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    HEXACHLOROBENZENE    JMPR 1974

    Explanation

         Hexachlorobenzene was studied by the Joint Meeting in 1969
    (FAO/WHO, 1970) and a "tentative negligible daily intake" of 0.0006
    mg/kg bw was established. The Joint Meeting in 1973 (FAO/WHO, 1974a)
    recommended that the term "tentative negligible daily intake" should
    not be used and the figure of 0.0006 mg/kg bw was retained as a guide
    for setting upper limits for residues until it was possible to
    allocate an ADI based on the results of comprehensive toxicological
    studies. The further work requested in 1969 included: Metabolic
    studies in animals including identification of the toxic product or
    products excreted in milk; short-term studies in non-rodent mammalian
    species and long-term studies especially in relation to the effect on
    bone-marrow; reproduction studies in rats.

         The following recommendation was made in 1973 (FAO/WHO, 1974a):
    In view of the potential toxicity of hexachlorobenzene and the lack of
    adequate toxicological data to assess its safety, WHO and FAO should
    promote and, where necessary, co-ordinate research needed on the
    seed-dressing fungicide.

         In view of the widespread occurrence of HCB residues in a wide
    range of food commodities and in the environment the 1973 Meeting also
    decided that this compound should be kept under continual review and
    that it should be reconsidered by the 1974 Joint Meeting. Further
    information was required to enable the Meeting to review proposals
    previously made.

         The report and monographs of the 1973 Joint Meeting were not
    available in time for governments and interested authorities to
    consider requests for additional information. The present Meeting had
    before it considerable information obtained by members from published
    and unpublished scientific literature and this provided the basis for
    reconsideration of the question of hexachlorobenzene residues.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

         The 1973 Joint Meeting reviewed the status of HCB and found that
    very little toxicological data required by the 1969 Joint Meeting had
    been received.

         The Meeting examined recently published reports relating to tests
    for mutagenic and teratogenic action (Khera, 1974), biochemical
    effects (Grant et al., 1974a,b), histopathology (Kuiper-Goodman, 1974;
    Kimbrough and Linder, 1974), tissue disposition studies (Villeneuve et
    al., 1974; Villeneuve, 1975; Villeneuve and Hierlihy, 1975), and
    reproduction studies (Somers et al., 1973). Although none of these
    reports included long-term studies, the results that were reported
    permitted the Meeting to reaffirm the value of 0.0006 mg/kg bw
    suggested by the 1973 Meeting (FAO/WHO 1974a) as a guide for setting
    upper limits for residues. Since the results of a long-term feeding
    and carcinogenesis study, known to be in progress, were not available,
    the Meeting deferred full evaluation for an ADI. The present Meeting
    allocated a value of 0.0006 mg/kg bw as a conditional ADI.

         This Meeting expressed concern that some effects attributed to
    HCB might be due to impurities in the test samples (Villanueva et al.,
    1974).

         It was noted that the number of reports of residues in foods,
    feeds and human tissues was increasing. The sources of these residues
    are known to include disposal of industrial and municipal wastes,
    contamination of other chlorinated pesticides, the approved use of HCB
    as a seed-dressing, and misuse of HCB-treated seeds in animal feeds.
    The meeting urges that:

    (1) support be given to an international monitoring program to
    identify the source and extent of contamination;

    (2) the presence of HCB as an impurity in other pesticides be
    monitored and minimized;

    (3) the recommendations for use as a seed dressing (FAO/WHO, 1974b) be
    carefully adhered to; and

    (4) HCB should be used only as a seed-dressing and only when no
    suitable substitute is available. Because of the persistent nature of
    HCB and its general occurrence in the environment, it must be
    recognized that even if all sources of emission could be stopped, some
    food contamination with HCB will continue for many years and the
    Meeting therefore urged that data required by the 1973 Joint Meeting
    (FAO/WHO, 1974a) be promptly obtained.

    RESIDUES IN FOOD AND THEIR EVALUATION

    SOURCE OF RESIDUES

         In the previous monograph (FAO/WHO, 1974b) reference was made to
    various industrial as well as agricultural sources of HCB residues.

         The Meeting was able to consider a number of publications
    indicating the widespread distribution of hexachlorobenzene residues
    derived, apparently, from many different sources. Siyali and Stricker
    (1973) report the presence of hexachlorobenzene along with other
    organochlorine pesticides in milk from a survey carried out in
    Australia. Johnson et al. (1974) report finding hexachlorobenzene
    residues in fish, fish eggs, fish fry and fish oil from a collection
    of samples taken throughout the United States in 1971 and 1972. The
    widespread occurrence points to the possibility that there are many
    different sources of HCB contamination. Zitko (1971) reports finding
    trace amounts of hexachlorobenzene together with PCB and other
    organochlorine residues in fresh water and marine fishes during a
    survey in Canada.

         The U.S. Environmental Protection Agency reported (1973) that
    whereas HCB residues had frequently been found in the fat of domestic
    animals from several regions of the U.S.A., examination of 150 samples
    of soil from 16 separate states revealed that there was no general
    widespread contamination of crop land soils with HCB residues at
    levels above the limit of determination (0.01 mg/kg). On the other
    hand residues of other organochlorine pesticides were frequently
    found, dieldrin being found in 30% of the samples examined.

         Gilbertson and Reynolds (1972) report finding significant levels
    of HCB in the eggs of common terns in Hamilton Harbour, Ontario,
    Canada. The level of HCB residues is similar to that of dieldrin,
    being noticeably lower than the level of DDT and PCB in the same eggs.
    This information suggests that there is a general low level of HCB
    contamination in the whole environment. HCB residues were reported to
    occur in soil and crops after repeated soil treatments with quintozene
    (Smelt and Leistra, 1974).

         In reporting studies on the loss of chloronitrobenzene fungicides
    from the soil, Caseley (1968) mentions that 400,000 lbs of quintozene
    was used annually in the San Joaquin Valley in California, U.S.A. in
    1963. The Joint Meeting has already referred (FAO/WHO, 1974b) to the
    significant contamination of quintozene with hexachlorobenzene,
    leading to residues of hexachlorobenzene in food produced with the aid
    of quintozene fungicides. Beck and Hansen (1974) refer to the fate of
    HCB in the soil following the use of quintozene.

    RESIDUES IN MEAT RESULTING FROM EXPERIMENTAL FEEDING

         A study of the tendency of broiler chickens to accumulate
    organochlorine pesticide residues from contaminants in their feed was
    carried out in The Netherlands (De Vos et al., 1972). Day old broiler
    chickens were fed combinations of various organochlorine pesticide
    residues at levels of 0.05, 0.15 and 0.3 ppm in the feed for a period
    of about 7 weeks. Birds were killed at regular intervals and samples
    of abdominal fat and other tissues examined for residues of the
    organochlorine pesticides. At the end of the 7 week period heptachlor
    epoxide residues were highest, followed by hexachlorobenzene,
    dieldrin, DDT, endrin and lindane.

         As shown in Table 1 the results of this experiment indicate a
    direct relationship between the amount of HCB in the feed and the
    amount in the fat of the chickens. The concentration in the abdominal
    fat of chickens receiving 0.15 ppm of HCB in their rations is
    approximately 3 times that of the corresponding birds receiving
    rations containing 0.05 ppm. Analysis of livers of the same broiler
    chickens indicate a similar relationship between the concentration of
    HCB in the feed and in the liver fat.

    
    TABLE 1  HCB residues, mg/kg, in chickens fed HCB in their diet (from DeVos et al., 1972.

                                                                                                

    Level (ppm) fed:          0.05                     0.15                       0.30

    Days on diet:      15      29      52       15      29      52        15       29       52
                                                                                                

    Carcasses
    (whole)           0.045   0.061   0.075    0.12    0.21    0.24      0.34     0.37     0.42

    Carcasses
    (fat basis)       0.76    0.62    0.68     2.3     2.0     1.8       6.2      3.5      3.1

    Fat (abdominal)   0.68    0.55    0.66     2.2     1.8     1.8       3.9      3.1      3.2

    Livers
    (whole)           -       -       0.020    -       -       0.043     -        -        0.14

    Livers (fat
    basis)            -       -       0.43     -       -       1.1       -        -        2.1

    Fried
    chickens          -       -       0.047    -       -       0.15      -        -        0.29

    Fried chickens
    (fat basis)       -       -       0.47     -       -       1.6       -        -        2.8
                                                                                                
    
    RESIDUES OF HCB IN SOIL AND CROPS RESULTING FROM
    TREATMENT OF SOIL WITH QUINTOZENE

         In a study of the disappearance of quintozene and its technical
    impurities and metabolites pentachlorobenzene, hexachlorobenzene and
    pentachloroaniline from soil Beck and Hansen (1974) calculated that
    hexachlorobenzene had a half-life of 969-2089 days when applied to
    soil in laboratory experiments at the rate of 10 kg/ha. The same
    authors studied samples of soil collected at two different locations
    representing different soil types from fields which had previously
    been treated with quintozene. They found HCB residues in 21 of the 22
    samples at levels ranging from 0.17 to 0.94 mg/kg with an average of

    0.38 mg/kg. Soil from fields which had not been treated for two or
    more years showed only slightly less HCB than soil from fields which
    had been treated more recently. They found no direct relationship
    between the hexachlorobenzene and quintozene residue levels in the
    soil. This is understandable because quintozene is metabolized whereas
    HCB is degraded only very slowly. It is obvious from these studies
    that soil treated with technical quintozene which contains
    hexachlorobenzene as an impurity may be expected to carry appreciable
    residues of hexachlorobenzene for a number of years. Other studies
    (Bech and Hansen, 1973) have shown that such residues may be taken up
    by potatoes and carrots.

         The Meeting had available results of studies in The Netherlands
    aimed at determining the HCB content of soils and crops following
    repeated treatment with quintozene. Samples of soil were collected
    from 22 fields which had been treated with quintozene from 1 to 12
    times during more than 10 years. These samples were all found to
    contain HCB residues at levels ranging from 0.001 to 0.41 ppm. There
    appeared to be no direct relationship between the level of HCB
    residues and the number of treatments which had been applied. However
    the fields had been cultivated many times during the period of use of
    quintozene and it is very likely that the residue would have been
    distributed among the mass of soil to a considerable depth, depending
    upon the form of cultivation (Smelt and Leistra, 1974). In the same
    studies the content of HCB in crops growing in contaminated soil was
    studied and the ratio of the plant residue to the soil residue was
    determined. As seen from table 2 there is a distinct uptake of HCB by
    root crops, and in the case of carrots the concentration in the root
    was from 12-19 times as high as in the soil. There is an even higher
    uptake by the roots of grass. There is evidence of a distinct
    translocation into the leaves of some crops, particularly carrots,
    grass and sugar beet. With the exception of carrots, grass and turnip
    roots, the concentration of HCB in the dry plant material is lower
    than in the corresponding soil.

    TABLE 2.

    Residues of HCB in dry mass of crops and soil, and ratio of
    plant residue to soil residue (from Smelt and Leistra, 1974)
                                                                             

    Crop,                               Residue (mg/kg)            Ratio,
      part of plant          No         crop         soil          crop/soil
                                                                             

    Potato,                  1          0.11         0.22          0.50
      tubers                 2          0.20         0.40          0.50
                             3          0.13         0.18          0.72
                             4          0.017        0.027         0.63
                             5          0.10         0.16          0.63
                             6a)        0.21         1.17          1.24
                             7a)        0.021        0.034         0.62
                             8a)        0.27         0.30          0.90

    TABLE 2. (cont'd)

                                                                             

    Crop,                               Residue (mg/kg)            Ratio,
    part of plant            No         crop         soil          crop/soil
                                                                             

    Tulip,                   1          0.12         0.30          0.40
    bulbs                    2          0.065        0.10          0.65
                             3          <0.002       0.003         <0.67
                             4          0.16         0.10          1.60

    Shallot,                 1          0.056        0.12          0.47
    bulbs

    Sugar-beet,              1          0.095        0.41          0.23
    beets below              2          0.012        0.027         0.44
    surface                  3          0.027        0.056         0.48
                             4          0.010        0.024         0.42

    Sugar-beet,              1          0.014        0.41          0.03
    crowns                   2          0.004        0.027         0.15
                             3          0.005        0.056         0.09
                             4          0.002        0.024         0.08

    Sugar-beet               1          0.022        0.41          0.05
    leaves                   2          0.010        0.027         0.37
                             3          0.017        0.056         0.30
                             4          0.006        0.024         0.25

    Grass,                   1b)        0.81         0.09          9.0
    roots                    2b)        0.56         0.14          4.0
                             3b)        0.19         0.07          2.7
                             4c)        0.25         0.027         9.2
                             5d)        0.76         0.033         23
                             6d)        0.039        0.001         39

    Grass,                   1b)        0.22         0.09          2.4
    lower part of            2b)        0.20         0.14          1.4
    blades (0-5 cm)          3b)        0.10         0.07          1.4

    Grass,                   1b)        0.028        0.09          0.31
    upper part of            2b)        0.042        0.14          0.30
    blades (above 5 cm)      3b)        0.016        0.07          0.23
                             4c)        0.021        0.027         0.78
                             5d)        0.003        0.033         0.09
                             6d)        <0.003       0.001         -
                             7d)        0.011        0.12          0.09

    Grass,                   6d)        <0.003       0.001         -
    hay                      7d)        0.011        0.12          0.09

    Carrot,                  1          1.25         0.065         19
    roots                    2          0.48         0.04          12

    TABLE 2. (cont'd)
                                                                             

    Crop,                               Residue (mg/kg)            Ratio,
    part of plant            No         crop         soil          crop/soil
                                                                             

    Carrot,                  1          0.44         0.065         6.8
    leaves                   2          0.25         0.04          6.2

    Turnip,                  1          0.18         0.062         2.9
    roots

    Turnip,                  1          0.014        0.062         0.23
    leaves
                                                                             

    a) sampled in early July.
    b) young grass, one to two months after sowing, about 20 cm long.
    c) as b), but about 10 cm long.
    d) pasture, one year old.


    EVIDENCE OF RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION

         A survey of 198 milk samples from a wide cross section of New
    South Wales was conducted over three years for pesticide residue
    assessment (Siyali and Stricker 1973). HCB residues were found in 12%
    of the samples, the highest residue reported being 0.005 mg/kg.

    METHODS OF RESIDUE ANALYSIS

         The Meeting had before it a number of papers concerned with the
    analysis of residues of hexachlorobenzene.

         The international co-operative study of organochlorine pesticide
    residues in terrestrial and aquatic wild life (Holden, 1970) included
    test samples containing small concentrations of HCB. Only a few of the
    17 co-operating laboratories were able to detect this residue and even
    these reported wide variations. On one sample the results were
    reported to range from a trace to 0.14 mg/kg and on another sample
    only two of the 17 laboratories reported finding HCB.

         A method of confirming the presence of HCB residues by chemical
    reaction suitable for use in most residue laboratories has been
    advanced by Baker (1973). When HCB in hexane solution is treated with
    sodium ethoxide, monoethoxypentachlorobenzene is formed. The method is
    useful in distinguishing HCB from various HCH (BHC) isomers.

         A method of sampling and an analytical procedure for determining
    HCB in air has been published by Mann et al. (1974). The method is
    suitable for determining the distribution of HCB from industrial or
    agricultural sources.

    NATIONAL REGULATIONS

         A new regulation has been announced by The Netherlands concerning
    the fungicide pentachloronitrobenzene (quintozene), which normally
    contains up to 2% of hexachlorobenzene as an impurity. In view of the
    high persistence of hexachlorobenzene and the fact that it is likely
    to enter the food chain, thus causing unduly high unintentional
    residues in animal products, the following restrictions are being
    imposed. As from 1 August 1974 only quintozene containing no more than
    0.1% of hexachlorobenzene and no more than 1% of pentachlorobenzene is
    approved for use as a fungicide on lettuce and on seed-potatoes. As
    from 1 May 1975 the same restriction will apply to the material for
    use on flower-bulbs and for all other uses. Meanwhile, investigations
    are being carried out by the Laboratory for Insecticide Research with
    respect to accumulation of hexachlorobenzene in soil and its uptake in
    plants.

    RECOMMENDATIONS

         The practical residue limits recommended in 1969 and 1973 are
    confirmed.

    REFERENCES

    Baker, B.E. (1973) Confirmation of hexachlorobenzene by chemical
    reaction. Bull. environ. Contam. Toxicol., 10(5):279-284.

    Beck, J. and Hansen, K.E. (1973) National Food Institute, DK 2860
    Soborg, Denmark.

    Beck, J. and Hansen, K.E. (1974) The degradation of quintozene,
    pentachlorobenzene, hexachlorobenzene and pentachloroaniline in soil.
    Pestic. Sci., 5:41-48.

    Caseley, J.C. (1968) The loss of three chloronitrobenzene fungicides
    from the soil. Bull. environ. Contam. Toxicol., 3(3):180-193.

    De Vos, R.H., Bouwman, J. and Engel, A.B. (1972) Residues of
    organochlorine pesticides in broilers from feed fortified with known
    levels of these compounds. Pestic. Sci., 3:421-432.

    FAO/WHO. (1974a) 1973 Evaluations of some pesticide residues in food,
    FAO/AGP/1973/M/9/1. WHO Pesticide residues series, No. 3.

    FAO/WHO. (1974) The use of mercury and alternative compounds as seed
    dressing. Report. FAO Agricultural Studies, No. 95; Wld. Hlth Org.
    techn. rep. ser., No. 555.

    Gilbertson, M. and Reynolds, L.M. (1972) Hexachlorobenzene (HCB) in
    the eggs of common terns in Hamilton Harbour, Ontario, Bull. environ.
    Contam. Toxicol., 7:371-373.

    Grant, D.L., Hatina, G.V. and Munro, I.C. (1974) Hexachlorobenzene
    accumulation and decline of tissue residues and relationship to some
    toxicity criteria in rats. Preprint of paper presented at IUPAC
    Conference, Helsinki, July 1974, submitted to Environ. Qual. and Saf.

    Grant, D.L., Iverson, F., Hatina, G.V. and Villeneuve, D.C. (1974)
    Effects of hexachlorobenzene on liver porphyrin levels and microsomal
    enzymes in the rat. Environ. Physiol., 4:159-165.

    Holden, A.V. (1970) International Co-operative Study of Organochlorine
    Pesticide Residues in Terrestrial and Aquatic Wildlife, 1967/1968.
    Pestic. Monit. J., 4:117.

    Johnson, J.L., Stalling, D.L. and Hogan, J.W. (1974) Hexachlorobenzene
    (HCB) residues in fish. Bull. environ. Contam. Toxicol.,
    11(5):393-398.

    Khera, K.S. Hexachlorobenzene: Teratogenicity and dominant lethal
    studies in rats. Food Cosmet. Toxicol. (In press)

    Kimbrough, R.D. and Linder, R.E. (1974) The toxicity of technical
    hexachlorobenzene in the Sherman strain rat. A preliminary study.
    Chem. Path. Pharmacol., 8:653-664.

    Kuiper-Goodman, T., Pontefroct, R.D. and Grant, D.L. (1974) X-Ray
    (TEM) microanalysis of iron accumulated in liver parenchymal cells of
    rats with porphyria. Proc. Microsc. Soc. Canada, 1:14.

    Mann, J.B., Enos, H.F., Gonzalez, J. and Thompson, J.E. (1974)
    Development of sampling and analytical procedures for determining
    hexachlorobenzene and hexachloro-1,3-butadiene in air. Environ. Sci.
    Technol., 8:584-585.

    Siyali, D.S. and Stricker, P. (1973) Hexachlorobenzene and other
    organochlorine pesticides in milk. Aust. J. Dairy Technol., 28:55-58.

    Smelt, J.H. and Leistra, M. Contents of HCB in soil and crops after
    repeated soil treatments with quintozene. Paper from Lab. for Research
    on Insecticides, Wageningen, Neth. (in press)

    Somers, E., Grant, D.L. and Phillips, W.E.J. (1973) Toxicodynamics of
    organochlorine compounds, from Pesticides and the Environment: A
    Continuing, Controversy, Symposia Specialists, North Miami, Florida.

    U.S. Environmental Protection Agency. (1973) HCB residues in cropland
    soils - Monitoring Note 3. Part of report presented to Hazardous
    Materials Advisory Committee.

    Villeneuve, D.C., Panopio, L.G. and Grant, D.L. (1974) Placental
    transfer of hexachlorobenzene in the rabbit. Environ. Physiol.
    Biochem., 4:112-115.

    Villeneuve, D.C. The effect of food restriction on the redistribution
    of hexachlorobenzene (HCB) in the rat. Toxicol. Appl. Pharmacol. (in
    press)

    Villeneuve, D.C. and Hierlihy, S.L. Placental transfer of
    hexachlorobenzene in the rat. Bull. environ. Contam. Toxicol. (in
    press)

    Villanueva, E.C., Jennings, R.W., Burse, V.W. and Kimbrough, R.D.
    (1974) Evidence of chlorodibenzo-p-dioxin and chlorodibenzofuran in
    hexachlorobenzene. J. agr. Food Chem., 22:916-917.

    Zitko, V. (1971) Polychlorinated biphenyls and organochlorine
    pesticides in some freshwater and marine fishes. Bull. environ.
    Contam. Toxicol.  6:464-470.
    


    See Also:
       Toxicological Abbreviations
       Hexachlorobenzene (EHC 195, 1997)
       Hexachlorobenzene (HSG 107, 1998)
       Hexachlorobenzene (ICSC)
       Hexachlorobenzene (PIM 256)
       Hexachlorobenzene (FAO/PL:1969/M/17/1)
       Hexachlorobenzene  (IARC Summary & Evaluation, Supplement7, 1987)
       Hexachlorobenzene  (IARC Summary & Evaluation, Volume 20, 1979)
       Hexachlorobenzene  (IARC Summary & Evaluation, Volume 79, 2001)