bromberger-Barnea B, Stephens NL.  1956.  Effects of antimony on myocardial
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Carozzi L. 1930.  Antimony.  Occupation and health.  Brochure 36, Vol. 1.
International Labor Office, Geneva, p. 115.  (Cited in Bradley and Fredrick,
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Casals  JB.  1972.  Pharmacokinetic and toxicological studies of antimony
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Casto BC, Meyers J, DiPaolo JA. 1979.  Enhancement of viral transformation
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Cancer Res. 39:193-198.  (Cited in Heck and Costa, 1982.)
                                       IX-1

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CEH. (1985).  Chemical Economics Handbook.  Menlo Park, CA:  SRI International.
Christopherson JB.  1921.  Further notes on the intravenous injection of antimony
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Chulay JD, Spencer HC, Mugambi M.  1985.  Electrocardiographic changes during
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Clemente GF, Ingrao G, Santaroni GP. 1982.  The concentration of some trace
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Davis A. 1975.  Clinically available antischistosomal drugs.  J. Toxicol. Environ.
Health 1:191-201.
Demmel U, Hock A, Kasp'erek K, Feinendegen LE. 1982.  Trace element concentration
in the human pineal body.  Activation analysis of cobalt, iron, rubidium, selen-
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Doll R.  1985.  Occupational  cancer:  A hazard for epidemiologists.  Int. J.
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Drummond GS, Kappas A.  1981.   Potent heme-degrading action of antimony and anti-
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antibilharzial drugs:  Tartar emetic  and  Bilharcid.  Environ. Mutagen. 4:83-91.
Ercoli N.   1968.  Chemotherapeutic and toxicological properties of antimonyl
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Felicetti SA, Thomas  RG, McClellan RO.  1974.  Metabolism  of two valence states
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Gerber GB,  Maes  J, Eykens  B.   1982.   Transfer of  antimony  and arsenic to the
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 1979.  Acute  toxicity studies of  some new organic trivalent antimonials.  0.
Egypt. Med. Assoc. 62(1/2):45-62.
Girgis GR,  Scott P, Schulert  AR,  Browne HG.   1965.   Acute  tolerance of mice to
tartar emetic.   Toxicol. Appl.  Pharmacol.  7:727-731.
Girgis NI,  Khayyal MT, McConnell  E, Norton J. 1970.  Penicillanmine as an adju-
 vant to  antimonial  therapy,  effect on electrocardiographic changes  in dogs.   East
Afr. Med.  0.  47:76-581.
                                        IX-2

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Goodwin LG, Page JE. 1943.  A study of the excretion of organic  antimom'als
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