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

    DIELDRIN

    Chemical name

         1,2,3,4,10,10-hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-
    endo-1,4-exo-5,8,-dimethanonaphthalene or 1,2,3,4,10,10-hexachloro-
    6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-exo-1,4-endo-5,8,-
    dimethanophthalene.

    Synonyms

         HEOD, Octalox, Alvit, Quintox.

    Empirical formula

         C12H8OCl6

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

         Dieldrin labelled with 14C is preferentially excreted together
    with its metabolites in the bile. Fifteen minutes after an intravenous
    injection, radioactive dieldrin and a hydrophilic metabolite were
    found in the bile (Mörsdorf, et al. 1963).

         Studies with 36Cl-dieldrin have shown that the initial
    distribution is general, but within a few hours of injection it
    concentrates more in the fat. Excretion of 36Cl averages about 5% per
    day and is markedly increased by a restriction of diet, which reduces
    the body fat. From the canulated bile duct, excretion accelerates as
    the rat loses weight exceeding 10% per day after a few days. Only 3%
    of the 36Cl is excreted as dieldrin unless the bile is canulated,
    when up to 10% may be excreted. The remainder of 36Cl is found in the
    metabolites and these are excreted to 90% in the faeces and 10% in the
    urine. The most important metabolite containing about 60% of the total
    36Cl is excreted in the bile (Heath & Vandekar, 1964).

         In experiments 14C dieldrin it was demonstrated that in the
    blood dieldrin is located mainly in the erythrocytes and plasma.
    Haemoglobin is largely but not entirely responsible for the binding to
    erythrocytes. In the plasma, dieldrin binds with soluble proteins
    (Moss & Hathway, 1964).

         After the feeding of dieldrin to animals it is stored in the
    adipose tissues. Although small amounts of dieldrin are found in
    liver, kidney and muscle tissues, the greatest amount of storage is in

    the fat where dieldrin is stored unchanged, (Bann et al., 1956;
    Butcher et al., 1957; Heath & Vandekar, 1964; Ivey et al., 1961;
    Lehman, 1956; Street et al., 1957). It is lost slowly from the body
    fat (Butcher et al., 1957; Heath & Vandekar, 1964). It is stored in
    human fat in significant amounts (Hunter et al., 1963).

         In studies on the urine of individuals exposed to dieldrin, on
    paper and column  chromatography 2 neutral polar metabolites of
    dieldrin were found. No dieldrin could be detected with this method,
    but dieldrin or a material having the same retention time was found by
    gas chromatography (Cueto & Hayes, 1962).

    Acute toxicity

                                                                 
    Animal       Route    LD50 mg/kg    References
                          body-weight
                                                                 

    Mouse        Oral         38        Borgmann et al., 1952
                                        Council of Europe, 1962

    Rat          Oral        37-87      Borgmann et al., 1952
                                        Council of Europe, 1962
                                        Gaines, 1960
                                        Heath & Vandekar, 1964
                                        Lehman, 1951
                                        Lu, et al., 1965
                                        Treon & Cleveland, 1955

    Guinea-pig   Oral         49        Borgmann et al., 1952
                                        Council of Europe, 1962

    Rabbit       Oral        45-50      Borgmann et al., 1952
                                        Council of Europe, 1962

    Dog          Oral        56-80      Borgmann et al., 1952
                                        Council of Europe, 1962

    Sheep        Oral        50-75      Borgmann et al., 1952
                                        Council of Europe, 1962
                                                                 

         In rats the LD50 for a day-old animal is 168 mg/kg body-weight,
    the same as in adults (Lu et al., 1965).

    Short-term studies

         Rat. In a 90-day feeding study, groups of 12 rats (6 male and 6
    female) were fed diets containing 25, 50 and 125 ppm of dieldrin; an
    increased mortality rate was observed at 125 ppm. In another
    experiment, groups of 10 male and 10 female rats were given 2, 5, 10,
    50, 100 and 150 ppm dieldrin. All rats on 150 ppm died. Histological

    liver changes were observed in rats on 10 ppm and above (Borgmann et
    al., 1952).

         Groups of 12 rats, 6 females and 6 males, were fed 2.5 and 25 ppm
    of technical dieldrin. The rats were killed after 2, 4, 6 and 8
    months. Food intake and growth were normal. No significant change in
    liver weight was found. Cytoplasmic alteration of the liver cells was
    found at both concentrations in males and females (Ortega et al.,
    1957).

         Dog. Dogs (1-4 animals per group) were given diets containing
    1, 3, 10, 25 and 50 ppm dieldrin on six days per week. The animals on
    25 and 50 ppm died after 5 and 33 days respectively. Dogs on 10 ppm
    survived for 9 months and on 1 and 3 ppm for 15 months. In the groups
    on 1 and 3 ppm the livers were significantly larger than those of the
    controls. Histological changes were noted in brains, liver and kidneys
    (Treon & Cleveland, 1955). Groups of 4 dogs (2 male and 2 female) were
    given 1 and 3 ppm of dieldrin in their diet for 68 weeks. The
    concentration of 3 ppm increased the liver/body-weight ratio and
    produced renal damage in 1 female. With 1 ppm of dieldrin, livers were
    enlarged but no histopathological changes were found. In the dogs fed
    3 ppm of dieldrin, 45.5 ppm were found in the fat, and in the dogs fed
    1 ppm, 3.4 ppm were found in the fat. In other organs, concentrations
    ranging from 2.9 ppm (liver) to 0.05 ppm (brain) were found (Borgmann
    et al., 1952; Treon & Cleveland, 1955).

         Dogs (both sexes) in groups of 3 or 4 were given dosage levels of
    0.2, 0.6 and 2.0 mg/kg per day by mouth for a maximum time of 313
    days. The highest dosage killed all the dogs. Two of the 4 dogs died
    when given 0.6 mg/kg body-weight per day (Borgmann et al., 1952).

         Three groups of 3 dogs were given orally 0.2 and 0.6 mg per day
    of recrystallized dieldrin per kg of body-weight for one year; 3 of
    them produced litters but none of the pups of the group given 0.6 mg
    survived, probably because of high quantities of dieldrin in the milk
    of the dams. Histological changes were found in the liver and/or
    kidneys of adult dogs (Kitselman, 1953).

         A group of 14 dogs was given dieldrin orally for 25 months at the
    following daily doses: 0.2 mg/kg (2 dogs), 0.5 mg/kg (4 dogs), 1, 2, 5
    and 10 mg/kg (2 dogs in each group). All the dogs given 2, 5 or 10
    mg/kg died in 35 days. All those given 1 mg/kg or 0.5 mg/kg (with one
    exception) died in one year. Convulsions and fatty liver changes were
    frequently seen. At 0.2 mg/kg no effects were observed (Fitzhugh et
    al., 1964).

         Rabbit. In a 90-day study, groups of 20 rabbits (10 female and
    10 male) were given dieldrin orally at dosage levels of 0.625, 1.25,
    2.5, 5 and 10 mg/kg body-weight per day. Survival rates were affected
    at all levels. At 2.5 mg/kg and above, all animals died (Borgmann et
    al., 1952).

    Long-term studies

         Mouse. Groups of approximately 200 young C3HeB/Fe mice,
    equally divided by sex, were fed a diet containing 10 ppm of dieldrin
    for their life-span (maximum 2 years). The dieldrin shortened their
    average life-span by 2 months, as compared with an equal number of
    controls, and significantly increased the incidence of hepatic tumours
    (Davis & Fitzhugh, 1962).

         Rat. Groups of 40 rats (20 male and 20 female) were fed diets
    containing 2.5, 12.5 and 25 ppm dieldrin for 2 years. The
    liver/body-weight ratio increased and characteristic histological
    liver damage was seen at all dosages (Treon & Cleveland, 1955).

         With groups of 16 female rats each, dieldrin was incorporated in
    the diet for three generations at 2.5, 12.5 and 25 ppm. Two litters of
    offspring were taken from each generation of these groups. The
    presence of dieldrin in the diet at 2.5 and 12.5 ppm initially reduced
    the number of pregnancies but this effect tended to disappear with
    continued feeding of the diet. All doses increased the mortality among
    the suckling young. The effect on survival during suckling was severe
    at 12.5 and 25 ppm dieldrin (Treon & Cleveland, 1955).

         In a 2-year experiment, groups of 24 rats (12 male and 12 female)
    were given 0.5, 2, 10, 50, 100 and 150 ppm dieldrin. Concentrations of
    50 ppm and above increased the mortality rate in a dose-response
    relationship. The liver/body-weight ratio increased and characteristic
    histological lesions occurred in the liver at all levels; these were
    minimal at 0.5 ppm but increased in severity with increasing dose.
    There was an increase in the number of tumours in the experimental
    groups, especially at the lower levels of feeding, in contrast to the
    control group (Fitzhugh et al., 1964).

         In other experiments, 40 males and 40 females were given dieldrin
    in the diet at a concentration of 75 ppm for 440 days. Twenty animals
    of each sex were used as controls. All the females and 22 males of the
    experimental group, and 5 control males died spontaneously before the
    end of the treatment. Seven males were killed in good conditions
    between 300 and 440 days and the last 11 males were killed after 440
    days. The liver/body-weight ratio was markedly increased in the rats
    killed during exposure, but it returned to normal after the end of it.
    "Lesions of the hepatic parenchyma that have been considered typical
    of exposure to the organochlorine insecticides in rats" were observed
    only in healthy animals killed during the treatment. Rats dying
    spontaneously or killed after withdrawal of the insecticide did not
    show such type of change (Hunter et al., 1964).

         Ewes. Thirty-six ewes were given 0, 1, 5 or 25 ppm of dieldrin
    in their diets for a period of 40 months including 4 gestation
    periods. At 25 ppm lambs died shortly after birth. Liver function as
    well as other physiological tests on the ewes did not show any changes
    related to the treatment with dieldrin (Shell, 1963).

    Comments on the experimental studies reported

         The primary mode of action of dieldrin is on the central nervous
    system. This is the mechanism of death in acute poisoning. Symptoms of
    central nervous system stimulation are also seen after repeated high
    doses. Repeated doses at lower levels give rise to liver damage and in
    this respect young dogs are more susceptible than rats.

         In one long-term rat feeding experiment, there was a general
    increase in tumour production in the experimental animals at the lower
    dosage levels as compared to the controls, but the liver was not
    particularly affected.

         Liver tumours, however, were significantly increased on a dosage
    of 10 ppm in one strain of mice susceptible to the development of
    these tumours. Some evidence has been presented that the same effect
    can occur in another strain of mice, but this requires more
    information.

         In rats, it has been suggested (Fitzhugh et al., 1964) that the
    apparent tumorgenic properties of dieldrin could be related to a
    "general" type of effect.

    EVALUATION

         From the data presented, an acceptable daily intake for man
    cannot be estimated. Until further evidence is forthcoming, every
    effort should be made to see that the intake of dieldrin for man is
    kept at the lowest possible level.

    Further work required

         Additional long-term toxicity studies in other species than the
    rat, including further reproduction studies. Determination of a
    no-effect level in more than one species.

    REFERENCES

    Bann, J. M. et al. (1956) J. Agr. Food Chem., 4, 937

    Borgmann, A. R. et al. (1952) Unpublished report, July

    Butcher, J. E. et al. (1957) Research report, Agricultural
    Experimental Station, Utah State Agricultural College

    Council of Europe (1962) Agricultural pesticides, Strasbourg

    Cueto, C. & Hayes, W. J., jr (1962) J. Agr. Food. Chem., 10, 366

    Davis. K. J. & Fitzhugh, O. G. (1962) Toxicol. Appl. pharmacol.,
    4, 187

    Fitzhugh, O. G., Nelson. A. A. & Quaife, M. L. (1964) Food &
    Cosmetic Toxicol., 2, 551

    Gaines, T. B. (1960) Toxicol. Appl. Pharmacol., 2, 88

    Heath, D. F. & Vandekar, M. (1964) Brit. J. industr. Med., 21, 269

    Hunter, C. G., Robinson, J. & Richardson, A. (1963) Brit. med. J.,
    3, 221

    Hunter, C. G., Stevenson, D. E. & Ferrigan, L. W. (1964) Data submitted
    by Shell Company

    Ivey, M. C. et al. (1961) J. Agr. Food Chem., 9, 374

    Kitselman, C. H. (1953) J. Amer. vet. med. Ass., 123, 28

    Lehman, A. J. (1951) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 15, 122

    Lehman, A. J. (1956) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 20, 95

    Lu, F. C., Jessup, D. C. & Lavallée, A. (1965) Food & Cosmetic
    Toxicol., 3 (In press)

    Mörsdorf, K. et al. (1963) Med. exp., 8, 90

    Moss, J. A. & Hathway, D. E. (1964) Biochem. J., 91, 384

    Ortega, P., Hayes, W. J. & Burham, W. F. (1957) Arch. Path., 64,
    614

    Shell Chemical Company (1963) Unpublished report

    Street, J. C. et al. (1957) Proc. West Sec. Amer. Soc. Anim. Prod.,
    46 (1)

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


    See Also:
       Toxicological Abbreviations
       Dieldrin (ICSC)
       Dieldrin (PIM 575)
       Dieldrin (FAO/PL:CP/15)
       Dieldrin (FAO/PL:1967/M/11/1)
       Dieldrin (FAO/PL:1968/M/9/1)
       Dieldrin (FAO/PL:1969/M/17/1)
       Dieldrin (AGP:1970/M/12/1)
       Dieldrin  (IARC Summary & Evaluation, Supplement7, 1987)
       Dieldrin (IARC Summary & Evaluation, Volume 5, 1974)