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    FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN 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 in Rome,
    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

    PROPHAM

    Chemical name

           Isopropyl N-phenylcarbamate; N-phenyl-isopropylcarbamate;
    isopropyl-carbanilate.

    Synonym

           IPC

    Empirical formula

           C10H13O2N

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Acute toxicity

                                                                    
    Animal        Route          LD50 mg/kg     References
                                 body-weight
                                                                    

    Mouse         Oral          approx. 3000    van Esch et al., 1958

    Mouse    Intraperitoneal    approx. 1000    van Esch et al., 1958

    Rat           Oral              9000        van Esch et al., 1958

    Rat      Intraperitoneal         600        van Esch et al., 1958
                                                                    

    Short-term studies

           Mouse. Groups of 30 mice, 15 females and 15 males were given
    the following oral doses of propham: one group, a single dose of 750
    mg/kg body-weight, a second group, once a week an oral dose of 750
    mg/kg body-weight, and a third group, 1000 ppm in the diet for 6

    months. Propham was used as initiator and croton oil was painted on
    the skin as a promoter. Although in some of the original groups skin
    papillomas developed following applications of croton oil in mice fed
    propham, this result could not be confirmed in a number of subsequent
    experiments carried on in the same institution. No lung tumours were
    found in these experiments. Positive controls given ethylurethane in
    the place of propham developed both skin papillomas and lung adenomas
    (van Esch et al., 1958; van Esch, 1965).

           Rat. Ten rats were fed for one month a diet containing 10 000
    ppm of propham. No differences in weight gain in comparison with the
    control rats were found (Brown & Gross, 1949).

           Groups of 4 rats were fed 400, 800 and 1600 ppm for 3 months; 
    the growth rate and reproduction was normal. No gross abnormalities 
    were seen in the lung, liver, intestine or kidneys (Schuurmans 
    Stekhoven et al., 1955).

           Pig. Groups of 4 pigs were fed 3300 ppm of propham for 19
    weeks. No differences in weight gain from the controls were found. At
    autopsy no gross abnormalities were seen. Liver, kidney and spleen
    were histologically normal. No changes in the blood picture were
    observed (van Esch & van Genderen, 1956-57).

    Long-term studies

           Mouse. Groups of 30 mice were given 10 000 and 20 000 ppm of
    propham in their diet for approximately 18 months. The mortality rate
    was very high, especially in the beginning. Further groups each of 50
    mice were given 1000 and 5000 ppm. The mice became emaciated, lost
    appetite and many of them died unless they were taken off the
    experimental diet every 2 weeks and placed on normal diet for an equal
    period. Loss of hair was noticed. At autopsy no benign or malignant
    tumours were found in the lungs or other organs.

           Sixty mice were given injections every 2 weeks of a suspension 
    of propham in lanolin into the right femoral muscle; the doses were
    equivalent to 40 mg/100 g body-weight. The injections were continued
    for 6 months. The duration of the experiment was 10 months. At the
    site of injection encapsulated injection material was present without
    reaction of the surrounding tissue. There was no evidence of any
    neoplastic reaction (Hueper, 1952).

           The experiment was repeated in 60 mice, but the injections were
    given in the right pleural cavity. The duration of the experiment was
    18 months. No evidence of tumour formation was present (Hueper, 1952).

           Rat. Fifteen adult rats were given 20 000 ppm propham in their
    diet for 18 months. The rats were given alternately the propham diet
    for 1-2 months and a normal diet for 1-2 weeks; at autopsy no tumours
    were found. No histopathological changes were seen (Hueper, 1952).

           Fifteen rats were given monthly injections of a suspension of
    propham in lanolin into the right femoral muscle in doses equivalent
    to 40 mg/100 g body-weight. The injections were continued for 6
    months. The duration of the experiment was 18 months. At the site of
    injection, encapsulated injected material was present with
    inflammatory foam cell reaction around it but no other reaction. The
    experiments were repeated with 15 rats but the injections were given
    in the right pleural cavity. The duration of the experiment was 18
    months. In these experiments no tumours of any kind were present
    (Hueper, 1952).

           Three groups each of 9 rats were given orally approximately 
    1000 and 1500 ppm propham and 1000 ppm ethylurethane in dry feed. 
    Twelve more animals were added as controls. The first group was fed 
    for 18 months, the other 2 groups for 15 months. After 15 and 18 
    months no lung tumours were seen (Engelhorn, 1954).

    Comments on experimental work reported

           The suspicion that propham could be a co-carcinogen for mice
    could not be confirmed. In other species experiments purposely
    designed did not indicate any tumorigenic effect.

    EVALUATION

           Not enough toxicological data on animals are available at 
    present to set a no-effect level.

    Further work required

           Biochemical studies. Further long-term feeding studies in the 
    rat and other species.

    Further work considered desirable

           Biochemistry of propham and further work on carcinogenicity.

    REFERENCES

    Brown, J. H. & Gross, P. (1949) Report of Ind. Hyg. Foundation to
    Pittsburgh Plate Glass Co.

    van Esch, G. J. (1965) Personal communication concerning data from the
    National Institute of Public Health, Utrecht, The Netherlands

    van Esch, G. J. & van Genderen, H. (1956-57) Preliminary reports of
    the National Institute of Public Health

    van Esch, G. J., van Genderen, H. & Vink, H. H. (1958) Brit. J.
    Cancer, 12, 355

    Engelhorn, R. (1954) Naunyn-Schmiedeberg's Arch. exp. Path.
    Pharmak., 223, 177

    Hueper, W. C. (1952) Industr. Med. Surg., 21, 71

    Schuurmans Stekhoven, J. H., Roskott, L. & Veenhof, M. J. (1955) T.
    Diergeneesk., 80, 400
    


    See Also:
       Toxicological Abbreviations
       Propham (Pesticide residues in food: 1992 evaluations Part II Toxicology)
       Propham (IARC Summary & Evaluation, Volume 12, 1976)