United States
Environmental Protection
1=1 m m Agency
EPA/690/R-08/020F
Final
7-29-2008
Provisional Peer Reviewed Toxicity Values for
Soluble Antimony Compounds
(Various CASRNs)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
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PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
SOLUBLE ANTIMONY COMPOUNDS (VARIOUS CASRNs)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
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updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
There are many forms of antimony that exist in the environment. The primary water
soluble antimony compounds with available toxicology data include antimony potassium tartrate,
antimony trichloride, and antimony trisulfide (ATSDR, 1992). IRIS records provide an oral RfD
for antimony (CASRN 7440-36-0) based on a chronic drinking water study with potassium
antimony tartrate (U.S. EPA, 2007). The chronic oral RfD of 4E-4 mg/kg-day for antimony (Sb)
is based on a LOAEL of 0.35 mg Sb/kg-day for reduced life span and serum chemistry changes
in male and female rats exposed to potassium antimony tartrate in drinking water for 2 years by
Schroeder et al. (1970). A composite uncertainty factor (UF) of 1000 was applied in derivation
of the RfD (UFs of 10 each to account for the LOAEL to NOAEL conversion, interspecies
extrapolation, and interindividual differences). The RfD of 4E-4 mg/kg-day is included in the
Drinking Water Standard and Health Advisories List (U.S. EPA, 2006). A 1980 Ambient Water
Quality Criteria Document (AWQCD) (U.S. EPA, 1980) and a 1985 Health Effects and
Environmental Profile (HEEP) for Antimony Oxides (U.S. EPA, 1985) are listed as the source
documents for the IRIS RfD, which was verified on November 6, 1985. The HEAST (U.S. EPA,
1997) refers to IRIS for the chronic RfD and adopts the chronic RfD as a conservative estimate
of the subchronic RfD. The HEAST (U.S. EPA, 1997) also includes separate chronic and
subchronic oral RfD values of 9E-4 mg/kg-day for antimony potassium tartrate calculated by
analogy to antimony by correcting for differences in molecular weight, citing the HEEP for
Antimony Oxides (U.S. EPA, 1985) and a Health Effects Assessment (HEA) for Antimony and
Compounds (U.S. EPA, 1987). No other relevant EPA documents were located in the CARA
lists (U.S. EPA, 1991, 1994).
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IRIS (U.S. EPA, 2007) includes an RfC for antimony trioxide, but no RfC for soluble
antimony compounds. The Agency for Toxic Substances and Disease Registry (ATSDR) has
prepared a toxicological profile for antimony (ATSDR, 1992), but did not derive oral or
inhalation MRL values. ATSDR concluded that reduced lifespan in the Schroeder et al. (1970)
study was not an appropriate basis for a chronic MRL and noted that subchronic oral studies did
not examine sensitive endpoints of myocardial damage (i.e., altered EKG), which is suggested to
be a critical endpoint by subchronic inhalation studies of antimony trisulfide.
A cancer assessment for antimony is not available on IRIS (U.S. EPA, 2007) or in the
HEAST (U.S. EPA, 1997). The HEEP (U.S. EPA, 1985) and HEA (U.S. EPA, 1987)
acknowledged there was suggestive evidence of lung cancer in female rats exposed to antimony
trioxide by inhalation, but declined to perform quantitative carcinogenicity assessments. In both
cases, the decision was based on EPA's Federal Register response to an Interagency Testing
Committee (ITC) recommendation for carcinogenicity testing of antimony (U.S. EPA, 1983) in
which the data available at the time were characterized as inadequate to reasonably predict
oncogenic risk in exposed humans. There is no evidence of lung cancer associated with other
forms of antimony. U.S. EPA (1992) assigned antimony in drinking water to weight-of-evidence
Group D (not classifiable as to human carcinogenicity) based on the reasoning that evidence of
lung cancer following inhalation exposure to antimony trioxide is of uncertain relevance to oral
drinking water exposure to antimony. Antimony is classified as Group D in the Drinking Water
Standard and Health Advisories List (U.S. EPA, 2006). The International Agency for Research
on Cancer (IARC) (1989) concluded that antimony trioxide is possibly carcinogenic to humans
(Group 2B), based on sufficient evidence in animals and inadequate evidence in humans. IARC
concluded that antimony trisulfide is not classifiable as to its carcinogenicity in humans (Group
3) due to only limited evidence for carcinogenicity in animals and inadequate evidence in
humans. ACGIH (2005) classified "antimony trioxide production" as a suspected human
carcinogen (Group A2), although "antimony and compounds" was not similarly classified. In
the time since these assessments were performed, additional studies in both humans and animals
have entered the literature. The available data regarding the carcinogenicity of antimony are
reviewed below.
Computer searches of TOXLINE (1990-1997), CANCERLINE (1990-1997), DART
(1989-1996), ETICBACK (1989-1996), TSCATS, CCRIS, EMIC and EMICBACK were
conducted in June 1996 and May 1997 for antimony and compounds. Update literature searches
were performed in January 1999 for the 1996 to 1999 time period in HSDB, RTECS, MEDLINE
and TOXLINE (and its subfiles) databases. A recent update literature search was performed in
January 2006 for the time period of 1999 to present in TOXLINE, MEDLINE (plus PubMed
cancer subset), BIOSIS and DART/ETICBACK. Databases searched without date limitations
included TSCATS, RTECS, GENETOX, HSDB and CCRIS. Search of Current Contents
encompassed July 2005 to January 2006. The literature search was updated to July 2008.
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REVIEW OF PERTINENT DATA
Human Studies
Oral Exposure. No data were located regarding the oral toxicity or carcinogenicity of soluble
antimony compounds in humans.
Inhalation Exposure. Several occupational exposure studies have examined the inhalation
toxicity of antimony compounds. Most of these studies characterize the effects of exposure to
antimony trioxide and other insoluble antimony compounds (e.g., metallic antimony, antimony
ore, antimony pentoxide). These studies are described in a separate provisional toxicity value
report for antimony trioxide. One study was available that described the effects of inhalation
exposure to antimony trisulfide in occupational workers (Brieger et al., 1954). Antimony
trisulfide is a water soluble antimony compound and a summary of this study is provided below.
Brieger et al. (1954) examined 113 factory workers exposed to antimony trisulfide for 8
months to 2 years. Air concentrations of antimony trisulfide ranged from 0.58 to 5.5 mg/m3,
with the majority over 3.0 mg/m3; the particle size was not reported. The workers also may have
been exposed to phenol formaldehyde. Blood pressure readings above 150/90 were observed in
14 of the workers; 24 workers had blood pressure readings under 110/70. Altered EKG readings
(mostly of the T-waves) were observed in 37 out of 75 of the workers. EKG changes were
detected in 12 out of 56 workers reexamined after antimony trisulfide use was discontinued. A
large number of workers complained of gastrointestinal disturbances (details not provided).
Gastrointestinal ulcers were detected in 7 out of the 111 workers examined (63 per 1000) as
compared to the incidence for the total plant population (59/3912, 15 per 1000). Respiratory
irritation was not reported.
Animal Studies
Oral Exposure. Repeated-dose oral exposure studies in animals have been conducted using
potassium antimony tartrate (Omura et al., 2002; Poon et al., 1998; NTP, 1992; Schroeder et al.,
1970; Schroeder et al., 1968; Kanisawa and Schroeder, 1969) and antimony trichloride (Marmo
et al., 1987; Rossi et al., 1987; Angrisani et al., 1988).
Omura et al. (2002)
The testicular toxicity of antimony was evaluated in Crj :Wistar rats (7-8/group) and
Cjr:CD-l mice (8-10/group) (Omura et al., 2002). Antimony potassium tartrate (purity > 99.5%)
(27.4 mg/kg-day or 10 mg Sb/kg-day) was administered by oral gavage to rats (3 days/week for
4 weeks) and mice (5 days/week for 4 weeks). Animals were sacrificed by carbon dioxide
inhalation 24 hours after the final gavage dose was administered. The testes, epididymides,
ventral prostate and seminal vesicle (without fluid) were removed and weighed.
Histopathological changes were evaluated in the testes and the number, motility and morphology
of sperm from the cauda epididymides were assessed. One control mouse died due to gavage
error. No significant effect on body weight or organ weight of reproductive tissues was
observed. Sperm parameters were not affected by antimony treatment and histopathology results
were essentially negative. A NOAEL value of 10 mg Sb/kg-day was derived for male
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reproductive effects in this study; a LOAEL value was not available (no effects were seen at the
highest dose tested).
Poon et al. (1998)
Sprague-Dawley rats (15/sex/group) were exposed to 0, 0.5, 5.0, 50 or 500 ppm antimony
potassium tartrate (99.95% pure) in the drinking water for 90 days (Poon et al., 1998). An
additional 10 rats/sex were included in the control and high-dose groups and these animals were
given tap water for a 4-week recovery period following exposure. Clinical signs were monitored
daily; body weights and food and water consumption were measured weekly. At the end of the
90-day exposure period, 50% of the animals were placed in metabolic cages to provide an
overnight urine sample. All animals were anaesthetized and exsanguinated via the abdominal
aorta to provide blood samples for routine hematology and clinical chemistry. Serum was also
analyzed for thyroxine (T4), thyroid hormone binding ratio, and thiobarbituric acid-reactive
substances (TBARS). At necropsy, the brain, thymus, heart, kidney, spleen and liver were
excised and weighed and the concentration of antimony was measured in these organs. The
concentration of antimony was also measured in a sample of abdominal fat, red blood cells
(RBCs) and serum. The following tissues and organs were processed for histopathological
examination: brain, pituitary, thyroid, trachea, salivary glands, thymus, lung, heart, liver,
kidneys, adrenals, spleen, pancreas, esophagus, gastric cardia, fundus and pylorus, duodenum,
jejunum, ileum, cecum, colon, urinary bladder, skin, bone marrow and gonadal tissues. Liver
homogenates were prepared and the specific activities of aniline hydroxylase, aminopyrine N-
demethylase, ethoxyresorufin-O-deethylase (EROD) and UDP-glucuronosyltransferase were
measured using 10,000 x g supernatants.
No clinical signs were evident in rats exposed to antimony potassium tartrate. In high-
dose rats (500 ppm, both sexes), there were observed reductions in water consumption (-35%),
food consumption (-12%) and body weight gain (% change not indicated). These parameters
rapidly returned to control levels during the 4-week recovery period. Based on the body weight
and drinking water consumption data, the authors calculated average daily antimony potassium
tartrate doses of 0, 0.06, 0.56, 5.58 or 42.17 mg/kg-day for male rats and 0, 0.06, 0.64, 6.13 or
45.69 mg/kg-day for female rats. These doses correspond to 0, 0.024, 0.22, 2.2 or 17 mg Sb/kg-
day for male rats and 0, 0.024, 0.25, 2.4 or 18 mg Sb/kg-day for female rats. Dose-dependent
increases were evident in tissue antimony concentrations in the spleen, liver, kidney, brain, fat
and serum, with the highest specific concentrations observed in the RBCs.
Among hematological parameters, high-dose males displayed a significant reduction in
the number of platelets (-12%) and RBCs (-5%) and a slight increase in mean corpuscular
volume (MCV) (+3%). The study authors suggest that this mild anemia may be related to
hematuria that was observed in 3 high dose male rats. High-dose females had an increased
monocyte count (+48%). Several changes were noted in clinical chemistry parameters. In
female rats, there was a dose-related reduction in serum glucose concentration at concentrations
of 5 ppm antimony and above (18% decrease at 500 ppm). The study authors suggest that this
may be related to an inhibition of phosphofructokinase, although the clinical relevance of this
change is not known. In high-dose female rats, the serum concentrations of creatinine, protein
and cholesterol were reduced by 11%, 7% and 24%, respectively and alkaline phosphatase
activity was decreased by 13%. A 12 to 14% increase in the thyroid hormone binding ratio was
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observed in female rats that drank water containing 50 or 500 ppm antimony. Creatinine
concentration and alkaline phosphatase activity were also reduced in high-dose male rats (10 and
41%, respectively). All clinical chemistry parameters were similar to control values by the end
of the 4-week recovery period. No treatment-related changes were observed in serum sorbitol
dehydrogenase, aspartate aminotransferase, creatinine kinase, thyroxin, or TBARS. No dose-
related changes were observed in hepatic mixed-function oxidase enzyme activities, with the
exception of ethoxyresorufin-O-deethylase, which was increased by 55% in high-dose male rats.
Glutathione transferase activity was increased in high-dose male (11%) and female (18%) rats.
Few gross lesions were evident at necropsy. A single male in the high-dose group had a
cirrhotic liver and one female in the 0.5 ppm group had a nodular, fibrotic spleen. Female rats in
the 50 ppm dose group had a lower thymus to body weight ratio than control rats (22% decrease)
and male and female rats from the high-dose groups had increased kidney-to-body-weight ratios
(8%> increase for males, 18% increase for females). No other organ weight changes were noted.
Histopathological changes were observed in the thyroid and liver, with lesser changes seen in the
thymus, spleen and pituitary gland. Thyroid effects included reduced follicle size, increased
epithelial height and nuclear vesiculation. Anisokaryosis and nuclear hyperchromicity were
observed in the liver. Increased portal density and increased perivenous homogeneity were also
noted in the cytoplasm of hepatocytes. Other observations included reduced cortical volume and
increased medullary volume in the thymus, sinus congestion in the spleen and cytoplasmic
vacuolation and inclusions in the pituitary gland. The study authors concluded that all
histological findings were mild adaptive changes and did not represent significant target organ
toxicity. Thyroid and liver lesions were found in control rats. The incidence and severity of
these lesions was generally increased in treated groups; however a clear dose-response
relationship was not apparent for many endpoints. An adjusted NOAEL of 18 mg Sb/kg-day was
derived from this study, because histological changes were considered adaptive in nature and
hematology and clinical chemistry findings were not indicative of significant toxicity. A
LOAEL value was not provided by this study (no adverse effects were seen at the highest dose
tested).
NTP (1992)
A 14-day drinking water study using antimony potassium tartrate (purity >99.4%) was
performed in F344 rats and B6C3F1 mice (5/sex/group) (NTP, 1992). The daily antimony
potassium tartrate doses calculated by the study authors were 0, 16, 28, 59, 94 or 168 mg/kg-day
in rats and 0, 59, 98, 174, 273 or 407 mg/kg-day in mice. These doses correspond to 0, 6, 11, 24,
38 or 67 mg Sb/kg-day in rats and 0, 24, 39, 70, 109 or 163 mg Sb/kg-day in mice. Animals
were observed twice per day. Body weights were measured on days 1, 8 and prior to sacrifice on
day 15, and water consumption was measured on day 7 or 8 and on day 15. Following sacrifice
by CO2 inhalation, the liver, thymus, right kidney, right testis, spleen, heart, brain and lungs were
removed, weighed and evaluated for histopathology. The tissue concentration of antimony was
measured in the blood, kidney, heart, liver and spleen.
Water consumption was decreased 20 to 30% in male rats receiving 38 and 67 mg Sb/kg-
day and 10-40%) in female rats receiving doses greater than 11 mg Sb/kg-day. No clinical signs
of toxicity or significant changes in body weight were observed in rats. Relative liver weight
was increased in male and female rats for the highest dose group (67 mg Sb/kg-day) and relative
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kidney weight was increased in female rats from this group. No histopathological changes were
observed in rats, with the exception of prominent staining of protein droplets observed in the
cytoplasm of renal tubule cells of male rats. Antimony concentrations were detected in the
kidney, heart, spleen and liver of rats, but were highest in blood (15 to 20 (J,g/kg). A NOAEL of
67 mg Sb/kg-day was derived for rats in this study based on the lack of histopathological effects.
A LOAEL dose was not determined from this study.
Body weight was significantly decreased in male mice at doses of 109 mg Sb/kg-day (7%
decrease) and 163 mg Sb/kg-day (25% decrease) and in female mice in the 163 mg Sb/kg-day
dose group (18% decrease) at 8 days of exposure. Body weight values recovered and were
similar to controls at the end of the study (day 16) for all dose groups except high-dose males
(7%> decrease on day 16). One female mouse from the high-dose group died during the study.
Water consumption was decreased in all treatment groups. Clinical signs of toxicity were
observed (i.e., rough haircoat, emaciation, abnormal posture, hypoactivity and decreased fecal
material consistent with water avoidance); however, the study report did not specify the dose
groups in which these signs were seen. Dose-related increases were observed in relative liver
weight (not further described). Liver and forestomach lesions were observed in male and female
mice from the high-dose group (incidence values were not provided). Gross lesions described as
small, white nodules, were observed in the forestomach of three male mice and one female
mouse. Histopathology revealed that these nodules consisted of focal areas of ulceration and
necrosis, with inflammation of the squamous mucosa extending to the muscularis of the
forestomach. Focal hyperplasia of the squamous epithelium of the forestomach was also
observed. Cytoplasmic vacuolization was observed in hepatocytes from all male and female
mice in the high-dose group. Centrilobular hepatocytes were slightly enlarged and showed
cytoplasmic staining; however, nuclear displacement was not observed. NOAEL and LOAEL
values could not be clearly determined from the mouse data in this study. Body weight
decreases and histopathological changes in the forestomach and liver were observed at the
highest dose; however, it is not clear whether clinical signs of toxicity were also evident in lower
dose groups.
Schroeder et al. (1970)
Schroeder et al. (1970) exposed groups of 51-52 male and 54-59 female Long-Evans rats
to 0 or 5 [j,g/mL of antimony as potassium antimony tartrate in the drinking water from weaning
through natural death (up to 45 months in this study). Rats were weighed periodically
throughout the study. Upon death, animals were necropsied and grossly visible tumors and other
lesions were described. An outbreak of pneumonia during this study led to the deaths of 9
treated males, 3 treated females, 19 control males and 12 control females. Survival curves were
corrected to take this non-treatment related mortality into account. Survival (corrected for
pneumonia mortality) of antimony-exposed rats was reduced after 12 months in males and after
21 months in females compared to untreated controls. Median life span was reduced over 100
days in both males and females, and longevity (defined as the mean age of the last surviving
10%) was significantly reduced in both sexes as well. Body weights (reported only for the first
18 months of the study) did not differ from controls. Heart weight was reduced by 19% in
treated male rats, as compared to control values. Heart weight was similar to controls for
females rats exposed to potassium antimony tartrate. The non-fasting serum glucose
concentration was decreased by 28% in treated male rats and 30% in treated female rats, as
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compared to controls. Serum cholesterol was increased in treated male rats (+26%) and
decreased in treated female rats (-16%), compared to serum cholesterol concentrations in control
rats. The incidence of grossly visible tumors at necropsy was not affected by antimony exposure
in male or female rats. The chronic oral RfD of 4E-4 mg/kg-day for antimony was calculated
from a LOAEL of 0.35 mg Sb/kg-day, a dose reported in IRIS to be associated with the 5 ppm
antimony concentration in drinking water (U.S. EPA, 2007).
Schroeder et al. (1968); Kanisawa and Schroeder (1969)
These researchers conducted a similar study in mice (Schroeder et al., 1968; Kanisawa
and Schroeder, 1969). Groups of 54-55 male and 54 female Charles River CD mice were given
0 or 5 [j,g/mL of antimony as the potassium tartrate in the drinking water from weaning through
natural death (up to 33 months in this study). The researchers estimated the antimony dose as
0.35 mg Sb/kg-day (5 |ig/mL x 7 mL/d/0.1 kg). The mice were weighed periodically and
observed for mortality. Dead animals were necropsied and examined for grossly visible tumors
and other lesions, which were sectioned, stained and examined by light microscopy. Survival
(%) of male and female mice exposed to antimony was similar to survival of controls throughout
the study. The median life span of exposed female mice was reduced by 49 days compared to
controls, but longevity (mean age of the last surviving 10%) was not affected. Body weights
were reduced significantly compared to controls after 6 months in female mice and after 18
months in male mice. Exposure to antimony had no effect on the incidence or type of tumors
detected by gross necropsy in male or female mice. These studies were of limited utility for the
evaluation of cancer effects due to use of a single dose level, failure to consider whether the dose
used approached the maximum tolerated dose (MTD), and reliance on gross necropsy for
detection of tumors (i.e., failure to perform thorough histopathological examination of test
animals). The LOAEL dose of 0.35 mg Sb/kg-day for antimony potassium tartrate was based on
decreased body weights in female mice. A NOAEL was not available for this study.
Marmo etal. (1987); Rossi et al. (1987); Angrisani et al. (1988)
Marmo and associates (Marmo et al., 1987; Rossi et al., 1987; Angrisani et al., 1988)
studied the effects of prenatal and/or postnatal exposure to antimony trichloride on vasomotor
reactivity in the developing NOS albino rat. Pregnant rats (30/group) were exposed to 0, 1 or 10
mg/L antimony trichloride in drinking water from the first day of pregnancy until weaning of the
offspring (22 days old) or during the postnatal period only (birth to 22 days old) (Marmo et al.,
1987). Pups were randomized within 12 hours of birth and distributed to lactating dams with a
litter size culled to 10 (equal numbers of male and female pups, if possible). Rat offspring were
exposed to antimony trichloride in their drinking water (0, 1 or 10 mg/L) from weaning until 30
or 60 days of age. Rat offspring (10/group, 30 or 60 days old) were anesthetized and the right
femoral vein was cannulated for injection of drugs. Arterial blood pressure was measured using
a catheter connected to the right common carotid artery. This study measured systolic blood
pressure and the response to either pressor or hypotensive agents or conditions in 30 or 60-day
old offspring. The pressor response was evaluated using a 40-second occlusion of the left
common carotid artery or intravenous (i.v.) injection of norepinephrine (0.1, 1, or 5 (J,g/kg for 5
seconds). The hypotensive response was measured after injection of isoprenaline (0.01, 0.1, or 1
[j,g/kg i.v. for 5 seconds) or acetylcholine (0.01, 0.1, or 1 (J,g/kg i.v. for 5 seconds).
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Exposure to antimony trichloride (prenatal/postnatal or postnatal only) did not affect
offspring arterial blood pressure, measured at 30 or 60 days after birth (Marmo et al., 1987).
Combined prenatal and postnatal exposure to antimony trichloride did not affect the pressor
response to carotid artery occlusion. Antimony trichloride decreased the pressor response to
norepinephrine and the hypotensive response to isoprenaline at both dose levels in 60-day old
rats. The hypotensive response to acetylcholine was decreased at the highest dose of antimony
trichloride in 60-day old rats, while the response of the low dose group was similar to controls.
No change in pressor or hypotensive responses was seen in 30-day old rats treated with antimony
trichloride during the prenatal and postnatal exposure periods. In rats exposed only during the
lactation period (postnatal dosing in dams) and in the drinking water after weaning, 60-day old
offspring from the high-dose group showed a decrease in pressor responses to carotid artery
occlusion and norepinephrine injection and a decrease in hypotensive response to isoprenaline
and acetylcholine. A decreased hypotensive response to isoprenaline and acetylcholine was also
seen in 30-day old offspring exposed to the highest dose of antimony trichloride. In the low-
dose group (postnatal exposure), a decreased response to norepinephrine and isoprenaline was
observed in 60-day old rats, while 30-day old rats were similar to controls. This study suggests
that vasomotor reactivity was affected by both prenatal and postnatal exposure to antimony
trichloride. However, blood pressure responses were only measured in 10 pups/dose group and
the report did not indicate whether each pup came from a different litter within that dose group
or whether some pups came from the same litter.
Rossi et al. (1987) reported additional findings (i.e., maternal blood pressure and
maternal and pup body weights) for the combined prenatal and postnatal exposure to antimony
trichloride described in Marmo et al. (1987). As described above, pregnant female NOS albino
rats (30 rats/group) received antimony trichloride in their drinking water (0, 1 or 10 mg/L) from
gestational day 1 through weaning. Rat offspring (randomized, distributed to lactating dams and
culled to 10/litter with equal sex ratio) were exposed prenatally and postnatally (through
lactation until weaning and in their drinking water from 22 to 60 days old at concentrations of 0,
1 or 10 mg/L). The systolic arterial blood pressure of dams was measured daily for the first 20
days of gestation using a blood pressure recorder on the tail radix of conscious dams. The
measurement of vasomotor reactivity in pups was described in Marmo et al. (1987) (see above).
Maternal body weights were recorded on days 10 and 20 of gestation and pup body weights were
measured on postnatal days 5, 10, 22, 30, and 60. The length of gestation and the number of
pups/litter was recorded.
No significant alterations in litter size or macroscopic effects were observed in the
offspring of dams exposed to antimony trichloride during gestation and lactation. Maternal body
weight was decreased by 8% (low-dose group) to 10% (high-dose group) on the 20th day of
gestation as compared to controls (statistically significant at both doses). It should be noted,
however, that basal maternal body weights for each treatment group on day 0 of gestation prior
to exposure were approximately 7% lower than the control group. Thus, the 8 to 10% deficit
from controls seen on gestation day 20 represents a relatively small change from the 7% deficit
at the start of gestation. Pup body weights were similar to controls at birth and at 5 days of age,
but were decreased in the high-dose group from the 10th (24% decrease from controls) to the 60th
(11% decrease from controls) day of age. Exposure to antimony trichloride did not affect
9

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maternal or pup systolic arterial blood pressure. The results of the vasomotor reactivity studies
in offspring were reported by Marmo et al. (1987) and are described above.
Angrisani et al. (1988) reported additional findings (i.e., maternal blood pressure and
maternal and pup body weights) for postnatal (only) exposure to antimony trichloride (0, 1 or 10
mg/L) in pregnant female NOS albino rats (30 rats/group, exposed from delivery through
weaning) and in rat offspring (randomized, distributed to lactating dams and culled to 10/litter
with equal sex ratio) exposed postnatally (through lactation until weaning and in the drinking
water from 22 to 60 days old at concentrations of 0, 1, or 10 mg/L). The systolic arterial blood
pressure of dams was measured on postnatal days 1, 22, and 60 using a blood pressure recorder
on the tail radix of conscious dams. The measurement of vasomotor reactivity in pups was
described in Marmo et al. (1987) (see above). Maternal body weights were recorded daily until
60 days after birth and pup body weights were measured daily between postnatal days 5 and 60.
Postnatal exposure to antimony trichloride did not affect maternal or pup body weights or
systolic arterial blood pressure. The results of the vasomotor reactivity studies in offspring were
reported by Marmo et al. (1987) and are described above.
In summary, exposure of dams and pups to antimony trichloride (prenatal and/or
postnatal) did not change the systolic arterial blood pressure in dams during gestation or after
birth, or in pups at 30 and 60 days of age (Marmo et al., 1987; Rossi et al., 1987; Angrisani et al.,
1988). The vasomotor response to injection of pressor or hypotensive agents was decreased at
both concentrations in 60-day old rats exposed prenatally and/or postnatally; however the clinical
significance of the reported changes is unclear and was not discussed by the study authors
(Marmo et al., 1987; Rossi et al., 1987; Angrisani et al., 1988). Combined prenatal and postnatal
exposure to antimony trichloride produced a small decrease in maternal body weight during
gestation (Rossi et al., 1987), while postnatal exposure during lactation did not affect maternal
body weight (Angrisani et al., 1988). Pup body weights were significantly lower than controls
starting at 10 days of age (24% decrease) and continuing through 60 days of age (11% decrease)
following combined prenatal and postnatal exposure to 10 mg/L antimony trichoride (Rossi et
al., 1987), but were not decreased by postnatal exposure only (Angrisani et al., 1988). The
relationship between decreased pup and dam body weights is unclear. Both maternal and pup
body weights were decreased in rats treated pre- and postnatally, but not in rats treated only
postnatally. This suggests that the effect in pups may be secondary to the effect in dams even
though pup body weights did not differ from controls until 10 days after birth.
Maternal doses for the gestational exposure period can be calculated using the average
maternal body weight during gestation (298 g; Rossi et al., 1987) and the drinking water
ingestion rate, calculated using the allometric relationship between drinking water ingestion and
body weight (0.041 L/day) (U.S. EPA, 1988). The gestational maternal doses were estimated to
be 0, 0.14, or 1.4 mg/kg-day antimony trichloride, or 0, 0.075, or 0.75 mg Sb/kg-day. The
maternal dose of 0.75 mg Sb/kg-day was considered the LOAEL for this study, based on
decreased maternal and pup body weights. The low dose of 0.075 mg Sb/kg-day was considered
a NOAEL due to the very slight effect on maternal body weight and absence of effect on pup
body weight at this dose.
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Inhalation Exposure. Most of the subchronic and chronic animal data on the toxicity of inhaled
antimony are from studies in which rats were exposed to antimony trioxide or other insoluble
forms of antimony (i.e., antimony ore). These studies are described in a separate provisional
toxicity value report for antimony trioxide. One study was available that described the effects of
inhalation exposure to antimony trisulfide on rabbits, rats, and dogs (Brieger et al., 1954). A
summary of this study is provided below.
Brieger et al. (1954)
Brieger et al. (1954) exposed groups of 6 male rabbits (strain not specified), 10 male
Wistar rats and 2 female dogs (strain not specified) to antimony trisulfide for 7 hours/day, 5
days/week for 6-10 weeks. Very limited information was provided regarding the conditions of
exposure. The study authors stated that animals were exposed to dust that was similar to an
industrial sample obtained from an abrasives facility and that the majority of particles at the
height of the nose and mouth of animals were 2 [j,m in diameter or less. The geometric standard
deviation was not reported and no further information was provided. Altered EKG readings,
indicative of myocardial damage, were observed in the rabbits exposed to 5.6 mg/m3 for 6
weeks, rats exposed to 3.07 mg/m3 for 6 weeks, and dogs exposed to 5.55 mg/m3 for 10 weeks,
but not in dogs exposed to 5.32 mg/m3 for 7 weeks. Histological evidence of myocardial damage
also was observed in the rabbits (flabby myocardium and swelling of myocardial fibers) and rats
(focal degenerative changes in myocardium). In the rats, pathological changes were observed in
the lungs during the gross necropsy; the alterations were characterized by the study authors as
"slight" and consisted of congestion and focal areas of hemorrhage. It is unclear if a microscopic
examination of the lungs was conducted. The authors noted that the lung congestion may have
been secondary to the heart effects. The LOAELs for myocardial effects in rabbits, rats and dogs
exposed to antimony trisulfide for 6, 6 and 10 weeks, respectively, are 5.6, 3.07 and 5.55 mg/m3
(4.0, 2.2, 4.0 mg/m3 antimony).
Other Studies
Injection Studies. Intraperitoneal injection studies using antimony potassium tartrate (purity
>99.4%) were conducted in F344 rats and B6C3Fi mice (10/sex/group) (NTP, 1992). A 16 day
range finding study used doses of 0, 1.5, 3, 6, 11 or 22 mg/kg-day in rats and 0, 6, 13, 25, 50 or
100 mg/kg-day in mice, administered as 12 injections given on consecutive week days. These
correspond to doses of 0, 0.6, 1.2, 2.4, 4.4 or 8.8 mg Sb/kg-day in rats and 0, 2.4, 5.2, 10, 20 or
40 mg Sb/kg-day. Mortality was observed in the high dose groups for both rats (3/20) and mice
(20/20). Liver lesions, characterized as necrosis and inflammation of the liver capsule, were
observed in 7 of 10 mice given 20 mg Sb/kg-day (both sexes). These lesions were not observed
in mice from the highest dose group that died prior to the end of the study. Liver necrosis and
kidney degeneration were observed in the high dose male rats that died prior to the end of the
study. A 13-week injection study used doses of 0, 1.5, 3, 6, 12 or 24 mg/kg-day given 3 times
per week, resulting in daily antimony doses of 0, 0.6, 1.2, 2.4, 4.8 or 9.6 mg Sb/kg-day.
Mortality was observed in 4 of 10 male rats in the highest dose groups. A reduction in body
weight was seen in both male (18%) and female (11%) rats from these groups. Relative liver
weight was increased in male and female rats from all dose groups (maximum increase of 20%
for males and 40% for females at 9.6 mg Sb/kg-day). Dose-related increases in serum alanine
aminotransferase and sorbitol dehydrogenase were also observed in male and female rats (data
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presented graphically). Liver degeneration and necrosis were observed in male rats (0/10, 0/10,
0/10, 2/10, 8/10 and 6/8 for 0, 0.6, 1.2, 2.4, 4.8 and 9.6 mg Sb/kg-day, respectively) and in
female rats (0/10, 0/10, 0/10, 0/10, 1/10 and 10/10 for 0, 0.6, 1.2, 2.4, 4.8 and 9.6 mg Sb/kg-day,
respectively). Kidney degeneration was also observed in the highest dose group in female rats
(3/10). No clinical signs of toxicity or gross or microscopic changes were observed in mice
exposed to antimony potassium tartrate in this study.
Miranda et al. (2006) evaluated the developmental toxicity and transplacental transfer of
meglumine antimoniate (pentavalent compound) following subcutaneous injection in pregnant
female Wistar rats (19-21/group). Antimony doses of 0, 75, 150 or 300 mg Sb/kg-day were
administered on GD 1-20. Rats were sacrificed by CO2 inhalation on GD21 and the number of
implantation sites, live/dead fetuses, resorptions and corpora lutea were counted. Living fetuses
were weighed, measured, examined for gross abnormalities and processed for evaluation of
skeletal (staining with Alizarin Red) and visceral abnormalities (micro-sectioning after fixation
in Bouin's solution). Maternal blood samples were collected each day from a separate group of
rats given 300 mg Sb/kg-day. Fetal blood samples were obtained from the offspring of this
group on GD21. Maternal and fetal body weights were reduced in the high-dose group (18% and
10%, respectively, at 300 mg/kg-day). Embryolethality was also observed in this dose group
(decreased number of live fetuses). The frequency of dilated ureter was increased in fetuses
from the 150 and 300 mg Sb/kg-day dose groups. Skeletal variations were also seen in the mid-
and high-dose groups (misaligned sternebrae, supernumerary ribs, misshapened basiooccipital
bone). Transplacental transfer of antimony was confirmed by fetal blood analysis with fetal
blood concentrations measured to be roughly one-third of the concentrations found in maternal
blood.
Alvarez et al. (2005) evaluated the ability of trivalent and pentavalent antimony
compounds to induce cardiomyopathy in guinea pigs. Guinea pigs received daily intramuscular
injections of pentavalent antimony (16 mg/kg antimony meglumine for 26 days) or trivalent
antimony (10 mg/kg antimony potassium tartrate for 8 to 12 days). Controls were given saline
injections. Treatment with trivalent antimony caused lethality in approximately 50% of the
animals. Survivors exhibited alterations in the EKG (i.e., T-wave flattening and or inversion,
depression of the ST segment and elongation of the RR and QT intervals). Ventricular myocytes
isolated from these animals showed impaired contraction responses to stimulus, altered whole
cell action potential and reduced calcium current. L-Carnitine was investigated as a protective
treatment for trivalent antimony cardiotoxicity. Combined treatment of L-carnitine and
antimony potassium tartrate produced a delay in antimony-induced mortality. Prior treatment
with L-carnitine (for 4 days) followed by combined treatment (for 6 or 12 days) decreased
mortality to less than 10% of treated animals. These animals exhibited a normal EKG and
isolated myocytes had normal contractility and whole cell action potential. Daily injections of
pentavalent antimony for 26 days caused an elongation of the QT interval of the EKG. Mortality
was not induced by pentavalent antimony treatment in this study and ventricular myocytes were
not isolated from these animals.
Genotoxicity Studies. The genotoxic potential of soluble antimony compounds is difficult to
assess, given the conflicting results of published studies. Antimony compounds were generally
negative in bacterial and mammalian cell mutagenicity assays. Both positive and negative
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findings were reported for in vitro DNA damage, chromosome aberrations and micronucleus
formation in mammalian cells. Conflicting data were also available for in vivo studies of
micronucleus formation. Genotoxicity data are presented in Table 1.
Antimony trichloride, antimony pentachloride and antimony potassium tartrate were
negative for reverse mutation in Salmonella typhimurium (Kanematsu et al., 1980; Kuroda et al.,
1991; Zeiger et al., 1992). Antimony trichloride was also negative for reverse mutation in
Escherichia coli (Kanematsu et al., 1980). Antimony trichloride and antimony pentachloride
were negative in an early rec assay for differential killing in DNA repair-proficient and DNA
repair-deficient strains of Bacillus subtilis conducted using the streak method (Nishioka, 1975),
but gave strong positive results in more recent rec assays conducted using more sensitive
methods (Kanematsu et al., 1980; Kuroda et al., 1991). Stibine (SbH3) and trimethyl stibine
(MesSb) produced DNA damage in a plasmid DNA nicking assay (pBr 322 plasmid DNA)
(Andrewes et al., 2004). Potassium antimony tartrate, hexahydroxyantimonate and
trimethylantimony dichloride produced negative results in this assay system.
Studies in mammalian cells have sometimes reported positive results for antimony
compounds. Antimony trichloride increased the frequency of micronuclei and caused DNA
strand breaks in isolated human lymphocytes (Schaumloffel and Gebel, 1998). Antimony
sodium tartrate produced an increase in the number of chromatid breaks in cultured human
leukocytes (Paton and Allison, 1972). Antimony acetate increased viral transformation in Syrian
hamster embryo cells in vitro (Casto et al., 1979). Antimony trichloride increased SCE in V79
Chinese hamster cells in vitro, although antimony pentachloride did not (Kuroda et al., 1991).
Antimony trichloride increased micronucleus formation and induced DNA strand breaks in V79
Chinese hamster cells, but did not cause DNA-protein crosslinks in these cells (Gebel et al.,
1998). Huang et al. (1998) also demonstrated that antimony trichloride increased micronucleus
formation in Chinese hamster ovary cells, human bronchial epithelial cells and human
fibroblasts. Delayed apoptosis was also observed in these cell types following treatment with
antimony trichloride. Antimony trisulfide produced chromosomal aberrations in Chinese
hamster ovary (CHO) cells in vitro, but did not produce gene mutation in the CHO cells or
neoplastic transformation in BALB/c-3T3 cells (Tu and Sivak, 1984). Antimony trichloride and
antimony potassium tartrate inhibited the repair of radiation-induced double-strand breaks in
CHO cells (Takahashi et al., 2002). Gurnani et al. (1992) reported that antimony trichloride
produced chromosomal aberrations in mouse bone marrow in vivo.
Potassium antimony tartrate was shown to decrease the growth of several lymphoid cell
lines through caspase- and reactive oxygen species-dependent apoptosis (Lecureur et al., 2002a,
2002b). Wyllie and Fairlamb (2006) showed that trivalent antimony (as potassium antimony
tartrate) was toxic to THP-1 macrophages from a human leukemia monocyte cell line. Trivalent
antimony significantly altered thiol homeostasis in these cells, suggesting that this may be a key
event in the mode of action of antimonials against leukemia cells. The pentavalent antimony
compound sodium stibogluconate did not affect thiol status and was not toxic to macrophages in
this study.
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Table 1. Genotoxicity Data for Antimony Compounds
Test System/ Endpoint
Results
Reference
Positive
Negative
Salmonella typhimurium/
reverse mutation
None reported
antimony trichloride,
antimony pentachloride,
antimony potassium tartrate
Kanematsu et al.
(1980); Kuroda et al.
(1991);	Zeiger et al.
(1992)
Escherichia coli/
reverse mutation
None reported
antimony trichloride
Kanematsu et al. (1980)
Bacillus subtilis/
Rec assay
antimony trichloride,
antimony pentachloride
antimony trichloride,
antimony pentachloride
Kanematsu et al.
(1980); Kuroda et al.
(1991); Nishioka (1975)
Plasmid DNA nicking assay
stibine and trimethyl
stibine
potassium antimony tartrate,
hexahydroxyantimonate and
trimethylantimony dichloride
Andrewes et al. (2004)
Human peripheral
lymphocytes/ micronucleus
formation
antimony trichloride
None reported
Schaumloffel and Gebel
(1998)
Human peripheral
lymphocytes/DNA strand
breaks
antimony trichloride
None reported
Schaumloffel and Gebel
(1998)
Human
leukocytes/chromatid
breaks
antimony sodium tartrate
None reported
Paton and Allison
(1972)
Syrian hamster
embryos/viral
transformation
antimony acetate
None reported
Casto et al., (1979)
V79 Chinese hamster
cells/SCE
antimony trichloride
antimony pentachloride
Kuroda et al. (1991)
V79 Chinese hamster
cells/micronucleus
formation, DNA strand
breaks
antimony trichloride
None reported
Gebel etal. (1998)
V79 Chinese hamster
cells/DNA-protein
crosslinks
None reported
antimony trichloride
Gebel etal. (1998)
Chinese hamster ovary
(CHO) cells, human
bronchial epithelial cells,
human fibroblast/
micronucleus formation
antimony trichloride
None reported
Huang et al. (1998)
CHO cells/ chromosome
aberrations
antimony trisulfide
None reported
Tuand Sivak(1984)
CHO cells/gene mutation
None reported
antimony trisulfide
Tuand Sivak(1984)
BALB/C-3T3
cells/neoplastic
transformation
None reported
antimony trisulfide
Tuand Sivak(1984)
CHO cells/inhibition of
DNA repair
antimony trichloride,
antimony potassium
tartrate
None reported
Takahashi et al. (2002)
Mouse bone marrow in
vivo/chromosome
aberrations
antimony trichloride
None reported
Gurnani et al. (1992)
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DERIVATION OF A PROVISIONAL SUBCHRONIC AND CHRONIC RfD FOR
SOLUBLE ANTIMONY COMPOUNDS
Subchronic RfD
Repeated-dose oral exposure studies in animals have been conducted using potassium
antimony tartrate (Omura et al., 2002; Poon et al., 1998; NTP, 1992; Schroeder et al., 1970;
Schroeder et al., 1968; Kanisawa and Schroeder, 1969) and antimony trichloride (Marmo et al.,
1987; Rossi et al., 1987; Angrisani et al., 1988). Table 2 presents a summary of the noncancer
results for the oral studies using soluble antimony compounds in experimental animals.
The subchronic toxicity study by Poon et al. (1998) found only mild adaptive changes in
rats, even at the high dose of 18 mg Sb/kg-day. Similarly, the short-term study by NTP (1992)
found only minor changes at doses as high as 67 mg Sb/kg-day in rats. NTP (1992) reported
more toxic effects in mice treated with high doses for 4 weeks, but effect levels could not be
identified due to inadequate reporting of results. Much lower doses were reported to produce
decreases in maternal and pup body weight with gestational and postnatal exposure in rats (Rossi
et al., 1987) and reductions in body weight and survival in rats and mice exposed to antimony in
the drinking water for life (Schroeder et al., 1968; Kanisawa and Schroeder, 1969; Schroeder et
al., 1970). The lowest LOAELs were observed in the chronic studies.
The chronic drinking water studies with potassium antimony tartrate in rats and mice
evaluated survival, body weight changes, limited clinical chemistry parameters (serum glucose
and cholesterol), and findings of gross lesions at necropsy (Schroeder et al., 1968, 1970;
Kanisawa and Schroeder, 1969). The discrepancy in effect levels between the chronic and
shorter-duration studies is a source of uncertainty, as is the uncorroborated report of effects on
maternal and pup body weights in rats exposed to low doses during and after gestation.
Therefore, the chronic drinking water studies, which reported the lowest LOAELs in the
database, were selected as critical studies for evaluating the potential effects of subchronic
exposure to soluble antimony compounds. Decreased body weight gain, reduced survival, and
altered serum chemistry (decreased serum glucose) were seen in rats chronically exposed to
potassium antimony tartrate in the drinking water. In the Poon et al. (1998) study, hepatotoxicity
and thyroid toxicity reported in the high dose-exposure group were also reported in control rats,
and other toxicological changes observed in the high dosage group are quite comparable to the
similar effects seen in chronic rodent studies. The critical effects observed at lower doses in
chronic and developmental studies are therefore considered appropriate for subchronic duration.
The chronic oral RfD of 4E-4 mg/kg-day for antimony on IRIS (U.S. EPA, 2007) is based on a
LOAEL of 0.35 mg Sb/kg-day for reduced life span and serum chemistry changes in male and
female rats exposed to potassium antimony tartrate in drinking water for 2 years by Schroeder et
al. (1970). This value was adopted as the subchronic p-RfD (4E-4 mg Sb/kg-day) for soluble
antimony compounds.
The subchronic provisional RfD value for soluble antimony (based on the metal content)
is appropriate for antimony potassium tartrate (CASRN 11071-15-1) and antimony trichloride
(CASRN 10025-91-9) but not oxides of antimony and may not be applicable for other salts.
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Table 2. Repeated-Dose Oral Toxicity Studies for Soluble Antimony Compounds
Species
Dose/duration
NOAEL
(mg Sb/kg-
day)
LOAEL
(mg Sb/kg-
day)
Effect
Reference
Cij: Wistar rats
(7-8 males/
group)
oral gavage (3 days/week
for 4 weeks) with antimony
potassium tartrate; 0 or 10
mg Sb/kg-day
10
NA
No effects on
reproductive tissues
or body weight
Omura et al.,
2002
Cjr:CD-l mice
(8-10 males/
group)
oral gavage (5 days/week
for 4 weeks) with antimony
potassium tartrate; 0 or 10
mg Sb/kg-day
10
NA
No effects on
reproductive tissues
or body weight
Omura et al.,
2002
F344 rats
(5/sex/group)
14-day drinking water study
with antimony potassium
tartrate; 0, 6, 11, 24, 38 or
67 mg Sb/kg-day
67
NA
Increased relative
liver and kidney
weights with no
histological changes
NTP, 1992
B6C3F1 mice
(5/sex/group)
14-day drinking water study
with antimony potassium
tartrate; 0, 24, 39, 70, 109 or
163 mg Sb/kg-day
NA
NA
Decreased body
weight, clinical
signs, histological
changes (liver,
forestomach) at high
dose; unclear if
clinical signs also at
lower doses
NTP, 1992
Male and
female
Sprague
Dawley rats
(15/sex/group)
13-week drinking water
study with antimony
potassium tartrate;
0, 0.024, 0.22, 2.2 or 17 mg
Sb/kg-day for male rats; 0,
0.024, 0.25, 2.4 or 18
mg/kg-day for female rats
18
NA
Mild adaptive
histological changes
(liver, thyroid,
thymus, spleen,
pituitary)
Poon et al.,
1998
Male and
female Long
Evans rats (51-
59/sex/group)
Lifetime drinking water
exposure to antimony
potassium tartrate;
0 or 0.29 mg Sb/kg-day for
males and 0 or 0.35 mg
Sb/kg-day for females
NA
0.35
Reduced survival
Schroeder et
al., 1970
CD mice (54-
5 5/sex/group)
Lifetime drinking water
exposure to antimony
potassium tartrate;
0.35 mg Sb/kg-day
NA
0.35
Body weight
reduction
Schroeder et
al., 1968;
Kanisawa and
Schroeder,
1969
Pregnant
female NOS
albino rats
(30/group); rat
pups (36-
90/group)
Maternal drinking water
exposure to antimony
trichloride during gestation;
0, 0.075 and 0.75 mg Sb/kg-
day
0.075
0.75
Decreased maternal
and offspring body
weight
Rossi et al.,
1987
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Chronic RfD
The chronic RfD of 4E-4 mg/kg-day for antimony is available on IRIS (U.S. EPA,
2007).
FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC AND CHRONIC RfC
FOR SOLUBLE ANTIMONY COMPOUNDS
Most of the available data on the toxicity of inhaled antimony is from occupational and
animal studies involving exposure to antimony trioxide. These studies are described in a
separate provisional toxicity value report for antimony trioxide. Brieger et al. (1954) found
evidence of myocardial damage (altered EKG readings) in workers occupationally exposed to
0.58-5.5 mg/m3 antimony trisulfide and in rabbits, rats and dogs exposed to 3-6 mg/m3 antimony
trisulfide for 6-10 weeks. Very limited information was provided in this study regarding the
conditions of exposure, and available dose response information was insufficient for the
derivation of an inhalation RfC for either subchronic or chronic durations.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
SOLUBLE ANTIMONY COMPOUNDS
Weight-of-Evidence Descriptor
Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"inadequate information to assess carcinogenic potential" of soluble antimony salts. Available
studies have found no evidence of carcinogenic activity by soluble antimony compounds.
However, the available studies were of inadequate experimental design to draw any conclusions
from the results. In the lifetime oral studies of antimony in rats and mice reported by
Schroeder's group (Schroeder et al., 1968; Kanisawa and Schroeder, 1969; Schroeder et al.,
1970), there was no evidence of compound-related tumor formation when Long Evans rats and
CD mice were exposed in drinking water to a single concentration of potassium antimony tartrate
(providing 5 ppm antimony). Although some effects on survival were seen in the rats exposed to
antimony and some treatment-related reductions in body-weight gain were noted in the mice,
exposure to antimony appeared to have no effect on the formation of gross tumors detectable at
necropsy. These studies were limited by the use of a single dose level and use of gross necropsy
alone to monitor tumor formation. Some studies suggest that certain antimony compounds may
be clastogenic; however, compounds were generally negative in bacterial mutagenicity assays
(see Genotoxicity Studies above). Also, some studies suggest that antimony potassium tartrate
may induce apoptosis through caspase- and reactive oxygen species-dependent processes
(Lecureur et al., 2002a, 2002b; Huang et al., 1998). Soluble trivalent antimony compounds have
been shown to cause apoptosis in leukemia cells and are being investigated as a novel therapy in
the treatment of this disease (Wyllie and Fairlamb, 2006; Lecureur et al., 2002a, 2002b).
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A separate provisional toxicity value report is available for antimony trioxide, which was
found to have "suggestive evidence of the carcinogenic potential" by the inhalation route of
exposure, based on human and animal studies.
Quantitative Estimates of Carcinogenic Risk
There are no appropriate human or animal data from which to derive an oral slope factor
or inhalation unit risk for soluble antimony compounds.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2005. 2005 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
ACGIH, Cincinnati, OH.
Alvarez M., C.O. Malecot, F. Gannier, and J.M. Lignon. 2005. Antimony-induced
cardiomyopathy in guinea-pig and protection by L-carnitine. Br. J. Pharmacol. 144(1): 17-27.
Andrewes, P., K.T. Kitchin and K. Wallace. 2004. Plasmid DNA damage caused by stibine and
trimethylstibine. Toxicol. Appl. Pharm. 194:41-48.
Angrisani, M., E. Lampa, M. Lisa et al. 1988. Vasomotor reactivity and postnatal exposure to
antimony trichloride. Curr. Therap. Res. 43(1): 153-159.
ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Toxicological Profile for
Antimony. Review Draft. U.S. Public Health Service. Atlanta, GA. TP-91/02.
Brieger, H., C.W. Semish III, J. Stasney and D.A. Piatnek. 1954. Industrial antimony poisoning.
Ind. Med. Surg. 23:521-523.
Casto, B.C., J. Meyers and J.A. DiPaola. 1979. Enhancement of viral transformation for
evaluation of the carcinogenic or mutagenic potential of inorganic metal salts. Cancer. Res. 39:
193-198.
Gebel, T., P. Birkenkamp, S. Luther and H. Dunkelberg. 1998. Arsenic (III), but not antimony
(III), induces DNA-protein crosslinks. Anticanc. Res. 18:4253-4258.
Gurnani, N., A. Sharma and G. Talukder. 1992. Cytotoxic effects of antimony trichloride on
mice in vivo. Cytobios. 70:131-136.
Huang, H., S.C. Shu, J.H. Shih et al. 1998. Antimony trichloride induces DNA damage and
apoptosis in mammalian cells. Toxicology. 129:113-123.
18

-------
7-29-2008
IARC (International Agency for Research on Cancer). 1989. IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans, Vol 47, Some Organic Solvents, Resin Monomers
and Related Compounds, Pigments and Occupational Exposures in Paint Manufacture and
Painting. IARC, World Health Organization, Lyon, France.
Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagenicity studies on metal
compounds. Mutat. Res. 77:109-116.
Kanisawa, M. and H.A. Schroeder. 1969. Life term studies on the effect of trace elements on
spontaneous tumors in mice and rats. Cancer Res. 29:892-895.
Kuroda, K., G. Endo, A. Okamoto, Y.S. Yoo and S. Horiguchi. 1991. Genotoxicity of
beryllium, gallium and antimony in short-term assays. Mutat. Res. 264:163-170.
Lecureur, V., D. Lagadic-Gossmann and O. Fardel. 2002a. Potassium antimonyl tartrate
induces reactive oxygen species-related apoptosis in human myeloid leukemic HL60 cells. Int. J.
Oncol. 20:1071-1076.
Lecureur, V., A. Le Thiec, A. Le Meur et al. 2002b. Potassium antimonyl tartrate induces
caspase- and reactive oxygen species-dependent apoptosis in lymphoid tumoral cells. Brit. J.
Haematol. 119:608-615.
Marmo, E., M.G. Matera, R. Acampora et al. 1987. Prenatal and postnatal metal exposure:
Effect on vasomotor reactivity development of pups. Curr. Ther. Res. 42(5):823-838.
Miranda, E.S., N. Miekeley, R.R. De-Carvalho and F.J.R. Paumgartten. 2006. Developmental
toxicity of meglumine antimoniate and transplacental transfer of antimony in the rat. Reprod.
Toxicol. 21:292-300.
Nishioka, H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat. Res. 31:185-
189.
NTP (National Toxicology Program). 1992. Toxicity studies of antimony potassium tartrate in
F344/N rats and B6C3Fi mice. U.S. Department of Health and Human Services, Public Health
Service, National Institutes of Health. NIH Publication No. 92-3130.
Omura, M., A. Tanaka, M. Hirata and N. Inoue. 2002. Testicular toxicity evaluation of two
antimony compounds, antimony trioxide and antimony potassium tartrate, in rats and mice.
Environ. Health Prev. Med. 7:15-18.
Paton, G.R. and A.C. Allison. 1972. Chromosome damage in human cell cultures induced by
metal salts. Mutat. Res. 16:332-336.
Poon, R., I. Chu, P. Lecavalier et al. 1998. Effects of antimony on rats following 90-day
exposure via drinking water. Food Chem. Toxicol. 36: 21-35.
19

-------
7-29-2008
Rossi, F., R. Acampora, C. Vacca et al. 1987. Prenatal and postnatal antimony exposure in rats:
Effect on vasomotor reactivity development of pups. Teratog. Carcinog. Mutag. 7:491-496.
Schaumloeffel, N. and T. Gebel. 1998. Heterogeneity of the DNA damage provoked by
antimony and arsenic. Mutagenesis. 13(3):281-286.
Schroeder, H.A., M. Mitchener, J.L. Balassa, M. Kanisawa and A.P. Nason. 1968. Zirconium,
niobium, antimony and fluorine in mice: Effects on growth, survival and tissue levels. J. Nutr.
95: 95-101.
Schroeder, H.A., M. Mitchener and A.P. Nason. 1970. Zirconium, niobium, antimony,
vanadium and lead in rats: Life term studies. J. Nutr. 100: 59-68.
Takahashi, S., H. Sato, Y. Kubota et al. 2002. Inhibition of DNA-double strand break repair by
antimony compounds. Toxicology. 180:249-256.
Tu, A.S. and A. Sivak. 1984. Evaluation of antimony thioantimonate in three in vitro short-term
assays. NTIS AD-A150 348.
U.S. EPA. 1980. Ambient Water Quality Criteria for Antimony. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Water Regulations and Standards Division, Washington, DC.
EPA/440/5-80/020.
U.S. EPA. 1983. Antimony Metal, Antimony Trioxide and Antimony Sulfide: Response to the
Interagency Testing Committee. Federal Register. 48:717.
U.S. EPA. 1985. Health and Environmental Effects Profile for Antimony Oxides. Prepared by
the Environmental Criteria and Assessment Office, Office of Health and Environmental
Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC. EPA/600/X-85/271.
U.S. EPA. 1987. Health Effects Assessment for Antimony (and Compounds). Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.
EPA/600/8-88/018.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC.
U.S. EPA. 1992. Drinking Water Criteria Document for Antimony. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati OH for the Office of Drinking Water, Washington DC. PB92-173293.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC.
20

-------
7-29-2008
U.S. EPA. 1997. Health Effects Assessment Summary Tables. Annual FY 1997. Office of
Solid Waste and Emergency Response, Office of Emergency and Remedial Response,
Washington, DC.
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum,
Washington, DC. Available at http://www.epa.gov/cancerguidelines.
U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, D.C. EPA 822-R-06-013.
U.S. EPA. 2007. Integrated Risk Information System (IRIS). Online. Available at
http://www.epa.gov/iris.
Wyllie, S. and A.H. Fairlamb. 2006. Differential toxicity of antimonial compounds and their
effects on glutathione homeostasis in a human leukaemia monocyte cell line. Biochem.
Pharmacol. 71:257-267.
Zeiger, E., B. Anderson, B., S. Haworth, T. Lawlor and K. Mortelmans. 1992. Salmonella
mutagenicity tests: V. Results from the testing of 311 chemicals. Environ. Mol. Mutagen. 19
(Supp 21): 2-141.
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