WORLD HEALTH ORGANIZATION
WHO Food Additives Series 1972, No. 1
TOXICOLOGICAL EVALUATION OF SOME
ENZYMES, MODIFIED STARCHES AND
CERTAIN OTHER SUBSTANCES
The evaluations contained in this publication were prepared by the
Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
16-24 June 19711
World Health Organization
Geneva
1972
1 Fifteenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 488; FAO
Nutrition Meetings Report Series, 1972, No. 50.
The monographs contained in the present volume are also issued by the
Food and Agriculture Organization of the United Nations, Rome, as FAO
Nutrition Meetings Report Series, No. 50A
(c) FAO and WHO 1972
TIN AND STANNOUS CHLORIDE
Biological data
Tin and some tin salts
Biochemical aspects
Tin has been discussed at the Tenth FAO/WHO Expert Committee on Food
Additives in 1967 (FAO/WHO, 1967). It is still uncertain whether tin
plays any essential biological role in the body. It is present in
small amounts in all human and animal organs and the body of normal
adult man contains about 352 mg. Tin is poorly absorbed from the
alimentary tract of animals and man, and it is chiefly excreted by 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 per cent. excretion in the faeces (Flinn & Inouye,
1928). More than 90 per cent. of tin tartrate was excreted in the
faeces (Schryver, 1909). Three rats given fruit juice (540 ppm tin)
at 5.4 mg/rat excreted 99 per cent. 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 receiving orally
fruit juice (730-2000 ppm tin) at 3.65-20 mg tin/kg body-weight did
not excrete any tin in their urine (Benoy et al., 1971).
Tin is widely distributed after parenteral injection especially in the
liver and spleen, where it deposits in the RES, most of it being
excreted eventually in the urine and a little in the bile (Barnes &
Stoner, 1959). 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. (Benoy et al., 1971; Browning, 1969.) Twenty
mice and 6 rats received 50 mg/kg tin citrate s.c., no 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 per cent. tin citrate excreted no tin in their
urine or faeces. Tin solutions of up to 9950 ppm had no effect on the
peristaltic reflex of isolated guinea-pig ileum (Benoy et al., 1971).
Tin in canned products is probably chelated by polyphenolic compounds
and proteins of the solid portion of canned fruits and vegetables
(Heintzke, 1959; 1960). In this complex form it is rather resistant
to liberation as free tin ions by the action of gastro-intestinal
secretions (Horio et al., 1970). However the presence of nitrate in
canned products does contribute to increased amounts of tin being
dissolved from the container (Horio et al., 1967; Cheftel, 1971).
Acute toxicity
Compound Animal Route LD50 (Mg/kg Reference
body-weight)
Sodium tin Ministry of Health &
citrate Mouse Oral 2700 Welfare, Japan, 1969
Tin metal itself, taken orally, is practically innocuous but inhaled
dust or fume 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 induces diarrhoea and vomiting in
cats (Omori, 1966). Four pigeons receiving 1.5-3.0 mg tin/kg in fruit
juice showed no adverse effects. Groups of 6 rats showed no adverse
effects after single oral doses of tin-containing fruit juices of 5.4
mg/rat or 24 hour ad lib ingestion of beverage at 65-190 mg tin/kg
or tin citrate at 36-300 mg tin/kg (Benoy et al., 1971). Cats
receiving stannous citrate by gavage at a rate of 9 mg/kg 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. Vomiting occurred at rates of 5.4 or
more mg tin/kg. 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
25-14 mg tin/kg or solid foods at rates of 4.5-8 mg tin/kg without
vomiting or signs of toxicity (Benoy et al., 1971).
Human observations
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).
Nine volunteers ingested 160 mg tin/kg for 23 days without adverse
effects. Almost all the ingested tin was recovered in the faeces
(Calloway & McMillen, 1966). Severe gastro-intestinal symptoms
affecting 32 people were reported after consumption of beverage
containing 2000 ppm tin (Warburton et al., 1962). On the other hand,
of 8 subjects ingesting a solution of 700 ppm tin, 2 had slight nausea
and one 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 100-494 ppm 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 old person after the consumption of canned tomato juice
with a tin content from 156-221 ppm. (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
beverage containing 250-385 ppm tin (Benoy et al., 1971). Eight
further cases were reported in 1969 following the ingestion of tomato
juice containing 247 ppm tin (Kojima, 1969). The tin content of
random samples from the same manufacturers ranged from 75 to about 500
ppm but it appeared from the epidemiological investigations that only
batches showing the higher levels had been responsible for the
incidents (Min. Health Welf. Japan, 1969). Fifteen out of 26 persons
consuming an orange juice drink containing about 300 ppm showed
gastric symptoms (Kojima, 1971). Five volunteers drank beverages
containing 498 to 1370 ppm tin at rates of 1.6-6.7 mg tin/kg. Nausea
and diarrhoea occurred only at the 1370 ppm level equivalent to
4.4-6.7 mg tin/kg but did not appear when ingestion was repeated one
month later (Benoy et al., 1971).
Short-term studies
Rat
Groups of rats were fed in their diet 0, 0.03, 0.1, 0.3 and 1.0 per
cent. of stannous oxalate, stannous phosphate, tin oxide, tin sulfide
and tin oleate for 28 days. The oxalate and phosphate produced
dose-related anemia, liver enlargement and histological evidence of
liver damage at doses of 0.3 and 1.0 per cent. in the diet (de Groot
et al., 1971).
Long-term studies
Mouse
Groups of mice received over several generations in their drinking
water sodium chlorostannate either at 1000 or 5000 ppm Sn, or stannous
oleate in their diet at 5000 ppm. No adverse effects were noted nor
was there any difference in tumour incidence between test and control
groups (Walters and Roe, 1965).
Rat
A group of 13 male and 17 female rats were fed on a diet containing 2
per cent. chlorostannate for over one year. Sixteen males and 17
females acted as controls. One mammary adenocarcinoma, one uterine
sarcoma and one adenocarcinoma near the jaw occurred in the test
group, none in the controls. The difference in tumour incidence was
probably not significant (Roe et al., 1965).
STANNOUS CHLORIDE
Acute toxicity
Animal Route LD50 mg/kg LD100 mg/kg Reference
body-weight body-weight
Mouse Oral - 40 Le Breton, 1962
Oral 250 - Pelikan et al.,1968
Oral 1 200 - Calvery, 1942
Rat Oral 700 - Calvery, 1942
Guinea-
pig Oral - 60 Le Breton, 1962
Rabbit Oral - 40 Le Breton, 1962
Oral 10 000 - Eckardt, 1909
Tin accumulated mainly in the liver, the kidneys and the heart. Cats
receiving stannous chloride by gavage at a rate of 9 mg/kg showed
salivation, vomiting and diarrhoea but no acute effects at neutral pH
(Cheftel, 1967). A 1 per cent. solution Of SnCl2, when applied for
18 hours to dermal scratches in rabbits, produced a reaction with
intraepidermal pustules but none on intact skin. Probably some
interference with enzymes occurs (Stone & Willis, 1968).
Short-term studies
Rat
Groups of 10 male and 10 female rats were given 0, 0.03, 0.1, 0.3 and
1.0 per cent. of stannous chloride in their diet for 4 weeks. No
effects were noted on behaviour and general condition. Body-weights
of both sexes were significantly reduced at the 0.3 and 1.0 per cent.
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 per cent.
levels. The relative liver weight was decreased in both sexes at the
1 per cent. level, but kidney weight was unaffected. Histopathology
revealed proliferation of the bile duct epithelium at the 1 per cent.
level only. No other abnormalities were detected (de Groot & Feron,
1970).
Guinea-pig
Groups of guinea-pigs received additional 770 mg Sn/kg body-weight 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 for 7 months. No abnormalities were observed and at autopsy
no tin accumulation was detected (FDA, 1953).
Comments
The inorganic salts of tin are of varying toxicity. Experiments in
animals and man point to almost complete faecal excretion of certain
orally administered inorganic tin salts, little being absorbed into
the body. 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. The gastro-intestinal effects of high tin levels may
be due to local irritation of the mucosa. Short-term feeding of some
tin salts including stannous chloride produced anemia and deleterious
effects on the liver of the species tested. Further studies are
required to clarify these matters, including studies of the tin
compounds as they occur in canned foods.
EVALUATION
The available data do not permit the establishment of a formal ADI.
This will have to await the outcome of further studies. There is no
reason to depart at present from the assessment given in the Tenth
Report of the Joint FAO/WHO Expert committee that the maximum safe
dietary level of tin is unknown but that extensive human experience
does not indicate the existence of any general acute toxicity hazard.
Although the amounts normally found in food, including canned food, do
not appear to pose any acute toxicological problem, further studies on
the biological effects of tin and its salts in several species are
required.
REFERENCES
Benoy, C. J., Hooper, P. A. & Schneider, R. (1971) Pd. Cosm. Tox., (in
press)
Browning, E. (1969) Toxicity of industrial metals, Butterworths,
London
Calloway, D. H. & McMillen, J. J. (1966) Amer. J. Clin. Nutr., 18, 1
Calvery, H. 0. (1942) Food Res., 7, 313
Cheftel, H. (1967) Working paper submitted to 4th Session Codex
Committee on Food Additives, Arnhem
Cheftel, H. (1971) Unpublished report
de Groot, A. P. & Feron, V. J. (1970) Unpublished report No. R 3187
submitted by Centraal Instituut voor Voedingsonderzoek
de Groot, A. P., Til, H. P. & Feron, V. J. (1971) Unpublished report
No. 3299 submitted to WHO
Eckardt, A. (1909) Z. Unters. Lebensm., 18, 193
FAO/WHO (1967) Wld Hlth Org. techn. Rep. Ser., 373
FDA (1953) Food borne injections and intoxications, Garrard Press, 2nd
ed., Champaign
Flinn, F. B. & Inouye, J. M. (1928) J. Amer. Med. Ass., 90, 1070
Heintzke, K. (1959) Ind. Obst. Gemuset., 44, 406
Heintzke, K. (1960) Dtsch. Lebensom -Rund., 56, 194
Horio, T., Iwamoto, Y. & Shiga, I., (1967) Comm. 5th Int. Congr.
Canning, Vienna
Horio, T., Iwamoto, Y. & Komura, S. (1970) Rep. Toyo Jun. Coll. Fd
Techn., (9), 1
Kojima, K. (1969) Unpublished reports submitted to WHO
Kojima, K. (1971) Unpublished reports submitted to WHO
Kolmer, J. A., Brown, H. & Harkins, M. J. (1931) J. Pharmacol., 43,
515
Ministry of Food, U.K. (1952) Food Standards Committee FSC/MC/Rep. 9
Ministry of Health and Welfare, Japan (1969) Unpublished data
submitted to WHO
Omori, Y. (1966) Proc. 11th Pacific Science Congr., Tokyo
Pelikan, Z., Halacka, K. & Cerny, E. (1968) Scripta Medica t.41 f.5-6
Pendergrass, J. & Pryde, A. W. (1948) J. industr. Hyg. T., 30, 119
Roe, F. J. C., Boyland, E. & Millican, K. (1965) Fd. Cosm. Tox., 3,
277
Schryver, B. S. (1909) J. Hyg. (Lond.), 9, 253
Schwartze, E. W. & Clarke, W. F. (1927) J. Phar. exper. Ther., 31,
224
Seifter, J. & Rambousek, E, S. (1943) J. Lab. clin. Med., 28, 1344
Stone, O. J. & Willis, C. J. (1968) Tox. Appl. Pharmacol., 13, 332
Walters, M. & Roe, F. J. C. (1965) Fd. Cosm. Tox., 3, 271
Warburton, S., Udler, W., Ewert. R.M. & Haynes, W. S. (1962) Publ.
Hlth. Rep., 77, 798
See Also:
Toxicological Abbreviations
Tin and stannous chloride (FAO Nutrition Meetings Report Series 48a)
Tin and stannous chloride (WHO Food Additives Series 17)