United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
-Washington DC 20460,
EPA 440 S-80-020.
October 1SSG
&EPA
Ambient
Water Quality
Criteria for
Antimony
Printed an Recycled Paper
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AMBIENT WATER QUALITY CRITERIA FOR
ANTIMONY
Prepared' By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards'.
Criteria and Standards Division •
Washington, D.C. }
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio ;
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Orego'n '
Duluth, Minnesota
Gulf Breeze, Florida '
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (F.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR' 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document |is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural" Resources Defense Counci1, et. al.vs. Train, 8 ,ERC 2120
(D.ET.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979). ;
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The'term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with {specific
stream uses when adopted as State water quality standards under Section
'303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the.criteria
developed under section 304. However, in many situations States, may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not unt|il their
adoption as part of the State water quality, standards that the'criteria
become regulatory. ,
Guidelines to assist the States in the modification of,criteria
presented -in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA. v ,'" .
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
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ACKNOWLEDGEMENTS
Aauatic Life Toxicology:
Charles E. Stephen, ERL-Duluth John E. Gentile, ERL-Narragansstt
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Paul Mushak (author) William B. Buck
University of North Carolina , University of Illinois
Christopher T. DeRosa (doc. tngr.) Edward Calabrese
ECAO-Cin University of Massachusetts
U.S. Environmental Protection Agency
Jerry F. Stara (doc. ragr.) ECAO-Cin Patrick Durkin
U.S. Environmental Protection Agency Syracuse Research Corp.
Paul B. Hammond Si Duk Lee, ECAO-Cin
University of Cincinnati U.S. Environmental Protection Agency
Magnus Piscator
Karolinska Institute
Technical Support Services Staff: D.J, Reisman, M.A. Garlough,'B.I. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade. D. Jones, B.J. Bordicks,
B.J. Quesnell . T. Highland, B. Gardiner, R. Swantack.
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TABLE OF CONTENTS
Criteria Summary
\
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-2
Plant Effects B-3
Residues , B-3
Miscellaneous B-3
Summary B-3
Criteria B-4
References B-ll
Mammalian Toxicology and Human Health Effects C-l
Introduction . . * C-V
Exposure ,C-3
Ingestion from Water C-4
Ingestion from Food C-4
Inhalation C-6
Integrated Multimedia Exposure Estimates C-6
Pharmacokinetics C-7
Absorption C-7
Distribution C-10
Metabolism - C-l9
Excretion . C-21
Effects ' C-22
Acute, Subacute, and Chronic Toxicity , C-23
Mutagenicity and Carcinogenicity C-27
Respiratory System Effects ' C-28
Cardiovascular System Effects C-32
Blood Effects C-34
Liver, Kidney, Spleen and Adrenal Effects C-34
Reproduction, Development and Longevity C-36
Skin and Eye Effects C-38
Summary of Animal Toxicology C-38
Human Health Effects C-39
Therapeutic Uses " "C-39
Effects on the Gastrointestinal System C-40
Effects on the Hepatic System C-41
Effects on the Cardiovascular System C-41
Effects on the Skin C-48
Other Effects , C-49
Summary of Therapeutic Use Effects C-49
Industrial Exposures C-50
Respiratory and Dermal Effects C-53
Myocardial Effects C-58
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Carcinogenis C-59
Blood Effects C-60
Reproduction and Development Effects C-60
Criteria Formulation C-62
Existing Guidelines and Standards . C-62
.Special Groups at Risk C-63
Basis for the Criterion G-65
Summary of Health Effects C-65
ttose-Effeet/Dose Response Relationships " . C-67
References C-72
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CRITERION DOCUMENT
ANTIMONY
CRITERIA
Aquatic Life
The available data for antimony indicate that acute and chronic toxicity
to freshwater aauatic life occur at concentrations as low as 9,000 and 1,600
ug/1, respectively, and would occur at lower concentrations among species
that are more sensitive than those tested. Toxicity to algae occurs at
concentrations as low as 610 vg/1. !
i
No saltwater organisms have been, adeauately tested with antimony, and no
i
statement can be made concerning acute or chronic toxicity.
Human Health
For the protection of human health from the toxic properties, of antimony
ingested through water and contaminated aauatic organisms, the ambient water
I
criterion is determined to be 146 ng/1. :
i
For the protection of human health from the toxic properities of
i
antimony ingested through contaminated aauatic organisms alone, the ambient
water criterion is determined to be 45 mg/1.
vn
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INTRODUCTION
Antimony, a silvery, brittle solid, belongs to group VB of the periodic
table and lies between arsenic and bismuth. It is classified as both a me-
tal and a metalloid. It has an atomic number of 51 and an atomic weight of
/
121.8, and its principal oxidation states are +3 and +5.
Antimony reacts with both sulfur and chlorine to form the triand pentav-
alent sulfides and chlorides. Oxidation to antimony trioxide, the major
commercial oxide of antimony, is achieved under controlled conditions. Sti-
- i
bine, antimony trihydride, is formed by the reduction of antimony compounds
in acid media using zinc or other reducing metals. j
Solubilities of antimony compounds range from insoluble! to fully solu-
ble. Most inorganic compounds of antimony are either only! slightly water
soluble or decompose in aaueous media. Antimonials -such as ipotassium anti-
i
tnony tartr'ate, in which organic ligands are bound to the element and em-
ployed therapeutically, are water soluble.
The brittle character of antimony metal precludes rolling, forging, or
drawing but accounts for imoroved hardness and lowered melting point in al-
i
Toys with lead, oismuth, tin, cooper, nickel, iron, and cobalt. In particu-
lar, the metal is heavily employed in antimonial lead, in bearings, and in
ammunition. ,
The most important antimony compound in commerce is probably antimony
trioxide, a colorless, insoluble powder, the properties of which place it in
high demand as a flame retarding agent for many commodities. It is insolu-
ble in water and dilute nitric or sulfuric acids but is soluble in hydro-
1 s
chloric and certain organic acids. It dissolves in oases to i give anti'monate.
A second form of antimony having commercial usefulness jis antimony tri-
sulf'de, SbS-, which is "converted to the trioxide for «use as a flame
-------
retardant. Other uses are in the manufacture of fireworks and matches. An-
timony trisulfide is insoluble in water but dissolves in concentrated hydro-
chloric acid with the evolution of hydrogen sulfide. It is also soluble in
strong alkali solution.
Antimony shows some definite cationic behavior but only in the trivalent
state. For example, antimony (!!!) forms complexes with inorganic and or-
aanic acids to oroduce 'antimonial salts such as the disulfate
(Sb(SQ4)2)~, the dioxalate Sb(C204)"2 and the well known . tar-
trate, (Sb(OH)C4H305)~ (Weast, 1977; Windholz, 1976).
Antimony is a naturally occurring element which comprises' between 0.2
and 0.5 ppm of the earth's crust. Environmental concentrations of antimony
at 35 Darts per thousand of salinity are reported as 0.33 ug/1 in seawater
and as 1,1 ug/1 in freshwater streams.
In the environment antimony may enter aauatic systems from natural
weathering of rocks, runoff from soils, and effluents from mining and manu-
facturing operations, as well as municipal and industrial discharges. Anti-
mony concentrations are generally in the low ppm range for uncontaminated
sediments, while sediments within 1 km of a copper smelter have "shown levels
of several thousand ppm (Crecelius, et-al. 1975).
Certain antimonial complexes undergo hydrolysis or oxidations reactions
and consequently are not long-lived in the environment. Both the oxide of
antimony and the trihalides are volatile compounds, while antimony trichlo-
ride releases hydroqen chloride aas in the presence'of moisture ,(U.S. EPA,
1976). Antimony trioxide can undergo photo-reduction in the presence of ul-
traviolet light in aoueous solutions (Markham, et al. 1958).
Several metals surrounding antimony in the periodic table undergo the
methylation of inorganic compounds by microorganisms to yield organometallic
A-2
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compounds that are stable and mobile in water and air. Parris; and BHnckman
(1976) report that although no obvious thermodynamic or kinetic barrier pre-
vents this reaction, biological methylation of antimony has not been
demonstrated. * '
A-3
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REFERENCES
Crecelius, E.A., et al. 1975. Geochemistries and arsenic, antimony, mer-
cury, and related elements in-sediments of Puget Sound. Environ. Sci.
Technol. 9: 325.
Markham, M.D., et al. 1958. Photochemical properties of antimony triox-
ide. Jour. Phys. Ghent. 62: 989.
Parris, G.E. and F.E. Brinckman. 1976. Reactions which relate to environ-
mental mobility of arsenic and antimony. II: Oxidation of trimethyarsine
and trimethylstibine. Environ. Sci. Technol. 10: 1128.
U.S. EPA. 1976. Literature study of selected potential environmental con-
taminants. Antimony and its compounds. EPA-550/2-76-002. Off. Tox.
Subst. Washington, D.C.
Weast, R.C. 1977. CRC Handbook of Chemistry and Physics. 58th ed. CRC
Press, Inc. Cleveland, Ohio.
Windholz, M. (ed.), 1976. The Merck Index. 9th ed. Merck and Co., Inc.
Rahway, New Jersey.
A-4
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Aqyati c L i fe To xico 1ogy*
INTRODUCTION
Antimony exists in three valence states (-3, *3» and +5), but the -3
i
i
state is not stable in oxygenated water. For the *3 state, antimony triox-
ide is not very soluble in water. On the other hand, antimony trichloride
is very soluble, but it will form the insoluble antimony oxychloride, The
+3 state also forms water soluble complexes with some acids, such as in po-
tassium antimony tartrate. Little seems to be known about the!aqueous chem-
istry of the +5 valence state.
i
The data base for antimony and freshwater organisms is small and indi-
cates that plants may be more sensitive than fish or invertebrate species.
There are no data to evaluate the effect of water quality on tjhe toxicity of
antimony.
The saltwater data base is limited to the results of four tests with
!
antimony trioxide.
All test results are expressed in terms of the metal, j
IFFECTS • «
Acute Toxicity
The acute toxicity to Daphnia magna has been determined toy four inves-
tigators using three different antimony compounds. Anderson1 (1948) deter-
I '
i
mined ,a 64-hour EC™ of 19,800 wg/1 for antimony trichloride (Table 6).
The 48-hour value for antimony potassium tartrate was 9,000 u;g/l (Table 1).
*The reader is referred to the Guidelines for Deriving Nater Quality Criter-
ia for the Protection of Aquatic Life and Its Uses in order to better under-
stand the following discussion and recommendation. The following taoles
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the Guidelines. l .
3-1
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Kimball (Manuscript) tested Daphnla magna and antimony trichloride with and
without feeding and calculated 48-hour LC5Q values of 12,100 and 18,800
wg/1, respectively (Tables 1 and 6). Test concentrations were measured in
the last two tests. These data for Daphnla magna indicate that feeding pro-
cedures and the use of three different antimony compounds did not, if at
all, 'significantly affect toxicity. The species acute value for Oaphnia
^
magna is 18,800 wg/1 (Table 1). The 96-hour LCgQ for the fathead minnow
is 21,900 tig/1 for antimony trichloride (Kimball, Manuscript).
Tests with antimony trioxide and the bluegill and Daphnia magna re-
sulted in SO percent effect levels greater than 530,000 yg/1 (Table 6).
No lethal effect on the saltwater mysid shrimp, Hysidopsis bahia, was
observed after 96.hours at static test concentrations as high,as 4,200 yf/1
(Table 6). The 96-hour LCg^ for the sheepshead minnow is between 6,200
and 8,300 vg/1 (Table 6).
Chronic Toxicity ,
\
A life cycle test with Daphnia magna and antimony trichloride produced
limits of 4,200 and 7,000 «g/l for a chronic value of 5,400 ug/1 (Table 2).
No adverse effects on the fathead minnow (U.S. EPA, 1978) were observed
during an embryo-larval test with antimony trioxide at the highest test con-
centration of 7.5 yg/1 (Table 2). However, a comparable test with antimony
trichloride (Kimball, Manuscript) produced' limits of 1,100 and 2,300 ug/1
for a chronic value of 1,600 yg/1.
The acute-chronic ratios for the cladoceran and the fathead minnow were
3.5 and 14, respectively (Table 2). These results provide a geometric mean
acute-chronic ratio of 7.0.
The species mean acute and chronic values are summarized in Table 3.
No chronic test has been conducted with a saltwater species.
B-2
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Plant Effects
The 96-hour ECcn values for chlorophyll a .-inhibition and reduction in
DU — i
cell numbers of the alga, Selenastrum caprtcornutum, are. 610 and 630 ug/1,
I
respectively (Table 4). Tnese results indicate that aquatic plants may be
more sensitive than fish and invertebrate species. !
No inhibition of chlorophyll a. or reduction in cell numbers of the
tlga, Skeletonema costatum, were observed at concentrations as high as 4,200
ug/1 (Table 4). ;
Re'sidues I
L- mmmm L- i *
There was no detectable bioconcentration of antimony by the bluegill
above control concentrations during a 28-day exposure to antimony trioxide
(Table 5).
! ,
Miscellaneous
The data in Table 6 have been discussed previously.
Summary >
There are insufficient data to determine whether or not water quality
affects the toxicity of antimony to freshwater or saltwater, aquatic life.
Tests with antimony potassium tartrate and antimony trichloride and Daphnia
magna suggest no difference in toxicity between these compounds. No acute
I
toxicity was observed for the less soluble antimony trioxijde and this- 'same
species. , The LCgQ and EC5Q values for Dapjinia magna 'and the _fatnead
minnow ranged from 9,000 to 21,900 yg/1. Chronic values and acute-chronic
ratios (in parentheses) .for the fathead minnow and Daphma I magna were 1,600
(14) and 5,400 ug/1 (3.5), respectively. The freshwater alga, Selenastrum
capricornutum, was more sensitive tnan the tested animaT species witn a
96-hour ECrQ for inhibition of chlorophyll" a_ of 610 ug/1. Whole body
i
analysis of bluecill Demonstrated no uptake beyond that present in control
f-isn.
3-3
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Several tests have been conducted with saltwater species and antimony
trioxide, but no definitive data resulted.
-CRITERIA
The available data for antimony indicate that acute and chronic toxici-
ty to freshwater aquatic life occur at concentrations'as low ,as 9,000 and
1,600 pg/1, respectively, and would occur at lower concentrations among spe-
cies that are more sensitive than those tested. Toxicity to algae occurs at
concentrations as low as 610 wg/1.
No saltwater organisms have been adequately tested with antimony, and
i
no statement can be concerning acute or chronic toxicity.
3-4
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Table I. Acute values for antimony
CO
I
Ul
Species Method*
Cladoceran, S, U
Daphnla magna
Cladoceran, 5, M
Daphnla magna
fathead minnow, " FT, M
Ptmephales promelas
» S = static, FT * flow-through, U =
""Results are expressed as antimony.
Species Mean
LC50/EC50 Acute Value
Chemical (|ig/l)**" (pg/ll**
FRESHWATER SPECIES
Antimony potas- 9,000 9,000
slum tartrate
Antimony 18,800 18,800
trichloride '
Antimony 21,900 21,900
trichloride
unmeasured, M = measured
not In terms of the compound.
Reference
Br logman & Kuhn, 1939
Kfmbal 1, Manuscript
Klmbal 1, Manuscript
No Final Acute Value Is calculable since the minimum data base requirements are not met.
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Table 2. Chronic values lor antimony
CD
i
Method*
Chemical
Chronic
Units Value
(ug/0"
Reference *
Cladoceran,
Daphnla rcaqna
LC
Fathead minnow, E-L
Plmephales promelas
Fathead minnow, E-L
Plmephales promelas
FRESHWATER
Antimony
trichloride
Antimony
trloxlde
Antimony
trichloride
SPECIES
4,200- 5,400
7,000
>7.5
, 1,100- 1,600
2,300
Klmball, Manuscript
U.S. EPA, 1978
Klmball, Manuscript
* LC = life cycle, E-L s embryo-larval
""Results are
expressed as antimony, not
In terms of the compound.
V
Acute-Chronic Ratios
Species
Cladoceran,
Daphnla roagna
Fathead minnow,
Plmephales promelas
Chemical
Antimony
" trichloride
Antimony
trichloride
Chronic Acute
Value Value
5,«00 18,800
1,600 21,900
Ratio
3.5
14
Geometric mean acute-chronic ratio «= 7.0
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Table 3. Species Man acute and chronic values for antimony
Species Mean Species Mean
Acute Valve* Chronic Value . Acute-Chronic
Number Species ' tug/1) (ug/l) Ratio*11
2
I
FRESHWATER
Fathead minnow, 21,900 1,600
Pimephales promelas
Cladoceran, 18,800 5,400
Daphnla magna
14
3.5
* Rank from high concentration to low concentration by species mean acute value.
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Table 4« Plant values for antimony (U.S. EPA, 1978)
td
I
oo
Species
Alga,
Selenastrum capricornutun
Alga, '
Selenastrum caprlcornutum
Alga,
Skeletonema CDS tat urn
Alga, *
Skeletonema cos tat urn
Chemical
FRESHWATER SPECIES
Antimony
trloxlde
Antimony
trloxlde
SALTWATER SPECIES
Antimony
tr 1 ox 1 de
Antimony
trioxlde
Effect
96-hr EC50 for
chlorophyll a
Inhibition
96-hr EC50 for
reduction in
eel 1 numbers
96-hr EC50 for
chlorophyll a
Inhibition ~
96- hr EC50 for
reduction In
eel 1 numbers
Result
4,200
>4,200
* Results are expressed as antimony, not In terms of the compound.
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Table 5. Residues for ant loony (U.S. EPA, 1978}
Bloconcentratlon Duration
Species , • Tissue Chamlca I Factor (days)
FRESHWATER SPECIES
Biueglll, whole body Antimony <1 28
Lepomts maerocMrus trloxlde
I
UJ
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Table 6. Other data for antimony
Species
Chemical
Duration
Effect
Result
(tig/D* Reference
Claduceran,
Ddphnla maqnd
Cladoceran,
Dtiphnla cnagna
Cladoceran,
Uaphnld magna
liluegill,
Lepomis inacrochi rus
Mysid shrimp,
tn Mysidopbls bdhld
1
\ • Sheepbhedd minnow,
° Cyprlnodon varieyatus
FKtSIIWATtR SPtCltS
Antimony 64 hrs bC50 19,800 Anderson, 1948
trichloride
Antimony 48 hrs LC50 >530,000 U.S. LHA, 1978
trloxlde
Antimony 48 hrb bC50 12,100*" Klmbal 1, Mdnuscrlpt
trichloride
Antimony 96 hrs LC50 >530,000 U.S. EHA, 1978
trloxlde
SALTWATtK SPECIES
Antimony 96 hrs LC50 >4,200 U.S. CPA, 1978
tr 1 ox i do
Antimony 96 hrs LC50 >6,20(X U.S. tPA, 1978
tri oxide <8,300
* Kosults are exprobbed as antimony, not In terms of the compound.
* "Animals fed.'
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REFERENCES
Anderson, B.S. 1948. The,apparent thresholds of toxldty to Daphnia magna
for chlorides of various metals when added to Lake Erie water,; Trans, /tat.
Fish. Soc. 78: 96.
Bringman, G.,and R. Kuhn. 1959. Comparative watertoxicology fnvestigations
i
on bacteria, algae, and daphnids. Ges. Ind. 80; 115.
Kimball, G. Acute and chronic effects of lesser known metals and one organ-
ic on fathead minnows (Pimephales promelas) and Daphnla magna. (Manuscript)
f
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No.
68-01-4646.
B-ll
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
A number of biological and adverse health effects in humans
and experimental animals are known to be caused by antimony in its
various chemical states. Most reported effects in raan arise from
either occupational exposure to antimony in the course of its min-
ing, industrial nrocessing, and commercial use or as side effects
seen with the medicinal use of antimonials as therapeutic agents in
inducing emesis or for the treatment of schistosomiasis, leishmani-
asis, trypanosomiasis, and ulcerative granuloma. Aside from sever-
I
al acute poisoning episodes occurring within the context of such
use, however, the toxicological threat posed by antimony to the
general public appears to be quite low. This is due in larqe oart
to the very limited amounts of the element that !have thus far
entered into environmental media that represent potential routes of
I
exposure for humans.
The aresent document opens with an initial discussion of the
chemistry of antimony relevant to environmental exposures or ef-
fects on organisms; this is followed by discussion of sources of
i
. .1
exposure and the pharmacokinetics of antimony — absorption, dis-
tribution, biological half-fine (s) , and excretion. Concise comment
ensues regarding certain in vitro and in vivo effects of antimoriv
observed -at the biochemical, subcellular, and cellular level; the
i
systemic toxicity of antimony, as delineated in animal toxicology
studies; and effects exerted by antimony on tian. [Lastly, various
factors of utility in the development of criterion rationale for
standard setting purooses are discussed.
0-1
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Antimony, a silvery, brittle solid, belongs to group VB of the
periodic table and lies between arsenic and bismuth. It is classi-
fied as both a metal and a metalloid. It has an atomic number of 51
and an atomic weight of 121.8, and its principal oxidation states
are +3 and +$.
Antimony reacts with both sulfur and chlorine* to form the tri-
and pentavalent sulfides and chlorides. Oxidation to antimony tri-
oxide, the major commercial oxide of antimony, is achieved under
controlled conditions. Stibine, antimony trihydride, is formed bv
the reduction of antimony compounds -in acid media using zinc or
other reducing metals.
Solubilities of antimony . compounds range from insolubte to
fully soluble. Most inorganic compounds of antimony are either
only slightly water soluble or decompose in aqueous media. Anti-
monials such as potassium antimony tartrate, in which" organic
ligands are bound to the element and employed therapeutically, are
water soluble.
The brittle character of antimony metal precludes rolling,
forging, or drawing but accounts for improved hardness and lowered
melting point in alloys with lead, bismuth, tin, cooper, nickel,
iron, and cobalt. In particular, the metal is heavily employed in
antimonial lead which is used in bearings and in ammunition.
The most important antimony compound in commerce is probably
antimony trioxide, a colorless, insoluble powder, the prooerties of
which place it in high demand as a flame-retarding agent for many
commodities. It is insoluble in water and dilute nitric or sulfur-
ic acids but is soluble in hydrochloric and certain organic acids.
It dissolves in bases to >give antimonate.
C-2
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A second form of antimony having commercial use is antimony
trisulfide, Sb2S3r which is converted to the trioxidfe for use as a
fire-retardant. nther uses are in the manufacture of fireworks and
matches. Antimony trisulfide is insoluble in water but dissolves
in concentrated hydrochloric acid with the evolution of hydrogen
sulfide. It is also soluble in strong alkali solution.
Antimony shows some definite cat ionic behavfor but: only in the
trivalent state. For example, antimony forms complexes with inor-
[
ganic and organic acids to produce antimonial salts such as the
_ —2 '
disulfate [Sb(SO4)21 / the dioxalate Sb(C2O4) , and the well known
tartrate, [Sb(OH)C4H305]~. . ,' '
EXPOSURE
Consumption of antimony in the united States Is of the order
of 40,000 metric tons per year (Callaway, 1969), of which half is
obtained from recycled scrap and the balance mainly imported from
countries such as Bolivia. Use in the-United States is directed
chiefly to the manufacture of ammunition, storage! batteries, and
i
fire-proofing of textiles.
i
It is not possible to quantitatively estimate the impact of
antimony use on various comoartments of the environment which are
exposure sources for man. A more meaningful approach is to consid-
er levels of antimony in those media with which human populations
come in contact. Of the two major antimony product-ion'si tes in the
U.S. only the one at Laredo, Texas, uses processes) that entail any
loss to ambient air. Improvements in emissions control have con-
siderably reduced but not eliminated the air levels in the vicinity
of the, smelter. The second production operation, [employing alkali
C-3
-------
leachates of Ag-Cu ore and subsequent electrowinning, recycles much
of its effluent-borne antimony with apparent minor loss to the
environment (Arthur D. Little Co., Inc., 1978} . -- Other, more gener-
al, sources of airborne antimony include fossil fuel combustion and
municipal incineration,
Ingestion from Water
Schroeder (1966) compiled data from surveys of municipal water
supplies in 94 cities and reported that levels were on average less
than 0.2 ug/1 (0.2 parts per billion) when measured in tap water.
In a related study, Schroeder and Kraemer (1974) noted that tap
water levels can be increased in soft water supplies owing to the
leaching of antimony from plumbing. This would mainly be reflected
in 'first-draw' water. The source of antimonv in plumbing material
would be that present in copper tubinq (0.005 percent) and galva-
nized iron (0,001 percent).
Ingestion from Food
It is far from clear what the average dailv dietary intake of
antimony is in the U.S. population, wide-ranging values have been
reported over the years.
The comprehensive results of the u.s. Pood and Drug Adminis-
tration's (FDA) survey of various trace metals including antimony
in various food classes, using neutron activation analysis, xhave
recently been reported by Tanner and Friedmann (1977). The median
level and range of antimony, levels for the food classes, expressed
as oarts per million, wet weight, are: dairy Products, ^ 0.004,
-------
Based on these recent figures, Tanner and Friedmann (1977)
y
calculate that the daily intake for antimony is too negligible to
assign a meaningful value.
Earlier reports of dietary intake of antimony indicated sig-
(
nificant amounts assimilated daily. It is likely that part of this
discrepancy is due to differences in analytical methodology.
Schroeder (1970) calculated a value of somewhat less than 100
ug/day as the average dietary intake for man, while ;Murthv, et al.
(1971) calculated a range of 0.25 to 1.28 mg/day for[institutional-
i
ized children. In this study, a weighted average dietary antimony
i
content of 0.36 rag/kg for these pediatric grouos was determined.
Support for the recently reported very low antimony content o€
i
dietary classes in the United States (Tanner and Friedmann, 1977)
) ' \ ''
is the survey of Clemente (1976), who reported the iuse of activa-
tion analysis in surveying food antimony content in'Italian diets.
A mean value of several micrograms Sb daily was obtained.
A bioconcentration factor (BCF) relates the concentration of,a
chemical in aquatic animals to the concentration in the water in
which' they live. An appropriate BCF can be used with data concern-
ing food intake to calculate the amount of antimony'which might be
i j
ingested from the consumption of fish and shellfish. An analysis
(U.S. EPA, 1980) of data from a food survey was -used to estimate
that the per capita consumption of freshwater and estuarine fish
and shellfish is 6.5 g/^ay (^teohan, 1980)".
A measured BCF of less than one1 was obtained for antimonv
using bluegills (U.S. ''SPA, 1978). For lack of other information, a
value of 1.0 can be used as the weighted average bioconcentration
0-5
-------
factor for antimony and the edible oortion of all freshwater and
estuarine aquatic organisms consumed by Americans.
Inhalation
Antimony is infrequently oresent in air at measurable levels.
National.Air Sampling Network data for 1966 showed possibly signif-
icant levels at only four urban stations (0.042 to 0.085 ua/tn ) and
three nonurban facilities (0.001 to 0.002 ug/m ) (Schroeder, 1970;
Woolrich, 1973). It can be generally stated that urban ambient air
levels of antimony are higher than nonurban levels, with the dif-
ference presumably reflecting the extent of greater fossil fuel
combustion, municipal incineration, and auto emissions in urban
areas.
Antimony is one of the elements which apoears to1 concentrate
in the smallest particles emitted in the fly ash from coal-fired
power plants (Davison, et al. 1974). These small-diameter oarti-
cles are both difficult to trap with conventional stack technology
and are the size which penetrate the deeoest in the oulmonarv tract
of man. While this suggests a relatively high level of respiratory
absorption of at least oart of the total airborne antimonv, it is
difficult to state that this poses any net hazard, given the over-
all low levels of total antimonv.
Integrated Multimedia Exposure Estimates
In terms of the aggregate contribution of various exoosure
sources to the total daily intake of antimony by human populations
in the United States, the total amount is cruite small and even neg-
ligible relative to other environmental agents of concern, e.g. ,
lead, «>ercurv, or cadmium. ^or example, if one accents the most
C-6
-------
recently available data on dietary antimony intake , (Banner and
Friedmann, 1977), then no appreciable additional antimony uptake
via the diet would be expected. Also, essentially the same applies
in reqard to nonaporeciable amounts of antimony being inaested via
water consumption. This is consistent with the limit«»d data of
Clemente (1976) who, using fecal and urinary antimony Bevels, con-
cluded that daily intakes of selected Italian populations were less
than 2.0 ug/<3ay. Also, an individual inhaling even the highest
3 ''
recorded ambient air level (0.085 ug/tti } for an urban setting would
I
be exposed to a total of 1.7 yg/day, assuming a daily inhalation
I
rate of 20 cubic meters. It therefore appears that over«illr multi-
i
media antimony exposure levels for the general U.S. population are
insignificant, or essentially negligible,, in comparison to occupa-
i
tional exposure levels at which discrete clinical health effects
have been observed. '
PHARMACOKINETICS ''
i
Absorption
Data for the absorption of antimony from the resoiratorv
tract, the gut, and skin are rather limited; as such, 'observed val-
i
ues may not broadly apply for all mammalian species, including man.-
Also, there is only very limited information on the €Jffects of age
or nutritional status in terms of increasing or decreasing the
extent of antimony absorption. In addition, the kinetics of anti-
mony uptake, distribution, and excretion are dependent on physical
i
and chemical characteristics of the antimonials employed as well as
I
the route of exposure and the species of experimental animals
studied.
-------
Antimony absorption from the respiratory tract is a function
of particle size and solubility in the lung. The latter is depen-
dent on the chemical form. This has been demonstrated experiment-
ally by Felicetti, et al. (1974b) and Thomas, et al. (1973), who
exposed .experimental animals to aerosols generated from solutions
containing Sb-labeled antimony potassium tarferate. Prior to
inhalation, the solutions were subjected to temperature treatment
ranging from 100°C to 1,000°C. The higher heat treatment probably
resulted in increasing degradation of the organic portion of the
molecule and yielded different patterns of deposition and retention
when inhaled. The lower temperature aerosols (100°C) were of a
large particle size (1.3 urn mass median aerodynamic diameter -
MMAD). They were deposited to a large extent on the upper resoira-
tory tract and were rapidly cleared via the mucociliary apparatus.
r
However, the approximately 20 percent of these aerosols which were
deposited in the lower respiratory tract were solubitized rapidlv
into the bloodstream. The higher temperature aerosols (500°^ and
1,000°C) contained smaller particles (MMAD less than 1.0 ym) and
were deposited deeper in the respiratory tract. These oarticles
were relatively insoluble in the lung and were only slowly absorbed
into the bloodstream. In a separate study (Felicetti, et al.
I974a) in which hamsters inhaled the 100°C aerosol, there was no
difference in the pulmonarv absorption of trivalent vs. oentavalent
i
antimony material.
Data pertaining to the extent of gastrointestinal (<^I) absorp-
tion of antimony in man "and animals are sparse. According to one
report (Felicetti, et al. 1974a), only 1 to 2 percent of antimony,
-------
as either the trivalent or pentavalent forms, is absorbed *rom the
GI tract of hamsters. It should be noted that these were the rela-
I
tively insoluble oxides. It is likely that the water-soluble or-
I
ganic derivatives of antimony would be absorbed to a, greater ex-
tent. Elinder and Friberq (1979) have noted that tartar emetic
i
(potassium antimony tartrate) solution is about 15 percent absorbed
'in'the GI tract of mice, based on earlier data of wai'tz,. et al.
!
(1965). " j
Little information exists regarding the absorption of antimony
i
through the skin. -Gross, et al. (1955a), using antimony trioxide
dust dispersed in a paste (25 mg) , applied the oxide to the1-skin of
I
rabbits and could see no sign of systemic effects. These workers
i
did not, however, carrv out any blood or tissue antimony determina-
tions. '
Few data exist regarding transolacental transfer of antimonv
i
in animals or man. Casals (1972) found no antimony in fetal tis-
t
f
sues from rat dams exposed to pentavalent antimony intramuscularly
for five doses, 125 or 250 Sb/kg, between days 8 and 14 of gesta-
tion. Similarly, James, et al. (1966) did not detect antimonv in
i
i
the tissues of lambs when ewes were daily given 2 mb/kg/day oral
doses of antimony potassium tartrate from the first Hav of gesta-
tion for either 45 days or 155 days. j
In humans, Belyaeva (1967) found antimony at detectable levels
in placental tissue, amniotic fluids, and cord blood in oregnant-
women who worked in antimony smelters durina pregnancy. It is dif-
ficult to evaluate the results of this study, since the analytical
method employed may not Permit specificitv for lust antimonv.
C-9
-------
Distribution
Blood is the main vehicle for transport of absorbed antimonv
to the various tissue compartments of the body. Several studies
have shown that the relative partitioning of antimony between the
erythrocytes and plasma is a function of element valency. That is,
trivalent antimony is primarily lodged in red cells, while plasma
carries the major .fraction of the pentavalent form (Felicetti, et
al. 1974a). Also, in a related in vitro studv («ahner, 1954) it was
found that erythrocyte antimony is primarily bound to the globin
moiety of hemoglobin. In this In vj^tro study, rodent erythrocytes
were- employed which may not be relevant for other species.
The levels attained and the clearance of antimonv from bloo'l
depend upon the route of intake, the chemical and physical form of
the antimonial used, and the specific parameters ,of exposure reai-
ntens employed in pertinent studies.
•Levels of antimony in blood have been determined after inhala-
tion of antimony aerosols by mice (Thomas, et al. 1973) , dogs
{Felicetti, et al. 1974b) , and rats (Diuric, et al. 1962). In
rats, unlike the other species, it was observed that inhalation
leads to a persisting elevation of antimony in the blood. Tiurier
et al. (1962) reported that animals inhaling antimon^ trichloride
retained a blood concentration of 10 percent of the body burden 20
days beyond cessation of exposure.
Mice inhaling antimony aerosols generated at three tempera-
tures (100°C, 500°C, and 1,000°C) and having corresponding mear
aerodynamic diameters of 1.6, 0.7, and 0.3. urn'at two days post-
exposure showed the corresponding fractions per milliliter of bloor
C-10
-------
of the body burden to be 0.43, 1.2 and 1.0 percent,! respectively
(Thomas, et al. 1973).
i i •
i!24
Waitz, et al. (1965) used-single oral doses of Sb-l.abeled
1
tartar emetic to assess the effect on blood levels in!mice. Levels
f
of antimony' in blood up to 25 hours post-exposure Jwere linearly
related to dose while clearance from blood was both' -linearly and
I
quadratieally related with time. These same workersjobserved that
i
oral exposure (8 mg Sb/kg) in monkeys led to average peak blood
levels of 18 ug Sb/dl as,observed 6 to 8 hours cost-exposure.
Changes in blood antimony levels have also been followed after
|
parenteral exposure of animals and humans. For example, a rapid
decline in blood levels was observed in rats injected' intravenously
124 •
(i.v.) with 11 mg/kg trivalent antimony as Sb-labeled tartar
emetic, with the amount of decrease approximating 30 ug/dl after
four hours. By comparison, the i.v. administration of 1.3 mg ^b/kg
i
to three monkeys as reported by Waitz, et al. (1965) led to peak
blood antimony levels of 125 to 190 ug Sb/^1 at ca. 15 minutes Post-
injection, followed by a raoid decrease to, 10 to- 20 ug Sb/dl at 24
I
hours.
i
Casals (1972) studied the pharmacokinetic properties of a
pentavalent antimony dixtran glycoside in mice, ratsj» and rabbits.
i
Rabbits given this agent at a Dosage of 14 mg Sb/kg intramuscularly
had serum antimony levels of 6.5 mg Sb/dl Serum (65 ug Sb/ml) at
five hours post-injection. ^fter 72 hours, levels ,had decayed to
ca. 2.0 mg Sb/dl (20 ug Sb/ml). i
124 '
Abdalla and Saif (1962) injected Sb-labeled Astiban, a tri-
i
valent antimonial, intramuscularly into human subjects at a dose
Oil
-------
range of 1.4-2.1 mg ^b/kg and could not measure blood levels after
single or repeated dosing. El-Bassouri, et al. (1963) similarly
noted a rapid fall o€ blood antimony levels when oediatric patients
with urinary schistosomiasis were given single inlections of vari-
ous trivalent antimonials (5 to 7 mg Sb/kg). Clearance of oentava-
lent antimony from blood in human subjects is also very rapid, with
negligible amounts seen after 24 hours in subjects aiven 'the oenta-
valent antimonials intravenously at 2 to 3 mg Sb/kg dosing levels.
Data for normal blood antimony levels in man are limited.
Sumino, et al. (1975) , reporting on seven Japanese autopsy samples,
found an average value of 1.3 ug ^b/fll (0.013 ug/ml) and a ranc?e of
-------
files, it appears that low ambient antimony exposure leads to high-
est levels in liver, followed by spleen and lung. ;
The tissue distributions of antimony in exposed j experimental
I
animals are tabulated in Table 1 according to the type and level of
i
exposure, the animal model employed, and the relative; distribution
i
of antimony among different tissues as observed in various studies.
Prom Table 1, it appears that tissue distribution of antinonv
\
is a function of valency state when inhaled, with levels of triva-
lent antimony increasing more rapidly in liver than the pentavalent
form, while skeletal uptake is greater with the pentavalent anti-
I
monial (Pelicetti, et al. 1974a) . '<
Antimonial aerosols with different .physicochemical character-
istics are absorbed from the lung at different rates. This is
i
illustrated by the fact that aerosols generated from antimony
t
potassium tartrate solutions are more soluble in the lung when gen-
erated at low (100°C) as opposed to high temperature, (500°C or
1
1,000°C) (Thomas, et al. 1973; Pelicetti, et al. 1974b) . The high-
er temperatures may have resulted in formation of oxides, f-Tith the
i
i
soluble aerosols, inhaled by dogs, radioactive antimony accumulated
i
in lung, thyroid, liver, and pelt, with the thyroid j gland having
the greatest concentration. The latter results are consistent with
the findings of Ness, et al. (1947) , who reported that the thyroid
i
was a target organ for antimony accumulation in dogs I when oroahic
antimonial compounds were iniected i.v. I
Parenteral administration of antimonials generally tends to
show a greater accumulation in the kidnevs, followed by liver, and
!
mineral tissue (Molakhia and Smith, 1969; Waitz, et a'l. 1965).
C-13
-------
TM1J.R 1
Tissue RlsLributions of Antimontals In Different Species Under Various Exposure Conditions
of Exposure
Species
Dosing (Antimonial)
Tissue Distribution
Reference
O
I
EKPOSURR
Normal mice
Mice infected
with S.
nansonT
INHALATION
I'XPOSURR
Mice
Hamsters
194
Oral (" Sh-labeled tartar
emetic)s Single dose, 16 iig
Sb/kg and greater
Oral |l2*Sb-labeled tartar
emetic)s 16 mg/kg daily for
2, 4, 6, fl or 10 days
i
Inhalation ( Sb aerosols):
124
Sb aerosols generated at
100°C, 500°C,. and 1,006°C
Inhalation < Sb aerosols);
generated at 100°c, 500°c,
and 1,000°C
Inhalation (trivalent and
pentavalent aerosols from
1 94
Sb-tartrate)s aerosols
generated at LOO C, 1.6 tim
mean aerodyn. diameter
tiiver antimony levels increase linearly
with dose and quadratleally wifch time
*
Liver antimony levels were unilorw firm
day to day with little accumulation
Aerosols generated at 100 C had ca. one-
tenth less antimony in lung compared to
500°c and 1,000°C. 100°c aerosol showed
iSt of body burden lodged in skeleton by
52 days, much more than Cor aerosols
fenerated ,at 500° and 1,000°
Sb levels were highest in lur.g, thyroid,
Hwer and pelt, with thyroid having greatest
accumulation £or 100 C aerosol and lump the
greatest level Cor 500° and 1,800° aerosols
Highest levels for both valency Corns were
seen in liver, skeleton and pelt, with
relatively greater amount of trivalent
antimony in liver than of pentavalent form
by day 5 post-exposure. Skeletal values
greater with pantavalent Corn
Haitz, et al, 1965
Waltz, et al. 1*965
Thomas, et al. 1973
Felicetti, et al. WSb
reiicettl, et al, 1974a
-------
TJUH.E 1 (continued)
Route of Exposure
Species
Dosing iAntlinonial)
Tissue Distribution
SYSTEMIC
o
I
Mice infected
with S.
mansonT
Rats
Rats
Mice
nog
Human
Intraperitoneally {tartar
emetic or Astiban-sodium
antimony dimereapto-stieci-
nate) : 5 mg/kg, tartar
emetic; 7.5 mg/kq Astiban
124
Intravenous ( Sb tartar
eiwtic}i 11 nig/kg, single
in-jectlon: 6 rat pairs at
0.5, 2, 4, 8, 24 and 72 hr,
Intravenous ( SbOCl or
Na122Sl>0,); sacrifice at
1 and 4 fiours
1 ?4
Intraperitoneally ( Sb
tartar «»metic| : 1) pr«»-
treated group with 35 mq
Sb/kq followed by labeled
35 me} Sb/kq dose} 2) con-
trol qcoup treated with
labeled 35 mq Sb/kq dose
Intravenous orqanic anti-
monial corapnunds '
124
_Intra"venoiis _l sh-ftstlhs»n-
sodium antimony dimercapto
succtt>ate) : "sinqle 100 «wj
dose, fol lowt»d [or 23 days
Roth antimonials led to highest uptakes in
liver and kidney by 48 he. Over 2-15 days,
levels in mineral tissue (bone and teeth)
began to exceed levels in other tissues.
Pelt levels were uniformly hiqh while brain,
thyroid and male reproductive organs showed
least uptake -
Kidney antimony levels were higher than liver
antimony levels at all time points
Highest antimony levels were seen in kidneys,"
bone and spleen: kidneys had 3.9% of the
dose/q with 122SbOTl and 1.31% of the dose/q
with Nal22Sb02
Mver levels oE antimony were equal for pre-
treatment and control groups. Heart, spleen
and kidney levels were lower in pretreatment
group
Thyroid hypothesized as antimony target organ
based on high Sb uptake
Largest arstiiRORy uptake was seen—In—liver-,
followed by the thyroid and the heart
Reference
Molakhia and Smith,
1969
Waitz, et al.
Matthews and Molinaio,
1963
Glrgis, et al. 1965
Ness, et al. 1947
nbdalra~and~SaTf,~
1962
-------
In the study of Abdalla and Saif (1962), an Egyptian male had
highest antimony uptake in liver, thyroid, and heart when given a
single innected dose of labeled Astiban (100 ma).
Tissue distributions in man have mainly involved the study of
autoosy material. Based on the detailed study of Sumino, et al.
(1975) , which used human tissue samples from Hyogo Prefecture in
central Japan, all organs had antimony levels of less than 0.1 com
wet weight, with a mean total body burden of about 1.0 mg. The skin
had the highest mean level, 0.096 +0.10 opm, followed by the adre-
nal gland, 0.073 +_ 0.14 and the lung, 0.062 + 0.056 ppm. Liver,
spleen, and heart levels were lower.
Lievens, et al. (1977) emploved radiochemical neutron activa-
tion analysis to measure a number of trace elements, including
antimony, in segments of normal liver from five autoosies of resi-
dents of Belgium. A mean value of 0.011 ug/g wet weight was ob-
tained, with a range of 0.003 to 0.020. This is within an order of
magnitude of the'mean liver level, 0.023 ug ?b/g wet weight, ob-
tained by Sumino, et al. (1975).
Specific human tissue analyses for antimony have also been
reoorted. For example, in one study, lung tissues from adults 4C
to 70 years of age in Glasgow, Scotland, were analvzed *=or antimony
content using neutron activation analvsis (Molakhia and Smith,
1967). A mean value of 0.095 ( + 0.105) ua/q wet tissue was ob-
tained, with a range of 0.007 to 0.452 ug. The distribution o>
antimony within the lungs analyzer" was such as to suggest the ele-
ment arose from airborne dust. In a related study, Kennedy (1966
measured diseased and normal luna tissue from 24 subjects for anti-
C-16
-------
mony content, obtaining a range of 0.005 to 0.87 |iq/a wet tissue.
Lungs with pulmonary lesions 'did not apoear to he different in
antimony content than control samples.
'Brune, et al. (1980), in their study of elements in kidney, '
liver, and'lung tissue from autopsy samples of retired workers who
were employed in a smelter and refinery/ noted that the median
level of antimony in lungs of former smelter workers were signifi-
cantly greater than controls. The median antimony levels in lung
tissue of one worker group (2-19 years between ' retirement and
' „ ?
death) was 0.32 ppm and a range of 0.023-2.6 (N=23), versus control
values of 0.029 ppm, range 0.011-0.054 (N=9). ^ince other data
i
from nonoccupational subiects sugaests little antimony accumula-
tion in the lungs, smelter workers may inhale a very insoluble form
of the element, possibly the sulfide.
Using neutron activation analvsis, Eoaenfeldt, et al. (1977)
measured antimony and other, trace elements in human decidua ob-
i
tained from Swedish subiects during the 12th to the 18th week of
i
pregnancy. In 14 samples, levels of antimony had a'geometric mean
value of 0.024 ug/g dry tissue and a range of 0.02; to 0.03. ^he
i - I
mean antimony level . in decidua was considerably less than that in
* i
endometrium in either proliferative or secretory phase.
In a study of human dental enamel, Rasmussen (1974) determined
the antimony content for 12 Danish subjects using neutron activa-
tion analysis and found a range of ^ 0.001 to 0.006 j!ig Sb/g enamel.
i
The range of levels in this study is less than that found by *!ixon,
I
et al. (1967), who reported 0.005 to 0.665 ug/g, also using activa-
tion technioues. The difference may reflect more complicated sam-
C-17
-------
pie manipulations in the latter study, which would have increased
the risk of contamination.
The antimony content of cardiac tissue from autoosies of 20
victims of accidental death was determined by Wester (1965), who
obtained a median concentration of 0.015 ug/q wet tissue using
activation analyses, with a range of 0.001-0.004. No differences
were seen with sex or age.
Levels of antimony in human brain are relatively low, consis-
tent with a low neurotoxicity potential for this agent as seen from
its therapeutic use. Hock, et al. (1975)f analyzing eight regions
of six brains, found a cerebral cortex value range of 0.025 to 1.71
ug/g dried tissue.
Based on the foregoing discussion, it appears that antimony
accumulates most highly in selected soft tissues, e.g., kidney,
liver, thyroid, certain other endocrine organs, and, to some ex-
tent, the heart.
According to the International Commission on Radiological °ro-
tection (ICRP, 1960), antimony is calculated to have a total human
body half-time of 38 days and tissue half-times of: liver, 38
days; thyroid, 4 days; lungs and bone, 100 days. The accuracy or
such estimates by the ICRP, however, has been Questioned.
Abdalla and Saif (1962) found the half-times in man of oaren-
terally administered antimony as chemotherapeutic agents to var
with the intramuscular and intravenous routes. For intramuscula
infection, half of the total dose was excreted by 30 davs whil
with i.v. treatment, half of the dose could not be recovered by 3
days.
C-18.
-------
From the whole-body.data of Waltz, et al. (1965), parenterally
administered Sb-tartar emetic in rats had a half-time of less
124
than 24 hours while Thomas, et al. (1973) showed that So-labeled
antimony'aerosols inhaled by mice gave whole-body data,that includ-
ed a half-'time of 29 days for the more rapidly cleared 100°C aero-
sols versus 39 days for the aerosols generated at higher tempera-
tures.
124 i
Using beagle dogs and ~3b-labeled antimony ,aerosols generat-
ed at 100°, 500°, and 1,OQO°C, Felicetti, et al.< (1974b), calculated
corresponding long-term biological half-times of; 100, 36, and 45
days, respectively. These authors also determined that with the.
same aerosol model and using hamsters, both tri-
and pentavalent
antimony body clearance had a fast component of several days and' a
' i ' '•
slower clearance component of 16 days. In this study, lung solu-
i
bility for the 500° and 1,000°C aerosols is .a key:factor.
i •
With regard to tissue accumulation, particularly in man, lim-
ited data suggest that both soft: and mineral tissue show little
i • \
tendency to accumulate in unexposed populations, although one
recent report (Brune, et al. 1980) suggests antimony accumulation
, p
occurred in smelter workers who had been retired from work activity
\ for at least several years. Even though, bone antimony tends to
i
have a longer half-time than antimony in body soft, -tissue, this is
considerably less than for certain other toxic heavy metals. -
Metabolism
Absorption of antimony in man and animals is mainly via the
respiratory and gastrointestinal tracts, the extent of absorption
" - i'
depending on factors such as solubility, particle -size, and chemi-
-------
cal forms. Absorption via the GI tract is on the order of several
psrcsnt with an-imcriy trioxiaa, 2 relatively insoluble compound,
and presumably would be much greater with soluole antimonials.
Blood is the main carrier for antimony, the extern: of parti-
tion between blood compartments depending on the valence state of
the element and the animal species studied. The codent exclusively
-ends to concentrate trivalent antimony' for long periods in the
erythrocyte. Whatever the species, it can generally be said that
pentavalent antiTnony is oorne by plasma and trivalent antimony in
the erythrocyte- Clearance from blood to tissues of antimony is
relatively rapic; this is especially true in the case of parenteral
administration and the use of pentavalent antirr.ony. -
The tissue distribution and subsequent excretion of antimony
is a function of both route of administrationj;-and valence state.
Trivalent antimony aerosols lead to the highest levels in the
lungs, skeleton, liver, pelt, and thyroid whi-ie pentavalent form
aerosols show a similar distribution with the exception of lower
l=velE in liver.
Parenterai administration to animals snows trivalent antimony
zccumulatinc in the liver and Kidney as well as in oelt and
~ * i -
thyroid.
In man, nonoccupational or nontherapeutic exposure s"hows very
low antimony levels in various tissues with limited'evidence of
ccc'jrsdat ion in smelter .%7or
-------
The half-time of antimony in man and animals is a function of
i
route of exposure and oxidation state. The rat. appears to be
unique in demonstrating a long biological half-time| owing to anti-
!
mony accumulation in the erythrocyte. In other species, including
man, moderate half-times on the order of days have hieen demonstrat-
i
ed. While most soft tissues do not apoear to accumulate antimony,
the skin does show accumulation owing to its high content' of sulf-
hydryl grouos. With respect to excretion, injection of trivalent
antimony leads to mainly urinary excretion in guinea oias, dogs,
i
and humans and mainly fecal clearance in hamsters, mice/ and rats.
i
Owing to its higher levels< in olasma, oentavalent antimony is
mainly excreted via the kidney in most species . <
Unexposed humans excrete less ,than 1.0 ug antimony daily via
urine, while occupational or clinical exposure may result in mark-
edly increased amounts.
I
Excretion , •
The kinetics of antimony excretion apoear to be a function of
the animal species, route of intake of the element, i arid the chemi-
i
cal form (oxidation state) of antimony. ! '
i
Parenteral administration of trivalent antimonials leads to
i
raoid urinary excretion in guinea pigs, dogs, and humans (Otto and
i
Maren, 1950; Abdalla and Saif, 1962) , while fecal clearance is more
important with hamsters, mice, and rats. !
Animals inhaling oentavalent antimony aerosols ]berid to excrete
i
i
the element by both the GI and renal tracts, reflecting entrv of
some of the inhaled material into the GI tract by mucociliary move-
ment and swallowina.
C-21
-------
Generally, pentavalent antimony is more rapidly excreted in
the urine than is the trivalent form, reflecting the attainment of
higher Plasma levels by the pentavalent form,
Little information on daily urinary output of antimony in man
is available. Clemente (1976) used neutron activation analysis to
determine that ^0.3 yg was excreted da,ily in an unexposed Italian
population. Under conditions of occupational exposure, urinary
excretion is elevated but highly variable from subject to subject
(Coooer, et al. 1968). Similarly, chemotherapeutic treatment o^
patients with antimony parasiticides leads to high levels of excre-
tion. These agents are fully soluble and given at comparatively
high doses. Abdalla and Saif (1962) have measured 24-hour levels
of antimony of ca. 20 to 40 ug/dl after parenteral administration
of 75 to 125 mg Astiban®.
As internal indices of exposure, usefulness of blood and/or
urine antimony levels are of undetermined value. Generally, uri-
nary levels of antimony increase under conditions of occupational
or chemotherapeutic exposure and it appears that such values would
reflect the intensity.of ongoing exposure. Similarly, blood levels
rapidly rise and fall with onset and removal of exposure1.
EFFECTS
Only a relatively limited data base exists in regard to the
study of biological and pathological effects of antimony in experi-
mental animals and humans. Such effects include various cellular
and subcellular effects, as well as toxic actions manifested at
organ system levels, ^he latter type of systemic toxicitv includes
damage to the lungs, heart, liver, spleen, and endocrine organs, as
well as toxic effects exerted on reproduction and ^evelomient.
C-22
-------
Acute, g-tbacute. and Chronic Toxicity
te toxicity tests with antimony and antimonial comoounds
wer
r
rried out by Bradley and Fredrick (1941).
gained after either oral or intraperitoneal
/•
are indicated in Table 2. As discussed latei
.„ doses included labored breathing, general
o>
V
siqns of cardiovascular insufficiency leading
nimals within a few days after exppsure. It s
of the antimony compounds tested, the trifluoride is mainly
nterest in regard to laboratory or experimental use, in con-
trast to most of the other agents being encountered
The observed
i.p.) adminis-
-, responses to
weakness, and
to death amona
hould be noted
in industrial
settings. _ , - ; > -'
Levina and Chekunova (1965) also studied LD^s for antimony
i
compounds, using subcutaneous (s.c.) and intratracheal administra-
tions in mice and rats, respectively. They obtained1 an LDt.n of 50
mg Sb/kg for antimony trifluoride with single s.c.
mice, whereas 50 ma Sb/kg was found to be without
effect during a 10- to 30-day observation period when
oxide, trisulfide, or oentasulfide were administered
, ly. Subcutaneous injection of antimony trioxide at
rag/kg, however, was universally (100 oercent) fatal.
tracheal doses of 2.5 to 20 wg of antimony trifluoride administered
to rats were also-100 oercent fatal, whereas lower doses of 1.0 to
1,5 mg were survived with minimum toxic effects being seen. Doses
of antimony trioxide and trisulfide/ were tolerated
with 20 mg of those compounds producing temoorary w
the only sign of toxicitv.
injections in
obvious toxic
antimony tri-
subcutaneous-
a dose of 500
S male intra-
much better,
eiqht loss as
C-23
-------
TABLE 2
cn of Antimony and Compounds*
Compound
Tartar emetic.
Tartar emetic
Antimony trifluoride
Antimony
Antimony
Antimony trisulfide
Antimony pentasulfide
Antimony trioxide
Antimony pentoxide
Species
Rat
Rat
Mouse
Rat
Guinea pig
Rat
Rat
Rat
Rat'
Route
oral
i .0.
- oral
i.o.
i.o.
i.o.
i.o.
i.o.'
i.p.
LD50
mq/kg
300
11
804
100
150
1,000
1,500
2,250
4,OQ"0
*As determined by Bradley and Fredrick, 1941
C-24
-------
This section discusses certain biochemical and subcellular
aspects of antimony toxicity per se, where studied as such. Other
i (
biochemical and cellular effects occurring as part of the systemic
i
i
toxicity of antimony are noted later •- under sections on specific
organ systems. , : .
I /
- Effects of antimgny at the biochemical level ar|e little under-
stood at present, and the available information is correspondingly
limited. Unlike many of the toxic heavy metals, which are cationic
i
in character and directly interact v/ith ligating groups such as the
sulfhydryl, amino, and carboxyl moieties of macr'omolecules and
I
rheir constituent units to form biocoordination complexes, antimony
i
I /
probably resembles arsenic in the nature of its bonding. Trivalent
antimony forms covalent bonds with sulfhydryl groups and pentava-
i
lent antimony, like pentavalent arsenic, competes with phosphate
i
to form ester linkages. !
Evidence for this assumed overlap of chemical behavior with
arsenic is mainly indirect. Tissues high in sulfhydryl groups,
*
such as sfcin, tend to show pronounced accumulation of antimony, as
noted above in the metabolism section. Further, in ithe rodent, the
red cell accumulation of trivalent antimony parallels that seen
•
with arsenic [National Academy of Sciences (NAS), 1977].
I f
In vitro studies directed to antimony's effects on enzymes and
v I
enzyme systems are very limited. In a study of homogenate of adult
i
S.'mansoni worms, Mansour and Bueding (1954) observed an effect of
" i '
stibophen or tartar emetic on phosphofructokinase,:as measured by
inhibition in the formation of fructose-1,5-diphosp|hate from fruc-
tose-6--pnospnate. No other glycolytic enzymes .appeared to be anti-
C-25
-------
mony-sensitive even at high concentrations, nor was phospho€ructo-
kinase from another source (rat brain preparations) as sensitive to
antimony. Pentavalent antimony was without"effect on any enzyme
studied.
Incubation of rat liver mitochondria for a brief period with
sodium antimony gluconate, a trivalent antimonial, »showed a concen-
tration-dependent effect on oxidative ohosphorvlation, presumably
localized at the tSADH-oxidase portion of the electron-transfer
chain (Campello, et al. 1970). ^he minimal concentration necessary
for this observation was ca. 4 x 10 M Sb.
In vivo effects of antimonials on enzymatic activity have been
sporadically noted in the literature. Parenteral administration of
antimony trioxide (163 mq/kg) in rats, for instance, led to i«-
v
creased activity of cholinesterase in myocardium but decreased
monoamine oxidase activity in brain and liver (Minktna, et al.
1973).
Certain other disturbances of biochemistry have also been
reported for antimonials. In a study of carbohydrate metabolism,
Sch'roeder, et al. (-1970) found that lifetime exposures of rats to
low levels of"antimony resulted in decreased serum glucose levels
in nonfasting animals. Other biochemical changes reported include
increased glutathione in the blood of antimony-exposed animals
{Maeda, 1934-} and increased nonprotein nitrogen and hemoglobin con-
tent in blood of rabbits exposed to tartar emetic (Maeda, 1934?
?ribyl, 1944).
Studies on the uptake and subcellular distribution of anti-
monials have been reported by Smith (1969) using in vitro tech-
C-26
-------
124 :
niques. ' Mouse liver slices incubated with Sb-,labeled tartar
i
emetic showed a marked antimony accumulation with accompanying cel-
lular necrosis. Total uptake was up to 18-fold greater than mea-
sured in healthy tissue. Subcellular fractionation 'indicated that
-about two-thirds of the label was in the particulat'e matter, ori-
marily the microsomal fraction. It is not clear/ however, whether
the cellular -necrosis observed was induced by the a|ntlipony per se
124 i
or strong beta emissions of the Sb isotope. Nor 'is it clear as
!
to whether the high uptake of the labeled compound occurred secon-
darily to the cellular damage. j
Mutagenicity and Carcinogenicity
i
The few chronic feeding studies that have investigated DOSSI-
ble antimony carcinogenicity in animals have produced negative
results (Kanisawa and Schroeder, 1969; Schroeder, .*?t al. 1970) ,
i
with no increases in tumorigenesis being observed at1 antimony con-
centrations of 5 com either administered via the diet or drinking
j
.
water. While the results were negative, the acceptance of this
compound as a noncarcinogen is precluded by the lack
of additional
exposure levels, including higher doses. !
Several studies have reported mutagenic potential for various
i
antimony compounds (Kanematsu and Kada, 1978; FlasseL, 1977; Paton
and Allison, 1972) . In their examination of 100 metajl compounds by
the rec-assay procedure, a test which assesses the differential
inhibition of cellular growth of a recombinant-def ic ie.nt strain of-
3. subtilis versus the wild strain, three antimonials - antfimony
~ i
trioxide, antimony trichloride, and antimony oentach' lor i^e - were
found to be Positive. Paton and Allison (1972) opserved toxic
C-27
-------
effects of tartar emetic on human leukocytes in culture at levels
_Q
as low as 10 M as measured by significant reduction in mitotic
index as well as an increase in the number of chroroatid breaks in
chromosomes.
Respiratory System Effects
As discussed later, certain tvpes of resoiratorv illnesses,
including pneumoconiosis, have been observed with human exposures
to antimony via inhalation. Some efforts, however limited, have
been made to study analogous types of respiratory ,toxicity in
experimental animal models under controlled laboratory conditions.
t *
In one of the earliest studies, Dernehl, et al. (1945) ob-
served resoiratory effects in guinea pigs exposed to antimony tri-
.. *
oxide via inhalation. Exposures to concentrations averaging 45.4
^
mg/m for 2 hr/day, 7 days/week for three weeks and 3 hr/day there-
after yielded marked resoiratory pathology. This included wide-
spread pneumonitis in animals estimated as retaining from 13 to 424
mg of antimony and scattered subpleural hemorrhages seen in all
animals retaining 50 mg or more of the antimony compound. The very
wide range of estimated effective or retained doses associated with
the observed health effects are notable.
In another study (Gross, et al. 1952) lipoid pneumonia was
induced in 50 rats exposed to antimony trioxide at 100 to 125 mg/n
(mean partfcle size = 0.5 um) for 25 hr/week for a 14.5 month-peri-
od. The lung pathology induced by antimony was characterized by:
(1) cellular proliferation, swelling, and desquamation of alveolar
lining cells; (2) fatty degeneration, necrosis, and rupture of
alveolar macrophages; and (3) oulmonary fibrosis.
C-28
-------
In a second .study by Gross, et al. (1955b), a' similar inhala-
i
s
I
tion exposure reaim.en was employed for exposure of 50 rats, while
20 rabbits were exposed at 89 mg/m for 25 hr/week for 10 months. A
i
relatively high mortality rate was observed: 18 percent ,for the
i
i
rats-and 85. percent for the rabbits, mainly attributable to anti-
mony-induced pneumonia. Pistological findings were similar to
those observed in the previous Gross, et al. (1952) study except
for somewhat less widesoread f ibrosis in the rat' lungs and more
pronounced interstitial pneumonia in the rabbits. ,Again, no lymph
i
i
node f ibrosis was obs-erved in either species, even thouah some
antimony deposits were seen in lymph nodes of each.J
\
Subsequent to the. Gross, et al. (1952, 1955b) reports, only
,1
two other studies (Levina and Chekunova, 1965? Cooper, et al. 1968)
r
provide much additional information regarding anti'monv effects on
the lungs. In the Levina and Chekunova (1965) study, for example,
-intratracheal injections of 20 mg of antimony trloxi'de, trisulficie,
i
or pentasulfide in rats resulted in immediate reductions in body
weights for several days and, upon sacrifice a month post-infec-
tion, lung histopathology findings indicating signs of macrophaqe
i
reaction, accumulation of lymphoiS elements around blood vessels
I
and bronchi, and accumulations of epitheloid cells 'in other areas.
By comparison to the above results, much more!severe effects
s j
were observed bv Levina and Chekunova (1965) with intratracheal
\ i
injections of a halogenated anti«fonial, i.e., antimonv tri fluoride.
That is, single doses of 2.5 to 20 tig of the trifluoride comoound
i
produced 100 percent mortality in exoosed rats, with death occur-
~f
ring due to asphyxia following the onset of labored breathing and
-------
convulsions within minutes after the injections. Acute serous'or
serohemorrhagic edemaf' causing a 3-fold increase in lunq weight,
was evident uoon oost-mortem inspection. In -rats surviving lower
exposures (1.0 to 1.5 mg) to the trifluoride compound, signs of
pulmonary edema were observed at sacrifice a month after exposure
although lung weights were normal then.
The 1968 studies by Cooper, et al. investigated the effects on
10 male and 10 female rats of exposure to powdered antimony' ore or
antimony trioxide. Those compounds were oresented in aerosol form
at a concentration of 1,700 mg/m durina 1-hour exposure sessions
repeated once every two months for up to one year, with reoresenta-
tive subjects exposed to each compound being sacrificed at inter-
j (C
vals during the study period. Immediately after exposure to the
X,
ore, but not the trioxide, transitory generalized pulmonary conges-
tion with some edema occurred, orobably due to an acute chemical
pneumonitis. Otherwise, the same types of effects were seen with
exposure to either the ore or the trjoxide. ^Hat is, at two months
after exposure to each compound, macrophages with massive accumula-
tions of phagocytized material were observed within alveolar spaces
or among cells of the septa, at* times forming focalized deposits
within many areas of the lung. Further exoosures resulted in in-
creasingly more extensive focalized deposits, with the phagocytic
response sti-11 being evident at the largest time ooints assessed
for each compound, i.e., 311 and 366 days after exposure for the
trioxide and ore compounds, respectively.
The above animal toxicology studies provide consistent evi-
dence for marked respiratory effects being exerted by antir*onv com-
>30
-------
pounds following inhalation exposure. The studies, however, have
been quite limited in that none have approached two crucial issues:
1 !
1
(1) assessment of antimony-induced alterations in 'pulmonary func-
tion? or (2) systematic definition of dose-effect/dose-response
relationships for either functional or histonathqlogical chanqes
I
associated with antimony exposure.
(liven the dearth of information bearing on the latter point,
it is not now possible to estimate, with any certainty, the no-
effect level for respiratory problems associated with exposure to
antimony. About all that csn be said is that this no-effect level
is likely higher for the trioxide compound than for antimony trt-
i
fluoride. Also of considerable importance is the fact that many of
the pathologic respiratory effects observed in th'e above anifal
studies do not always comport well with observations in cases of
i
•human exposure to antimony compounds. This is especially notable
j
in regard to the lack of evidence in humans of the extensive pulmo-
nary fibresis seen in rodents following inhalation exposure to
antimony. On the other hand, there do exist reports of observa-
tions indicating increased phagocytic acitvity and'.DCO!iteration of
lung macroohages in both animals (Levins and Chekunova, 1965;
I
Cooper, et al. 1968) and humans (McCallum, 1967} following inhala-
i
i
tion exposure to antimony compounds? the increased macrophage pres-
i
ence and phagocytosis activity, however, is of uncertain pathologi-
cal significance, occurring as it does in a nonspecific fashion in
response to inhalation of dusts or particulate matter. Probably of
i
more consequence are the observations in the above animal toxicolo-
gy studies of licoid and interstitial oneumonia following inhala-
tion exposures.
I
C-31
-------
Cardiovascular System Effects
Consistent with observations in humans, several animal toxi-
cology studies have yielded data documenting marked effects of
antimony compounds on the heart. For example,' myocardial damage
has been reported following exposures to antimony compounds via
inhalation (Brieger, et al. 1954) , acute inlection, and oral inges-
tion (Bradley and Fredrick, 1941).
As indicated earlier (Table 2), Bradley and Fredrick (1941)
determined &OCQS for various antimony compounds administered to
rats, mice, or guinea pigs orally or via direct i,p. injection.
Animals dying within a few days after injection showed labored
t
breathing, body weight loss, general weakness, and other evidence
*
of myocardial insufficiency? post-mortem examination revealed" myo-
cardial congestion with engorgement of cardiac blood vessels and
dilation of the right side of the heart. Histooathological evi-
dence of myocardial damage was also observed'in hearts of animals
surviving the E^en tests, including marked variations in myocardial
fiber staining seen with most all of the antimony compounds and a
distinct increase in connective and fibrous tissues of the myocar-
dium in the antimony potassium tartrate treated animals.
Bradley and Fredrick (1941) also 'fed animals antimony potassi-
um tartrate and antimony metal in daily doses that ranged up to 100
mg/kg and 1,000 mg/kg, respectively, for up to one year. Signifi-
cant myocardial effects were reported to have occurred at both the
100 and 1,000 mg/kg dose levels? the potassium tartrate compound,
' i
for example, consistently produced myocardial damage, indexed by
observed proliferation faf connective and fibrous tissues of the
•32
-------
myocardium and alterations in staining of myocardial fibers similar
to those observed in animals surviving the acute injection tests.
Ambiguous statements regarding results obtained at'lower exposures
make it impossible to determine if any "no-effect" level was ascer-
tained for the myocardial effects seen at the 100' or 1,000 mq/kq
dose levels. ;
Additional evidence 'for antimony-induced tnyocardial effects
i
was obtained in a series of inhalation studies conducted bv
Brieger, et al. (1954). Rats, rabbits, and dogs were exposed to
dusts with concentrations of antimony trisulfide ranqing from. 3.1
I
to 5.6 mg/m for 7 hr/day, 5 days/week for at least!six weeks. Not
i
only was parenchymatous degeneration of the myocardium observed in
the rats and rabbits, but also, consistent functional deficits were
seen as indexed by EGG alterations, e.g., flattened T-wave pat-
i
terns. The inhaled antimony particles were found ;to be generally
^2 urn in size. !
The particular types ,of changes observed in the above animal
experiments are consistent with myocardial effects seen in humans
exposed to antimony compounds. Altered T-wave SCG patterns, for
1
example, have also been observed in humans occuDattonally exposed
i
to antimony trisulfide (Brieger, .et al. 1954; Klueik and Ulrich,
1960) at levels comparable to those employed in the above animal
r "
experiments, e.g~., at 3.0 to 5.6 mg/m (Brieger,1 et al. 1954).
Unfortunately, no systematic evaluation exists for dose-effect/
.dose-response relationships for antimony-induced myocardial ef-
fects in experimental animal models, making it impossible at this
time to suggest accurate estimates of "no-effect" plevels for the
i
myocardial damage.
- i
i
C-33 '
-------
Blood Effects
Only very limited, information has been generated in recrard to
antimony effects on blood elements in experimental animals. Brad-
ley and Fredrick (1941), for example, reported normal blood parame-
ters for rats exposed in their LD5Q studies, except for distinctly
increased eosinophilia after kD5Q doses of "all of the antimony com-
pounds tested (see Table 2).
In the only other study providing information, Dernehl, et al.
(1945) observed blood changes in guinea pigs exposed by inhalation
to doses of antimony trioxide that averaged 45 mg/m ; the exposures
employed were stated to be for two hours daily for three weeks and
then for three hours daily for several weeks. The blood changes
observed included decreased white blood cell counts, decreased
polymorphonuclear leukocytes, and increased lymphocyte counts,
while red blood cell counts and hemoglobin levels were normal.
Liver, Kidneyf___SDleen» a*nd Adrenal Effects
Scattered information exists regarding antimony effects on
certain other internal organs, e.o.,' the liver, kidneys, sraleen,
and adrenal glands. Bradley and Fredrick (1941), for example,
observed liver effects in their studies on i.e. LD5Q for different
antimony compounds. Such liver effects included periportal conges-
tion, increased blood piamentation, increased numbers of olasma
•
cells, and w-ild heoatotoxemia indexed by functional hypertrophy of
hepatic cells. As for spleen effects, no changes were seen with
antimony oxides, but slight congestion and diffuse hyperplasia was
seen after exposure to antimony metal or tartrate. In the kidneys
of animals receiving the metal or tartrate, glomerula* congestion
C-34
-------
was observed with coagulated material being present in kidney
•* i
tubules.
[
Dernehl, et al. (1945) later observed fattv ^degeneration of
[
the liver in rats exposed to antimony trioxide via inhalation of
which at least 77 mg of antimony was retained in tlpeir lungs. Ab-
normal spleen pathology was also detected and included such changes
I
as hyperplasia of lymph follicles, decreased numbers of polymorpho-
nuclear leukocytes, abnormal amounts of blood pigment, and larae
i
!
numbers of antimony-laden phagocytes. J
I
i
Liver and kidney changes were also observedj by Levina and
Chekunova (1965) after 25 s.c. ,doses of ,15 mg/kg of antimonv tri-
fluoride administered to rats over a 1-month Period!. In the liver,
areas of edema, fatty infiltration and cloudy swellina were ob-
served. Somewhat more marked degenerative changes were seen in the
kidneys, e.g., swelling of epithelial cells lining the convoluted
tubules, nuclear -pykriosis and desquamation of epithelium, hemor-
i
rha'ges, protein masses in tubular lumina, and occasional .shrunken
glomeruli. '
In regard to effects on the adrenals, one study (Minkina, et
al. 1973) evaluated the effects of antimony trioxide infections
administered to rats subcutaneously five times per week for three
months, for aJtotal dosage of 165 mg. After 20 infections, a broad-
( '
ening of the co~rt-ical layers of the adrenals was [observed due to
growth of the fascicular and reticular zones; this (was accompanied
by increased nuclear diameters and monoamine oxi^ase activity taken
by. the'authors to be indicative of increased adrenjocortical func-
tional activity.
C-35
-------
Reproduction, Development, and Longevity
One of the few pertinent studies on reproductive effects of
antimony is that reported by Belyaeva (1967) in which female rats
were exposed either to antimony dust via a sinqle i.p. injection of
50 mg/kg or to antimony trioxide dust for 4 hr/day for 1.5 to 2
months at a concentration of 250 mg/m . The females were mated in
estrous three to five days after the acute injection, whereas the
inhalation exposure was continued throughout gestation following
mating. Of the 30 acutely-treated dams, 15 failed to conceive com-
pared to only one failure-among control dams. Of the 24 chronical-
ly exposed females, eight failed to conceive versus no failures
among 10 control females. In each case, both acutely and chroni£-
i
ally exposed dams produced fewer offspring than the unexposed con-
trol animals. Histological examinations of females from both expo-
sure groups and control animals revealed uterine and ovarian
changes likely to interfere with maturation and development of egg
cells. For instance, ovarian .follicles of exposed animals often
lacked ova or contained misshapen ova or ovarian cortical hypere-
mia; or cysts were present. At times, metaplasia of the uterus or
fallopian tubes was also seen. The most marked histopath9logic
changes were found in the animals receiving i.o; injections of
antimony metal.
In another pertinent report on antimony and reproduction,
Casals (1972) observed no effects, i.e., no fetal abnormalities,
following administration of a solution of antimony dextran glyco-
side containing 125 or 250 mg Sb/k.g to pregnant rats on five days
between days 8 and 14 of gestation. It is interesting that no
C-36
-------
effects on fetal development were observed in the Casals studv at
much hiqher exposure levels employed than those used in the
I
Belyaeva (1967) study-, where^a significant impact was reported on
conception and the number of offsoring born to antimony-exposed
dams.
In addition to the above studies on reproduction, a few inves-
tigations provide information on the potential effects of oral
exposures to antimony on postnatal growth, development, and longev-
ity. For example, Gross, et al. (1955a) compared effects of feed-
ing two groups of 10 rats each a synthetic diet containing 2 per-
i
cent antimony trioxide with results obtained for 20 control animals
fed the same diet without antimonv for a comparable 8-wonth period.
^
The antimony-exposed animals exhibited a slower rate of arowth over
i
the 8-month period, reaching a final average weight of 300 g versus
350 g for the control rats. No other effects were .detected upon
i
microscopic examination of various tissues despite notable accumu-
lations of antimony in blood and soft tissues of exposed animals.
i
Schroeder, et al. (1970) also reported on the effects of
chronic oral exposure to antimony but at a much lower exposure
t i
level of 5 ppm (as the metal) administered via drinking water adul-
teration with potassium antimony tartrate. The 5' ppm exposure
level was reported to have negligible effects on growth or-mature
weight of antimony-exposed animals, but,the life spans of such ani-
mals were shortened significantly? that is, males sur|vive
-------
variations in serum cholesterol from control levels were observed
for both male and female rats exposed to antimony. The effects on
longevity, suggestive of toxicity in rats being induced by oral
exposure to 5 ppm of antimony, were also observed for female mice
chronically exposed to 5 npm of antimony in their drinking water in
another study (Kanisawa and Schroeder, 1969).
Skin and Eye Affects
A series of experiments conducted by Cross, et al. (1955a)
investigated the irritant effects of antimony trioxide in the skin
and eyes of rabbits and rats. Antimonv trioxide (mean oarticle
size of 1.3 urn), with up to 0.2 percent arsenic as a contaminant,
was administered in 1 mg quantities in 1 ml of an aaueous susp.feri-
t
sion directly into one eye of each animal. No signs of irritative
effects on the conjunctiva or cornea were evident at one, two, or
seven days post-injection.
In cutaneous toxicity tests, antimony trioxide 'dust '('2.6 a)
was mixed into an aqueous methyl cellulose paste and was anolied to_
shaved areas of the torso. After one week, during which the treat-
ed area was covered, no local skin reactions were observed on or
around the treated areas. Also, no si<^ns of systemic toxicitv were
observed, suggesting that dermal absorption of antimony had Proba-
bly not taken place - although no measurements of antimony in blood
or in excreta were carried out to confirm that suggestion.
Summary of Animal Toxicology
d on the above studies, it is clear that certain resnira-
tory effects are consistently induced in rodents after inhalation
exposures to antimony; this includes increased macroohage prolifer-
C-38
-------
ation and activity, pulmonary fibrosis, and certain typos of pneu-
monia. Probably of even greater significance for oresent purposes
are marked myocardial functional and histooathological effects con-
sistently demonstrated to occur as the result of either inhalation
i
or oral ingestion exposure to antimony. Unfortunately, however,
insufficient data exist to allow no-effect levels to be character-
ized for either the respiratory or myocardial effects;. Nor is
i
there sufficient evidence to state with confidence no-JefEect levels
I
for either the growth or shortened lifespan and altered blood chem-
i
istry effects observed in some studies with chronic oral exposure
to antimony in the diet or drinking water.
HUMAN HEALTH EFFECTS ;
Essentially no information on antimony-induced j human health
1
i
effects has been derived from community epidemiology studies re-
i
fleeting, to a large extent, the lack of any heretofore identified
i
environmental health problems being associated with antimony. In
order to project what might occur in regard to environmental health
- i
problems, then, it is necessary to draw upon the only available
data bases, i.e., literature on effects observed with theraoeutic
or medicinal uses of antimony compounds and industrial exposure
studies. In each type of literature some examples of acute toxic
effects and others of a more chronic nature have been documented.
Therapeutic Uses" l
\ . [
Various antimony compounds still are drugs, of choice for
treating schistosomiasis. The route of administration is generallv
' - iv
intramuscular or intravenous. Fairhall and Hyslop (1947) reported
i
that antimony is better tolerated w^en administered intravenously
C-39
-------
than orally. These'investigators indicated that death way result
after an oral dose of 150 mg while 30 to 150 mg is recommended for
intravenous treatment. The scope of accidental overdosing problems
that once existed with therapeutic uses of antimonials is reflected
by Khalil's (1936) estimates that a 0.2 percent mortality resulted
from one million antimony treatments annually in Egypt.
Symptoms observed following accidental overdosing are illus-
trative of certain types of health effects seen at lower dose lev-
5
els, albeit in less severe form. -
Heart-related complications, convulsions, and severe vomiting
were associated with an overdose of sodium ahtimonyl gluconate
given to a 10-year-old African child (<5apire and Silverman, 1979) .
. /
Severe myocardial involvement was indicated after the schistosomia-
sis patient had been given a dose of 300 mg daily for six days.
Convulsions and vomiting occurred near the end of the course of
treatment. During the convulsions, heart rate was rapid and'irreg-
ular and the pulse was- feeble and irregular. Multiple ventricular
extrasystoles with runs of paroxysmal ventricular tachycardia were
observed on the EGG trace., A diagnosis of acute antimony poisoning
with cardiotoxicity was made. After initiation of chemotherapy,
the EGG abnormalities persisted for 48 hours, although to a reduced
degree. The patient thereupon reverted to sinus rhvthm. Principal
i
effects appeared in the ST segment and in the T-wave. Only occa-
i ' *>
sional changes in the ORS axis were noted.
Effects on the Gastrointestinal System
Nausea and vomiting are symptoms most commonly reported.
Zaki, et al. (1964) injected schistosomiasis patients intramuscu-
C-40
-------
larly with a 10 percent solution of Astiban (^b with ja +3 valence),
I
3 to 5 ml per day for 5 days. Vomiting was seen inj 45 percent of
the patients; nausea, gastric discomfort, and/or anorexia was ob-
served in 44 percent? and diarrhea in only 6 percent.
i
Effects on the HepaticSystem ,
T'Thile impaired liver function may result in symptoms normally
i
associated with gastrointestinal involvement, more severe liver
- i
damage is a rare complication in antimony therapy. "owever,
McKenzie' (1932) and O'Brien (1959) have attributed some fatalities
I
I
to liver necrosis.
i
Routine clinical investigations of liver function, such as
serum bilirubin, rarely are undertaken in antimony therapy. Sever-
al cases involving a simultaneous rise of SCOT and Sf^PT at the
onset of therapy were reported by woodruff (1969). i Variations in
s
serum ornithine carbanyl transferase, parallel to that of transami-
i
nases, were suggestive of a hepatic lesion (Soitaels and Bouna-
meaux, 1966) . These investigations concluded that al h€;patic lesion
i
is a central feature of antimony toxicity and th-at it is caused by a
progressive accumulation of Sb in the liver.
i
Effects on the Cardiovascular System ]
Changes in the electrocardiogram (ECG) reading of heart action
have been consistently associated with intravenous Sb therapy.
Various degrees- of suppression of the amplitude |in the T-wave,
inversion of the T-wave, and prolongation of the QT interval are
i -
the most typical changes described (Mainzer andi'Krause, 1940;
^chroeder, et al. 1946; Davis, 1961; Sapire and Silverman, 1970;
i
Abdalla and Badran, 1963). The T-wave changes seem, to be the nost
-------
frequent, appearing in 100 percent of the treated patients in some
studies. Changes that occur less.frequently ares (1) diminution
of amplitude of the QRS complex, {2} bradycardia, (3) changes in
the ST segment, and (4) ventricular arrhythmias. While enzyme
impairment, antimony deposits in the heart, atitonomic nervous sys-
tem dysfunction, and other functional impairments have been sug-
gested as leading to EGG changes, they generally are not considered
to be indicative of persistent cardiac damage (Schroeder, et al.
1946? Davis, 1961? Sapire and Silverman, 1970).
A description of the EGG changes following antimony sodium
tartrate therapy was provided by Honey (1960) . in all but one of
the 59 patients, EGG changes were seen toward the end of the course
t
of therapy. Changes ranged from verv slight to severe. In the
absence of a history of antimony sodium tartrate administration,
the severe changes would have been interpreted as indicating severe
myocardial disease. The effects described by Honey have also,been
seen upon therapy with other antimonial drugs (Mainze.r and Krause,
•1940? Schroeder, et al. 1946; Tarr, 1947? Abdalla and Badran, 1963;
Herminaini, et al. 1963? Dancaster, et al. 1966? Sapire and Silver-
man, 1970? Wave, et al. 1962? Hsu, et al. I960? Somers and Rosa-
nelli, 1962? Awwaad, et al. 1961? Badran and Abdalla, 1967?
,0'Brien, 1959).
Honey (J.960) indicated that the following changes were charac-
teristic: the P-wave often becomes tall and broad, while R-wave
voltage is significantly lowered. Mo changes in PR or ORS inter-
vals were observed although the QT interval increased in most
cases'. The most characteristic abnormalities were in the ST seg-
C-42
-------
ment and T-waves. The earliest change was a reduction in amplitude
i
of the T-wave in all leads. In severely affected cases, the T-wave
became completely inverted. No consistent change in pulse rate was
i
observed, a-ithough one case of serious ventricular; arrhythmia was
i
seen. Honey theorized that the longest intervals were associated
wich sinus arrest or sinoatrial block. '
The EGG changes that are 'observed have, been [associated with
both trivalent and pentavalent antimonial therapy. ; Trivalent com-
pounds are more widely used. The drugs most effective in the
treatment of schistosomiasis, also cause the greatest: disturbance to
i
the heart. The percentage of patients having altered ECGs has
often approached 100 percent after intravenous administration of'
i i»
trivalent: antimony potassium or -sodium tartrate (Honey, I960;'
i
Schroeder, et al. 1946; Tarr, 1947). Altered.. ECGs occur in less
than 80 percent of these individuals receiving trivalent compounds
intramuscularly. j
EGG changes following treatment with pentavalent compounds
|
have been infrequently observed. Administration cjf trivalent and
i
pentavalent drugs to 30 patients with schistosomias|is or leishmani-
I
asis resulted in flattened T-waves, anomalous QT intervals, and
' ''
Tivocardiai ischemia of the subepicardial layer. Only five patients
received the pentavalent drugs (Germiniani, et al.1 1963). Davis
(1961) observed that EGG changes following treatment with pentava-
lent: compounds are much less severe than wich trivalent compounds.
In part, this may be due to the observation that trivalent com-
i
pounds are only slowly eliminated by the kidney, whereas pentava-
C-43
-------
lent compounds are metabolized by the liver and are excreted more
rapidly (Sapire and Silverman, 1970).
Lopez and da Cunha (1963) did not observe any treatment-relat-
ed ECG alterations in patients receiving the pentavalent drug. The
total dose of pentavalent Sb ranged from'4.Q5 to 19.35 gm given
intravenously over 5 to 10 days. On the other hand, the total dose
of trivalent antimony ranged from 214 to 510 mg given intravenously
over 2 to 9 days. All patients given trivalent antimony sodium
gluconate exhibited diffuse alterations in ventricular reoolariza-
tion, seen primarily in the T-wave, and in one case, accompanied by
a sinus tachycardia. In the group, receiving m-methyl glucatnine
antimoniate (pentavalent), only one patient showed ECG change^.
k
The arrhythmia observed was attributed to the patient's advanced
case of kala-azar. Similarly, Tarr (1947) was unable to find ECG
alterations in three patients treated with the pentavalent com-
pounds , ethylstibamine or glucostibamine sodium. However, typical
changes in the T-wave of patients given either of two trivalent
compounds (antimony potassium tartrate or stibophen) were observed.
ECG changes in Egyptian adults, adolescents, and children
treated with antimony dimercaotosuccinate (TWSb) have been reported
by Abdalla and Badran (1963) . The course of treatment consisted of
five daily intramuscular injections of 6 mg TWSb/kg body weight
(total dose •= 30 mg/kg or 7.5 mg ?b/kg) administered to 25 adult
patients. The patients had normal ECGs prior to treatment. ECGs
were monitored after the completion of the treatment course. Tn
five patients, ECGs also were performed 0.5 hours after the first,
third, and fourth injections. Among the changes observed (number
C-44
-------
of Patients exhibiting effects are shown in oararttheses) were:
diminution in amplitude of the P-wave (12), prolongation of the PR
I
interval (2) , decrease in PR Interval (4), decrease in the ampli-
tude of the QRS icomplex (10), increase in amplitude of the ORS com-
plex (1) , slight depression of the ST segment (3) , and T-wave
•
changes (24). No changes in the ECG were observed immediately or
up to two hours after the first injection. The effects of the
treatment on the myocardium were cumulative; they started after the
t
third dose and were more marked after the fourth and fifth doses.
ECGs exhibited normal behavior within 4 to 6 weeks following treat-.
ment. , ,
i
Davis (1961) found SCG abnormalities after treating 19 male
i
African children or adolescents, ages 11 to 20, with antimonv
dimercaptosuccinate intravenously. mhe total dosage given for
Schistosoma mansoni and £. haematobium ranged from 1
days to 2.0 am in three days. FICCJs were monitored
. 0 gm in five
before treat-
ment, daily during treatment, and for the first two or three days
i
after treatment. All patients exhibited inverted T-waves in one or
!
more leads following treatment. Inversion was observed at diffe-
rent times, and no dose-response was ascertained. Maximum ampli-
tude was observed on the last day of treatment or during the first
* i
three days after - treatment. Persistent abnormalities were seen in
i
7 of-12 cases at "28 to 33 days and in two of five cashes at 54 days
V I
after treatment. These abnormalities were either persistent Inver-
sion of the T-wave in the right unipolar precordial\leads or the
failure to regain their amplitude before treatment: ^ransitory
I
i s
prolongation of the QT interval was noted in 9 of 19. series of
>45
-------
recordings. The investigators found that 15 patients had isoelec-
tric, or inverted, T-waves before treatment. These individuals
exhibited the onset of frank inversion or an increase in the T-wave
amplitude of inversion following treatment. The authors commented
that T-wave inversion before treatment occurs among Africans of all
ages and is a common finding among African children.
The EGG changes observed uoon treatment were largely reversi-
ble over a period of weeks and roughly paralleled the excretion
rate of Sb. It was suggested that temporarv mvocardial damage
resulted from accumulation of trivalent Sb. ~
Honey (1960) suggests that Asians and Africans are more sus-
ceptible than Europeans to the cardiotoxic effects of Sb. Of «:15
African or Asian patients, 11 had severe EGG chanqes while 7 o^C45
Europeans had changes classified as "severe."
Huang, et al. (1960) noted a greater susceptibility to anti-
monial drugs among females as opposed to males. Severe cardiac
arrhythmia was more frequently found in female patients, especially
those undergoing menstruation or lactation. The investiaators were
not aware of any such episodes occurring in pregnant women.
Antimony dimercaptosuccinate treatment was observed bv
Abdalla and Badran (1963) to result in more marked EGG changes than
when potassium antimony tartrate, another trivalent compound, was
employed. Inversion of the T-wave occurred in 32 percent of those
receiving TWSb but in only 10 percent of those receiving the tar-
trate compound.
Decreases in T-wave amplitude and elevations of the ?T seament
were observed in Egyptian patients receiving sodium antimony bis-
C-46
-------
(pyrocatechol-2,4-disulfonate), a trivalent compound (Zaki, 1955).
This compound also was used by O'Brien (1959) to treat 20 young,
i
West African soldiers for schistosomiasis. The total dose of anti-
mony given intravenously was 807.5 mg over a period ojf 20 days. One
individual -exhibited gross ventricular dysrhythmia.l Recovery was
i
complete after administration of /British Anti-Lewisite. Near the
v
end of treatment, all individuals had abnormal ECGs. Abnormalities
were elevation "of the ST segment followed by a sharp inversion of
i
the T-wave in the right ventricular unipolar precardial leads. EGG
1
traces were normal three months after treatment. Temporary heart
i
i
muscle damage was suggested as a result of treatment.
I
A Stokes-Adams syndrome was observed by Dancaster, et al.'
I <
(1966) in a 26-year-old female biharziac patient receiving antimony
sodium gluconate. During the 24 hours following the fourth daily
' \
injection, she lost consciousness six times, and once she stopped
breathing. The first EGG taken exhibited .changes compatible with
hypokalemia. The T-wave flattened and the U-wave |was prominent.
K
An EGG taken 24 hours later suggested inferior myoc|ardial infarc-
i
tion. The EGG returned to normal over a period of| six weeks. A
1 . -
.direct effect of antimony on the myocardium or, a Coronary spasm
caused by Sb was suggested. Similar case histories with other
i
antimonial drug regimens are cited by Sapire and Siljverman (1970) ,
Wave, et al. (1962), Hsu, et al. (1960), and OlBrien (1959).
Woodruff (1969), Sapire and Silverman""(1970) , arid Honey (1960)
\
suggest that dose-response results are unclear. Hvipersensitivity
and the tvpe of antimonial are more important factors than total
i
dose. The rr.ost severe EGG changes have been found to occur with the
C-47
-------
smallest doses. Honey (1960) noted that the action of antimony on
the myocardium appeared to be cumulative as followed on an individ-
ual basis.
Lu and Liu (1963) reported that cardiac intoxication caused 70
to 97 percent of the reported antimony drug-related deaths, fol-
lowed by hepatic or generalized intoxication. Mo data were qiven.
Honey (1960) reported that cardiac edema and fragmentation of mvo-
cardial fibrillar structures were found upon autopsy on a person
who died after 12 injections of antimony sodium tartrate. Total
amount administered was. lo"5 grams. The heart showed appearances of
a very recent moderate-size myocardial infarction. The analyses
for Sb were: blood, 0.17 mg/100 gm; liver, 0.20 tig/kg; skeletal
muscle, 3.0 rag/kg; and heart muscle, 2.0 mg/kg. I
The effect of antimonial therapy on heart rate was examined by
Tarr (1947) . An increase averaging 10 to 15 beats per minute was
found in 48 treatment courses. A decrease averaging 10 to 15 beats
per minute was found in 77 cases; no change was found in the remain-
ing 56 cases. Tarr was unable to observe any relationship between
the T-wave and heart rate changes. Others have failed to observe
significant changes in heart rate in patients receiving antimonial
drugs (Honey, 1960; Schroeder, et al. 1946'; Abdalla and Badiran,
/ '
1963; waye, et al. 1962). /
Effects on fehe Skin
Side effects resulting from antimony exposure or therapy in-
clude skin rashes, generalized urticaria, maculopapular eruptions,
irritation around the eyes, and pruritis. ^kin rashes appear in
approximately 10 to 25 percent of the patients (Zaki, et al. 1964;
C-48
-------
Hamad, 1969; Pedrique, et al. 1970). ySkin irritation and rashes
have most often been observed following exposure to antimony triox-
I
ide (Renes, 1953; Paschoud, 1964) and have usually been associated
with hot environments during the summer months (McCallum, 1963).
Antimony ox-ychloride, oentachloride, and trisulfide have not been
reported to cause dermatitis. , \ ' -
Other Effects j
Harris (1956) reported that therapeutic use of Faudin, an
antimony compound, can cause acute hemolytic anemia. | Erythrocytes
gave a positive antiglobulin test. In vitro experiments demon-
i
strated that serum factors capable of agglutinizing normal red
- ' i
i
cells and sensitizing them to become positive upon Coombs testings,
i
as well as hemolyzing both trypsinized and normal red cells, could
i
not be found unless the drug was present. \
Trivalent compounds were associated with two csises of optic
neuropathy associated with visual disturbances and indefinite fun-
j
dus changes which occurred a few days following treatment (Forsyth,
1958).
Summary of Therapeutic Use Effects > I
As indicated above, Gastrointestinal symptoms including
i -
severe nausea and vomiting are associated with acute high thera-
peutic exposures to antimonial compounds. In addition, rather
severe myocardiai symptoms and convulsions have also b|een 'seen with
acute high doses of antimonial medicines, and some cases; of deaths
i
attributed to liver necrosis have been reported. [with chronic
i
exposures to lower dose levels of medicinal antimony compounds,
i
myocardiai effects stand out as being of key concern. I Interesting-
C-49
-------
ly, skin rashes and other irritative skin chanqes also occur in a
certain oercentage of patients during treatment with antimonial
compounds; this provides evidence for skin chartqes being amonq
health effects directly attributable to antimony and not necessari-
ly being due to exposure to arsenic or other contaminants variously
closely associated with antimony during the course of dermal or
inhalation exposures In industrial situations.
Industrial Exposures
Antimony in nature commonly is found in deposits containinq
other elements and minerals such as arsenic, lead/ selenium, and
silica; it is therefore not unexpected that exposures to several
such materials encountered along with antimony during its produc-
tion and use tend to complicate interpretation of results ffcom
studies of health effects associated with Industrial antimony expo-
sures. Again, acute high exoosures to antimonv in occupational
settings are illustrative in terms of highlighting the ranqe of
effects associated with the metal; many effects are observed in
less severe form at lower, more chronic exposure levels.
General symptoms and the clinical oathology of- antimonv Intox-
ication were discussed by Gocher (1945) in a survey of eight cases
involving various industries. Many symptoms observed match these
seen with overdosing with therapeutic uses of antimonials; such
symptoms of_ acute industrial antimony poisoning includes (1) ano-
rexia, (2) nausea, (3) vomiting, (4) diarrhea, (5) headache,
1 (6) dizziness, and (7) irritation of the upper respiratory tract.
In addition, rhinitis, bronchitis, gastric disturbances, colic,
faintness, and feeble heart rates may be observed. Symptoms o€
C-50
-------
chronic severe intoxication may also include occipital, headaches,
dizziness, and muscular pain. Eosinophilia, moderate lanemia, and
leukopenia may be present. The degree to which Sb may be absorbed
may be indicated by the reticulocyte count. An increase in reticu-
locytes always was found. Hemoglobin varied between 70jand 80 per-
cent, and the red blood cell count fell between 3.8 and 5 million.
i
Leukocytes averaged 7,800 in chronic cases and between! 10,800 and
E
8,400 in acute cases. Glucosuria and albuminuria were] present in
i
half the cases. \
Acute intoxication due to exposure to antimony pentachloride
-
was reported by Cordasco and Stone (1973). A 39-year-!old man was
i
exposed to an unknown amount of the compound following, a gas leak
from a reactor. Second and third degree burns were reported. Re-
spiratory distress was diagnosed upon hospital admission. Marked
moist rales in both basal and mid-lung fields were noted. Pulmo-
nary edema, persistent progressive respiratory distress; and respi-
i
ratory acidosis ensued. Following long-term, intensive |respira,tory
care, th.e patient improved.
•Antimony trichloride was believed responsible for; an episode
of acute intoxication of seven men exposed to fumes. X pump leak-
ing a hot mixture of antimony trichloride and hydrochloric acid was
responsible. All workers had upper respiratory tract irritation
which was attributed to the hydrochloric acid. Fivej of the men
developed gastrointestinal disturbances, including abdominal"pain
i
and persistent anorexia. Red and white blood cell counts and hemo-
!
globin levels were normal in four of the workers. Chest radio-
graphs of all seven workers were normal.
-------
Antimony in the urine was in excess of 1 rna/1 in five of the
seven men for up to two days after exposure. The highest concen
tration (one subject, two days after exoosure) was 5.1 rnq/l. In-
termittent analyses on subsequent days indicated urine antimonv
/
content drooped rapidly. Subsequent air analyses three feet down
wind from the pump revealed that the atmosphere contained UD to 73
3 3
mg Sb/m- and 146 mq hydrochloric acid/m .
Among 78 workers exposed to antimony sulfide ore during ,min
ing, concentrating, and smelting ©Derations, cases of nasal-sental
perforations, laryngitis, tracheitis, and pneumonitis were rs
ported in 3.5, 11.0, 10.0, and 5.5 oercent of the workers, respec
tively (Renes, 1953) . Rhinitis and dermatitis were reported in 2<
t
percent of the workers. Among 7 of 9 workers severely affected
v
urinary levels of Sb ranged from trace amounts to 60 iig/100 ml
There was a progressive increase in the number of severe illnesse
i . '
with increasing length of employment. Air levels of Sb ranged f re
4.69 to 11.31 mg/m . Average arsenic levels were 0.73 ma/m . Th
size of the particles was less than 1 u. Most cases of 'dermatiti
were seen during a1 1-week period of heavy exposure. The lesion
were described as nodular and ulcerative. In those complaining o
larvngitis, erosions or ulcerations of the vocal cords were alway
observed. Chest x-rays of six men, acutely ill from "heavy" expo
sure to smelter fumes, exhibited definite oneumonitis. No evidenc
of peripheral parenchymal pulmonary damage was found. Symptomati
treatment and removal from exoosure for several days provided re
•lief. Although emissions control measures were installed and low-
3
ered average Sb levels in the air to 6.8 ma/m and arsenic to 0 . 5
mg/m , work-related illnesses were still occurring.
• C-52
-------
The symptoms observed by Renes were reported to be character-
istic of both Sb and arsenic intoxication. However, the most com-
mon early signs of arsenic intoxication were not reoorted among
these workers. In addition, higher arsenic exposures ((in the elec-
tric furnace area) were not reflected by the wore intense or in-
creased numbers of illnesses in that area. Renes concluded that
antimony trioxide, the predominant air contaminantr was resoonsible
for the illnesses. - I
Respiratory andDermal Effects
Effects ori pulmonary function have been reported by Cooper, et
al.- (1968) among workers exposed to dust from antimony ore and
antimony trioxide. In a total exposure population of 28 workers,
pulmonary function studies were performed on 14 whoihad been ex-
i
posed to antimony trioxide for periods of 1 to 15 years. - Benign
pneumoconiosis was found by roentqenography in 3 of 13 workers
exoosed to both types of dust. Five additional roentaenograohs
1
exhibited suspicious find.ings. The pattern of pneumpconiosis was
one of small rounded and irregular opacities of the "P" and "s"
types. Antimony excretion was variable and without correlation to
the roentgen findings. Atmospheric concentrations o*- Sb monitored
1 3
in 1966 at 36 plant locations ranged front 0.081 to 75;mg/m . High-
est levels (138 mg/m ) were associated with the bagging operations.
i
Particle diameters were ^not reported* ECGs from jseven workers
i
(three of whom had pneumoconiosis) showed six with normal tracings
and one with slight bradycardia. No correlations between urinary
i
Sb levels (7 to, 1,020 ug/1), roentgenographic abnormalities, and
pulmonary function tests could be established. •
0-53
-------
Pneumoconiosis also was diagnosed by Le Gall (1969) in 10 of
40 furnace workers exposed to antimony oxide for periods of 6 to 40
years. Concentrations of antimony trioxi^e in the factory ranged
from 0.3 to 14.7 mg/m . " Most particles were reported to be smaller
than 3 .um in diameter. Le Oall, however, reported that the ore
used contained from 1 to 20 percent silica. Although there was no
overt illness, the radiographs showed moderate, dense reticulonodu-
lar formations scattered through the pulmonary fields. Urine spec-
imens from a few workers were analyzed, but Sb was not found. Tt is
thus difficult to separate possible silica effects from presumed
antimony effects reported here.
Pneumoconiosis and dermatitis in an unspecified number of
t
antimony processing plant workers were found by- McCallum (1963;) .
i C.
The skin rashes consisted of pustules around sweat and sebaceous
glands and resembled lesions associated with chicken pox or small-
pox. Rashes were not observed on face, hands, or feet, but partic-
ularly were found on the forearms and thighs. Simple,pneumoconio-
'sis was diagnosed by radiographic examination. The lung changes,
in nearly all cases, were symptomless. Two of the men subsequently
developed tuberculosis. One had chronic bronchitis and respiratory
obstruction. Pulmonary function tests suggested that the latter
individual also had emphysema, but no pulmonary fibres is was de-
tected. Spot samples of urine from three with Pneumoconiosis had
Sb concentrations of 425, 480, and 680 ug/1. Air analyses at vari-
ous plant locations (Newcastle-upon-Tyne, U.K.) indicated that Sb
concentrations in the work environment generally exceeded 0.5 jng/m
with particles averaging less than 1 um in diameter. 'Hiahest con-
C-54
-------
centrations (tz31 mg/m ) were found when molten metal -was Poured.
This study is especially valuable in linking the above effects to
I
relatively ourer antimony exposures than typically occur in other
industrial settings.
Upon reinvestigation of this plant, McCallum (1967) discovered
26 cases of antimony pneumoconiosis. Of the 262 men employed at
Hewcastle-upon-Tyne, 44 had pneumoconiosis ascribed; to Sb. All
cases were of the simple type. One antimony worker 'who died from
i
carcinoma of the lung was found to have had accumulations of
-------
whom were less than 40 years old. There were four cases of- tubercu-
losis. Other find-ings included catarrhal symptoms of the upoer
respiratory tract, conjunctivitis, and ulcerated nasal seotae. » >Jo
symptoms suggestive of damage to the gastrointestinal tract, liver,
cardiovascular system, and central and peripheral nervous systems
were observed. Dermatitis was found in 16 workers, 13 of who™
worked at blast furnaces. The dermatitis was described as vesicu-
lar, varioliform, and efflorescent. The efflorescence underwent-
necrosis in the center and left hyperoigmented scars. In e'ighr
workers with pneumoconiosis {of 20 selected blast furnace workers),
normal ventilatory function was exhibited in three cases anc1
slightly reduced in four. Blood pressure values were reported as
t *
being somewhat lower in five of the eight workers with pneumocorxic
'.
sis. No data were provided. ECGs and hepatograms were normal.
Due to the presence of other air contaminants (ferric oxide,
silica, and arsenic trioxide) , it is unclear to what extent anti-
mony caused the observed findings. Antimonv trioxide constitute-
\
36 to 90 percent of the mixed dusts to which the workers were ex
posed. The particle sizes were predominantly under 0.5 u.
In an antimony smelter in West Serbia, Yugoslavia, 'simpl~
pneumoconiosis was found in 31 of 62 workers (Karaiovic, et al.
I960)'. Emphysema and chronic bronchitis also were observed in som«=
of the workers. Neither bronchio-pulmonary lesions nor symptoms o;
systemic poisoning were found, although skin effects were common.
Various lung-related disorders were ^ound by Klucik, et al.
(1962) in an investigation of workers at a Czechoslovakian antimony
processing plant. T'hese workers were exposed to smoker antimon.
C-56
-------
jxide dust, and antimony trisulfide for periods 'ranging from a
, *w years to 28 years. The incidence was as follows: pharyngitis
i
(76.5 percent), bronchitis and rhinitis (54.3 percent), pneumoconi-
osis (20.8 percent), symptoms of emphysema (41.9 percent), and per-
I
forations of the septa (33.2 percent). The average size of the
i
dust and trioxide particles were 1.03 and '2.84 urn,' respectively.
Development of the pneumoconiosis ended at the micrianodular size.
It did not become complicated with tuberculosis. , -
i"
Dermatitis, believed to result from the action of antimony
I - •
trioxide on the dermis after dissolving in sweat and penetrating
\
the sweat ducts, was reported by Stevenson (1965). Dermatitis was
found in 23 of 150 workers exposed to SbO, at the Neweastle-upon-
J I
Tyne works. All affected workers were exposed to hot environments;
'17 worked at the furnaces. The antecubital area was most often
I
involved. Dermatitis subsided in 3 to 14 days after workers were
i
transferred to cooler areas. Microscopic examination of the le-
sions revealed epidermal cellullar necrosis with associated acute
dermal inflammatory cellular reaction. The lesions were found
i
close to sweat ducts. Stevenson noted that SbCU is soluble in lac-
tic acid, which is present in sweat in increased amounts following
i
heavy exercise. Patch tests with dry SbO- or SbO-, in water were
J 4 i
negative.
Skin patch tests on 45 women and seven men with
a mixture of
powdered SbO3 and 0.29 percent arsenic covered with moistened gauze
i
pads were negative over a 3-week period (Linen and Sigmund, 1976).
Antimony trioxide was not considered a primary skin irritant or a
skin sensitizer. 'r
-------
Myocardial Effects t
Heart abnormalities associated with occupational exoosur
Sb have also been investigated.
Changes in ECG traces were correlated with exposure to
Klucik and-Ulrich (1960). However, concomitant exposure to ar
may have contributed to the observed changes. Only ECG abnor
ties and subjective complaints were correlated. 'Abnormal ECGs
found in 8 of 14 metal workers with frequent subjective comnlai
A decrease in blood pressure and ECG changes were found am
a work force of 89 antimony production workers in the USSR
rovnaya, 1972). More than half of the work force (average length
of employment of 11 years) complained of cardiac oain. Decreased
e
contractile force and lower electrical activity of the myocardium
accompanied by increased excitability were found. Extrasystolic
arrhythmia was observed in 12 workers; systolic noise was heard in
23. ECGs showed diminution of *»_, R-, and T-waves and a simultane-
ous slowdown of intraventricular conductivity to 0.1 percent at
0.002 seconds. Balistocardiographs showed 12 cases evaluated as
Brown's 3rd degree. The investigators concluded that diffuse dam-
age to the ventricles of the myocardium and a diminution of its
contractile ability were indicated.
Sudden death and heart complications associated with exnosure
to antimony trisulfide in a manufacturing setting were discussed bv
Brieger, et~al. (195'4) . An increase in the number of sudden deaths
among factory workers engaged in the manufacture of resinoid grind-
i
ing wheels was observed after the use of lead was discontinued and
'antimony trisulfide substituted. Following replacement, six sudden
-------
deaths and two deaths due to chronic heart Disease occurred amona
!
125 workers exposed for 8 to 24 months. Prior to replacement of
* [
lead, only one death (coronary thrombosis) occurred ln| 1(5. years in
i
that department. Antimony trisulfide was found in air concentra-
tions exceeding 3.0 mg/m . <
Phenol formaldehyde resin also was used in the manufacturing
, . |
process but workplace concentrations were not reported! In a clin-
ical survey of 113 workers, EC*"? changes in 37 of 75 workers were
found. These changes primarily involved the T-wave. 0€ the 113
men examined in the surv.ey, 14 had blood pressures exceeding 150/80
I
mm and 24 had pressures lower than 100/70 mm. *To mention was made
of smoking, drinking, or medical histories of the workers, ^ollow-
/ I
i
ing the cessation of use of antimony trisulfide, no additional
deaths or abnormal cardiac effects were observed. •.
# (
Carcinogenesis .
i
An investigation of the role ^b may play in inducing lung can-
cer among antimony workers was conducted by Davies '(1973) . The
1
study was initiated in 1962-after it was learned that a man engaged
I
in the processing of antimony had died from lung cancer. A retro-
spective study found seven other deaths froT luna !cancer among
* • i
antimony workers in the preceding eight years. Four!of these men
i
had worked at the Mewcastle-upon-Tyne antimony works. The other
1
three men had worked in an antimony processing blant ,that had dis-
continued ooerations. Smoking habits were not reported nor was
!
information on the exact procedures used for computing the reported
death rates; also the death rates observed were lowe,r ithan expected
rates for the workers.
r-59
-------
Blood Effects
Symptoms of light and chronic intoxication were found by.
Rodier and Souchere (1957) in a study of 115 Moroccan antimony mine
workers. A mean leukocyte count of 4,900 per mm was found in 44
percent of the workers. A red blood cell count of less than 4 mil-
lion per mm was found in 47 percent of the workers.
-------
Aiello (1955) observed a higher rate of oremature deliveries
among women workers in antimony smelting and processing. Premature
deliveries occurred in 3.4 oercent of the study group and in 1.2
i
percent of the controls. Women workers had frequent cases of dys-
I
menorrhea as well as some cases of eoistasis.
C-61
-------
CRITERION FORMULATION
ExistingGuidelines and standards
At the present time, no standards exist regarding allowable
amounts of antimony in food or water. This reflects the fact that
only very small trace amounts of antimony have ever been found in
food or water samples from United States surveys; this also re-
flects the general lack of any past Dublic health problems associ-
a'ted with antimony exposures via food or water intake. The only
present standards that exist, then, are those established for the
protection of workers in occupational settings.
Existing occupational standards for exoosure to antimony are
reviewed in the Mational Institute for Occupational Safety and
*
Health (MIOSH, 1978) criteria document, OccuDational Exposure <• to
i
Antimony. These standards aptsly most specifically to airborne
antimony but may be useful for purposes of deriving a recommended
standard for water.
As stated in the NIOSH (1978) document, the American Confer-
ence of Governmental Industrial Hygienists (ACGIH), in 1977, listed
the TLV for antimony as 0.5 mg/m along with a notice of intended
change to a proposed TLV of 2.0 mg/m for soluble antimony salts.
The proposed TLV was based mainly on the reports of Taylor (1966)
and Cordasco (1974) on accidental poisoning by antimony trichloride
and pentachloride, respectively. Prooosed limits of 0.5 mq/m, for
handling and use of antimony trioxide and 0.05 mg/m for antimony
trioxide production, however, were also included in the
(1977) notice of intended changes.
C-62
-------
The Occupational Safety and Health Administration earlier
V'"
adopted the 1968 ACGIH TLV for antimony of 0.5 mg/m as the Federal
i
standard (29 CPR 1910.1000). This limit is consistent with limits
adopted by many other countries as described in Occupational Expo-
i
sure Limits for Airborne Toxic Substances - A Tabular Compilation
I
of Values from Selected Countries, a publication released by the
International Labor Office in 1977. The NIO«W (1978> document also
presented a table of exposure limits from several countries, repro-
'[
duced here as Table 3; the typical standard adopted was 0.5 mg/m ,
3 ' '
as indicated in Table 3. The 0.5 mg/m level was also recommended
as the United States occupational exposure standard by the
i
(1978) criteria document, based mainly on estimated no-effect lev-
els for cardiotoxic and pulmonary effects. i
Special Groups at Risk i
i _
At this time, none of the available information permits con-
I
elusive identification of populations at special risk l:or antimony
i
exposure except, of course, for occupationally exposed individuals.
•i
All other types of general environmental exposures, from all media
! i
I
and sources, appear to represent essentially negligible antimony
exposure levels for humans, as discussed earlier.
If antimony exposure levels were to reach substantially hiaher
i
levels in the air or water, however, then -individuals' with existing
i
chronic respiratory or cardiovascular disease problems would likely
be among those at special risk in light of probable exacerbation of
one or both types of health problems by antimony.
C-63
-------
TABLE 3
Hygienic Standards of Several Countries for Antimony,
Compounds in the Working Environment
Country
Standard
3
(mg/m )
Qualifications
Finland
Federal Republic of Germany
Democratic Republic of Germany
Rumania
USSR
Sweden
USA
Yugoslavia
0.5
0.5
0.5
0.5
0.5
0.3
1.0
1.0
0.5
0.5
0.5
Not stated
8-hour TWA
Not stated
Not stated
For antimony dust
For flour ides and chlorides
(tri-and pentavalent);
obligatory control of
HP and HC1
For trivalent oxides
and sulfides
For pentavalent oxides
and sulfides
Not stated
8-hour TWA
Not stated
Hodified from Occupational Exposure Limits In Airborne Toxic Substances,
international Labour Office (1977)
-------
Basis for the Criterion t
Summary of Health Effects
At the present time, there are essentially no exisstinq convmu-
nity epidemiology studies that provide information |on health ef-
fects associated with antimony exoosure among the general popula-
tion of the United States or other countries. Thiss is primarily
due, as indicated earlier, to the lack of anv recognizable oublic
health problems having been previously associated with environment-
-r I
al exposures to antimony. Rather, one is limited to extrapolating,
as best as can be done, from human occupational health and animal
toxicology studies. I
Pulmonary, cardiovascular, dermal, and certain |ef1:ects on re-
production, development, and longevity are among the health effects
best associated with antimony exposure. The oulmonary effects,
however, are almost exclusively associated with inhalation expo-
sures and have much less relevance than the other effects in con-
!
sidering possible bases for development of criteria for a water
f
standard.' The pulmonary effects are, therefore, not considered
here,, but rather the main emphasis is placed on the latter types of
effects listed.
Cardiovascular changes have been well associated with exposure
(
to antimony and probably represent the most serious a'nt Lmony-relat-
i
ed human health effects demonstrated thus far. Specifically, in
humans, various ECG changes, e.g., altered T-wave patterns, have
f
\ '
been consistently observed following exoosures to either trivalent
I
or pentavalent antimonial compounds and have been interpreted as
being indicative of at least temporary cardiotoxic effects of anti-
C-65
-------
mony. Indications of even,more severe, oossibly permanent myocair-
dial damage in humans have been obtained in the form of histopatho-
logical evidence of cardiac edema, myocardial fibrosis, and other
signs of myocardial structural damage. Parallel findings of func-
tional .changes in EGG patterns and of histooathological evidence of
myocardial structural damage have also been obtained in animal tox-
icology studies using controlled exposures to antimony compounds.
As for the other types' of effects reasonably well associated
with antimony exposures, only very limited data exist regarding
such effects, and they are presently insufficient to allow defini-
tive conclusions to be drawn regarding important exposure parame-
ters determining their induction in humans. For example, certain
skin irritation effects, e.g., rashes, have been noted to oc^ur
with high levels of occupational antimony exposure, especially
under conditions of extreme heat; similar dermal effects have been
reported for at least some patients undergoing therapeutic treat-
ments with systemic injections of antimonials. There does not yet
exist, however, any evidence to suggest that dermal effects would
result from oral ingestion of antimony compounds. In regard to
effects on reproduction, development, and longevity, the available
evidence linking such effects to antimony is almost entirely de-
rived from animal toxicology studies and consists primarily of data
suggesting that: (1) prenatal exposures can interfere with concep-
tion, (2) chronic oral exposure via feeding can result in postnatal
retardation of growth as indexed by body weight aain, and
(3) chronic oral exposure via drinking water can induce alterations
in certain blood chemistry parameters and significantly shorten
C-66
-------
survival time or lifespan. Such effects, however ,\ haive not yet
i
I
been well replicated in other animal studies; onlyi.very limited
~
analogous an timo*hy-induced effects on reproduction have yet been
i
demonstrated to occur in humans. \
In summary, myocardial effects are among the most serious and
best characterized human health effects that can {presently be
linked with antimony exposure; as such, setting an ambient water
i
criterion predicated on protecting the general public from anti-
1
mony-induced myocardial effects is the most desirable course of
action if sufficient information on dose-effect relationships for
•
myocardial" effects exists. Failing that, then, thej verv limited
animal toxicology literature on reproduction, development,- and lon-
gevity effects would offer an alternative basis. ' !
Dose-Bffect/Dose-Response Relationships • i
The previous section summarizes the verv limited information
presently available regarding a qualitative description of adverse
health effects associated with antimony exposure. Ideally, the
i
main objective of the present section would be to provide further
information regarding the characterization of dose|-ef feet/dose-
r
response relationships that hold for the induct iori of the key
health effects expected to provide a basis for setting a criterion
i
for antimony. In regard to the definition of "dosp-effeet" and
i
"dose-response" relationships, Pfitzer (197fi) explains the dis-__
i ~~
tinction between effect and response in the following terms: "Ef-
fect is taken to indicate the variable chanae due to a dose in a
i
specific subject; and "response" is the number of individuals in a
group showing that effect, i.e., the number of "reactors" showina a
-------
specific effect at a particular defined dose level." Unfortunate-
ly, it is virtually impossible to characterize key antimony-induced
health effects in such quantitative terms due to the very limited
data base that presently exists.
For example/ data reported for the studies by Brieqer, et al.
(1954) suggest an inhalation no-effect level for myocardial effects
as likely being around 0.5 mg/m . Air concentrations of antimony
trisulfide ranging from 0.58 to 5.5 mg/m (with most < 3.0 mg/m )
were associated with the induction of altered EGG patterns and some
deaths attributed to myocardial damage among certain antimony work-
ers (Brieger, et al. 1954). Also, in parallel studies on animals,
Brieger, et al. (1954), observed ECG alterations in rats and rab-
bits at antimony exposures of 3.1 to 5.6 mg/m , confirming that
antimony per se can specifically produce myocardial effects of the
type observed with the occupational exposures. nnfortunately for
present purposes, however, no adequate data exist on oral exposures
to antimony compounds which would support reasonable estimates re-
garding likely no-effect levels for the induction of myocardial
effects via antimony ingestion. Nor is there sufficient informa-
tion on relative absorption rates following oral or inhalation ex-
posures to antimony to allow for extrapolation of likely dose-
effect relationships for oral exposures from the limited inhalation
exposure data. Consequently, it is presently impossible to recom-
mend a water criterion level based on projected no-effect levels
for myocardial damage.
The TLV for antimony is also inappropriate as a basis for a
water quality criterion. It is clear from the reports used over
C-68
-------
the vears by ACGIH for setting an antimony TLV that the value is
arrived at with a minimum of hard data. The reports, on careful
reading, provide little information on the acute effects of anti-
monials by virtue of the fact that the agent(s) are the corrosive
halides to which workers had very short accidental exposure. Cor-
dasco (1974) tabulated data on three cases of pulmonary trauma in
workers having industrial accidents involving antimony chloride.
Another report by Taylor (1966) dealt with short exposure of work-
ers to antimony chloride with one air level given for both hydro-
chloric acid and antimony chloride. Antimony trichloride and pen-
tachloride are corrosive compounds which would be exoected to have
effects on the respiratory tract that reflect both hydrochloric
acid injury as well as the hydrolyzed antimony effect. <~>ne would
not expect any comparability in behavior or effect in man after
oral intake.
In the absence of sufficient information to develop a criteri-
on based on the TLV or known antimony myocardial effects in humans,
the most viable alternative is to focus on animal toxicology stud-
ies demonstrating antimony-induced effects on reproduction, devel-
opment, and longevity. From the animal studies, those pertaining
to prenatal reproductive effects, e.g., Belyaeva (1967) and Casals
(1972) , employed inhalation exposures or systemic inlections of
antimony compounds, and their result cannot presently be extrapo-
lated very well to project the likely impact of oral exposures.
Similarly, the few human studies where effects on reproduction were
reported (Belyaeva, 1967; Aiello, 1955) deal with inhalation expo-
sures in occupational settings and cannot now be used to extrapo-
late likely oral exposure no-effect levels.
C-69
-------
Turning to effects on postnatal development and longevity, a
study by Gross, et al, (I955a) presents evidence for growth retar-
dation occurring when rats were chronically fed diets containing
two percent antimony tnoxide, but a no-effect level for growth
retardation cannot be deduced from the results reported. The stud-
ies by Schroeder (Kanisawa and Schroeder, 1969; Schroeder, et al.
1370) containing data on antimony effects on growth and longevity,
on the other hand, indicate that oral exposure to 5 ppm of antimony
in drinking water had nc effect on the rate of growth of either rats
or mice. The 5 ppm exposure level, howeverf was effective in pro-
ducing significant reductions in life spans for animals of both
species and altered blood chemistries for exposed rats. It is,
therefore, recommended that the 5 ppm exposure level producing such
effects be taken as a "lowest observed effect level" (LOEL) in ani-
mals that likely approximates the "no-effect" level for antimony
induced effects on growth and longevity. Calculation of an accept-
aole daily intake (ADI) for man using the value of 5 mg/1 of anti-
mony and the uncertainty factor of 100, in view of no presently
available nuinan epidemiological data regarding such effect, would
result in a recommended criterion of 145 ug/1.
ADI = 5 ma/1 x 25 ^./day/rat = 4^1? ug/kg/day, and
100 x 0.3 kg/rat
ADI for 70 kg hurran = 4.17 x 70 = 292 ua/kg/day.
-•tenon =
2 1 •*• (0,0065 kg x F)
C-70
-------
then
Criterion = 292 ug/kg/dav
2 I/day + (0.0065 kg/day x 1.0 I/kg)
= 145 yq/1,
where
100 = uncertainty factor
2 = amount of water ingested, I/May
0.0065 = amount of fish/shellfish products consumed, kg/day
F « 1.0 Bioconcentration factor
Drinking water contributes 99 percent of the assumed exposure,
while eating contaminated fish oroducts accounts for one oercent.
The criterion level for antimony in ambient water can alternatively
be exoressed as 45 mg/3., if exposure is assumed to be from the con-
sumption of fish and shellfish alone.
C-71
-------
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