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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

    CHLORDANE

    Chemical name

         1,2,4,5,6,7,8,8-octachloro-3a,4,7,7a-tetrahydro-4,7,
    methanoindane or
    1,2,4,5,6,7,10,10-octachloro-4-7-8-9-tetrahydro-4,7-methyleneindane or
    1,2,4,5,6,7,8,8-octachloro-2,3,3a,4,7,7a-hexahydro-4,7-methanoindane.

    Synonyms

         Toxichlor; Octachlorodihydro-dicyclopentadiene; Octachlor.

    Empirical formula

         C10H6Cl8

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

         Chlordane is absorbed from the alimentary tract. It is stored in
    adipose tissue of sheep, goats, and cows and accumulates in the milk.
    Cows' milk contained 0.1 to 0.2 ppm of chlordane after the animals had
    been fed a diet containing a concentration equivalent to 0.36 to 0.42
    mg/kg body-weight for 150 days (Carter et al., 1953). Some
    water-soluble metabolites are excreted. Organically bound chlorine is
    excreted in the urine of rabbits (Stohlman & Smith, 1950).

         Both technical chlordane and one of its pure isomers
    (gamma-chlordane) have been shown to have stimulating effects on rat
    liver microsomes for the metabolism of certain drugs (Burns et al.,
    1965; Hart & Fouts, 1963; Hart et al., 1963; Kutzman et al., 1964).

    Acute toxicity

                                                                 
    Animal      Route     LD50 mg/kg     References
                          body-weight
                                                                 

    Rat         Oral       200-590*      Ambrose et al., 1953
                                         Ingle, 1954
                                         Stohlman et al., 1950

                Oral        335-430      Gaines, 1960
                            150-225      Ingle, 1954

    Mouse       Oral          430        US Food & Drug Admin., 1947

    Rabbit      Oral       100-300*      Stohlman et al., 1950
                             20-40       Ingle, 1954

    Goat        Oral          180        Welch, 1948

    Sheep       Oral       500-1000      Welch, 1948

    Chicken     Oral        220-230      Turner & Eden, 1952
                                                                 

    * The differences are explained by the use of different solvents, and
    by the fact that the chlordane mentioned in the older literature
    contained a considerable amount of the very toxic hexachlorocyclo
    pentadiene (Ingle, 1954; Lehman, 1952).

         Man. In adults a dose of 104 mg/kg proved fatal (Derbes et al.,
    1955), An 18-year-old female showed convulsions but recovered after a
    dose of approximately 30 mg/kg (amount retained after vomiting
    estimated to be 10 mg/kg). In two infants respectively 15 months and 3
    years of age, 10 and 40 mg/kg gave severe poisoning (Stormont &
    Conley, 1955).

    Short-term studies

         Rat. When a diet containing 1000 ppm of chlordane was fed to 12
    male rats, all of them died within 10 days. At 500 ppm 12/12 died
    within 70 days, at 300 ppm 9/12 were alive after 100 days (Stohlman et
    al., 1950).

         Daily oral doses of 6.25-25 mg/kg given to 5 rats for 15 days
    produced no tremors or convulsions, but daily doses of 50 mg/kg
    produced toxic symptoms and 2 of the animals died. With 100 mg/kg all
    the animals died (Ambrose et al., 1953). Intracytoplasmic bodies in
    the liver-cells were found at all levels and their number was in
    proportion to the dose used (Ambrose et al., 1953).

         Rats in groups of 12 (6 females and 6 males) were fed for periods
    up to 9 months, 2.5 ppm or 25 ppm of a sample of technical chlordane
    containing 60-75% chlordane and 25-40% unrelated products.
    Centrolobular cell hypertrophy, peripheral migration of cytoplasmic
    granules and the presence of cytoplasmic bodies were observed in 1
    male at 2.5 ppm and in 5 males at 12.5 ppm (Ortega et al., 1957).

         Dog. Chlordane was given in varying oral doses to dogs for 7
    days; convulsions were seen in 1 dog at 200 mg/kg (lowest dose) but
    700 mg/kg (highest dose) did not produce any effect (Batte & Turk,
    1948).

         When 4 groups of 2 to 4 dogs were given chlordane orally in doses
    between 5 and 80 mg/kg body-weight daily they all died within periods
    of 25 days to 93 weeks (Lehman, 1952).

         Sheep. Chlordane administered by stomach-tube to sheep in a
    dose of 0.5 g/kg body-weight produced toxic symptom (incoordination,
    partial blindness) in 5 to 6 days. A dose of 1 g/kg body-weight
    produced severe respiratory and nervous symptoms at 16 hours and death
    after 48 hours (Welch, 1948).

    Long-term studies

         Rat. In one experiment published in 1952, 24 rats (12 of each
    sex) were given 2.5, 25 and 75 ppm of chlordane in the diet for 2
    years. The sample of chlordane used had an LD50 of 450 mg/kg (Lehman,
    1951). It was found that 25 and 75 ppm gave moderate to severe signs
    of intoxication; 2.5 ppm still caused liver histological damage, the
    nature of which has not been reported (Lehman, 1952).

         In another experiment, groups of 40 rats (20 males and 20
    females) were fed concentrations of 5, 10, 30, 150 and 300 ppm of
    "technical chlordane" in the diet over a 2-year period. Throughout the
    experiment tremors and convulsions appeared or could be induced at 30
    or more ppm. Following fasting, no neurological symptoms appeared at 5
    or 10 ppm. Growth rate was affected at 150 or 300 ppm. Liver
    histological damage was observed in the form of hypertrophy of
    centrolobular cells, cytoplasmic oxyphilia and hyalinization, nuclear
    karyorhexis or cellular pyknosis, presence of fat in the cytoplasm and
    some bile-duct proliferation. These changes were obvious at 150-300
    ppm slight at 30 ppm, minimal at 10 ppm and absent at 5 ppm (Ingle,
    1952).

         In a subsequent experiment from the same laboratory, which was
    carried on between late 1953 and late 1955, "technical chlordane of
    recent manufacture" was used. Groups of 40 rats were given chlordane
    at 2.5, 5, 10, 25, 50, 75, 150 or 300 ppm. A control group was given
    no chlordane. Changes concerning food consumption, growth and
    mortality were seen only in the 300 ppm group. Liver cell changes were
    not present in the animals given 2.5-25 ppm. At 50 ppm only
    "cytoplasmic peripheralization" was present. At higher doses the
    changes were as those previously described (Ingle, 1955).

         In a study published in 1953 a sample of chlordane exhibiting an
    oral LD50 for the rat of 590 mg/kg was used. Groups of 5 rats of each
    sex were given 0, 10, 20, 40, 80, 160, 320, 640 or 1280 ppm of
    chlordane in their diets for approximately 407 days. The animals at
    640 and 1280 ppm died early. At lower dosages, survival was
    unaffected. Increased liver-weight (in comparison with the control
    group) was observed over 320 ppm. In a sample of liver of a male at
    320 ppm the average nuclear volume was 3773 compared to 2683 in a
    control rat. Cytoplasmic vacuoles containing fat and clusters of
    granules at the periphery of the cytoplasm were often seen. In the
    males they were equivocal at 10 ppm, absent at 20 ppm and infrequent
    at 40 ppm. In the females these lesions were common and were seen only
    at 80 ppm and over (Ambrose et al., 1953).

    Comments on experimental studies reported

         It appears that at least in two reports concerning the rat a dose
    level was found at which no histopathological changes occurred
    (Ambrose et al., 1953; Ingle, 1955). Such dose levels appear to be in
    the order of 20-25 ppm in the diet (1-1.25 mg/kg/day). This figure
    applies to samples of "late" chlordane and would require clear
    specifications concerning the formulations of chlordane falling into
    this category. This cannot be done at the present time because of
    incomplete information about chemical structure and toxicity of
    impurities occurring in technical chlordane.

    EVALUATION

    Estimate of acceptable daily intake for man

         Because:

    (i) there is still some doubt about the composition of the chlordane
    entering into commerce;

    (ii) some metabolic problems, e.g. the effects of chlordane on the
    hydroxylation of steroids, are not resolved (Burns et al., 1965;
    Kutzman et al., 1964);

    (iii) of the fact that, with one or two small exceptions, the animal
    experiments have been limited to only one species, viz. the rat;

    (iv) of the possible persistence of this compound in the environment,

    the Committee considers that caution should still be exercised, and
    that every effort should be made to see that the intake of chlordane
    for man should be kept at the lowest possible level.

    Further work required

         Standardization of the technical product. Investigation on the
    nature and toxicity of the residue occurring in the plant.
    Determination of a maximum no-effect level in other species than the

    rat. Long-term toxicity in other species than the rat. Reproduction
    studies.

    REFERENCES

    Ambrose, A. M. Christensen, H., Robbins D. & Rather. L. (1953) Arch.
    Industr. Hyg., 7, 197

    Batte, E. G. & Turk, R. D. (1948) J. econ. Ent., 41, 102-103

    Burns, J. J., Cucinell. S. A.. Koster, R. & Conney, A. H. (1965)
    Ann. N.Y. Acad. Sci., 123, 273

    Carter, R. H. et al. (1953) J. Dairy Science, 36, 1172

    Dadey, J. L. & Kammer, A. G. (1953) J. Amer. med. Ass., 153, 723

    Derbes, J. V. et al. (1955) J. Amer. med. Ass., 158, 1367

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

    Hart, L. G. & Fouts, J. R. (1963) Proc. Soc. exp. Biol. (N.Y.),
    114, 388

    Hart, L. G., Shultice, R. W. & Fouts, J. R. (1963) Toxicol. Appl.
    Pharmacol., 5, 371

    Ingle, L. (1952) Arch. industr. Hyg., 6, 357

    Ingle, L. (1954) Velsicol Special Bull., 309-7

    Ingle, L. (1955) Data submitted by Velsicol Corporation to WHO in 1964

    Kutzman, R., Jackobson, M., Schneidman, K. & Conney, A. H. (1964)
    J. Pharmacol. exp. Ther., 146, 280

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

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

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

    Stohlman, E. F. & Smith, M. I. (1950) Advances in Chem. Ser., 1,
    228

    Stohlman, E. F., Thorp, W. T. S. & Smith, M. I. (1950) Arch.
    industr. Hyg., 1, 13-19

    Stormont, R. T. & Conley, B. E. (1955) J. Amer. med. Ass., 158,
    (15), 1364

    Turner, H. F. & Eden, W. G. (1952) J. econ. Ent., 45, 130

    US Food and Drug Administration (1947) Quarterly Report No. 3

    Welch, H. (1948) J. econ. Entomol., 41, 36-39
    


    See Also:
       Toxicological Abbreviations
       Chlordane (EHC 34, 1984)
       Chlordane (HSG 13, 1988)
       Chlordane (PIM 574)
       Chlordane (FAO/PL:1967/M/11/1)
       Chlordane (FAO/PL:1969/M/17/1)
       Chlordane (AGP:1970/M/12/1)
       Chlordane (WHO Pesticide Residues Series 2)
       Chlordane (WHO Pesticide Residues Series 4)
       Chlordane (Pesticide residues in food: 1977 evaluations)
       Chlordane (Pesticide residues in food: 1982 evaluations)
       Chlordane (Pesticide residues in food: 1984 evaluations)
       Chlordane (Pesticide residues in food: 1986 evaluations Part II Toxicology)