Effects on Experimental Animals Although there is evidence that tin is essential for the normal growth of rats, no evidence exists that it is essential for other species including man. Inorganic tin Local effects Many of the reported effects of inorganic tin are localized because of its irritant properties. Vomiting and diarrhoea are typical signs that follow oral intake of foods with a high tin content. In cats tin concentrations of 540 mg/litre or 1370 mg/litre in orange juice caused vomiting in 1/11 animals and 3/10 animals, respectively. However, these levels did not produce any effects in dogs. The only adverse effect produced in guineapigs by both short-term and prolonged exposure to 3 mg of tin tetrachloride per m3 of air was transient irritation of the nose and eyes, but these findings have not been corroborated. Application of 1 % tin(II) chloride or 0.25 % tin(II) fluoride to the abraded skin of rabbits caused intradermal pustule formation and epidermal destruction, but did not have any effect on intact skin. Systemic effects The major systemic effects of inorganic tin salts in animals include ataxia, twitching of the limbs, and fore-and hindleg weakness progressing to paralysis. In rats, growth retardation and decreased haemoglobin levels may follow administration of tin(II) chloride, orthophosphate, sulfate, oxalate, and tartrate at a dietary level of 3 g/kg. However, administration of iron prevents the development of anaemia. Higher dietary levels of tin (10 g/kg) over several weeks may induce testicular degeneration, pancreatic atrophy, and a spongy state of the white matter of the brain. Doses of pentafluorostannite of 100 mg/kg body weight may also affect growth, and a dose-related decrease in haemoglobin levels may be seen with doses exceeding 100 mg/kg; no effect on growth was found at a dose of 20 mg/kg administered orally to rats. A single intravenous injection of pentafluorostannite at a concentration of 35 mg/kg body weight or tin(II) chloride dihydrate (SnCl2-2H20) at 44.4 mg/lkg in rats produced extensive necrosis, mainly in the proximal tubules of the kidney. A subcutaneous dose of tin(II) chloride at a concentration of 5.6 mg/kg body weight caused a 20--30 fold increase in the haem oxidation activity in the kidney; this effect was dose-related. Administration of tin(II) chloride at a concentration of 5 mg/litre, from weaning to natural death, did not affect longevity in mice or in male rats, but caused a decrease in longevity in female rats combined with an increased incidence of fatty degeneration of the liver. There is no conclusive evidence concerning the carcinogenicity or teratogenicity of inorganic tin. Organotin compounds Local effects Some butyltin compounds are known to produce gastrointestinal irritation; submucosal, subserosal, and intraluminar haemorrhages were seen in mice after a single oral dose of 4000 mg/kg body weight. Dibutyltin dichloride administered at a dose of 50 mg/kg body weight per day, for one week, produced gastroenteritis in rats. Gastroenteritis was also produced in rats by administration of tricyclohexyltin hydroxide (25 mg/kg body weight per day, for Dermal application of dibutyltin dichloride (10 mg/kg body weight per day, for 12 days) caused severe local damage. Local irritation was produced in rats by applications to the shaved skin of bis(tributyltin) oxide in doses of 0.36--0.95 mg/kg; necrosis was produced at doses of 1.4-185 mg/kg. Triphenyltin acetate also irritated the skin of the rat, whereas triphenyltin hydroxide was reported not to irritate the skin of the rabbit but to be extremely irritating to the eyes. Systemic effects The systemic effects of monosubstituted, disubstituted, and trisubstituted organotin compounds differ. In general, mono- and diorganotin compounds are less toxic than triorganotin compounds. The toxicity of trialkyltin compounds decreases as the number of carbon atoms in the alkyl chain increases. Dibutyltin compounds can produce inflammatory changes in the bile duct. Single oral doses of dibutyltin dichloride at 50 mg/kg body weight produced this effect in rats, and higher doses produced more severe injury; necrotic changes were also produced in the liver of mice and rats. Bile duct injury in rats and rabbits was seen following dermal application of dibutyltin dichloride (10 mg/kg body weight). Dioctyltin compounds produced slight changes in the germinal centres of the spleen and steatosis of hepatocytes in mice at a single oral dose of 4000 mg/kg body weight. Pulmonary oedema may be seen in rats following intravenous administration of diethyldipropyl-, diisopropyl-, and dipentyltin compounds. Dibutyltin compounds can slow down growth in rats. The no-observed-effect dietary level was reported to be 40 mg/kg for a 3 month feeding period and 20 mg/kg for 6 months. Recent studies showed that dioctyltin dichloride and dibutyltin dichloride administered at dietary levels of 50 and 150 mg/kg, respectively for 6 weeks, caused a dose-de- pendent atrophy of the thymus and thymus-dependent organs and suppression of the immunological response in rats, but not in mice and guineapigs. Some trialkyltin compounds produce a characteristic lesion in the central nervous system consisting of oedema throughout the white matter. Orally administered trimethyl- and triethyltin compounds are more potent in inducing this lesion than the higher homologues. The first changes in the rat brain were visible after 3 days of administration of triethyltin hydroxide at a dietary level of 20 mg/kg. Maximum changes were found after 2 weeks. Typical signs of such intoxication included prostration and weakness of the limbs progressing to flaccid paralysis. The effects disappeared when exposure ceased. Administration of triphenyltin compounds produced a reduction in weight and in food intake in many species. Lethargy was a typical symptom and histological changes in the liver and spleen were also seen. A decreased immunological response with a reduction in the number of leukocytes and of plasma cells in the lymph nodes of guineapigs has been reported. A 2-year study indicated a no-observed-effect level for triphenyltin acetate of 0.1 mg/kg body weight per day. A single intrarumenal dose of tricyclohexyltin hydroxide at 50 mg/kg body weight produced central nervous depression and diarrhoea in sheep, whereas a dose of 15 mg/kg did not result in any adverse effects. At higher doses, pulmonary congestion, tracheal haemorrhage, enteritis, and eleatrocardiographic changes were seen. Noobserved-effect doses for long-term intake in the rat and dog were given as 3 mg/kg body weight per day and 0.75 (mg/kg) per day, respectively. Tetraalkyltin compounds may produce muscular weakness, paralysis, respiratory failure, tremors, and hyperexcitability as acute effects in mice and dogs, while late effects are similar to those seen with triorganotin poisoning. There is no evidence that organotin compounds are carcinogenic or teratogenic. Reported effects of triphenyltin hydroxide on the testes and ovaries of rats require further confirmation. Information concerning the mechanism of the toxic action of organotin compounds is inadequate. Several dimethyl- and dioctyltin compounds inhibit the oxidation of keto-acids and block mito- chondrial respiration. Trialkyltin compounds inhibit oxidative phosphorylation. Effects in Man Inorganic tin Inhalation of elemental tin does not produce any effects in man, whereas extended exposure to tin(IV) oxide dust and fumes can produce a benign pneumoconiosis termed stannosis. This condition develops after at least 3--5 years of exposure and is characterized by small dense shadows in the pulmonary X-ray picture without impairment of pulmonary function. Fibrosis is not seen. The generally-accepted maximum allowable concentration of tin(IV) oxide in the air of work rooms of 2 mg/m3 appears to give protection against this disorder. Symptoms that have been reported following ingestion of food with a high tin content include nausea, vomiting, diarrhoea, stomach cramps, fatigue, and headache. The lowest concentration of tin reported in association with such outbreaks was about 250 mg/litre in canned orange and apple juice. Five human volunteers did not experience any symptoms from the ingestion of fruit juices containing concentrations of 500--730 mg/litre but all had gastrointestinal disturbances at a level of 1370 mg/litre (corresponding to 4.4--6.7 mg/kg body weight). Ingestion of 50 mg of tin through eating canned peaches that contained tin concentrations of about 300--600 mg/kg caused acute symptoms in 2 out of 7 persons. The relative importance of, on one hand, the total amount of tin ingested and, on the other hand, the concentration of tin in relation to the development of symptoms has not been satisfactorily assessed. Organotin compounds Local effects Dibutyl- and tributyltin compounds produced skin irritation in workers 1--8 h after contact. Experimental application to the skin of volunteers showed that some compounds (e.g., dibutyltin dichloride and tributyltin chloride) produced this effect, whereas others such as dibutyltin maleate and tetrabutyltin did not. Di- and tributyltin compounds caused eye irritation after brief contact. A 20 % solution of triphenyltin acetate produced irritation of the skin and the mucous membranes of the upper respiratory tract while tricyclohexyltin hydroxide was reported not to cause skin irritation at a concentration of 0.01 mg/kg body weight. Systemic effects The majority of accidental poisonings involving systemic effects have been due to occupational exposure to triphenyltin acetate. Systemic effects reported to have followed both dermal and inhalation exposure include general malaise, nausea, gastric pain, dryness of the mouth, vision disturbance, and shortness of breath. Hepatomegaly and elevated levels of liver transaminase activity have been found in some cases. Recovery has generally been complete but liver damage has been known to persist for up to 2 years. The hazard associated with the use of organotin compounds was unmasked by an episode of intoxication in 1954 involving over 200 cases, 100 of which were fatal. The cause was the ingestion of an oral preparation containing diethyltin diiodide at 15 mg/capsule. It was suggested, however, that ethyltin triiodide, triethyltin iodide, and tetraethyltin were present as impurities. Predominant symptoms and signs included severe headache, nausea and vomiting, visual and psychological disturbances, and sometimes loss of consciousness. At autopsies and decompressive surgery, cerebral oedema of the white matter was found. In many cases, symptoms lasted for at least 4 years; follow-up information on the subjects involved is not available.