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    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)