TECHNICAL REPORT DATA
'(Pttase read Instruction* on the revene btfort completing]
1. REPORT NO.
EPA/600/8-88/055
3. RECIPIENT'S ACCESSION NO.
PB88-178926
4. TITLE AND SUBTITLE
6. REPORT DATE
Health Effects Assessment for Tin and Compounds
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
«. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME ANO ADDRESS
10. PROGRAM ELEMENT MO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT ANO PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
s. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS fTMspage)
Unclassified
22. PRICE
EPA Form 2220-1 (R«v. 4-77) PREVIOUS EDITION is OBSOLETE
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EPA/600/8-88/055
May, 1987
HEALTH EFFECTS ASSESSMENT
FOR TIN AND COMPOUNDS
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
#
This document has been reviewed 1n accordance wUh the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with tin and
compounds. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE and the CHEMFATE/OATALOG data bases. The basic literature searched
supporting this document 1s current up to May, 1986. Secondary sources of
Information have also been relied upon In the preparation of this report and
represent large-scale health assessment efforts that entail extensive peer
and Agency review. The following Office of Health and Environmental Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1979. Mini-Reviews on the Cardnogenldty, Mutagenlc-
Hy, Teratogen1c1ty and Chronic Toxlclty of Selected Compounds.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(s) addressed.
.»
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has"not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$Q)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
b> other routes 1s Insignificant.
111
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Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained 1n U.S.
EPA (1983).
For compounds for which there Is sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Several chronic and subchronlc oral studies have been performed with
several Inorganic salts of tin. No adverse effects were noted In rats or
mice fed diets containing 2000 ppm stannous chloride for 105 weeks 1n one
study (NTP, 1982). An RfD of 0.62 mg/kg/day (43.4 mg/day) was derived from
the NOEL In rats 1n the NTP (1982) study. This RfO Is supporte'd by evidence
Indicating that ordinary dietary levels of tin 1n humans consuming moderate
amounts of canned food range from 1-38 mg/day without adverse effects.
A CS of 28.7 was calculated based on hlstologlcal effects 1n livers and
kidneys of rats treated with 5 ppm tin as stannous chloride In the drinking
water for life (Schroeder et al., 1968).
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Oacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral. .
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS...'. .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS.
CARCINOGENICITY .
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA ....
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDci)
Paqe
. . . 1
. . . 4
. . . 4
. . . 4
. . . 5
. . . 5
. . . 5
. . . 10
. . . 10
. . . 10
. . . 12
. . . 12
. . . 12
. . . 12
. . . 12
. . . 13
. . . 13
. . . 13
. . . 13
. . . 14
. . . 15
. . . 15
. . . 16
. . . 17
, . . 17
. . . 17
. . . 18
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RfO) 18
6.2.1. Oral (RfD0) 18
6.2.2. Inhalation (RfOi) 20
6.3. CARCINOGENIC POTENCY (q-|*) 21
6.3.1. Oral 21
6.3.2. Inhalation 21
7. REFERENCES 22
APPENDIX: Summary Table for Tin and Compounds 30
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LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
CS Composite score
DNA Oeoxyrlbonuclelc add
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfD Reference dose
RfOj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD§i Subchronlc Inhalation reference dose
RfD$0 Subchronlc oral reference dose
RVj Dose-rating value
RVe Effect-rating value
TLV Threshold limit value
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Tin Is a metallic element that belongs to Group IV A of the periodic
table. Tin occurs In the earth's crust as nine different minerals. The
most commercially significant ores of tin are cassHeMte (SnO_) and the
complex sulfldlc ores.
Tin with a valence of +2 and +4 forms stannous [I.e., tin (II)]
compounds and stannic [I.e., tin (IV)] compounds. Types of tin compounds
Include those that contain tin (II) and tin (IV) compounds, complex stan-
nltes (HSnX_) and stannates (M.SnX,), coordination complexes, organic
J e. 0
tin salts where the tin Is not bonded through carbon, and organotln
compounds, which contain ohe-to-four carbon atoms bonded directly to tin
(G1tl1t2 and Moran, 1983).
Physical properties of tin and some of Us compounds are listed In
Table 1-1.
The most environmentally Important processes for the degradation of
organotln compounds are probably photodegradatlon with sunlight and
mlcroblal degradation. At the levels that organotln compounds are found 1n
the environment, they will eventually be converted to oxides or hydroxides,
carbonates or hydrated cations (Blunden and Chapman, 1982). The rate of
removal of aliphatic groups from tin compounds reportedly decreases with
Increasing size of the group, and unsaturated and aromatic groups are
cleaved more rapidly (Strand, 1983). In air, tin Is commonly found asso-
ciated with dust particles (Bleler, 1984). The deposition half-life Is
usually on the order of days for dust particles, depending upon the particle
size and characteristics (Nrlagu, 1979). Detection of methyl tins In
rainwater (Strand, 1983) Indicates that these compounds may be removed by
0106h -1- 10/27/86
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wet deposition and the volatile organotln compounds may transport long
distances. In water, tin has been observed to partition Into sediments and
bloconcentrate 1n aquatic organisms (Strand, 1983). Stannous compounds are
unstable In dilute aqueous solution.
Above pH 6, stannous solutions oxidize very rapidly. The chemistry of
tin (IV) compounds Is substantially different. They are stable In solution
(Banks, 1969). Environmental methylatlon of tin may explain the presence of
methyl tin compounds 1n natural water and sediment samples (Rapsoman1k1s and
Weber, 1985). Methylatlon may result 1n the formation of volatile tetra-
methyl tin [vapor pressure 100 mm Hg at 23°C (Perry and Green, 1984], which
may account for the worldwide occurrence of methyl tin compounds (Rapso-
manlkls and Weber, 1985).
Information regarding the environmental chemistry and fate of tin and
Us compounds 1n soil could not be located 1n the available literature.
0106h -3- 10/27/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
In general, tin compounds are not absorbed well from the gastrointesti-
nal tract. Volunteers 1n a balance experiment given diets containing 0.11
or 49.67 mg tin (as stannous chloride) dally for 20 days appeared to absorb
50 and 3% of the tin, respectively, as estimated from dietary and fecal tin
recovery (Johnson and Greger, 1982). Using tin 113 (a gamma emitter), Hlles
(1974) demonstrated that female rats absorbed 2.85 and 0.64X of a single
oral dose (20 mg) of either Sn (II) or Sn (IV), respectively. These
estimates were based on recovery of radioactivity In the urine and several
tissues 48 hours after treatment. Tin compounds tested Included tin (II or
IV) fluoride, tin (II or IV) citrate, and tin (II) pyrophosphate. Kutzner
and Brode (1971) reported that rats and rabbits absorbed <2% of orally
administered tin from stannous chloride. Kojlma et al. (1978) demonstrated
that dtrlc acid or other organic adds can Increase the absorption of tin
from the gastrointestinal tract of rats.
2.2. INHALATION
Schafer and Femfert (1984) reported that data regarding the absorption
of Inhaled Inorganic tin are limited. There have been reports of the devel-
opment of stannosls, a benign form of pneumoconlosls resulting from exposure
to dust or fumes of tin oxide (Pendergrass and Pryde, 1948; Bartak et al.,
1948; Cutter et al., 1949); however, upon examination of tissues from a man
with pneumoconlosls who had been exposed occupatlonally to stannic oxide,
Dundon and Hughes (1950) concluded that the amount of tin absorbed from the
lungs was Insignificant.
0106h -4- 02/04/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
Discussions of toxldty In this document are restricted to tin and Us
Inorganic salts and compounds. The manifestations of toxldty associated
with these compounds are similar and suggest that toxldty 1s due to the tin
moiety. There are a number of organotln compounds that will not be
discussed because they exhibit markedly different toxic effects, which are
not clearly associated with the tin moiety, but are more likely associated
with the organic compound per se (ACGIH, 1986).
3.1. SUBCHRONIC
3.1.1. Oral. DeGroot et al. (1972) fed various compounds of tin to
weanling Wlstar rats for either 4 or 13 weeks. Groups of 10 males and 10
females were fed diets containing 0, 0.03, 0.10, 0.30 or 1.0% of stannic
oxide, stannous oxide, stannous orthophosphate, stannous oxalate, stannous
sulflde, stannous chloride, stannous sulfate, stannous oleate or stannous
tartrate for 28 days. Additional groups of 10 males and 10 females were fed
either stannous chloride or stannous oxide 1n the diet at the levels pre-
viously mentioned for 90 days. Endpolnts monitored Included mortality,
growth, food consumption and utilization, hematology, urinalysis, serum
biochemistries, and gross and microscopic pathology. No compound-related
adverse effects were observed among rats fed stannic oxide, stannous sulflde
or stannous oleate for 4 weeks. Anemia and reductions In growth, food
consumption and food use efficiency were observed, however, among rats fed
either 0.3 or 1% of stannous chloride, orthophosphate, sulfate, oxalate or
tartrate; microscopic evidence of liver damage (homogeneous liver cell
cytoplasm; slight but definite oval cell type hyperplasla of bile ducts)
also was observed 1n males and females fed 1.0% of the same compounds.
0106h -5- 02/04/87
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Similar hepatic changes, though of lesser Intensity and frequency, were
observed among rats fed 0.3% stannous chloride, stannous oxalate or stannous
orthophosphate. Females given stannous orthophosphate had a dose-related
Increase 1n relative liver weight at >0.1%.
No compound-related adverse effects were observed among rats fed stan-
nous oxide for 13 weeks. In the 13-week study with stannous chloride, rats
fed 1.0% were killed after 8 weeks on test because of high mortality.
Necropsy of these rats revealed anemia, distinct liver changes (described
above), severe pancreatic atrophy, enteritis, moderate testlcular degenera-
tion, "a spongy state of the white matter of the brain" and acute broncho-
pneumonia. DeGroot et al. (1972) speculated that some of these changes were
due to starvation. Poor appetite and reduced growth were also observed
among rats fed 0.3% stannous chloride, but these changes were observed only
for the first 2 weeks. Thereafter, growth and food consumption among rats
fed 0.3% were similar to controls. Slight anemia (males only) and liver
changes (described above) were also observed among rats fed 0.3%. No
compound-related adverse effects were observed among rats fed 0.03 or 0.1%
stannous chloride for 13 weeks. DeGroot et al. (1972) concluded that 0.1%
of tin compounds 1n the diet (22-33 mg of tln/kg/day; estimated by Investi-
gators) was a "no-effect-level."
FrHsch et al. (1977) fed groups of 10 male Sprague-Dawley rats either 0
or 0.5 g tin/100 g (50 ppm) food for 1 month. Stannous chloride was the
source of tin. Tin-fed rats had decreased food consumption and growth,
marked anemia and marked gastrointestinal Irritation.
Dreef-Van Der Meulen et al. (1974) fed groups of 10 male and 10 female
weanling Wlstar rats diets containing up to 0.8% stannous chloride for 13
weeks. Animals of the test group were accustomed to the Ingestlon of the
0106h -6- 02/04/87
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tin by Increasing the dietary level from 0.1% In week 1 with weekly Incre-
ments of 0.1% to a final level of 0.8% (TWA equivalent Intake of 246 mg
tln/kg/day). Controls were maintained on the basal diet. During the first
weeks of the experiment (1-4) when tin levels were low, no distinct differ-
ences occurred between test and control groups. Effects attributed to
stannous chloride Included slight reduction 1n growth {males only), slight
anemia, Increased relative liver and kidney weights, gastrointestinal Irri-
tation, hlstologlc changes In the liver and pancreatic atrophy. Decreased
serum alkaline phosphatase activity, Increased relative weights of the
heart, adrenals and thyroid, and activated appearance of thyroid follicles
were observed among rats fed stannous chloride, but these effects were
considered to be of questionable toxlcologlcal significance.
Janssen et al. (1985) demonstrated that tin-Induced changes 1n the
gastrointestinal tract are Independent of food Intake. Groups of 10 male
Wlstar rats were fed 0, 250 or 500 ppm tin (from stannous chloride) for 4
weeks. A fourth group was pair-fed with the 500 ppm tin group. In a second
study, groups of four male Wlstar rats were fed either 0 or 900 ppm tin
(from stannous chloride) for 4 weeks. Dose-related decreases 1n body
weight, food consumption, and food utilization were observed 1n all tin-fed
groups and 1n the reduced Intake (pair-fed) group. The growth reduction 1n
the pair-fed group was comparable with the 500 ppm tin-fed group. Hemo-
globin concentrations were also reduced 1n tin-fed rats. Increased relative
weights of the stomach, cecum and colon appeared to be caused by the
decrease In body weight, due either to food restriction or to tin feeding.
Increased relative weight of small Intestine was In part caused by decreased
body weight. Comparison of the reduced-diet group and the 500 ppm group
suggested that tin feeding resulted 1n Increased absolute weights of the
0106h -7- 02/04/87
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small Intestine. Changes Indicative of Increased cell turnover (Increased
migration of epithelial cells along the flllus, formation of ridge-like
v1ll1, decreased number of v1H1 per unit surface) were observed 1n the
small Intestines of rats fed tin.
OeGroot (1973) examined the effects of dietary Iron and copper on the
hematologlcal and growth changes caused by stannous chloride 1n a series of
4- to 6-week studies on weanling Wlstar rats. In a 6-week study, groups of
10 males and 10 females were fed 0 or 5300 ppm tin (from stannous chloride)
1n standard diets or In diets supplemented with copper or Iron or both.
Significant reduction 1n growth and hemoglobin levels were observed In rats
exposed to tin In the standard diets. Supplementary Iron (200 ppm) or
copper (75 ppm) or both retarded these effects. In a study where groups of
10 male rats were fed 0, 150, t500 or 1500 ppm tin wHh or without high
levels of copper and Iron (10 times the required amount), there were no
effects on hemoglobin, serum Iron or Iron-binding capacity; the only effect
was decreased growth 1n rats In the two higher dose groups. In another
4-week study, groups of 10 males and 10 females were fed 0, 50, 150 or 500
ppm tin (from stannous chloride) 1n diets that were adequate In copper and
either marginally adequate or high 1n Iron. Decreased growth, food consump-
tion and efficiency, hemoglobin and serum Iron were observed among rats fed
500 ppm, regardless of the Iron content of the diet; however, these effects
were more severe among rats fed the diet with marginal Iron content.
Decreased Iron binding capacity was observed among rats fed 500 ppm tin 1n
the diet with marginal Iron content. Among rats fed 150 ppm tin, the only
effects were reduced hemoglobin 1n males (both levels of Iron) and reduced
body weight In females (high Iron only). No effects on growth or the blood
were observed 1n rats fed 50 ppm tin with any level of Iron 1n the diet. In
0106h -8- 02/04/87
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another study, groups of 10 male and 10 female rats were fed either 0 or 150
ppm tin In diets adequate In Iron with three different levels of copper for
4 weeks. A decrease 1n hemoglobin and serum Iron levels was observed In
rats fed tin and 3 ppm copper and 1n males fed tin with 6 ppm copper, but
not 1n females fed tin and either 6 or 50 ppm copper or males fed tin with
50 ppm copper.
Yamaguchl et al. (1980) gavaged groups of six weanling male Wlstar rats
with 0, 0.3, 1.0 or 3.0 mg tin/kg every 12 hours for 90 days. Tin was
administered as stannous chloride In an HC1 solution. The variables evalu-
ated Included enzyme activities In the serum, liver, femur and kidneys, and
calcium content of the femur. Rats gavaged with 3.0 mg/kg had significant
decreases In relative weight of the femur, calcium content of the femoral
dlaphysls and eplphysls, calcium concentration, lactic dehydrogenase and
alkaline phosphatase activities In the serum, and succlnate dehydrogenase
activity 1n the liver. Significantly reduced sucdnlc hydrogenase activity
1n the liver and significant reductions 1n calcium content and add phospha-
tase activity 1n the femur were observed among rats gavaged with 1.0 mg/kg.
A slight but not significant decrease 1n the calcium content of the femoral
eplphysls was seen 1n rats treated with 0.3 mg/kg. Yamaguchl et al. (1980)
considered 0.6 mg/kg/day (0.3 mg/kg, twice dally) to be the no-effect level.
Yamaguchl et al. (1981) conducted a study with weanling male Wlstar rats
to assess the effects of tin on bone. Groups of 10 rats were fed diets con-
taining 0, 10, 50, 100 or 250 ppm tin (from stannous chloride) for 90 days.
Significant decreases 1n serum calcium and Inorganic phosphate, and 1n
femoral calcium content and add phosphatase activity were observed 1n rats
fed 100 or 250 ppm. Rats fed 50 ppm tin had significantly reduced serum
calcium and femoral caldum. No effects were observed among rats fed 10 ppm.
0106h -9- 02/04/87
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Savolalnen and Valkonen (1986) Investigated the effects of stannous
chloride on brain and muscular chollnesterase In male Wlstar rats. Groups
of 30 male rats, averaging 0.365 kg In body weight, were given 0, 0.44 (100
mg/l), Ul (250 mg/l) or 2.22 mM (500 mg/l) stannous chloride
(SnCl_«2H_0) 1n drinking water for 1-18 weeks. Groups of five rats
were killed and examined after 1, 4, 8, 12, 15 and 18 weeks of treatment. A
significant Increase 1n brain acetylchollnesterase activity was observed 1n
the high-dose group after only 1 week of treatment. Dose-related and
significant Increases 1n both brain and muscle acetylchollnesterase activity
were observed among rats exposed to both 1.11 and 2.22 mM stannous chloride
after 18 weeks of treatment. Tin concentration 1n brain tissue rose
steadily over the experimental period.
3.1.2. Inhalation. Data pertaining to subchronlc Inhalation of tin
compounds could not be located In the available literature.
3.2. CHRONIC
3.2.1. Oral. No compound-related effects on growth, survival or hlsto-
loglcal appearance of tissues were observed among groups of F344 rats or
B6C3F1 mice (50/sex/spedes) fed either 1000 or 2000 ppm stannous chloride
In the diet for 105 weeks (NTP, 1982); however, male control mice had
significant lower survival than both low- and high-dose male mice (64, 84
and 90% of control, low- and high-dose males survived to the end of the
study).
Schroeder and Balassa (1967) gave 5 ppm tin as stannous chloride In the
drinking water to Charles River CO mice for life beginning at weaning.
Dietary tin concentration was 0.28 ppm. The treated gr^jp consisted of 54
males and 54 females. A group of 59 males and 79 females was maintained as
controls. There were no compound-related effects on growth,, mortality,
0106h -10- 02/04/87
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grossly examined tissues or hlstologlcally examined tissues from hearts,
lungs, kidneys, livers and spleens. Although stannous tin accumulated 1n
the spleen and to a lesser extent the heart, no compound-related toxldty
was observed.
Schroeder et al. (1968) gave 5 ppm tin as stannous chloride In the
drinking water to 56 male and 56 female Long Evans rats for life. The diet
contained 0.28 ppm tin. A group of 56 males and 76 females were maintained,
though because some experiments Involved "general anesthesia and blood
letting", some of the rats (-20) were not necropsled. Endpolnts evaluated
In the study Included mortality, growth, longevity, serum glucose, urinary
protein and glucose, gross pathology, and microscopic examination of liver,
kidney, lungs, heart and spleen. The mean Hfespan of females given tin was
significantly reduced 1n comparison with female controls. Tin-fed rats of
both sexes had Increased Incidences of fatty degeneration of the liver
(37/80 treated vs. 27/88 controls) and vacuolar changes 1n the proximal
convoluted tubules of the kidney (26/81 treated vs. 16/88 controls).
Roe et al. (1965) conducted an 80-week study with Inbred August hooded
rats, but Interpretation of the results 1s complicated by changes 1n dose
schedule and the presence of chronic murlne pneumonia 1n most of the rats
alive from 1 year to the end of the study. Nursing rats were fed diets
containing either no tin or 2% sodium chlorostannate from the time they gave
birth until their offspring were weaned. The weanlings were continued on
the test diets as follows. Rats whose dams were fed 2% sodium chlorostan-
nate (19 males and 18 females) showed no signs of toxldty at weaning, and
were fed 2% sodium chlorostannate In the diet for 7 weeks, the control diet
for 4 weeks, then continued on the test diet (2%) for the remainder of the
study. A group of 20 males and 20 females was maintained as controls. No
nonneoplastlc effects were observed 1n rats fed 2% sodium chlorostannate. •
0106h -11- 02/04/87
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3.2.2. Inhalation. Other than case reports of stannosls (see Chapter 2),
data pertaining to chronic Inhalation of tin could not be located 1n the
available literature.
3.3. TERAT06ENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. DeGroot et al. (1973) reported moderate testlcular degener-
ation In male Wlstar rats fed 1% stannous chloride 1n the diet for 8 weeks
(see Section 3.1.1.).
3.3.2. Inhalation. Data pertaining to the teratogenldty or reproductive
toxlclty of Inhaled compounds of tin could not be located 1n the available
literature.
3.4. TOXICANT INTERACTIONS
Tin affects the homeostasls of essential metals such as copper, Iron and
zinc. DeGroot (1973) and DeGroot et al. (1972) observed that the anemia and
growth retardation observed In rats fed t1n-fort1fled diets could be retard-
ed or Inhibited by Including high levels of copper or Iron (or both) In the
diet. Injection of tin and Iron Into jejunal loops from rats resulted 1n a
decreased absorption of water and Iron (Schafer and Forth, 1983). There was
no effect of tin on zinc uptake 1n humans when tin and zinc were given
together orally 1n ratios of 2:1, 4:1 or 8:1, but zinc uptake was Inhibited
when tin. Iron and zinc were administered 1n ratios of 1:1:1 and 2:1:1
(Solomons et al., 1983). Oral exposure to tin also changed the distribution
of copper, Iron and zinc In the organs (Greger and Johnson, 1981; Chm1eln1ka
et al., 1981; Dwlwedl et al., 1980; Chlba et al., 1984).
0106h -12- 02/04/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
Data pertaining to the carcinogenic potential of Inhaled or Ingested tin
1n humans could not be located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. NTP (1982) conducted a bloassay on stannous chloride with
F344 rats and B6C3F1 mice. Groups of 50 males and females of each species
were fed 0, 1000 or 2000 ppm stannous chloride In the diet for 105 weeks.
Growth and survival were comparable among all groups of controls and treated
animals, except that survival In male control mice was significantly less
than that In tin-fed male mice (64, 84 and 98% of the control, low- and
high-dose male mice survived to the end of the study). The Incidence of
C-cell adenomas but not carcinomas of the thyroid was significantly
Increased In treated male rats In comparison with matched controls (2/50,
9/49, 9/50 In control, low- and high-dose groups, respectively). The
combined Incidence of C-cell adenomas and carcinomas was significantly
elevated above that of the matched controls 1n both low- and high-dose male
rats (2/50, 13/49, 8/50 for controls, low- and high-dose groups, respec-
tively). When the combined Incidence of C-cell adenomas and carcinomas In
the treated groups are compared with historical controls, the Incidence 1n
the low-dose group remains significant but that In the high-dose group does
not. The historical control Incidence was 11.1% (32/288), 2.3% (8/288) and
8.3% (24/288) for combined adenoma or carcinoma, carcinoma and adenoma,
respectively. Since the Incidence of C-cell carcinomas or adenomas was not
significantly elevated In the high-dose group In comparison with historical
controls, and since the Incidence of C-cell hyperplasla did not differ among
control and treated male rats (control, 1/50; low dose, 1/49; high dose,
0106h -13- 10/27/86
-------
2/50), NTP (1982) concluded that stannous chloride did not cause thyroid
tumors In either sex of either species. NTP (1982) concluded that stannous
chloride 1s not carcinogenic to either F344 rats or B6C3F1 mice.
NTP (1982) reported that 2-year oral studies conducted by Schroeder et
al. (1968) on Long Evans rats and Schroeder and Balassa (1967) on Charles
River mice were Inadequate to assess the carc1nogen1c1ty of stannous
chloride since only low levels of compound were tested (0.28 ppm In feed and
5 ppm 1n water) and since hlstopathologlcal examination was limited to
selected tissues. These studies concluded that stannous chloride was not
carcinogenic.
Innes et al. (1969) failed to observe an Increased Incidence of tumors
1n mice given trlphenyltln acetate by gavage and 1n the diet for 18 months.
Roe et al. (1965) tentatively concluded that diets containing 2% sodium
chlorostannate or 0.5-1% stannous 2-ethyl hexoate were not carcinogenic to
Inbred August hooded rats (see Section 3.2.1.). Three malignant tumors
(mammary adenocardnoma, uterine pleomorphlc sarcoma, adenocardmoma In the
jaw) were observed among 30 rats fed 2% sodium chloroastannate. No neo-
plasms were observed among 30 controls or among rats that survived for >1
year on a diet that contained 0.5-1.0% stannous 2-ethyl hexoate. Inter-
pretation of the results of this study, however, are complicated by changes
In dose schedule and by the presence of chronic murlne pneumonia In most of
the rats 1n the study.
4.2.2. Inhalation. Data pertaining to the carcinogenic potential of
Inhaled tin could not be located In the available literature.
Q106h -14- 02/04/87
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4.3. OTHER RELEVANT DATA
McLean et al. (1983) demonstrated that tin (II) from stannous chloride,
but not tin (IV) from stannic chloride caused alkaline sucrose gradient
detectable damage to DNA In Chinese hamster ovary cells. Stannous chloride,
stannic chloride and sodium stannate did not Induce mutations In repair-
deficient strains of Badlus subtnis (N1sh1oka, 1975). Tr1phenylt1n
acetate and trlphenyltln hydroxide did not Induce mutations 1n oral dominant
lethal studies on mice (Epstein et al., 1972).
4.4. WEIGHT OF EVIDENCE
Based on the negative results of the NTP (1982) bloassay 1n both rats
and mice, stannous chloride can be classified 1n IARC Group 3 or U.S. EPA
Group D, I.e., Inadequate evidence to refute or demonstrate a carcinogenic
potential U.S. EPA (1986) Guidelines for Carcinogen Risk Assessment. While
the NTP (1982) concluded that Us rat and mice studies did not show a
carcinogenic response, this conclusion has some weaknesses. Other bloassays
while flawed are not adequate for further evaluation either. The Inhalation
route has not been evaluated and DNA damage has been shown 1n one test.
These factors combined make the available evidence Inadequate to either
demonstrate or refute a carcinogenic potential for stannous chloride 1n
humans. Since other compounds of tin have not been tested for carcinogenic
potential, tin In general should be classified In U.S. EPA Group D, I.e.,
not classified as to the human carcinogenic potential
0106h -15- 04/29/87
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5. REGULATORY STANDARDS AND CRITERIA
OSHA (1985) and ACGIH (1986) recommended a TLV of 2 mg/m3 for occupa-
tional exposure to Inorganic compounds of tin except stannate (SnH.).
ACGIH (1986) stated that the recommended TLV 1s designed to protect against
stannosls.
0106h -16- 02/04/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfDcn). Although several subchronlc studies with
oU
Inorganic tin have been performed DeGroot et al., 1972; Dreef-Van Der
Meulen, 1974; Yamaguchl et al., 1980, 1981; Janssen, 1985; Savolalnen and
Valkonen, 1986), only the studies by DeGroot et al. (1972) and Savolalnen
and Valkonen (1986) are sufficient for risk assessment. In the study by
Savolalnen and Valkonen (1986), male Wlstar rats (6/group) were given either
0, 100, 250 or 500 mg/l (0, 8.3, 20.8 or 41.6 mg tln/kg/day) stannous
chloride In their drinking water for 18 weeks. Tin exposure resulted 1n a
dose-related Increase 1n brain and muscle acetylchollnesterase activity at
the two highest doses. There was no effect on brain or muscle acetyl-
chollnesterase activity at the low dose. Weight gain of the exposed rats
did not differ from controls at any exposure level. No other parameters
were measured. The actual tin content of the food or water (before addition
of SnCl-) was not measured. A NOEL of 100 mg/l (8.3 mg tln/kg/day) and
a LOAEL of 250 mg/l (20.8 mg/kg/day) were defined 1n this study.
DeGroot et al. (1972) fed stannous oxide or stannous chloride to groups
of 10 male and 10 female Wlstar rats at dietary levels of 0, 0.03, 0.1, 0.3
and 1.0% for 90 days. Individual body weights, organ weights, serum
chemistry, haematology, urlnalysls and gross and microscopic pathology of
selected organs were measured. The feeding of stannous oxide at various
dietary levels up to 1.0% did not result In any significant changes 1n any
of the parameters examined. Rats fed diets containing 1% stannous chloride
showed growth retardation within the first 2 weeks of exposure. Growth was
completely stopped by week 4 1n males and In females after week 6. Slight
anemia, reduced testes weight and liver pathology were observed among rats
0106h -17- 05/14/87
-------
fed 0.3% stannous chloride. No compound-related effects were observed among
rats fed 0.03 or 0.1% stannous chloride for 13 weeks. The authors concluded
that the 0.1X dose level (22-33 mg/kg/day estimated) was a NOEL.
Although the subchronlc studies by Savolalnen and Valkonen (1986) and
OeGroot et al. (1972) are sufficient for risk assessment, the RfOcn
wU
derived from either study (0.08 or 0.33 mg/kg/day) would be lower than the
value recommended for the RfDQ. Therefore, the RfDQ of Q.,62 mg/kg/day
or 43.4 mg/day 1s recommended for the
6.1.2. Inhalation (RfDSI). There were no data available on the effects
of tin Inhaled by animals. ACGIH (1986) has recommended TLV of 2 mg/m3 to
protect against stannosls. Since there are no appropriate data on the
Inhalation toxlclty of tin, an RfO-j cannot be derived.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDJ. Long-term oral animal studies (NTP, 1982;
Schroeder et al . , 1968) are available for the derivation of an RfDQ for
Inorganic tin. In the NTP (1982) study, groups of 50 F344 rats and B6C3F1
mice of each sex were fed diets containing 0, 1000 or 2000 ppm stannous
chloride for 105 weeks. No compound-related effects were observed on growth
rate, survival or hlstopathology of tissue at either dose level among
tin-fed mice or rats. In the second study (Schroeder et al., 1968),
Long-Evans rats (56/sex) were given 5 ppm tin In their drinking water for
life. Their diet contained 0.28 ppm tin. Mean Hfespan of tin-exposed
females was significantly reduced when compared with controls. Tin-exposed
rats of both sexes had Increased Incidences of fatty degeneration of the
liver and vacuolar changes 1n the kidney.
0106h -18- 05/15/87
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The risk assessment for oral exposure to tin 1s -complicated by several
factors. Studies of human dietary Intake of tin Indicate that 1f only fresh
meat, cereals and vegetables are eaten, an Individual Ingests 0.1-1.0 mg
tin/kg bw/day {Schroeder et al.t 1964; Upton et al., 1966). If, however,
moderate levels of canned fruit juices, fish and vegetables are eaten,
dietary Intake of tin may reach 38 mg/day (Tlpton et al., 1966; Plscator,
1979). Increasing the proportion of canned food 1n the diet may Increase
dietary Intakes to 500 ppm, equivalent to 14 mg/kg/day, assuming a food
factor for humans of 0.028 (U.S. EPA, 1985). An average dally human dietary
Intake of tin was calculated by Schroeder-, et al. (1964) to be 4 mg/day.
Illness 1n humans has not been associated with levels of Inorganic tin 1n
the diet of 1-38 mg/day (Lourla et al., 1972), but acute tin poisoning has
been associated with levels >1370 ppm In Individual food Hems (Schafer and
Femfert, 1984). A level of 250 mg of Inorganic tin/kg of canned food 1s
generally accepted as a maximum tolerance level.
An RfDQ of 38 mg/day or 0.54 mg/kg/day could be derived using the
human dietary Intake level for tin of 38 mg/day as a NOAEL. Assuming that a
large proportion of the population. Including subgroups are exposed to this
level, no uncertainty factor would be applied. However, because actual
exposure to this level 1s unknown, and because the effects of marginal
dietary deficiencies or marked excesses of other nutrients that may Interact
with tin have not been studied 1n humans and no long-term human studies are
available, an RfDQ based on dietary levels In humans would be Inappro-
priate.
An RfDQ could be derived based on the LOAEL of 0.7 mg/kg/day for liver
degeneration, vacuolatlon of renal tubules and decreased survival In rats
exposed to 5 ppm tin 1n their drinking water and 0.28 ppm diet (Schroeder et
0106h -19- 05/14/87
-------
al., 1968). The application of an uncertainty factor of 1000 (TOO to
account for 1ntra- and 1nterspec1es extrapolation and 10 for the use of a
LOAEL) to the LOAEL would result In an RfDQ of 0.0007 mg/kg/day or 0.049
mg/day for a 70 kg human. This RfDQ 1s questionable as only one dose
level was used In the study and several subchronlc and chronic studies
suggest NOEL and NOAELs at much higher levels In rats, mice and humans.
Using the NOEL of 2000 ppm (62 mg/kg/day) for rats exposed to stannous
chloride 1n the diet for 2 years (NTP, 1982), an RfOQ of 0.62 mg/kg/day or
43.4 mg/day can be derived by the application of an uncertainty factor of
100. This RfDg 1s further supported by dietary tin Intake level of 0.54
mg/kg/day (38 mg/day) at which no adverse effects 1n humans have been
associated.
It 1s possible to derive a CS for tin. The highest value, 28.7, Is
derived from the study of Schroeder et al. (1968) on the basis of fatty
degeneration of the liver, vacuollzatlon of the renal tubules and decreased
longevity 1n female Long-Evans rats given 5 ppm tin In drinking water (0.7
mg/kg/day) for life. An RV of 7 was assigned on the basis of these
effects. A higher RV was not assigned for decreased longevity since this
effect was not reported 1n rats or mice exposed to 2000 ppm stannous
chloride 1n the diet for 105 weeks (NTP, 1982). An MED of 8.4 mg/day Is
derived by multiplying the animal dose, 0.7 mg/kg/day, by the product of the
cube root of the ratio of animal (0.35 kg) to human reference weight and the
human reference weight (70 kg). The MED of 8.4 mg/day corresponds to an
RVd of 4.1. Multiplying the RVd by the RVg yields a CS of 28.7.
6.2.2. Inhalation (RfD,). There were no data available on the Inhala-
tion of tin 1n animals; therefore, an RfD, for tin cannot be derived. A
TLV of 2 mg/m3 by ACGIH (1986) and OSHA (1985 has been recommended.
0106h -20- 05/15/87
-------
ACGIH (1986) did not report how this particular level of exposure was
determined, but 1t Is Intended to be protective of stannosls.
6.3. CARCINOGENIC POTENCY
6.3.1. Oral. Since compounds of tin have Inadequate evidence from which
to assess the human carcinogenic potential (NTP, 1982; Innes et al., 1969),
no potency factor 1s derived.
6.3.2. Inhalation. Since there were no data available on the carcino-
genic potential of Inhaled tin, no potency factor 1s derived.
0106h -21- 05/15/87
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