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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: publication from EFSA
Justification for type of information:
Datawaiving from SnCl_2 to SnSO_4, Sn^(2+)-ion is responsible for adverese effects

Data source

Reference Type:
review article or handbook
Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Tin
European Food Safety Authority
Bibliographic source:
The EFSA Journal (2005) 254, 1-25
Report date:

Materials and methods

Objective of study:
Test guideline
equivalent or similar to guideline
OECD Guideline 417 (Toxicokinetics)
not specified
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Tin sulphate
EC Number:
EC Name:
Tin sulphate
Cas Number:
Molecular formula:
λ²-tin(2+) sulfate

Test animals

other: rat, mice, strain and sex see free text
other: see free text

Administration / exposure

Route of administration:
other: see free text
Duration and frequency of treatment / exposure:
see free text
Doses / concentrations
Doses / Concentrations:
see free text
No. of animals per sex per dose / concentration:
see free text
Control animals:
other: see free text

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
It has been reported that gastrointestinal absorption of tin by the rat is extremely low. In one study, groups of 8 male Wistar rats (approximately 250 g) were fasted for 17 hours after which a dose of radiolabelled 113SnCl2 (50 mg/kg body weight; 0.5 μCi/mg tin) was administered by gavage in either: (1) water; or with (2) aqueous sucrose at 5 g/kg body weight; (3) aqueous ascorbic acid at 0.5 g/kg body weight; (4) aqueous potassium nitrate 0.1 g/kg body weight; (5) an aqueous solution of all three compounds at the same dose; or in (6) 20% alcohol solution, equivalent to 2 g ethanol/kg body weight; or (7) a solution of albumin at 2.5 g/kg body weight; or (8) 1:1 (v/v) sunflower oil-1% Tween 20 emulsion at 10 mL/kg body weight. 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 0-24 and 24-48 hours. Animals were then sacrificed and excreta and selected organs and tissues analysed for radioactivity. Group mean values of the proportion of the administered dose excreted in the faeces within 48 hours or remaining in the gastrointestinal tract ranged from 98.7-99.8%. The mean percentage of the 113Sn dose detected in the urine was less than 1.1% and in the organs
and tissues examined was less than 0.005% (Fritsch et al., 1977a; WHO, 1980; ATSDR, 1992 and 2002).
The effect of the anion and oxidation state on the gastrointestinal absorption of inorganic tin salts, labelled with 113Sn, was studied in the rat. Following a 24-hour fast, groups of 10 female rats (Charles River, 200-225 g) were given a single 20 mg Sn/kg body weight oral dose of Sn2+ citrate, fluoride or pyrophosphate or Sn4+ citrate or fluoride. Changing the anion from citrate to fluoride did not alter the absorption of either oxidation state and approximately 2.8% and 0.6% of the Sn2+ and Sn4+, respectively, were absorbed. With pyrophosphate as the anion, absorption of Sn2+ was significantly lower than with the citrate or fluoride, an observation which the author ascribed to the greater tendency of pyrophosphate to form insoluble complexes with tin as compared to the citrate and fluoride anions (Hiles, 1974). In a 28-day study in which groups of 6 weanling female rats were fed with the Sn2+ and Sn4+fluoride salts (20 mg Sn/kg body weight, on 6 days/week) the steady state urinary excretion was circa 0.35% and 0.12% of the total dose of tin from the Sn2+ and Sn4+ salts, respectively, confirming the greater absorption of the Sn2+ ion (Hiles, 1974). In a comparative study of the absorption of tin, tracer dose of 113SnCl2 (2.6-4.4 mg Sn) were administered intravenously, intraperitoneally and by gavage to female RF mice, male Sprague-Dawley rats, male African white-tailed rats, male rhesus monkeys and male beagle dogs. In all species more than 95% of the oral gavage dose was excreted via the faeces within 3 days, whereas a greater percentage (15.9-62.8%) of the parenteral doses was excreted via the urine during the same time (Furchner and Drake, 1976). Orange juice containing 540 mg Sn/kg derived from corrosion of the can or a solution of tin citrate (1200 mg Sn) was administered to Wistar rats (gender not given), and faeces and urine were collected over 48 hours or 18 hours respectively. No tin was detected in the urine collections whereas the faecal excretion of tin was 99% or 94-98% respectively (Benoy et al., 1971).
Details on distribution in tissues:
When expressed as a percentage of a dose administered orally to rats, tissue distributions for Sn2+ and Sn4+, respectively were skeleton, 1.02% and 0.24%, liver, 0.08% and 0.02%; and kidneys 0.09% and 0.02% (Hiles, 1974). When radioactive stannous chloride was administered by stomach tube to anaesthetised rats the bulk of the dose was excreted in faeces, and there was highly variable distribution of the absorbed fraction in the internal organs as measured for periods of up to 21 days (Kutzner and Brood, 1971).
Tin concentrations were measured in the liver, kidneys and femur of groups of 6 male weanling Wistar rats administered 0, 0.3, 1.0 and 3.0 mg Sn2+/kg body weight orally every 12 hours for a period of 90 days. There was a clear dose-related increase in femur concentration with statistical significance achieved at the 1.0 mg Sn2+/kg body weight dose. In the highest dose group the femur concentrations were 10-fold higher than the control values of 2.05 ± 0.41 μg/g wet tissue and these were associated with significant reductions of the diaphysis and epiphysis concentrations of calcium. The concentrations of tin in the livers of control rats were 0.24 ± 0.01 μg/g wet tissue and the levels were significantly increased by 58% at the highest dose. There were no significant increases in the kidney concentrations of 0.22 ± 0.41 μg/g wet tissue (Yamaguchi et al., 1980).
Male Wistar rats were given SnCl2.2H2O in their drinking water for 1-18 weeks at concentrations of 100 mg/L (0.44mM), 250 mg/L (1.11 mM) or 500 mg/L (2.22 mM). Tin accumulated in the brain at the highest concentration (2.22 mM) throughout the experiment, but elevated tin concentrations in brain were found only after 15 and 18 weeks at 1.11 mM and tin did not increase in the brains of rats given 0.44 mM. Blood tin increased after one week at the highest dose (2.22 mM) without further accumulation, whereas blood tin levels did not differ from controls at the 2 lower doses. Tin exposure caused a dose-dependent increase in the cerebral and muscle acetylcholinesterase activity at the two highest doses (Savolainen and Valkonen, 1986).
Transfer into organs
Transfer type:
secretion via gastric mucosa
slight transfer
in rat, mice, human
Details on excretion:
The absorption of inorganic compounds of tin from the gastrointestinal tract in humans and animals is reported to be low with as much as 98% being excreted directly in the faeces. The nature of the inorganic tin compound and its oxidation state appears to determine the extent of absorption (Calloway and McMullen, 1966; Hamilton et al., 1972b; Tipton et al., 1966 and 1969; Fritsch et al., 1977a; WHO, 1980; ATSDR, 1992 and 2002).
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: 29d in mice

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
The methylation of inorganic tin compounds by a mechanism involving the oxidation of a stannous compound to the Sn (III) radical and the reaction of this with the cobalt-carbon bond of vitamin B12 to give a methylated tin derivative have been described. However, it is probable that this can only occur in anaerobic conditions (Ridley et al., 1977 a and b; Wood et al., 1978; ATSDR, 1992 and 2002).

Applicant's summary and conclusion

Interpretation of results: no bioaccumulation potential based on study results
There is no bioaccumulatiom based on inorganic Sn^2+ compounds, but an effect on other trace elements (e.g. on iorn and so to the hemoglobin level).
Occasional high intakes of tin are associated with high consumption of canned foods, and regulatory limits of tin content in canned foods (200 mg/kg) and beverages (100 mg/kg) have been established to protect against possible local acute effects on the gastrointestinal tract.
Short-term human studies indicate that high intakes of tin (about 30-50 mg tin/day or per meal) may reduce the absorption of zinc, but not other minerals such as iron, copper, manganese or magnesium. However, the possible long-term effects, if any, of such intake levels on status of zinc or other minerals have not been investigated. The current mean daily intake of tin in EU countries (e.g. ranging up to about 6 mg/day in the UK) appears to be well below the lowest intakes reported to cause adverse effects on zinc

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