IPCS INCHEM Home


    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

    DDT

    Chemical name

         1,1,1-trichloro-2,2-di-(p-chlorophenyl) ethane;
    trichloro-di-(4'-chlorophenyl) ethane.

    Synonyms

         Chlorophenothane; Zeidane, Gesarol, Neocid, Dicophane

    Empirical formula

         C14H9Cl5

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

         DDT is only slightly absorbed by the skin, but the degree of
    absorption depends on the vehicle used. It may be absorbed after
    inhalation.

         After oral administration, most of the dose is found unchanged in
    the faeces, but some absorption may occur, particularly in the
    presence of lipids. The absorbed DDT is transformed into
    2,2-di-(p-chlorophenyl)-1,1-dichloro-ethylene (DDE) (Pearce et al.,
    1952; Mattson et al., 1953) and into 2,2-di-(p-chlorophenyl)-acetic
    acid (DDA) (Spicer et al., 1947; Judah, 1949; Hayes et al., 1956).
    Some unknown compounds are also found (Spicer et al., 1947; Hayes et
    al., 1956, Rothe et al., 1957; Cueto et al., 1956). A certain amount
    of DDT and DDE accumulates in the fat (Laug et al., 1950; Hayes et
    al., 1958; Maier-Bode, 1960; Laug et al., 1951). DDA is excreted in
    the urine and in a combined form in the bile. DDT is also found in the
    milk (Spicer et al., 1947; Telford & Guthrie, 1945; Wilson et al.,
    1946; Woodard et al., 1945; Smith et al., 1948; Biddulph et al., 1950;
    Gannon & Decker, 1960). This solubility in fats, combined with the
    relative chemical stability of the insecticide, explains its
    cumulative nature. In the rat a concentration of 10 ppm in the diet
    has been shown to interfere with the storage and metabolism of vitamin
    A in the liver (Phillips, 1963).

    Acute toxicity

                                                                      
    Animal             Route           LD50 mg/kg       References
                                       body-weight
                                                                      

    Rat                Oral             150-420*        Negherbon, 1959

    Rat             Intravenous           40-60         Negherbon, 1959

    Mouse              Oral             150-400*        Negherbon, 1959

    Guinea-pig         Oral                400          Negherbon, 1959

    Rabbit             Oral             250-400*        Negherbon, 1959

    Rabbit        Intraperitoneal         2 100         Negherbon, 1959

    Dog             Intravenous       Approximately     Negherbon, 1959
                                           50

    Cat                Oral             400-600*        Negherbon, 1959

    Monkey             Oral               >200          Negherbon, 1959

    Horse              Oral               >300          Negherbon, 1959

    Chicken            Oral              >1 300         Negherbon, 1959
                                                                      

    * The LD50 dose of DDT varies within wide limits, depending on sex,
    and the type of vehicle used.

         The toxic effects, revealing involvement of the central nervous
    system (such as hypersensitivity, excitability, generalized trembling,
    convulsions, paralysis) appear within 5-10 minutes of intravenous
    administration and after a latent period of some hours following oral
    administration. Death occurs as a result of respiratory arrest in the
    rat, rabbit, cat and monkey, and of ventricular fibrillation in the
    dog. It is the consensus of the literature that the significant action
    of DDT is on the nervous system; when ventricular fibrillation occurs,
    it is precipitated by adrenaline released from the adrenal medulla by
    stimulation of the sympathetic nervous system (Phillips & Gilman,
    1946).

         In rats given a single oral dose of DDT sufficient to kill about
    half of them, the severity of symptoms corresponded with the
    concentration of the unchanged compound in the brain (Dale et al.,
    1963). Furthermore, approximately the same concentration of DDT is
    found in the brain of rats killed by DDT no matter whether the dosage
    is acute, subacute, or chronic (Hayes & Dale, 1964).

         The fatal dose for man is difficult to establish but is generally
    taken to be of the order of 500 mg/kg body-weight. A dose of the order
    of 10 mg/kg body-weight can give rise in some subjects, but not in
    all, to toxic symptoms (nausea, headache, sweating), and with doses of
    16 mg/kg body-weight upwards, convulsions often occur (Anon., 1951).

    Short-term studies

         Rat. Rats, in groups of 8 males and 8 females, were gives diets
    with 1, 5, 10 and 50 ppm of DDT for 23 weeks. At concentrations of 5
    ppm and higher, histopathological changes in the liver were found
    (Laug et al., 1950).

         A series of experiments was carried out with small groups of
    rats, 178 males and 104 females in all, which were given diets
    containing DDT in concentrations from traces up to 5000 ppm for
    periods ranging from one to 14 months. In some cases observation of
    the animals continued after cessation of treatment. At levels above
    400 ppm changes in growth rate were noted. Above 200 ppm liver
    enlargement was seen. In the male animals with intakes of 5 ppm and
    above, specific histological lesions in the liver were seen. These
    lesions consisted of hypertrophy of the parenchymal cells, increased
    lipid deposits, marginal localization of cytoplasmic granules and,
    above all, the appearance of complex cytoplasmic inclusions of a lipid
    nature, called "lipospheres". In the females these liver lesions were
    only seen in diets containing 200 ppm or more. Necrotic lesions were
    seen only at concentrations above 1000 ppm (Ortega et al., 1956). The
    authors noted that lipospheres and other changes considered
    characteristic of DDT were more prominent in male rats although
    females store more of the compound and were more susceptible to
    poisoning. For this and other reasons, they speculated that the
    changes might be adaptive. They noted also that earlier work had
    failed to demonstrate similar changes in other species (Ortega et al.,
    1956). Later work in the same laboratory failed to demonstrate such
    changes in monkeys treated with DDT for 7.5 years (Durham et al.,
    1963).

         In an electron-microscopical examination of the liver of rats fed
    diets containing 5-1000 ppm of DDT for 2-18 months, the following
    cytoplasmic abnormalities were found: slight proliferation of the
    endoplasmic reticulum; peripheral distribution of the ribosomes and
    intracytoplasmic inclusions consisting of aggregates of membranes very
    rich in lipids (Ortega, 1962).

         Daily oral doses of DDT 0.2 mg/kg for 10 days produced functional
    changes in the conditional reflex pattern which appeared after 5-7
    doses and persisted 5-7 days after the end of exposure (Andronova,
    1956).

         Behavioural studies have also been made on groups of rats fed
    diets containing 100, 200, 400 and 600 ppm DDT. Problem solving and
    speed of locomotion were unaffected by these doses of DDT. There was a

    significant alteration in the patterns of locomotion in these rats and
    their reactions to stress involving visual stimuli were reduced
    (Khairy, 1959).

         Dog. Dogs were given DDT orally. Those receiving 100 mg/kg
    body-weight daily died within 7 weeks. Animals subjected to lower
    doses survived and seemed normal even after 50 weeks (Draize et al.,
    1944). When the experiment was continued for 3 years, the animals
    receiving doses of 50 and 80 mg/kg body-weight developed jaundice and
    haemorrhagic symptoms. Those receiving 10 mg/kg body-weight daily
    showed no ill effects (Hayes et al., 1956; Lehman, 1952).

         Dogs were given DDT by stomach-tube, in the form of a 10%
    solution in peanut oil in doses ranging from 150 to 350 mg/kg
    body-weight for about 90 days. Some of the animals died. The authors
    noted neurological symptoms, showing involvement of the cerebellum as
    revealed by histological lesions (Haymaker et al., 1946).

         Three dogs were given intramuscular injections of DDT in the form
    of a 10% solution in olive oil at the rate of 100 mg/kg body-weight
    daily for 25 to 30 days. A control animal received 1 ml of olive oil
    in the same way. The experimental animals showed a temporary loss of
    weight. The kidneys were discoloured and on histological examination
    showed tubular damage. At the same time, proliferation was observed in
    the lymphoid tissues (lymph nodes, spleen, bone marrow) and the wall
    of the small intestine, but the blood showed no leukaemic
    characteristics (Gerebtzoff et al., 1950; Gerebtzoff & Philippot,
    1952).

         Monkey. Monkeys given DDT orally in a dose of 0.2 mg/kg
    body-weight for 7-9 months developed symptoms of hepatitis. After a
    year, the animals showed liver enlargement and hyperglycaemia
    (Shillinger et al., 1955). These liver changes were not confirmed in
    another experiment on monkeys lasting 7.5 years (Durham et al., 1963).

    Long-term studies

         Rat. Groups of 12 male rats were subjected for 2 years to diets
    containing 100, 200, 400 and 800 ppm of DDT, in the form of a 10%
    solution in corn oil. In another experiment groups each of 24 rats (12
    males and 12 females) were given, during the same period, diets
    containing 200, 400, 600 and 800 ppm. Also additional groups of 24
    animals received 600 and 800 ppm incorporated in their feed in a dry
    state. In the groups receiving 400 ppm and above, an increase in the
    mortality rate was seen in relation to the dose. Apart from nervous
    symptoms at doses of 400 ppm and above, typical liver lesions were
    found at all concentrations. Hepatic cell tumours were seen in 4 out
    of 75 animals and 11 other rats showed nodular adenomatoid hyperplasia
    (Fitzhugh & Nelson, 1947).

         In an experiment with rats fed for 2 years on a diet containing
    10 ppm of DDT, histological liver lesions were also observed
    (Fitzhugh, 1948). Groups of 80 young rats each (40 male and 40 female)

    were fed 0.25, 12.5 and 25 ppm of DDT. The histological lesions of the
    liver observed were always slight and, according to the authors,
    non-specific, but nevertheless they were more frequent with DDT than
    with aldrin or dieldrin, which were administered in the same
    concentrations for comparative purposes (Treon & Cleveland, 1955).

         Experiments with 25 young rats did not show any harmful effects
    after daily application by stomach-tube of a dose of 10 g of DDT
    equivalent to a dietary intake of 0.1-0.15 ppm for 17 months (Klimmer,
    1955).

         Monkey. Twenty-four Rhesus monkeys, 12 males and 12 females,
    were divided into groups and fed over periods as long as 7.5 years or
    more on diets containing respectively 5, 50, 200 and 5000 ppm of DDT.
    All the animals subjected to the concentration of 5000 ppm showed
    convulsions, accompanied by loss of appetite and a fall in weight. At
    a concentration of 200 ppm or below (the latter dose corresponding to
    daily doses of 2.2-5.54 mg/kg body-weight), no harmful effects were
    observed and, in particular, no histological lesions in the liver or
    disturbances in the functioning of that organ, as shown by the
    bromsulfthalein test (Durham et al., 1963).

         Observations on man. An experimental study was carried out of
    the effects on man of prolonged ingestion of small doses of DDT (in
    the form of oily solutions in capsules or emulsions in milk). The
    authors used for this study, 51 volunteers; 17 received a normal diet,
    17 received 3.5 mg/kg body-weight and 17 received 35 mg DDT daily. The
    last dose is approximately 0.5 mg/kg body-weight. Administration was
    continued for as long as 18 months. The authors noted that the
    accumulation of the insecticide in the fatty tissues and the urinary
    excretion of its metabolite, DDA, were proportional to the dose of DDT
    ingested. A state of equilibrium was reached after about a year and
    the concentration of DDT accumulated in the fatty tissues reached an
    average of 234 ppm (101-367 ppm) in subjects who had ingested 35 mg of
    DDT per day. Throughout the whole experiment, no subject complained of
    malaise, nor did any ill-effects appear that could be attributed to
    the ingestion of DDT (Hayes et al., 1956). The essential results were
    confirmed in a separate investigation in which dosage with DDT lasted
    for 21 months and the volunteers were observed for an additional 27
    months. Fourteen men received 35 mg/man/day; 6 received 3.5
    mg/man/day, and 4 men served as controls. The study also revealed the
    relationship between storage of DDT And the urinary excretion of DDA
    and demonstrated that the loss of DDT from storage in man following
    cessation of dosage is slow - only about two-thirds in 27 months,
    (Hayes et al., in preparation).

         Observations were made on 40 workers engaged, over a period of
    years, in the manufacturing of specialities based on DDT, under
    conditions where suitable precautions had not been taken to protect
    their skin. According to the DDA concentration found in the urine,
    these subjects had absorbed daily as much DDT as volunteers who had
    ingested 35 mg of the insecticide per day in the experiment mentioned

    above. Thorough medical and biological tests failed to reveal any
    toxic symptoms, even in workers exposed to the toxic product for 6.5
    years (Ortelee, 1958).

         More recent studies of the same and other workers, some with
    longer exposures, confirmed the essential findings.

         It has been shown by Durham et al. (1965) that the storage of DDT
    in man is directly proportional to intake over a wide range of dosage
    (0.04 to 35.0 mg/man/day) so that from the level in the fat the daily
    intake can be estimate. From this relationship and from recent
    measurements of DDT stored in human fat (Dale et al., 1965) it is
    clear that the highest average intake of DDT of any human population
    yet observed is about 0.68 mg/man/day. However, in the only country
    where samples have been taken repeatedly, the level of storage of DDT
    by the general population did not increase from 1950 through 1963, the
    last year for which information is now available (Quinby et al.,
    1965).

    Comments on experimental studies reported

         DDT has been studied extensively in several species of animals.
    The rat is particularly susceptible. Concentrations as low as 5 and 10
    ppm in the diet have caused changes in some male rats but these are
    inconstant, reversible and they are always most prominent in the least
    susceptible sex.

         Of much greater importance is the enormous amount of work which
    has been done on the effects of this compound in man. Doses equivalent
    to 0.5 mg/kg body-weight daily have been given experimentally to a
    group of significant size for as long as 21 months without effect
    apart from storage in the fat.

    EVALUATION

         This has been based on the studies on man.

    Estimate of acceptable daily intake for man

         0-0.01 mg/kg/body-weight.

    REFERENCES

    Andronova, G. P. (1956) Dissertation, F. F. Erisman's State Research
    Institute for Hygiene, Moscow

    Anon. (1951) Report of the Committee on Pesticides of the Council on
    Pharmacy and Chemistry, J. Amer. med. Ass., 145., 725

    Biddulph, C., Bateman, G. Q., Bryson, M. J., Harris, J. R., Greenwood,
    D. A., Binns, W., Miner, M. L., Harris, L. E. & Madsen, L. L. (1950)
    Advances in Chemistry, 1, 237

    Cueto, C., Barnes, A. G. & Mattson, A. M. (1956) J. Agr. Food Chem.,
    4 (2), 943

    Dale, W. E., Copeland, N. F. & Hayes, W. J., jr (1965) Bull. Wld.
    Hlth Org. (In press)

    Dale, W. E., Gaines, T. B. & Hayes, W. J., jr (1963) Science, 142,
    1474

    Draize, J. H., Woodard, G., Fitzhugh, O. G., Nelson, A. A., Smith, R.
    B. & Calvery, H. O. (1944) J. Amer. chem. Soc., 22, 1503

    Durham, W. F., Armstrong, J. F. & Quinby, G. E. (1965) J.
    Environment. Hlth (In press)

    Durham, W. F., Ortega, F. & Hayes, W. J., jr (1963) Arch. Int.
    Pharmacodyn., 141, 111

    Fitzhugh, O. G. (1948) Ind. Eng. Chem., 40, 704

    Fitzhugh, O. G. & Nelson, A. A. (1947) J. Pharmacol. exp. Ther.,
    89, 18

    Gannon, N. & Decker. G. C. (1960) J. Econ. Ent., 53, 411

    Gerebtzoff, M. A. & Philippot, E. (1952) Experientia (Basel, 8
    (10), 395

    Gerebtzoff, M. A., Philippot, E. & Dallemagne, M. J. (1950) C.R.
    Soc. Biol. (Paris), 144, 1135

    Hayes, W. J., jr & Dale, W. E. (1964) Toxicol. Appl. Pharmacol., 6
    349

    Hayes, W. J., jr, Dale, E. & Pirkle, C. I. (In preparation)

    Hayes, W. J., jr, Durham, W. F. & Cueto, C., jr (1956) J. Amer. med.
    Ass., 162 (9), 890

    Hayes, W. J., jr, Walker, K. C., Elliott, J. W. & Durham, W. F. (1958)
    Arch. industr. Hlth, 18, 398

    Haymaker, W., Ginzler, A. M. & Ferguson, R. L. (1946) Amer. J. M.
    Soc., 212, 423

    Judah, J. D. (1949) Brit. J. Pharmacol., 4, 120

    Khairy, M. (1959) Quart. J. exp. Psychol., 11, 84

    Klimer, O. R. (1955) Arch. exp. Path. Pharmak., 227, 183

    Laug, E. P., Kunze, F. M. & Prickett, C. S. (1951) Arch. industr.
    Hyg., 3, 245

    Laug, E. P., Nelson, A. A., Fitzhugh, O. G. & Kunze, F. M. (1950)
    J. Pharmacol. exp. Ther., 98, 268

    Lehman, A. J. (1952) Quart. Bull. Assoc. Food & Drug Officials,
    U.S., 16, 3, 47, 126

    Maier-Bode, H. (1960) Med. exp. (Basel), 1, 153

    Mattson, A. M., Spillane, J. T., Baker, C. & Pearce, G. W. (1953)
    Anal. Chem., 25, 1067

    Negherbon, W. O. (1959) Handbook of Toxicology, Philadelphia &
    London, Saunders, vol. III

    Ortega, P. (1962) Fed. Proc., 21, 306

    Ortega, P., Hayes, W. J., jr, Durham, W. F. & Mattson, A. (1956)
    Publ. Hlth Monogr. 43, 27 (33 references)

    Ortelee, M. F. (1958) Arch. industr. Hlth, 18, 433

    Pearce, G. W., Mattson, A. M. & Hayes, W. J., jr, (1952) Science,
    116, 254

    Phillips, W. E. G. (1963) Canad. J. Biochem., 41, 1793

    Philips, F. & Gilman, A. (1946) J. Pharmacol. exp. Ther., 86, 213

    Quinby, G. E., Hayes, W. J., jr, Armstrong, J. F. & Durham, W. F.
    (1965) J. Amer. med. Ass., 191, 175

    Rothe, C. F., Mattson. A. M., Nuelsein, R. M. & Hayes, W. J., jr
    (1957) Arch. industr. Hlth, 16 (1), 82

    Shillinger, U. I., Naumova, L. P. & Pererman, S. W. (1955)
    Vep. Pitan., 14, 41

    Smith, R. F., Hoskins, W. M. & Hullmer, O. H. (1948) J. econ. Ent.,
    41, 759

    Spicer, S. S., Sweeney, T. R., von Oettingen, W. F., Lillie, R. D. &
    Neal, P. A. (1947) Vet. Med., 42 (8), 289

    Telford, H. S. & Guthrie, J. E. (1945) Science, 102, 647

    Treon, J. F. & Cleveland, F. P. (1955) J. Agr. Food Chem., 3, 402

    Wilson. H. F. et al. (1946) J. econ. Ent., 39, 802

    Woodard, G., Ofner, R. R. & Montgomery, C. M. (1945) Science, 102,
    177
    


    See Also:
       Toxicological Abbreviations
       Ddt (ICSC)
       DDT (JECFA Evaluation)
       DDT (PIM 127)
       DDT (FAO/PL:CP/15)
       DDT (FAO/PL:1967/M/11/1)
       DDT (FAO/PL:1968/M/9/1)
       DDT (FAO/PL:1969/M/17/1)
       DDT (Pesticide residues in food: 1979 evaluations)
       DDT (Pesticide residues in food: 1980 evaluations)
       DDT (Pesticide residues in food: 1984 evaluations)
       DDT (JMPR Evaluations 2000 Part II Toxicological)