TIN AND STANNOUS CHLORIDE
Explanation
Tin was previously evaluated for tolerable intake for man by
the Joint FAO/WHO Expert Committee on Food Additives in 1966, 1970,
1971, 1975 and 1978 (see Annex I, Refs. 12, 22, 26, 37 and 48).
Toxicological monographs were prepared in 1971 and 1978 (see Annex I,
Refs. 27 and 49).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
Introduction
To date the role of tin as an essential trace metal has not been
firmly established although there is some evidence that it may be
essential in the rat. Concentrations of tin in most foods are
usually less than 1 part per million (ppm), whereas in canned foods,
especially those with an acidic pH, considerably higher levels, e.g.,
100-500 ppm (0.01-0.05%) or more may be found. Various estimates of
dietary tin intake have been reported ranging from about 200 µg/day
(Hamilton et al., 1972) to 5.8-8.8 mg/day (Tipton et al., 1969).
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Results from a number of studies in both humans and several
animal species show that ingested inorganic tin is poorly absorbed and
is excreted mainly in the faeces with additional slow elimination in
the urine (Browning, 1969). Administration of 2 mg tin daily to rats
in their drinking-water was followed by 99% excretion in the faeces
(Flinn & Inouye, 1928). More than 90% of tin tartrate was excreted in
the faeces (Schryver, 1909). Three rats given fruit juice containing
540 ppm (0.054%) tin at dosages of 5.4 mg tin/rat excreted 99% of the
ingested tin in their faeces but none in their urine. Only minute
traces remained in the body after 7-36 days (Benoy et al., 1971).
Ninety-six per cent. of a single oral dose of 12 mg tin citrate
administered to 6 rats was recovered from their faeces, none appearing
in the urine. Groups of 2-5 cats ingesting fruit juice containing
730-2000 ppm (0.073-0.2%) tin (3.65-20 mg tin/kg bw) did not excrete
any tin in their urine (Benoy et al., 1971).
The effect of anion complement and oxidation state on
gastrointestinal absorption of inorganic tin in the rat was studied by
Hiles (1974). Following a 24-hour fast, 200-225 g rats were given
(per os) a single 20 mg Sn/kg bw dose of Sn(+2)-citrate, -fluoride
or -pyrophosphate or Sn(+4)-citrate or -fluoride. Changing the anion
complement from the citrate to the fluoride did not alter the
biological fate of either valency form, while approximately 2.85% and
0.64%, respectively, of the Sn+2 and Sn+4 were absorbed. Within 48
hours post-dosing, Hiles reported that about 50% of the absorbed tin
was excreted. When expressed as a percentage of the administered dose,
tissue distributions for Sn+2 and Sn+4, respectively, were skeleton,
1.02 and 0.24%; liver, 0.08 and 0.02%; and kidneys, 0.09 and 0.02%.
With pyrophosphate as the anion, absorption of Sn+2 was significantly
lower than with the citrate or fluoride, an observation which Hiles
ascribed to the greater tendency of pyrophosphate to form insoluble
complexes with tin as compared to the citrate or fluoride.
In a more recent study, Fritsch et al., (1976) also reported that
gastrointestinal absorption of tin by the rat is extremely low. In
that study, groups of 8 male rats weighing approximately 250 g were
fasted for 17 hours after which a 50 mg/kg bw dose of Sn113Cl2
(0.5 µCi/mg tin) was administered by gavage in either: (1) water; (2)
sucrose at 5 g/kg bw; (3) ascorbic acid at 0.5 g/kg bw; (4) potassium
nitrate at 0.1 g/kg bw; (5) a mixture of all 3 compounds; (6) 20%
alcohol solution; (7) a solution of albumin at 2.5 g/kg bw; or (8) 1:1
(v/v) sunflower oil - 1% Tween 20 emulsion at 10 ml/kg bw. Rats were
placed in metabolic cages, fasted for another 6 hours and then
received a basal diet ad libitum. Urine and faeces were collected
from 0 to 24 and 24 to 48 hours. Animals were then sacrificed and
excreta and selected organs and tissues analysed for radioactivity. In
all groups, 90-99% of the administered dose was excreted in the faeces
within 48 hours. Only traces of Sn113 were detected in the urine and
the organs and tissues examined.
The possible relationship between the degree of solubility of
inorganic tin compounds and their absorption from the gut has been
studied by a number of investigators. Goss (1917a,b) showed that a
large portion (37-82%) of the tin in a variety of canned vegetables
and fruits (beets, beans, tomatoes, cherries, etc.) existed as
insoluble (non-dialysable) complexes which were resistant to simulated
gastric digestion. Heintzke (1959, 1960) reported that tin in canned
products is most likely chelated by polyphenolic compounds and
proteins of the solid portion of canned fruits and vegetables. More
recently, Debost & Cheftel (1979) studied the distribution of tin in
green beans from detinned cans and in tin-free green bean purée
incubated under nitrogen with stannous citrate. Results indicated that
stannous ions were strongly bound to insoluble bean constituents other
than by electrostatic attraction or physical adsorption. In such a
complex form, tin is rather resistant to liberation as free tin ions
by the action of gastrointestinal secretions (Horio et al., 1970).
However, the presence of nitrate in canned products has been shown to
increase the amount of tin being dissolved from the container (Horio
et al., 1967; Cheftel, 1967).
Tin is widely distributed in tissues following parenteral
injection, especially in the liver and spleen where it deposits in the
reticuloendothial system (RES), most of it being excreted eventually
in the urine and a limited amount in the bile (Barnes & Stoner, 1959).
Hiles (1974) has suggested that the liver utilizes both the RES and
the biliary system to remove systemic Sn+2 and only the RES for Sn+4
removal. Tin tends to be retained in the tongue, liver, kidneys, bones
and least in the brain, while rats and rabbits accumulate both
inorganic and organic tin in their skin and keratinized appendages
(Browning, 1969; Benoy et al., 1971). Twenty mice and 6 rats received
50 mg/kg bw tin citrate s.c., without tin appearing in the urine or
faeces. Five mice injected s.c. with 2 mg tin citrate showed only
traces in the kidney after 18 hours, the bulk remaining at the
injection site. Groups of 10 or 20 mice injected s.c. or i.v. with 0.1
or 0.2 ml of 1% tin citrate excreted no tin in their urine or faeces.
Tin solutions of up to 9950 ppm (0.995%) had no effect on the
peristaltic reflex of isolated guinea-pig ileum (Benoy et al., 1971).
Based on studies such as those by Theuer et al. (1971) and Hiles
(1974), it is generally accepted that only trace amounts of inorganic
tin will cross the placental barrier and that this placental transfer
is of little toxicological significance. A contradiction to this may
be found in a recent report by Chmielnicka et al. (1981), in which the
authors refer to unpublished data from their laboratory clearly
demonstrating that tin penetrates the placental barrier in the rat.
The authors state that "considerable concentrations of this metal were
noted in embryos of rats exposed to SnCl2".
Metabolism
The biological turnover of tin in tissues and organs has been
studied by a number of investigators. In the rat, a half-life of
between 34-40 days was estimated (Hiles, 1974) for inorganic tin in
bone (femur), while half-lives of 85 and 50 days were reported for tin
in liver and spleen, respectively (Marciniak, 1981). Using whole body
counter methodology, Brown et al. (1977) determined a biological half-
life of approximately 30 days for inorganic tin in the mouse.
TOXICOLOGICAL STUDIES
Special studies on the bioalkylation of tin
Concern for the possible bioalkylation of tin can be found in a
number of reports in which the bioalkylation of metals is discussed
(Ridley et al., 1977; Wood et al., 1978, 1979). In 1978, Dizikes et
al. reported on a mechanism by which inorganic tin could be
bioalkylated via reductive cobalt-carbon bond cleavage of
alkylcobalamins (e.g., methyl- and ethylcobalamin). Although such
reactions have not been reported in humans it is of interest to note
that Braman & Tompkins (1979) reported finding trace levels of
monomethyl and dimethyltin in urine specimens from humans with no
known exposure to either alkyl tin compound.
Special studies on carcinogenicity
Mouse
Groups of mice received 1000 or 5000 ppm (0.1 or 0.5%) tin as
sodium chlorostannate in drinking-water or 5000 ppm (0.5%) tin as
stannous oleate in their diet for a 1-year period. Upon terminal
sacrifice a lower incidence of malignant lymphoma, hepatoma and
pulmonary adenoma was observed in the tin-exposed animals when
compared to controls. No other toxic effects were found (Walters &
Roe, 1965).
Rat
Chronic studies were conducted with rats fed diets containing no
added tin (control), 2% sodium chlorostannate or 1% and then 0.5%
stannous 2-ethyl hexoate. Out of 30 rats (13 male, 17 female) that
survived for a year or more on the 2% chlorostannate diet, 3 malignant
tumours (1 an adenocarcinoma of mammary origin, 1 a pleomorphic
sarcoma in the uterus and 1 an adenocarcinoma in the region of the
jaw) were observed on terminal sacrifice. No neoplastic changes were
seen in the rats (11 male, 16 female) receiving the stannous 2-ethyl
hexoate diet or in control animals (16 male, 17 female). While the
appearance of 3 tumours in the chlorostannate group was believed to be
of a spontaneous nature and not in all probability of significance the
investigators cautioned that further experimentation with more animals
in each treatment group would be needed to resolve this matter (Roe et
al., 1965).
Gross and histological examinations were made on organs and
tissues from male and female rats following long-term retention of
i.v. injected stannic oxide. One to 4 injections were made over a
period of several weeks, with each injection delivering 250, 500, 750
or 1000 mg of tin oxide/kg bw. The rats survived 4-26 months after
injection with a mean survival time of 10 months. A total of 25
treated and 13 untreated rats were examined. There was no evidence of
fibrosis or neoplasia, or any reaction other than phagocytosis and
storage of the stannic oxide in the mononuclear cells of the
reticuloendothelial system (Fischer & Zimmerman, 1969).
Rabbit and dog
Male and female rabbits were given 1-5 injections (i.v.) of tin
oxide each at a dose of 250 mg/kg bw. Post-treatment survival ranged
from 6 to 26 months with a mean survival time of 19 months. Gross and
microscopic examination was made on tissues from 9 treated and 4
untreated animals. Three mongrel dogs received (i.v.) doses of stannic
oxide similar to those given to rabbits. The dogs were sacrificed 4-5
years later and tissues removed for examination. There was no evidence
of fibrosis or neoplastic change in any tin-containing tissue from
either the rabbit or dog. As in the rat, there was noticeable
phagocytosis and storage of tin in the reticuloendothelial system
(Fischer & Zimmerman, 1969).
Special studies on the essentiality of tin
Tin is present in small amounts in all human and animal organs.
The body of normal adult humans contains about 352 mg. Prior to the
studies of Schwarz et al. (1970), concern for tin focused mainly on
its potential toxicity in animals and humans. Under rigorous
experimental conditions, Schwarz and co-workers were able to
demonstrate enhanced growth in rats fed purified, tin-free diets
supplemented with 1-2 ppm (0.0001-0.0002%) tin. While a number of tin
compounds were effective, the greatest increase in growth, e.g.,
53-59% above controls, was observed when stannic sulfate
(Sn(SO4)2.2H2O) was used as the source of tin. Schwarz (1974)
postulated that tin may serve as the active site of metalloenzymes
(unspecified) involved in various physiological oxidation-reduction
reactions. Until further studies are conducted with other species and
in other laboratories, it remains uncertain whether tin plays any
essential physiological role in the body.
Special studies on interaction with "essential" dietary elements
Little is known about the biochemistry involved in the metabolism
of inorganic tin in the body or the exact mechanisms by which this
element affects physiological processes. It is known, however, that
tin interacts with a number of trace elements, many of which have
vital functions in the body. For example, during a life-time study,
approximately 500 rats of both sexes were offered a diet containing
0.28 ppm (0.000028%) tin and "doubly deionized" drinking-water
supplemented with 5 ppm (0.0005%) tin, as stannous chloride (Schroeder
& Nason, 1976). Post-morten analyses were conducted for a number of
elements in the liver, lung, heart, kidneys and spleen. Compared to
controls, 5 ppm (0.0005%) tin was shown to significantly increase
liver copper (P < 0.005) and zinc (P < 0.001). At considerably
higher dietary tin levels, e.g., 206 ppm (0.0206%) (as stannous
chloride), liver copper and zinc concentrations in the rat were
significantly lower (P < 0.05) when compared with control animals
receiving 1 ppm (0.0001%) dietary tin at the end of a 21-day feeding
period (Greger & Johnson, 1981). The test animals also had higher
(P < 0.05) concentrations of iron in their livers, while lower
(P < 0.05) levels of zinc and higher (P < 0.05) levels of tin were
found in their tibias and kidneys. Chmielnicka et al. (1981) also
reported "considerable disturbances" in zinc and copper metabolism due
to tin in the rat. Following a total of 7 s.c. injections of a
stannous chloride solution at a dose of 2 mg Sn/kg bw, administered
every other day, a 3-fold increase was observed in liver zinc in test
animals when compared to control rats. While not significant, there
were clear reductions in the zinc concentrations in kidneys and heart
tissues with significant (P < 0.01) decreases in zinc levels in the
lungs, spleen and brain of test animals. The test animals also showed
increased (P < 0.01) concentrations of copper in their livers but a
significant (P < 0.01) decrease in blood and brain copper levels.
In addition to its effects on copper, zinc and iron metabolism,
tin has also been shown to interact with calcium. Yamaguchi et al.
(1979) demonstrated an inhibitory effect of tin on the intestinal
absorption of calcium in rats orally dosed with stannous chloride
(30 mg Sn/kg bw, every 12 hours) during a 3-day period. There was a
significant (P < 0.01) increase in the tin content of the duodenal
mucosa in treated animals from 4.7 ± 0.27 to 11.5 ± 0.80 ppm
(0.00047 ± 0.000027 to 0.00115 ± 0.00008%), while calcium content
decreased from 37.7 ± 9.46 to 13.5 ± 1.39 ppm (0.00377 ± 0.000946 to
0.00135 ± 0.000139%). Calcium-binding activity as well as alkaline
phosphatase activity of the mucosa were also depressed (P < 0.01) in
the treated animals. These results were interpreted as evidence of an
inhibitory effect of tin on active transport of calcium in the
duodenum. An effect of tin on serum and kidney calcium concentrations
in the rat has also been reported (Yamamoto et al., 1976; Yamaguchi et
al., 1977). Male rats, each weighing about 120 g, received single i.p.
injections of tin as stannous or stannic chloride at dose levels
ranging from 2.5 to 30 mg Sn/kg bw. Calcium concentration in the
kidneys of treated rats increased in a dose-dependent manner with most
of the increase occurring in the renal cortex. This accumulation of
calcium in the kidneys was associated with a significant, dose-related
decrease in serum calcium levels. The valency form in which the tin
was administered did not have a significant effect on the results
(Yamamoto et al., 1976). By gavaging male rats with 30 mg Sn/kg bw at
12-hour intervals for 3 or 10 days, Yamaguchi (1980) also demonstrated
increased renal calcium concentrations with concurrent reductions in
serum calcium. Femoral calcium levels also fell while pancreas calcium
content was increased. Yamaguchi et al. (1977) proposed that the
observed increase in renal calcium levels in rats dosed with inorganic
tin is due to increased synthesis of a calcium-binding protein in the
renal cortex, which according to Pitorowski & Szymanska (1976) is not
metallothionein. In addition to the interactions, discussed above, tin
may well interact with a number of other essential elements as well as
toxic metals such as lead. The latter has been postulated by Vander et
al. (1979) based on an "in vitro" study on lead transport by renal
cortical and medullary tissues which indicated a shared renal
transport pathway between lead and tin. Confirmation of the
competition between these 2 elements awaits further study.
Tin metal itself, taken orally, is practically innocuous but
inhaled dust or fumes may cause benign symptomless pneumoconiosis. The
inorganic salts are caustic and of variable toxicity. On the other
hand, some alkyl and aryl derivatives are highly toxic. Inorganic tin
compounds and mixed colloidal tin and tin stearate have been used as
antistaphylococcal and anthelminthic agents (Kolmer et al., 1931).
Oral administration of 45 mg tin/kg bw was shown to induce
vomiting and diarrhoea in cats (Omori, 1966). In subsequent studies
with adult cats weighing 1.7-2.9 kg, Omori et al. (1973) reported that
administration of 10 ml/kg bw of orange juice containing 472 ppm
(0.0472%) tin resulted in vomiting in about 80% of the cats examined.
Oral administration of a tin complex prepared from stannic chloride
and sodium citrate was found to induce severe salivation and emesis in
all test animals at tin concentrations of 9 mg/kg bw or more. Benoy et
al. (1971) reported no adverse effects in pigeons orally dosed with
1.5-3.0 mg tin/kg bw in fruit juice or in groups of 6 rats after
single oral doses (5.4 mg tin/rat) of tin-containing fruit juices or
24-hour ad libitum ingestion of beverage at 65-190 mg tin/kg bw or
tin citrate at 36-300 mg tin/kg bw. Cats receiving stannous citrate by
gavage at a rate of 9 mg/kg bw showed salivation, vomiting and
diarrhoea, but no acute effects at neutral pH (Cheftel, 1967). Groups
of 11 cats received single doses of fruit beverages at 2.5-20 mg
tin/kg bw. Vomiting occurred at rates of 5.4 or more mg tin/kg bw.
Rabbits receiving a daily oral dose of 1 g stannous acetate or
tartrate daily for 10 days died in 37-43 days (Cheftel, 1967). Groups
of 4 dogs received single doses of beverages at rates of 2.5 to 14 mg
tin/kg bw or solid foods at rates of 4.5-8.0 mg tin/kg bw without
vomiting or showing signs of toxicity (Benoy et al., 1971).
The acute toxicity of sodium pentafluorostannite in mice and rats
was investigated by Conine et al. (1975). The oral LD50 values for
male mice and rats, under fed conditions, were 592.9 mg/kg bw and
573.1 mg/kg bw, respectively. Following a 16-18-hour fasting period,
the oral LD50 doses for male and female rats were 223.1 mg/kg bw and
218.7 mg/kg bw, respectively. Symptoms accompanying toxic doses
included ataxia, depression and muscular weakness.
Acute toxicity
LD50
Compound Animal Route (mg/kg bw) Reference
Sodium tin citrate Mouse Oral 2 700 Ministry of Health and
Welfare, Japan, 1969
Tin-citric acid Mouse Oral 2 700 Omori et al., 1973
complex (29.5% Sn) (male)
Sodium Mouse Oral 593 Conine et al., 1975
pentafluorostannite (male)
(66.8% Sn)
Rat Oral 219 Conine et al., 1975
(fasted, female)
Rat Oral 223 Conine et al., 1975
(fasted, male)
Rat Oral 573 Conine et al., 1975
(fed, male)
Short-term studies
Rat
Groups of rats were fed diets containing 0 (control), 0.03, 0.1,
0.3 or 1.0% of various salts or oxides of tin for 28 days. Parameters
studied included mortality, appearance and behaviour, food intake,
body weight change, blood and urine chemistries, organ weights and
gross as well as micropathology of tissues. There were no adverse
changes in any of these parameters in rats fed stannous sulfide,
stannous oleate or stannous or stannic oxides, even at dietary levels
up to 1.0%. The innocuous nature of insoluble tin compounds such as
stannous oxide was also readily apparent in a longer-term, 13-week
feeding trial. In the case of the more soluble tin salts ingestion of
tin for 4 weeks as the chloride, orthophosphate, sulfate, oxalate or
tartrate at dietary levels of 0.3% and 1.0%, resulted in depressed
food intake, poor growth, anaemia and histological evidence of liver
damage (e.g., atypical homogenous liver cell cytoplasm and hyperplasia
of the bile duct epithelium) in both male and female rats. The hepatic
changes occurred more frequently and to a greater extent in the 1.0%
treatment groups, especially in those fed stannous chloride, stannous
oxalate or stannous orthophosphate (De Groot et al., 1973a, b). Based
on this 4-week study, the authors determined an oral no-effect level
for the active tin salts to be 0.1% or about 22-33 mg tin/kg bw per
day in diets containing adequate iron. The no-effect level could be
lower in those instances where dietary iron levels were marginal. In
subsequent studies with the rat, De Groot (1973, 1976) confirmed the
greater toxicity of the soluble tin compounds as well as the
ameliorating effect of supplemental dietary iron and copper on the
activity of such compounds, especially with respect to haematological
changes.
STANNOUS CHLORIDE
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Effects on enzymes and other biochemical parameters
A number of non-fatal, acute changes in physiological and
biochemical processes due to the administration of stannous chloride
have also been reported. A significant, dose-dependent reduction in
both volume and total acidity of gastric secretion was observed in
male rats following single i.p. injections of 15 or 30 mg tin/kg bw. A
concurrent reduction in serum calcium levels was also noted (Yamaguchi
et al., 1976, 1978). These investigators suggested that rather than a
direct effect on the gastric secretory cells, tin may interfere with
the neurological events involved in gastric secretion and/or in the
release of gastrin from the G cells of the stomach.
In 1976, Kappas & Maines reported on the potential toxicological
consequences of tin-induced alterations in tissue enzyme chemistries.
Tissue homogenates and microsomal fractions were prepared from various
organs removed from freshly killed male rats that 16 hours prior to
sacrifice had received single s.c. injections of stannous chloride
solution at doses ranging from 5.6 to 56.4 mg/kg bw. A number of
parameters of haeme metabolism were examined including delta
aminolevulinate (ALA) synthetase, haeme oxygenase, as well as
cytochrome P-450 dependent ethylmorphine demethylase and microsomal
cytochrome P-450 content. A 3-fold increase in haeme oxygenase
activity was observed in the liver as well as a 30% decrease in P-450
mediated drug metabolism and microsomal content of cytochrome P-450.
The ALA synthetase activity was not significantly altered. A striking
as well as consistent 20-30-fold increase in haeme oxygenase activity
was found in renal tissue at a treatment level of 56.4 mg stannous
chloride/kg bw, together with a 50% reduction in microsomal content of
cytochrome P-450. This effect of tin on renal haeme oxygenase activity
was dose related and, even at the lowest test dose of 5.6 mg/kg bw, a
6-fold increase in haeme oxidation activity was noted.
Reduced serum calcium levels and linear increases in bile calcium
content were observed in rats receiving single oral doses of 10, 30 or
50 mg tin/kg bw. The augmented bile calcium content was not due to any
increase in hepatic calcium levels (Yamaguchi & Yamamoto, 1978). In
another study, in which rats were orally dosed with 30 mg tin/kg bw
every 12 hours for either 3 or 10 days, Yamaguchi (1980) reported
significant decreases in serum and femoral calcium levels. After the
10-day dosing period, there were significant increases in renal and
pancreatic tissue calcium content, but no change in liver, spleen,
heart or lung calcium values. When rats were orally dosed (every 12
hours) for 3 consecutive days with 1, 3, 10 or 30 mg tin/kg bw, dose-
related decreases occurred in duodenal alkaline phosphatase and liver
phosphorylase activities with significant decreases at the 2 highest
doses. Femoral calcium levels were also reduced in a dose-related
manner. Under these experimental conditions and based on the observed
results, it was suggested that the critical organ in the non-fatal
acute toxicity of inorganic tin is bone and that an oral no-effect
dose is 3 mg tin/kg bw (Yamaguchi et al., 1980 a,b).
The activity of acid phosphatase in the femur of rats was
increased by oral administration of stannous chloride solution
(Yamaguchi & Okada, 1979).
TOXICOLOGICAL STUDIES
Special study on the effect of tin on bone strength
The effects of tin, as stannous chloride, on the mechanical
strength of bone was investigated in the rat during a 4-week study
(Ogoshi et al., 1981). Groups of 22-30 male weanling rats were exposed
to 0 (controls), 50, 150, 300 or 600 ppm (0, 0.005, 0.015, 0.03 or
0.06%) tin in their drinking-water. The commercial rat chow fed to all
animals was found to contain a background level of 52.4 ppm (0.00524%)
tin. The compressive strength of the distal epiphysis of the femur was
significantly decreased in the 300 and 600 ppm (0.03 and 0.06%)
treatment groups.
Special studies on carcinogenicity
Mouse
Male and female mice (54/sex/treatment group) were given 5 ppm
(0.0005%) tin, as stannous chloride, in their drinking-water during a
life-time study. Growth rates, survival and tumour incidence in the
tin-exposed mice were comparable to control animals (Schroeder &
Balassa, 1967; Kanisawa & Schroeder, 1967).
Groups of male and female B6C3F1 mice were fed test diets
containing 0 (control), 1000 or 2000 ppm (0, 0.1 or 0.2%) stannous
chloride for a period of 105 weeks (NCI, 1981). Survival, body weight
gain and feed intake of the dosed and control animals were comparable
during the study. The incidence of female mice with either
hepatocellular adenomas or carcinomas showed a significant dose-
related trend (controls, 6%; 1000 ppm (0.1%) group, 8%; 2000 ppm
(0.2%) group, 16%). However, the highest incidence was within the
historical range for female B6C3F1 mice (4-18%) and, thus, was not
considered to be related to stannous chloride treatment. A similar
situation was also seen with the incidence of histiocytic lymphomas
among the female mice. It was concluded that under the conditions of
the bioassay, stannous chloride was not carcinogenic for B6C3F1 mice.
Rat
A 105-week feeding study was conducted with male and female F-344
rats (50/sex/treatment group) maintained on diets containing 0
(control), 1000 or 2000 ppm (0, 0.1 or 0.2%) stannous chloride (NCI,
1981). Daily feed consumption, body weight changes and survival were
not significantly different between any treatment group of either sex
during the course of the study. Certain tumours, e.g., C-cell adenomas
and carcinomas (combined) of the thyroid and adenomas of the lungs in
male rats showed positive trends with tin exposure. However, when
compared with historical control data for the F-344 rat, it was
concluded that the increased incidences observed were within the
normal variation for such tumours in aging animals and therefore were
unrelated to the administration of stannous chloride. Under the
conditions of the experiment, stannous chloride was not carcinogenic
for male or female F-344 rats.
Special studies on reproduction
Rat
A multigeneration reproduction study over 3 generations of rats
(CPB:WU randomly bred) was carried out using levels of 0 (control),
200, 400 and 800 ppm (0, 0.02, 0.04 and 0.08%) tin in the diet. The
stannous chloride was allowed to react in aqueous medium with the
casein component of the diet, in order to simulate the form of tin
likely to be found in canned food. The iron content of the diets was
maintained at 70 ppm (0.007%), but for the F2 generation onwards was
increased to 140 ppm (0.014%). A teratogenicity study was carried out
with 20 females/group of the F2b generation. Rats from F3b and F3c
generations were submitted to clinical and pathological examination.
There was no effect on fertility of females, number of young born per
litter and body weight. There was a decrease in body weight gain
during lactation that was related to the tin content of the diet. The
mortality of F2 generation litters during the first 10 days of
lactation was higher than controls, but decreased following an
increase in iron in the diet. Haematological studies showed that there
was a marked decrease in haemoglobin in the pups at weaning age, that
was related to the tin content of the diet. After weaning, haemoglobin
content returned to normal. Microscopic changes were observed in the
liver and spleen in the F3b pups at weaning but were not observed in
young at 4 weeks of age. A visceral and skeletal examination of the
F2b generation rats did not show any tin-related teratogenic effects.
The growth of the parent rats was not adversely affected in any
generation (Sinkeldam et al., 1979).
Special studies on teratogenicity
The teratogenic potential of inorganic tin was evaluated in mice,
rats and golden hamsters (FDRL, 1972). Stannous chloride was orally
administered in doses of 0 (control), 0.5, 2.3, 11.0 or 50 mg/kg bw
for 10 consecutive days (day 6 through 15 of gestation) in pregnant
mice and rats and for 5 consecutive days (day 6 through 10) in
pregnant hamsters.
The administration of up to 50 mg/kg bw of stannous chloride to
pregnant mice, rats and hamsters had no apparent effect on nidation or
on maternal or foetal survival. The number of abnormalities in either
soft or skeletal tissues of foetuses from tin-exposed females did not
differ from that occurring spontaneously in the controls.
Acute toxicity
LD50 LD100
Animal Route (mg/kg bw) (mg/kg bw) Reference
Mouse Oral - 40 Le Breton, 1962
Oral 250 - Pelikan et al., 1968
Oral 1 200 - Calvery, 1942
Rat Oral 700 - Calvery, 1942
Oral 2 275a - Conine et al., 1975
Oral 3 190b - Conine et al., 1975
Guinea-pig Oral - 60 Le Breton, 1962
Rabbit Oral - 40 Le Breton, 1962
Oral 10 000 - Eckardt, 1909
a 24-hour LD50 value under 16-18-hour fasted conditions.
b 24-hour LD50 value under fed conditions.
The acute toxicity of orally administered stannous chloride has
been studied in a number of species. As illustrated by the LD50 data
above, there can be considerable species-related differences in
sensitivity to tin. Even at lower levels of exposure, species
differences are apparent. Benoy et al. (1971) found the cat to be more
sensitive to oral administration of tin (from canned orange juice)
than either the dog or rat. At varying doses of tin from 5.4 to 14
mg/kg bw, only the cat showed noticeable signs of gastrointestinal
disturbance. These observations are consistent with those reported by
Cheftel (1967) indicating that cats receiving stannous chloride, by
gavage, at a rate of 9 mg/kg bw showed excessive salivation as well as
vomiting and diarrhoea.
In addition to extreme gastrointestinal irritation, fatal oral
doses of stannous chloride have been associated with a number of signs
of toxicity including anorexia, depression, ataxia and muscular
weakness (Conine et al., 1975). A number of alterations in tissue
integrity has also been reported including necrosis of the liver and
spleen in mice (Pelikan et al., 1968) and mottling, hyperaemia and
tubular necrosis of the kidneys in the rat (Conine et al., 1975).
Short-term studies
Rat
Groups of 10 male and 10 female rats were given 0, 0.03, 0.1, 0.3
and 1.0% of stannous chloride in their diet for 4 weeks. No effects
were noted on behaviour and general condition. Body weight of both
sexes was significantly reduced at the 0.3% and 1.0% levels when
compared with controls. Food efficiency was similarly impaired. Of the
haematological data only the haemoglobin content of erythrocytes was
reduced in both sexes at the 0.3% and 1.0% levels. The relative liver
weight was decreased in both sexes at the 1% level, but kidney weight
was unaffected. Histopathology revealed proliferation of the bile duct
epithelium at the 1% level only. No other abnormalities were detected
(De Groot & Feron, 1970).
Two groups of young male rats (10 per group) were fed diets
containing 0 or 5000 ppm (0 or 0.5%) stannous chloride, equivalent to
about 1500 mg/kg bw, for 1 month. Each test animal received, daily,
radioactive Sn113Cl2 (2 µCi/day) in an HCl/KCl solution. Control
animals received the carrier only. Two additional groups of rats were
fed as described for 1 month. These animals were used for histological
examination of various organs and tissues. Body weight and food
consumption were depressed. Food efficiency, protein efficiency and
nitrogen balance were within normal limits. Ninety-nine per cent. of
the administered labelled tin was excreted in the faeces and less than
1% in the urine. The radioactivity in the gastrointestinal tract,
organs and carcass was negligible. The treated animals developed
anaemia characterized by a significant drop in haemoglobin and
haematocrit values. Relative weights of the liver, spleen and kidney
were increased. Histological examination of the treated animals
revealed a marked congestion of the kidney and cortex of the adrenals.
There was also congestion and desquamation of the mucosa in the upper
gastrointestinal tract from the stomach to ileum (Fritsch et al.,
1977a).
Groups of 10 male and 10 female rats were fed diets containing 0,
0.03, 0.1, 0.3 or 1.0% stannous chloride during a 90-day study.
Animals receiving the 1% diet showed immediate effects within the
first 7 days, including gross abdominal distention, minimal to no
growth, anorexia and anaemia. By the eighth week, several animals had
lost weight and a number had died. This particular group was
terminated in the ninth week and upon autopsy various gross
pathological conditions were found, including distention of the
intestines, small oedematous pancreas and greyish-brown livers.
Histopathological evaluations revealed moderate testicular
degeneration, severe pancreatic atrophy, a spongy state of the white
matter of the brain, acute bronchopneumonia, enteritis and distinct
liver changes (atypical homogenous liver cell cytoplasm and mild
proliferation of bile duct epithelium). In view of the marked
reduction in appetite in the 1% group, it is difficult to assess the
exact degree to which tin was responsible for the observed
pathological changes. Animals fed the 0.3% diet showed some abdominal
distention and loss of appetite during the first 2 weeks of the 90-day
study. After the second week, appetite returned to normal as did
growth. Significantly lower haemoglobin levels were determined in both
sexes between the fourth and ninth week. However, by the end of the
study only males on the 0.3% diet had lower (P < 0.05) haemoglobin
and haematocrit values. Terminal autopsy and histological evaluations
of the 0.3% group showed only minor treatment-related changes in some
of the animals of both sexes (e.g., atypical homogenous cytoplasm of
the hepatocytes and bile duct epithelial proliferation). There were no
treatment-related effects seen in rats fed the 0.03% or 0.1% stannous
chloride diets (De Groot et al., 1973a).
In another 90-day study, De Groot et al. (1973b) fed male and
female rats semi-purified diets containing either 35 or 250 ppm
(0.0035 or 0.025%) iron and supplemented with 0, 50, 150, 500 or
2000 ppm (0, 0.005, 0.015, 0.05 or 0.2%) tin as stannous chloride.
Growth depression, reduced appetite and food efficiency were observed
at the 500 and 2000 ppm (0.05 and 0.2%) tin level in both sexes.
Distinct signs of anaemia occurred in animals in the 2000 ppm (0.2%)
group, but only transitory decreases in haemoglobin were seen in rats
receiving the 500 ppm (0.05%) tin diet. Pancreatic atrophy and
histological changes in the liver, kidneys, spleen, testicles and
heart were seen in some animals in the highest tin group. In all
instances where effects of dietary tin were determined, the degree of
severity was usually more pronounced in animals receiving the low iron
diets. It was concluded that 150 ppm (0.015%) dietary tin was an oral
no-effect level for the rat, an amount that is equivalent to
approximately 7.5 mg/kg bw per day.
Groups of young male rats (50 g) were fed a basal diet
supplemented with 0, 4000 or 8000 ppm (0, 0.4 or 0.8%) (0, 200 or
400 mg/kg bw) stannous chloride for 6 months. During the last 2 weeks
of the study, each treated animal received 2 µCi Sn113Cl2 daily by
gavage. Control animals received only the HCl/KCl carrier. Three
additional groups, each consisting of 5 rats, were fed as above and
were used for histological examination. Body weights of the treated
animals were depressed. Food consumption was decreased during the
first 8 weeks of the study. The peri-epididymal fat tissue,
haemoglobin, haematocrit and serum iron were decreased in both test
groups. Relative weights of the testes, heart and brain in the low
level group and spleen, adrenals, kidney, testes, seminal vesicles,
heart and brain in the high-dose group were increased. Histological
examination revealed a marked atrophy of the exocrine pancreas, as
well as interstitial oedema in the kidneys and adrenals. The
gastrointestinal tract, from the stomach to lower ileum, showed signs
characteristic of irritation, oedema and congestion of the mucosa with
accumulation of mucus (Fritsch et al., 1977b).
The dose-effect of stannous chloride on a number of biochemical
parameters was investigated (Yamaguchi et al., 1980a,b) in male
weanling rats during a 90-day study. Oral doses of 0 (control), 0.3,
1.0 or 3 mg tin/kg bw were administered at 12-hour intervals
throughout the study. A slight non-significant decrease in the calcium
content of the femoral epiphysis occurred at 0.3 mg tin/kg bw. At
1.0 mg tin/kg bw, significant reductions were produced in liver
succinate dehydrogenase activity as well as decreased calcium content
and alkaline phosphatase activity in the femoral epiphysis. The
3.0 mg/kg dose resulted in significant decreases in relative weights
and calcium concentration of the femur, serum lactic dehydrogenase and
alkaline phosphatase activities, hepatic succinate dehydrogenase
activity and calcium content and alkaline phosphatase activity in the
femoral diaphysis and epiphysis. The decrease in calcium content of
the femoral epiphysis was considered to be the most specific
biochemical manifestation of the toxic effect of tin. Based on this
90-day study with weanling rats, an oral no-effect level for inorganic
tin was estimated to be lower than 0.6 mg/kg bw per day.
Guinea-pig
Groups of guinea-pigs received additional 770 mg Sn/kg bw in
their diet for 5 months without observing any abnormalities. At
autopsy, no accumulation of tin was found (FDA, 1953).
Cat
Groups of cats received in their diet, fish containing additional
210 mg Sn/kg bw for 7 months. No abnormalities were observed and at
autopsy no tin accumulation was detected (FDA, 1953).
Long-term studies
Rat
Stannous chloride was added to the drinking-water of rats at a
dose of 5 ppm (0.0005%) tin over the life-span of the animals
(Schroeder et al., 1968). Growth rates and overall survival were not
affected, although the longevity of the tin-exposed female rats
appeared to be reduced slightly. There were no indications of
increased tumorigenicity among the tin-exposed animals.
Groups each of 60 rats (Cpb-WU, random bred) equally divided by
sex were maintained on test diets containing 0 (control), 200, 400 and
800 ppm (0, 0.002, 0.004 and 0.008%) tin for a period of 115 weeks.
Observations were made on general appearance and behaviour and growth,
food intake and food efficiency. Haematological parameters were
measured at weeks 4, 13, 26, 52, 78 and 102, serum blood chemistry at
weeks 26, 52 and 102, and urinalysis at weeks 13, 26, 52, 78 and 102.
At week 115 all surviving rats were killed and a complete autopsy was
performed followed by a microscopic examination of the principal
organs and tissues. Residual tin was also measured in blood, liver,
kidneys, brain, pancreas and femur (bone). There were no differences
in mortality rates between the various groups. There were no effects
on growth or food intake, but food efficiency was decreased at the
highest dose level. Haemoglobin and haematocrit values were decreased
at all dose levels at weeks 4 and 13, but during the second year of
the study were similar to controls. No other compound-related changes
were reported for haematological parameters, serum chemistry and
urinalysis. At autopsy the only effect noted was an increase in the
relative weight of the spleen. No compound-related histological
effects were reported. There was no indication of any compound-related
effect on the site and incidence of tumours. Tin did not accumulate in
the organs examined with the exception of bone in the 800 ppm (0.08%)
group (Sinkeldam et al., 1981).
OBSERVATIONS IN MAN
Chronic industrial exposure to tin dust or fumes causes benign
pneumoconiosis (Pendergrass & Pryde, 1948). Stannic oxide deposits in
the lung with little absorption owing to insolubility (Browning,
1969).
Although food-borne tin is generally regarded to be of relatively
low oral toxicity, there is little question that, at excessively high
levels, a greater potential exists for overt reaction. Unfortunately,
there is considerable controversy over the levels of tin in foods and
beverages that can be expected to cause acute effects such as
abdominal cramps, nausea, emesis and/or diarrhoea.
Nine adult male volunteers weighing 65-83 kg ingested between
116-203 mg tin/day (equivalent to about 1.6-2.9 mg tin/kg bw per day)
for 23 days without adverse effects. Almost all the ingested tin was
recovered in the faeces (Calloway & McMullen, 1966). Severe
gastrointestinal symptoms affecting 32 people were reported after
consumption of a beverage containing 2000 ppm (0.2%) tin (Warburton et
al., 1962). On the other hand, of 8 subjects ingesting a solution of
700 ppm (0.07%) tin, only 2 had slight nausea and 1 diarrhoea
(Cheftel, 1967). Acute poisoning incidents have been reported in 15
students following the consumption of a canned orange beverage ranging
in tin content from 100 to 494 ppm (0.01-0.0494%) and 8 cases
elsewhere. The symptoms observed were vomiting, diarrhoea, fatigue and
headache. Similar incidents have also been reported in 7 out of 9
persons and 1 elderly person after the consumption of canned tomato
juice with a tin content from 156 to 221 ppm (0.0156-0.0221%) (Horio
et al., 1967). Nausea, vomiting and diarrhoea in an unspecified number
of people in the Middle East was ascribed to the ingestion of canned
orange and apple juices containing 250-385 ppm (0.025-0.0385%) tin
(Benoy et al., 1971). Eight further cases were reported in 1969
following the ingestion of tomato juice containing 247 ppm (0.0247%)
tin (Kojima, 1969). The tin content of random samples from the same
manufacturers ranged from 75 to about 500 ppm (0.0075-0.05%), but it
appeared from the epidemiological investigations that only batches
showing the higher levels had been responsible for the incidents
(Ministry of Health and Welfare, Japan, 1969). Fifteen out of 26
persons consuming orange juice containing about 300 ppm (0.03%) tin
showed gastric symptoms (Kojima, 1971). Five volunteers drank
beverages containing between 498-1370 ppm (0.0498-0.137%) tin at rates
of 1.6-6.7 mg tin/kg bw. Nausea and diarrhoea occurred only at the
1370 ppm (0.137%) level (equivalent to 4.4-6.7 mg tin/kg bw) but did
not appear when ingestion was repeated 1 month later (Benoy et al.,
1971).
A total of 113 cases of acute gastrointestinal illness during a
3-month period (Barker & Runte, 1972) were associated with the
ingestion of canned tomato juice. Of these illnesses, 48 occurred as
isolated events in private homes or restaurants while the others
occurred during or after 2 banquets, 1 involving 43 cases and the
other 22 cases. Clinical features included acute abdominal bloating,
cramps, diarrhoea, emesis and headache. The incubation period ranged
from as few as 15 minutes up to 14 hours post-ingestion, whereas the
median incubation period varied from 30 to 90 minutes. Duration of the
symptoms ranged from as little as 1/2 hour up to 3 weeks with median
durations of 12-24 hours. Analyses of the suspected tomato juice
revealed concentrations of tin ranging from a low of 131 ppm (0.0131%)
to 405 ppm (0.0405%) with mean values between 245 and 363 ppm (0.0245
and 0.0363%).
In the case of chronic toxicity to inorganic tin, there is
virtually no human data available.
Comments
The inorganic salts of tin are of generally low but varying
toxicity. Experiments in animals and man point to almost complete
faecal excretion of certain orally administered inorganic tin salts,
with little being absorbed into the body. Short-term feeding studies
in experimental animals with various tin salts including stannous
chloride produced anaemia, changes in a number of tissue enzyme
activities and deleterious effects to the liver and kidneys. Blending
stannous chloride with casein in an aqueous medium in an attempt to
simulate the form of tin that is present in food resulted in a
transient anaemia in a life-time feeding study in rats. This tin
complex was also shown not to have an effect on the reproductive
performance of rats, although a transient anaemia was observed in the
offspring prior to weaning. Tin crosses the placental barrier but has
not been shown to be teratogenic. Inorganic tin was not carcinogenic
in a life-time feeding study in rats and mice. Chronic exposure of
experimental animals to high levels of tin results in increased levels
of tin in bone tissue. This is also associated with an increase in
acid phosphatase activity and decreased calcium content and
compressive strength of the femur.
There is a lack of information concerning the chemical form(s) in
which inorganic tin exists in canned foods or beverages. Additional
information may be helpful to a better understanding of acute tin
toxicity resulting from the ingestion of products containing high
levels of tin. However, it has been shown that a large proportion of
the tin in canned vegetables is resistant to simulated gastric
digestion, and thus may not be available for further metabolism.
Tin contamination resulting from the canning of a multiplicity of
food items, even at the relatively large levels occurring with low pH
or in the presence of nitrates, does not appear to give rise to acute
untoward effects in man, except in special circumstances. While the
number of reported cases of acute tin intoxication in man due to
ingestion of canned foodstuffs containing high levels of tin are
limited, it appears that as total tin levels approach or exceed
200 ppm (0.02%), especially in beverages, the potential for acute
gastric disturbances is greatly enhanced. The gastrointestinal effects
of high tin levels appear to be due to local irritation of the mucosa.
At this time there is no evidence of cumulative adverse effects
of low levels of tin in the diet of man.
Although it has been suggested that ingested inorganic tin may
undergo biomethylation to the more toxic forms of alkyl tin, there is
no conclusive evidence that this occurs in experimental animals or
man.
EVALUATION
At this time, there is no evidence of chronic adverse effects in
man associated with chronic exposure to tin. The main problem is an
acute manifestation of gastric irritancy. The threshold concentration
for this effect is about 200 mg/kg in the food.
Estimate for provisional maximum tolerable daily intake for man
2 mg/kg bw (includes food additive use of stannous chloride).
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