BHC (TECHNICAL)     JMPR 1973


         BHC technical was reviewed previously by the Joint Meeting
    (FAO/WHO, 1969). The 1968 Joint Meeting did not recommend an ADI
    because technical HCH was not standardized as to its composition of
    various isomers of differing toxicological potency and action, and
    because of lack of adequate toxicological data on the different
    isomers. It was recommended that before an ADI could be established
    additional toxicological data of the following nature was necessary:
    short- and long-term feeding studies and a reproduction study on
    individual isomers and commonly marketed technical products, metabolic
    studies of isomers in animals, determination of effects on liver
    microsomal enzymes and interactions of isomers of HCH and residue
    levels in tissues.


    Biochemical aspects

         A single oral dose of 200 mg/kg of BHC enhanced the metabolism of
    pentetrazol by rat liver homogenates in vitro and hastened the
    disappearance of this drug in vivo when the BHC was given four days
    prior to pentetrazol treatment (Vohland and Koransky, 1972a, b).

         Liver growth inducing action of single doses of 200 and 400 mg/kg
    (p.o.) of BHC in rats has been confirmed. This was due both to
    increased numbers and volume of hepatocytes. Although liver weight had
    returned to normal by four weeks after administration, liver DNA and
    number of cell nuclei remained above control values
    (Shulte-Hevmenetol, 1971).

         In rats administered BHC technical at 50 mg/kg for 7 days the
    order of accumulation of isomers was beta > alpha > gamma > delta;
    the order of excretion in urine was alpha > gamma > delta > beta;
    and the duration of excretion was beta > alpha > gamma > delta.
    The beta isomer was found not only in livers of rats treated with
    this isomer but also in livers of rats given the other isomers
    indicating possible isomerization (Katama, 1971). Following oral
    administration to rabbits for 14 days antibodies against DDT and BHC
    were found more frequently than against organophosphates six months
    after discontinuation of exposure (Nikolayev and Usmanova, 1971).

         Morphological changes in nasal mucous membrane of rabbits were
    investigated during oral administration of BHC at 1 mg/kg/day. After
    40-50 days mucosal dystrophy advances to catarrhal rhinitis and
    further degenerative changes (Sadriyeva et al., 1971).

         A substantial effect of beta-BHC on mice fetal development was
    observed following s.c. or oral administration to pregnant mice at
    various stages of gestation. The translocation of beta-BHC from
    mother to fetus was estimated to be 1/5-1/8 of the residue observed
    in the mother (Yamagishi et al., 1972).


    Short-term studies


         Male mice (20/group) were fed diets containing 0, 6.6, 66 and 660
    ppm BHC (technical) for 24 weeks. The mixture consisted of the
    following percentage composition of isomers alpha - 67%, beta - 11%,
    gamma - 15%, delta - 6.4% and others 0.6%. At the end of 24 weeks,
    the mice were killed and examined grossly and histologically. All
    mice in the 660 ppm group had liver "tumors", their liver weights
    were 3.7 times those of control, and the livers had a rough surface
    with many large, yellowish nodules up to 1.0 cm in diameter.
    Microscopic examination showed the nodules to be hepatomas. No
    remarkable changes were seen in the controls or in the 6.6 and 66 ppm
    groups (Nagasaki et al., 1971a, b).

         In a subsequent investigation 12 groups of 20 mice were fed one
    of the following diets: basal diet (controls) or 500, 250 or 100 ppm
    of each of the alpha, beta, gamma and delta isomers of BHC. The
    animals were killed and examined after 24 weeks of feeding as above.
    Hepatomas were observed in all the animals fed 500 ppm of the
    alpha-isomer and in nine animals fed 250 ppm of the alpha-isomer,
    none of the other groups had hepatomas. The authors concluded that
    the alpha-isomer was probably responsible for the hepatomas produced
    by the crude HCH that was used in the first experiment (Nagasaki et
    al., 1972a).

         The residual accumulation of alpha-BHC in the 500 ppm dosed group
    was 11.44 ppm and beta was 12.37 ppm (Tomii et al., 1972). In a
    continuing study, rats were fed BHC technical and various isomers at
    0, 250, 500 and 1000 ppm for 24 and 48 weeks. Increased liver weight
    was observed only at 500 ppm and above after 24 weeks. At 48 weeks one
    of seven rats fed alpha BHC at 1000 ppm developed a hepatoma while
    three others showed hypertrophic nodules without signs of malignancy.
    No BHC induced hepatomas were reported. It was concluded, alpha-BHC
    is considered to have carcinogenicity potential in the liver and rats
    are less sensitive than mice (Nagasaki et al., 1972b).

         BHC (technical) and the individual isomers were fed to CR-JC
    strain mice at dose levels of 0 and 600 ppm for six months. Livers
    were significantly overweight at 26 weeks with hepatomas observed in
    all treated mice. A high incidence of malignant hepatomas were noted
    in the groups fed the pure isomers only. These authors conclude that
    the alpha isomer or a metabolite is the most carcinogenic (Goto et
    al., 1972a, b).

    Observations in man

         Although low concentrations of all four of the primary isomers of
    HCH have been detected in human tissues or body fluids, the
    beta-isomer is found most frequently and at highest concentration.
    Analyses of human milk from women in 24 prefectures in Japan revealed
    average residues of 0.150 ppm in town residents and 0.105 ppm in
    country residents. Depending upon the prefecture, average values
    ranged up to 0.4 ppm. beta-HCH residues in human milk far exceed the
    residues of DDT and dieldrin (Tanabe, 1972). In man the
    concentrations of the isomers, in decreasing order, was beta >
    alpha > gamma > delta (Tatsukawa et al., 1972).


         The 1968 Joint Meeting did not recommend an ADI because technical
    BHC was not standardized as to its composition of various isomers of
    different toxicological potency and activity. Although certain data
    are available on persistence of the isomers, there was a lack of
    adequate toxicological data on other isomers. It was recommended that
    before an ADT could be established additional toxicological data of
    the following nature were necessary: short- and long-term feeding
    studies and a reproduction study on individual isomers and commonly
    marketed technical products, metabolic studies of isomers in animals,
    determination of effects on liver microsomal enzymes and interactions
    of isomers of BHC and residue levels in tissues.

         Essentially no new data of the type requested have been
    submitted. The Meeting, therefore, concluded that there is still
    insufficient information for an evaluation of the potential health
    injurious effects of technical BHC. The demonstration of hepatoma
    production in mice by feeding 500 and 250 ppm of the alpha-isomer, the
    major constituent of technical BHC for only 24 weeks was regarded as a
    matter for concern. In other studies the beta and alpha-isomer have
    also been demonstrated to produce hepatoma in mice at levels of 200
    and 400 ppm in the diet, respectively.


         There is insufficient information to estimate a no-effect level
    and hence, no ADI can be recommended. Additionally the beta-isomer
    is quite persistent in the environment and frequently occurs in
    human fat and blood.



         Residues of technical BHC are widely distributed throughout the
    world's food supply, especially in meat and milk. They appear
    regularly in total diet studies in the United States of America
    (Duggan, 1972), Canada (Smith et al., 1973) and Czechoslovakia as well
    as in commodity surveys (occasionally at high levels) in Japan (milk,

    milk products, fish, imported meat) (Minigawa et al., 1972; Otsuki et
    al., 1972; Sakai et al., 1972; Takeda et al., 1972), Czechoslovakia
    (milk fat) (Rosa, 1973), France (animal feed, milk) (Marion, 1973),
    India (green leafy vegetables) (Viswerwariah and Jayaram, 1972) and
    Great Britain (imported cereals, nuts forage, pulses) (Hill, 1973;
    Macherbe, 1973).

         This insecticide was first evaluated in 1968 at which time no
    recommendations for tolerances could be made due to lack of data on
    results from supervised trials, on the composition of the technical
    product, or on the nature of the terminal residues. At this
    re-evaluation there were no data available on residues resulting from
    supervised trials on agricultural crops or animals (other than from
    the grazing of sheep on treated pasture), therefore no tolerances or
    practical residue limits could be recommended.


         As the insecticidal activity of technical BHC is accounted for by
    its content of the gamma isomer and as the gamma isomer is disposed of
    more rapidly by animals and is generally less persistent in the
    environment than the alpha and beta isomers, which are the isomers
    found most widely in food intake studies, every encouragement should
    be given to the replacement of technical BHC by lindane (99% gamma
    BHC) or alternative pesticides wherever possible.


    Required (before an acceptable daily intake can be established and
    before residue limits can be recommended)

    1.   Additional chronic feeding studies appropriately designed
         to detect carcinogenic action. The studies should be carried out
         on all isomers if possible, but at least on the alpha-isomer and
         a typical technical mixture. A species other than the mouse would
         be appropriate.

    2.   Further comparative studies of the effects of the four
         primary isomers on reproduction, including teratogenicity.

    3.   The composition of BHC (technical) available and in use
         in various countries.

    4.   The uses made of these technical products, particularly
         the rates and frequencies of application and the identities of
         the crops involved.

    5.   The levels of the residues of the individual isomers
         found in plants, animals, and their products.


    1.   Studies to establish the extent to which one isomer may
         alter the action or storage of another isomer.


    Duggan, R. E. and Corneliussen, P. E. Dietary intake of
    1972                pesticide chemicals in the United States (III),
                        June 1968 - April 1970. Pesticides Monit. J. 5
                        (4): 331

    Goto, M., Hattori, M., Miyagawa, T. and Enomoto, Beitraege
    1972a               zur oekologischen Chemie. II. Hepatoma-Bildung in
                        Maeusen nach Verabreichung von HCH-Isomeren in
                        hohen Dosen. [Contributions to ecological ch
                        chemistry. II. Hepatoma development in mice after
                        administration of BHC isomers at high dosages.]
                        Chemosphere, 1 (6): 279-282

    Goto, M., Hattori, M. and Miyagawa, T. (1972b) Beitraege zur
    1972b               oekologischen Chemie. Toxicitaet von alpha-BHC in
                        Maeusen. [Contributions to ecological chemistry.
                        Toxicity of alpha-BHC in mice.] Chemosphere, 1
                        (4): 153-154

    Hill, E. O. and Thompson, R. H. Pesticide residues in
    1973                foodstuffs in Great Britain: organochlorine
                        residues in imported cereals, nuts, pulses, and
                        animal foodstuffs. Pestic, Sci. 4 (1): 33

    Kamata, T. Hygienic studies on pesticide residues.
    1971                I. Distribution, storage and urinary excretion of
                        BHC (alpha-, beta-, gamma- and delta-isomers)
                        in the rat after peroral administration. Nippon
                        Eiseigaku Zasshi (Jap. J. Hyg.), 26 (4):
    Maeherbe, S. P. Private communication. BHC residues in
    1973                sheep exposed to BHC treated karoo veldt,

    Marion, R. Les principales causes de la présence de résidue
    1973                de pesticides organochlores dans le lait au niveau
                        de Is production. Présentation des résultats des
                        deux années de l'enquete effectuée par; l'ITEB.
                        Private communication from D. Demozay

    Minawaga, O. et al. Pesticide residues in dairy products
    1972                and meat (III). Organochlorine pesticide residues
                        in fishes and shellfishes. J. Food Hyg. Soc.
                        Japan, 13 (4): 317

    Nagasaki, H., Tonni, S., Mega, T., Marugami, M., Nobuyuki) I.
    1971a               Development of hepatomas in mice treated with
                        benzene hexachloride. GANN, 62: 431

    Nagasaki, H., Tonni, S., Mega, T., Marugami, M. arid Ito, N.
    1971b               Development of hepatomas in mice treated with
                        benzene hexachloride. Gann (Jap. J. Cancer Res.),
                        62 (5): 431

    Nagasaki, H. Tonni, S., Mega, T., Marugami, M. and Nabuyki, I.
    1972a               Hepatocarcinogenic effect of alpha-, beta-, and
                        gamma-, and delta- isomers of benzene
                        hexachloride in mice. GANN,63: 393

    Nagasaki, H., Tonni, S., Tsumashika, T., Marukami, M., Arai, M.
    1972b               and Ito, N. [On the experimental tumorigenesis of
                        the liver of mice and rats by the induction of BHC
                        isomers. Alpha, beta, gamma- and delta.] Nippon
                        Gangakkai Kiji (Proc. Jap. Cancer Ass.), 31:

    Nikolayev, A. I. and Usmanova, I. Ya,  O vyyavlenii antitel
    1971                k pestitsidam. [production of antibodies to
                        pesticides.]  Lab. Delo, 11: 676-678

    Otsuki, K., Sekita, H., Takeda, M. and Tanabe, H. Studies on
    1972                analysis of pesticide residues (VI).
                        Organochlorine pesticide residues in the imported
                        meat. J. Food Hyg. Soc. Japan, 13 (4): 338

    Rosa, J. Data on exposure of the population of Czechoslovakia
    1973                by chlorinated insecticides from milk, milk
                        products and whole day's diets in 1971/72. Private
                        communication to FAO

    Sadriyeva, R. V., Absalyamov, I. F. and Flebkashanskaya, N. V.
    1971                Dinamika morfologicheskikh izmeneniy v slizistoy
                        obolochke nosa pri dlitel'nom vvedenii malykh doz
                        geksakhlorana. [The dynamics of morphological
                        changes in the nasal mucous membrane in prolonged
                        peroral administration of small doses of
                        hexachlorane.]  Vestn. Otorinolaringol. 33:

    Sakai, K. et al. Pesticide residues in dairy products and meat
                        (II). Organochlorine pesticide residues in dairy
                        products. J. Food Hyg. Soc. Japan, 13 (4): 310

    Shulte-Hermann, R., Schlicht, I., Koronsky, W., Leberl, C.,
    1971                Eulenstedt, C. and Noack, G. Hyperplasia and
                        hypertrophy of rat liver induced by ý-hexachloro-
                        cyclohexane and butylhydroxytoluene. Retention of

                        the hyperplasia during involution of the enlarged
                        organ. Virchows Arch. Abt. B Zellpath. 9:

    Smith, D. C., Leduc, R. and Charbonneau, C. Pesticide
    1973                residues in the total diet in Canada. III - 1971
                        Pestic. Sci. 4 (2): 211

    Takeda, M. et al. Pesticide residues in dairy products and
    1972                meat (I). Organochlorine pesticide residues in
                        milk. J. Food Hyg. Soc. Japan, 13 (4): 299

    Tomii, S., Nagasaki, H. and Mega, Y. [Studies on BHC as a
    1972                carcinogen.] Nippon Eiseigaku Zasshi (Jap. J.
                        Hyg.), 27 (1): 113

    Viswerwariah, K. and Jayaram, M. The effect of processing
    1972                in lowering the BHC residue in green leafy
                        vegetables.  Pestic. Sci. 3 (2): 345

    Vohland, H. W. and Koransky, W. Effect of alpha-hexachloro-
    1972a               cyclohexane on metabolism and excretion of
                        pentetrazel (cardiozol) in the rat. Nauyn-
                        Schmiedeberg's Arch. Pharmacol. 273: 99-108

    Vohland, H. W., Koransky, W. and Zufelde, H. Effect of
    1972b               ý-hexachlorocyclohexane on the convulsive activity
                        of pentetrazol (cardiozol) in the rat. Nauyn-
                        Schmiederberg's Arch. Pharmacol. 275 (3):

    Yamagishi, T., Takeba, K., Fujimoto, C., Morimoto, K. and
    1972                Haruta, M. [On the effects of beta-BHC on the
                        fetus of mouse (IV).] Rinsho Eiyo (J. Clin.
                        Nutr.), 41 (5): 599-604

    See Also:
       Toxicological Abbreviations