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    FAO Meeting Report No. PL/1965/10/2
    WHO/Food Add/28.65

    EVALUATION OF THE HAZARDS TO CONSUMERS RESULTING FROM THE USE OF
    FUMIGANTS IN THE PROTECTION OF FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met 15-22 March
    19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

             
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65.

    CARBON TETRACHLORIDE

    Compound

         Carbon tetrachloride

    Chemical name

         Carbon tetrachloride

    Synonym

         Tetrachloromethane

    Empirical formula

         CCl4

    Structural formula

    CHEMICAL STRUCTURE 

    Relevant physical and chemical properties

    Physical state (atmospheric pressure, 20C): colourless liquid

    Boiling-point: 76.8C

    Odour: sweetish, chloroform-like

    Lowest concentration in air which is detectable by odour: 70 ppm

    Flash point: non-flammable

    Solubility:

         Water: insoluble

         Organic solvents: miscible with most organic solvents

    Specific gravity (liquid): 1.60

    Specific gravity (gas): 5.32

    Uses

         Carbon tetrachloride is used extensively as a fumigant, either
    alone or mixed with other more toxic fumigants including ethylene
    dichloride, ethylene dibromide, acrylonitrile, carbon disulfide and
    methyl bromide. Carbon tetrachloride is not highly toxic to insects
    but since it penetrates to great depths is used for the treatment of
    grain in deep silo storages where the disadvantage of its relatively
    low toxicity can be overcome by a long exposure period, e.g., of seven
    or even 14 days. It is applied as evenly as possible over the grain
    surface by hand or preferably by a mechanically driven pump. A typical
    rate of application is one gallon per 12 tons of grain.

    Residues

         Carbon tetrachloride is taken up physically and without chemical
    action. The amount taken up by unground whole wheat can be accounted
    for by assuming it forms an ideal solution in the wheat oils. Ground
    wheat absorbs additional amounts of carbon tetrachloride evidently not
    held in solution (Pepper et al., 1947).

         Wheat treated on a laboratory scale with a high concentration of
    carbon tetrachloride (approximately 300 mg per litre at 20C for 24
    hours) contained 49 ppm four days after treatment and 10 ppm after 55
    days. Flour produced from wheat containing 10 ppm of carbon
    tetrachloride had 5.7 ppm. No carbon tetrachloride was found in bread
    baked from this flour (sensitivity of method 0.5 ppm) (Deshusses and
    Desbaumes, 1950).

         In an extensive study of the persistence of fumigant residues in
    wheat and its milled products (Conroy et al., 1957), it was shown that
    grain fumigated in the laboratory with a commonly used application
    rate of carbon tetrachloride:carbon disulfide mixture (80:20) had the
    following residues of carbon tetrachloride: original wheat 115 ppm;
    after milling, flour 21 ppm, shorts 39 ppm, bran 88 ppm. Maximum
    levels of carbon tetrachloride in 30 bushel-batches of wheat after
    treatment with normal and triple USDA dosage levels of carbon
    tetrachloride: carbon disulfide mixture (80:20) were 15 and 25 ppm
    respectively. After cleaning and tempering, the residues of the wheat
    fumigated at the triple dosage level fell to 9 ppm and after milling
    the bran contained 12 ppm. Flour milled from the wheat treated with a
    triple dosage contained 1.5 ppm of carbon tetrachloride. During
    shipment, residues of carbon tetrachloride in flour decreased from 1.5
    ppm to 0.7 ppm.

         Maximum residue of carbon tetrachloride in 33 samples of
    commercially treated wheat one to five months after fumigation was 50
    ppm. The maximum residues in corn, rough rice, oats and grain sorghum
    were all lower than for wheat.

         Wheat fumigated with carbon tetrachloride: ethylene dichloride
    mixture (25:75) showed an average residue of 200 ppm of carbon
    tetrachloride 24 hours after fumigation. The first turning reduced the
    level to 145 ppm (at 65F) and the residue, after two additional
    turnings was 100 ppm. Two more turnings resulted in only about 10%
    further reduction. The highest persistent residues of carbon
    tetrachloride in commercial usage would be about 130 ppm.

         Carbon tetrachloride added to baking flour (Munsey et al., 1957)
    at approximately 10 times the maximum levels found in the flour after
    normal fumigation did not persist in the bread. (Sensitivity of
    method, 1 ppm.)

    Effect of fumigant on treated crop

         Carbon tetrachloride does not appear to combine chemically with
    the constituents of food crops. The level of residues in the wheat
    germ which has a high fat content was found to be less than 50% of
    that in the bran (Conroy et al., 1957).

    BIOLOGICAL DATA

    Biochemical aspects

         Carbon tetrachloride causes widespread liver damage. When fed
    orally to dogs most of it is excreted unchanged by the lungs (Robbins,
    1929). Monkeys inhaling 14CCl4 absorbed about 30% of the amount
    inhaled and excreted at least 51% of the dose unchanged in the expired
    air. Some was metabolized since 14CO2 was detected in the expired
    air and radioactive carbon was present in the urea and carbonate
    fractions of the urine. Most of the radioactivity in the urine was
    present as unidentified metabolites. Body fat contained the highest
    concentration of radioactive material (McCollister et al., 1951).

         After subcutaneous administration to rats only traces were
    excreted in urine and faeoes, over 90% being excreted through the
    lungs. Carbon tetrachloride was detected in the expired air 49 hours
    after a dose of 43 mg/kg. Red blood cells retained about 2.5 times
    more carbon tetrachloride than did plasma (Soucek, 1961).

         After administration to rabbits, 51% was eliminated by
    respiration and 49% in urine and faeces. Highest concentrations were
    found in nerve, bone marrow and the suprarenal gland (Fabre et al.,
    1961).

    Toxicological studies

    1. The fumigant

         Because of the high toxicity of carbon tetrachloride vapour,
    stringent precautions must be taken to protect those handling it.
    Maximum permissible concentration in the atmosphere recommended for

    industrial hygiene is 10 ppm (65 mg/m3) (Anon, 1964). It may be
    absorbed through the skin and if ingested can be absorbed from the
    alimentary tract.

    Acute toxicity
                                                                  
    Animal   Route        LD50 mg/kg      References
                          body-weight
                                                                  

    Mouse    oral          12 800         Dybing & Dybing, 1946
    Rat      oral           7 460         Smyth,
    Rat      oral           2 920         McCollister et al., 1956
                                                                  

    Short- and long-term studies

         Carbon tetrachloride has been extensively studied from the point
    of view of its biochemical and pathological effects on the liver.
    These investigations have been recently reviewed by Rouiller (1964).
    Carbon tetrachloride has been shown to produce malignant liver tumours
    when given by mouth to mice and hamsters, but this effect is not found
    in rats (World Health Organization, 1964).

         Groups of three or four male rats were exposed -- single doses of
    varying concentrations of carbon tetrachloride vapour for different
    lengths of time and an estimate of the single doses having no
    observable adverse effects was made (Adams et al., 1952). For 3000
    ppm, the maximum time was 0.1 hour; for 800 ppm, 0.5 hour and for 50
    ppm, 7.0 hours.

         Intermittent exposure of animals to carbon tetrachloride vapour
    for seven hours (about 140 exposures in 200 days) showed a no-effect
    level (with full macroscopic and microscopic examinations of organs
    and tissues) at 5 ppm for rats and guinea-pigs. For monkeys (one
    animal only studied) the no-effect level was estimated at 25 ppm and
    for rabbits 10 ppm (Adams et al., 1952).

         In an earlier study (Smyth et al., 1936) guinea-pigs, rats and
    monkeys were exposed to different levels of carbon tetrachloride
    vapour for periods up to 10 months. A no-effect level was not
    clearly demonstrated in these experiments but an estimate was made
    that 100 ppm for eight hours per day indefinitely would be "safe".

         Man. Smyth et al. (1936) examined 96 men exposed to average
    concentrations of from 5 ppm to 117 ppm of carbon tetrachloride. Of
    these, 19 had been exposed for 10 years and 11 of these showed
    abnormal clinical findings. Of 88 workers exposed to less than 100
    ppm, 43 gave no abnormal results but tests on the remainder gave
    evidence of some abnormality.

         Thirteen workers were exposed to carbon tetrachloride vapour
    averaging 30 ppm (0.19 mg/l) for varying periods. One showed acute
    toxic symptoms including subicteric increase of bilirubin which
    disappeared after one month. Serum colloidal stability tests were
    normal but were found altered one month after the onset, returning to
    normal only after five months. Indications of hepatic changes in the
    other workers were revealed by santonine and quinine liver function
    tests (Sassi and Paruccini, 1954).

    2. The fumigated foodstuff

         Chickens fed for five days, pigs for 12 days and cattle for 7.5
    days with grain freshly treated with a fumigant containing 64% (by
    weight) of carbon tetrachloride showed no observable effect. The
    levels of CCl4 in the grain were not stated and no histopathological
    examinations were made (Rowe et al., 1956).

    Comments on experimental studies reported

    1. Carbon tetrachloride has a relatively high chronic vapour toxicity
    and industrial safety levels, calculated from vapour toxicity tests on
    several species, have been reduced to 10 ppm in ambient air. Carbon
    tetrachloride is actively metabolized when absorbed.

    2. Carbon tetrachloride produces tumours in the mouse and hamster, but
    not in the rat or other species, and differs from many other
    carcinogens in only producing tumours in the organ which is also
    damaged by acute exposure, namely the liver. In view of the widespread
    industrial experience with this chemical compound, it was considered
    that there was no evidence to suggest that man was sensitive to this
    action of carbon tetrachloride.

    3. When used as a fumigant for grain, most of it is lost during
    shipment and storage but residues may persist even in milled products.
    No carbon tetrachloride was found in bread baked with flour containing
    5.7 ppm carbon tetrachloride.

    4. Although it dissolves in the fats present in the grain there is no
    evidence of chemical reaction with the food constituents.

    Evaluation

         On the available toxicological evidence it is impossible to
    calculate an acceptable daily intake for carbon tetrachloride. Because
    of its toxic effects on the mammalian liver, it should be used as a
    fumigant only on condition that no residues (the sensitivity of the
    present analytical method being 0.01 ppm) of the unchanged compound
    reach the consumer.

    Further work required

    1. Further investigation of the amount of the residual carbon
    tetrachloride remaining in the food after treatment and the effect on
    this of processing and cooking.

    2. Long-term feeding studies should be carried out on two mammalian
    species.

    REFERENCES

    Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D. & Irish,
    D. D. (1952) Arch. industr. Hyg., 6, 50

    Anon. (1964) Threshold limit values for 1964, Arch. environm.
    Hlth., 9, 545

    Conroy, H. W., Walkden, H. H. & Farrell, E. (1957) J. Ass. Off. Agr.
    Chemists, 40, 192

    Deshusses, J. & Desbaumes, P. (1950) Mitt. Lebensmitt. Hyg., 41,
    39

    Dybing, F. & Dybing, O. (1946) Acta pharmacol. (Kbh.), 2, 223

    Fabre, R., Truhaut, R. & Laham, S. (1961) Proceedings of the
    Thirteenth International Congress on Occupational Health, New York,
    p. 686

    McCollister, D. D., Beamer, W. H., Atchison, G. J. & Spencer, H. C.
    (1951) J. Pharmacol. exp. Ther., 102, 112

    McCollister, D. D., Hollingsworth, R. L., Oyen, F. & Rowe, V. K.
    (1956) Arch. industr. Hlth, 13, 1

    Munsey, V. E., Mills, P. A. & Klein, A. K. (1957) J. Ass. Off. Agr.
    Chemists, 40, 201

    Pepper, J. H., Hastings, E. & Douglas, T. A. (1947) J. econ. Ent.,
    40, 64

    Robbins, B. H. (1929) J. Pharmacol. exp. Ther., 37, 203

    Rouiller, C. (1964) The liver, Academic Press Inc., New York, vol.
    2, pp. 335-476

    Rowe, V. K., Hollingsworth, R. L. & McCollister, D. D. (1956) J.
    Agric. Food Chem., 2, 1318

    Sassi, C. & Paruccini, C. (1954) Med. d. Lavoro, 45, 93

    Smyth, H. F., jr, Chemical Hygiene Fellowship, Mellon Institute,
    Pittsburgh (Unpublished data)

    Smyth, H. F., Smyth, H. F., jr & Carpenter, C. P. (1936) J. industr.
    Hyg., 18, 277

    Soucek, B. (1961) Pracov. Lk., 13, 287

    World Health Organization (1964) Wld Hlth Org. techn. Rep. Ser.,
    276, 44
    


    See Also:
       Toxicological Abbreviations
       Carbon Tetrachloride (EHC 208, 1999)
       Carbon Tetrachloride (HSG 108, 1998)
       Carbon tetrachloride (ICSC)
       Carbon tetrachloride (FAO/PL:1967/M/11/1)
       Carbon tetrachloride (FAO/PL:1968/M/9/1)
       Carbon tetrachloride (WHO Pesticide Residues Series 1)
       Carbon tetrachloride (Pesticide residues in food: 1979 evaluations)
       Carbon Tetrachloride (IARC Summary & Evaluation, Volume 71, 1999)