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.


         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).



    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".


         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.


    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


         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).


         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

        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


         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




    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).


    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


         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.


         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


         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


         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.,

         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.


         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).


         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


         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).


         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,

         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.,

         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.


         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


         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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    See Also:
       Toxicological Abbreviations
       Tin and stannous chloride (FAO Nutrition Meetings Report Series 48a)
       Tin and stannous chloride (WHO Food Additives Series 1)