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

    LINDANE

    Chemical name

           gamma-1,2,3,4,5,6-hexachlorocyclohexane

    Synonym

           gamma-BHC, gammexane, gamma-HCH

    Empirical formula

           C6H6Cl6

    Structural formula

    BIOLOGICAL DATA

    Biochemical aspects

           Lindane is absorbed from the digestive tract, particularly in the
    presence of lipids. Once absorbed, lindane is distributed to various
    tissues or organs, accumulating above all in the fat depots (Van
    Asperen, 1957), liver and kidneys. The rate of accumulation of lindane
    in growing animals is however, much lower than that of beta-BHC or of
    DDT. In rats ingesting repeated small doses of lindane, the
    concentration in the fat depots is in a state of equilibrium with the
    concentration of the diet (Lehman, 1953). The data on lindane
    metabolism are very incomplete. According to certain in vitro tests
    it would seem that part is broken down in the liver. The unchanged
    compound is eliminated in the faeces and urine and is found in the
    milk (Ray et al., 1953; Van Asperen, 1957; Ware & Gilmore, 1959). Very
    little information is available about its effects on basic enzyme
    systems. Growing animals are particularly susceptible to its toxic
    action.

    Acute toxicity

           From the viewpoint of acute toxicity, lindane is the most toxic
    of all the isomers present in the technical hexachlorocyclohexanes. It
    is a neurotropic poison causing excitation of the central nervous
    system with convulsions followed - if the dose is sufficiently high
    - by depressive phenomena leading to death from respiratory collapse.

    Animal             Route       LD50 mg/kg    References
                                   body-weight

    Rat                Oral         125, 200     Dallemagne & Philippot,
                                                  1948
                                                 Lehman, 1948
                                                 Lehman, 1951
                                                 US Public Health
                                                  Service, 1956
                                     177-230     Negherbon, 1959

    Rat           Intraperitoneal     35-85      Negherbon, 1959

    Mouse              Oral            86        Negherbon, 1959

    Guinea-pig         Oral          100-127     Lehman, 1948
                                                 Lehman, 1951
                                                 Negherbon, 1959

    Rabbit             Oral          60-200      Cameron, 1945
                                                 Negherbon, 1959

    Dog                Oral          40-200      Negherbon, 1959
                                    (lethal)

    Dog             Intravenous        7.5       Negherbon, 1959
                                    (lethal)

           The fatal dose for man is estimated to be 150 mg/kg body-weight,
    i.e., of the order of 10 g for an adult weighing 70 kg. Children are
    particularly susceptible.

    Short-term studies

           Rat. When rats were fed a diet containing 400 ppm lindane for 4
    weeks, hepatic lesions appeared (Doisy & Bocklage, 1949).

           Forty-eight rats (24 male and 24 female) were given lindane by
    stomach-tube in a daily dose of 32 mg/kg body-weight for 6 months.
    Nervous symptoms (trembling, spasms), fatty degeneration of the liver
    and of the epithelium of the renal tubules, vacuolization of the
    cerebral cells and a marked  increase in mortality rate were observed.
    With 10 mg/kg body-weight for 17 months no abnormalities were revealed
    (Klimmer, 1955). These findings of functional disturbances in the
    central nervous system were in accordance with previous results
    (Herken, 1950 and 1951; Kewitz, 1952; Kewitz & Reinert, 1952); when 60
    rats were fed for 12 months with a diet containing 2, 3, 4, 5 and 10

    ppm of lindane, the general behaviour of the animals, their
    body-weight, histological findings and the post-mortem examination
    showed no abnormalities (Melis, 1955).

           Rabbit. Two rabbits were subjected to successive administration
    by the intramuscular route of daily doses of 40 mg lindane for 19
    days, 80 mg for 9 days and 160 mg for three days. The animals died and
    showed inter alia hepatic degeneration (Dallemagne & Philippot,
    1948).

           Dog. Dogs fed 10 mg/kg body-weight for 18 to 49 days showed
    hepatic lesions (Woodward & Hagan, 1947).

           Five dogs were given daily intramuscular injections of a 10%
    solution of lindane in oil ranging from 20 to 390 mg/kg body-weight.
    This repeated administration of lindane brought about convulsions,
    paralysis and anorexia (Dallemagne & Philippot, 1948).

           Man. Of 148 spray operators who applied lindane during an
    antimalaria campaign, about 46% became affected. The clinical
    examination showed digestive and respiratory disorders, cutaneous
    symptoms, and neurological effects (asthma, polyneuritis). There is a
    lack of precise information on the chemical composition of the
    hexachlorocyclohexane employed, on the conditions of application and
    on the amount absorbed (Wassermann et al., 1960; Wassermann et al.,
    1961).

    Long-term studies

           Mouse. Groups of 30 mice each were subjected to dermal
    applications of 0.5% lindane in acetone. The applications were given
    twice weekly over a period of 15 months. Another group of animals
    received subcutaneous implantation of paraffin wax pellets containing
    3% of lindane and were observed for 10 months. No abnormalities were
    found (Orr, 1948).

           Rat. Groups of 20 rats (10 males and 10 females) were given
     for 2 years diets containing 5 to 1600 ppm of the alpha- beta-, and
    gamma-isomers of lindane. These experiments clearly showed that the
    gamma-isomer was the least toxic and the beta-isomer the most toxic.
    The organs injured were the liver and to a lesser extent the kidneys.
    In the case of lindane, the lowest concentration causing significant
    liver charges was 100 ppm. No significant effect was noted at
    concentrations of 50 ppm or lower (Fitzhugh et al., 1950).

           With the aim of detecting any carcinogenic action, 3 groups of 
    20 young rats (10 males and 10 females) were fed diets containing 25, 
    50 and 100 ppm of lindane throughout their life-span. At the 2 highest
    concentrations, slight hypertrophy of the liver was observed, while
    with 100 ppm there was a slight tendency to fatty degeneration of this
    organ. At the lowest concentration. 25 ppm, there was no toxic effect,
    in particular, no histological lesions were detected in the liver or
    kidney. None of the concentrations used gave any significant increase

    in the percentage of tumours as compared with the control group
    (Truhaut, 1954).

           Groups of 12 rats (6 males and 6 females) were fed diets
    containing 50 and 100 ppm of lindane; histological lesions were found
    in the liver parenchyma (Ortega et al., 1957).

           Twenty-five young rats were given lindane daily by stomach-tube
    at a dosage of 10 µg/kg body-weight (corresponding to about 0.1 and
    0.15 ppm) for 17 months. No abnormalities were found (Klimmer, 1955).

    Comments on the experimental studies reported

           In all these animal species, lindane has proved to be a
    cumulative poison causing hepatic and renal lesions and disturbances
    of the central nervous system. The dog seems particularly susceptible
    to neurological effects.

    EVALUATION

    Level causing no significant toxicological effect in the rat

           Twenty-five ppm of lindane approximately equivalent to 1.25 mg/kg
    of bodyweight.

    Estimate of the maximal acceptable daily intake for man

           0-0.0125 mg/kg.

    Further work desirable

           Investigation on the chemical nature of the residue occurring in
    the plant. Additional biochemical studies. Long-term feeding studies
    in other species than the rat.

    REFERENCES

    Cameron, G. R. (1945) Brit. med. Bull., 3, 780

    Dallemagne, M. J. & Philippot, E. (1948) Arch. Int. Pharm. Ther.,
    76, 274

    Doisy, E. A. J. & Bocklage, B. C. (1949) Proc. soc. exp. Biol.
    (N.Y.), 71, 490

    Fitzhugh, O. G., Nelson, A. A. & Frawley, J. P. (1950) J. Phamacol.
    exp. Ther., 100, 59

    Herken, H. (1950) Arztl. Wschr., 5, 193

    Herken, H. (1951) Arzneimittel-Forsch., 1, 356

    Kewitz, H. (1952) Arch. exp. Path. Phamakol., 216, 161

    Kewitz, H. & Reinert, H. (1952) Arch. exp. Path. Pharmakol., 215,
    93

    Klimmer, O. R. (1955) Arch. exp. Path. Pharmakol., 227, 183

    Lehman, A. J. (1948) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 12, 82

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

    Lehman, A. J. (1953) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 17, 3-12

    Melis, R. (1955) Nuovi Ann. Ig., 6 (2), 90

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

    Orr, J. W. (1948) Nature, 162, 189

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

    Ray, E. E. et al., (1953) J. Amer. vet. med. Ass., 123, 448

    Truhaut, R. (1954) Communication au symposium intern. de la prevention
    du cancer, Sao Paulo

    United States Public Health Service (1956) Clinical memoranda on
    economic poisons

    Van Asperen, K. (1957) C.R. 4è Congrès Intern. de lutte contre les
    ennemis des plantes, Hambourg, 2, 1619

    Ware, G. W. & Gilmore, L. O. (1959) J. Econ. Ent., 52, 349

    Wasserman, M., Sandulescu, G., Iliescu, S. & Mandric, G. (1960)
    Arch. Mal. prof., 21, 195

    Wassermann, M., Pendefunda, G., Merling, M., Mihail, G., Sandulescu,
    G. & Vancea, G. (1961) Arch. Mal. prof., 22, 308

    Woodard, G. & Hagan, E. C. (1947) Fed. Proc., 6, 387
    
    See Also:
       Toxicological Abbreviations
       Lindane (EHC 124, 1991)
       Lindane (HSG 54, 1991)
       Lindane (ICSC)
       Lindane (PDS)
       Lindane (PIM 859)
       Lindane (FAO/PL:1967/M/11/1)
       Lindane (JMPR Evaluations 2002 Part II Toxicological)
       Lindane (FAO/PL:1968/M/9/1)
       Lindane (FAO/PL:1969/M/17/1)
       Lindane (WHO Pesticide Residues Series 3)
       Lindane (WHO Pesticide Residues Series 4)
       Lindane (WHO Pesticide Residues Series 5)
       Lindane (Pesticide residues in food: 1977 evaluations)
       Lindane (Pesticide residues in food: 1978 evaluations)
       Lindane (Pesticide residues in food: 1979 evaluations)
       Lindane (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Lindane (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)