"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$bCl3 was administered orally. When 124sbd3 was given
intravenously to cows, 2.4% of the total dose was excreted in the feces, 51% in
the urine, and 0.08% in the milk.
1-1
-------
Antimony shows little tendency to accumulate in the body. Levels of
antimony have been reported in human milk and tissue. A mean of 3 ng Sb/g of
milk was reported in Italian women. A mean concentration of 17.51 x 10-8 g/g
dry weight of 90 pineal glands was reported in humans for both sexes. A median
concentration of 0.015 ppm was found in the bone tissue of industrially exposed
workers, whereas only 0.007 ppm was found in the control group. .In mice fed
125$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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
-------
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
-------
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
-------
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