Following evaluations at the 1969 and 1973 meetings (FAO/WHO,
    1970b, 1974b) when some Practical Residue Limits were recorded, the
    1974 Meeting allocated a Conditional ADI to hexachlorobenzene. The
    latter meeting also urged that:

         1.   support be given to an international monitoring programme 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 be carefully
              adhered to; and

         4.   HCB should be used only as a seed-dressing and only when no
              suitable substitute is available.

         The results of further toxicological studies have become
    available and are evaluated in the following monograph amendment.



         Orally administered HCB was slowly absorbed from the gut in
    rats, mainly via the lymphatic system and was stored in the fat
    (Iatropoulos et al., 1975). Recovery of orally administered 14C-HCB
    in rats was dose-dependent, more 14C being recovered from faeces
    than from urine. Several investigations on the metabolic pathway of
    HCB were performed in the rat and pentachlorophenol,
    pentachlorothiophenol, tetrachlorohydroquinone,
    tetrachlorothiophenol and 2,4,5-trichlorophenol could be identified
    as major urinary metabolites (Mehendale et al., 1975., Koss et al.,
    1976; Renner and Schuster, 1977). Unchanged HCB was found mainly in
    faeces and fat (Engst et al., 1976).

         After the administration of 14C-HCB in the diet to rhesus
    monkeys over a period of 10-15 months 99% of the radioactivity
    excreted in faeces was unchanged HCB, whereas the major urinary
    metabolites were identified as pentachlorophenol and
    pentachlorobenzene (Rozman et al., 1977).

         HCB was found in milk of cows and rats (Fries and Marrow,
    1976; Mendoza et al., 1976; Mendoza et al., 1975).


    Special studies on carcinogenicity


         Groups of 30-50 male and 30-90 female Swiss mice were
    maintained on a diet supplemented with 0, 50, 100 or 200 ppm HCB
    for life. Survival was impaired in the group given 200 ppm in which
    more than 50% animals of both sexes died before 50 weeks of age and
    only 2 males were alive at 90 weeks. The incidence of liver-cell
    tumours was 10% in both sexes given 100 ppm and 34% in males and
    16% in females at 200 ppm. No liver tumours were found in the
    control and lowest dose group. In treated animals, incidence of
    other tumours did not differ from controls or were decreased
    because of shortening of lifespan. In a further group of 30 mice of
    each sex fed a diet containing 300 ppm HCB for 15 weeks, survivors
    at 90 weeks were 17 females and 4 males, among which 1 mouse of
    each sex developed liver-cell tumours (Cabral et al., 1978).

         In another study the production of lung adenomas in strain A
    mice was investigated following multiple i.p. injections of HCB,
    three times weekly at doses of 0, 8, 20 and 40 mg/kg for 8 weeks.
    24 weeks after the first injection the survivors were killed. The
    only organ microscopically examined was the lung. Incidences of
    lung adenomas in treated animals were not significantly increased
    compared to the control. This test system is relatively unsensitive
    to hepatocarcinogens (Theiss et al., 1977).


         Groups of 30-60 female and 30-60 male Syrian golden hamsters
    were fed a diet containing 0, 50, 100 and 200 ppm HCB for lifespan.
    After 50 weeks the survival rate of the treated animals was
    comparable to the controls, after 70 weeks however shorter lifespan
    occurred in both sexes at the highest dose level of 200 ppm; marked
    weight reduction was observed at this dose level. Tumours of the
    thyroid, hepatomas and haemangioendotheliomas of the liver were
    found only in the treated animals, a dose-relationship of
    incidences was evident. Hepatomas occurred in 47% of the male and
    female animals in the 50 ppm group, in 57% of female and 87% of
    male animals in the 100 ppm group and in 85% of males and females
    in the 200 ppm group. Liver haemangioendotheliomas were found in 0
    and 3% at 50 ppm, in 7 and 20% at 100 ppm and 12 and 35% at 200 ppm
    in female and male animals respectively. Three of the
    haemangioendotheliomas occurring in the highest dose group
    metastasised. The incidence of thyroid adenomas was significantly
    increased compared to control in males treated with 200 ppm (Cabral
    et al., 1977).

    Special study on reproduction


         The effect of HCB on reproduction was studied by feeding the
    test compound to groups of 20 females and 10 males at dietary
    levels of 0, 10, 20, 40, 80, 160, 320 and 640 ppm over 4
    generations. Dose levels of 320 and 640 ppm caused the death of 20
    and 50% respectively of the females of the Fo generation.
    Fertility was reduced at 320 ppm and above, the average litter size
    was decreased from 160 ppm onwards. Marked reduction of the
    survival to day 5 after birth of the pups in various generations
    was observed; less than 60% of the pups of the F1 generation fed
    160 ppm and only about 40% of the pups of the F2 generation fed
    160 ppm survived the 5-day period. None of the pups of females fed
    320 and 640 ppm HCB survived. Lactation was also adversely affected
    by the treatment in the dose groups of 80 ppm and above and a
    significant decrease in birth weights was observed at this dose
    levels. Relative liver weight for pups from dame fed 40 ppm were
    significantly increased. No gross abnormalities were found in the
    pups (Grant et al., 1977).

    Special study on teratogenicity


         The oral administration of HCB at a dose level of 100 mg/kg
    b.w. on gestational day 7-16 to 10 CD-1 mice resulted in 13%
    abnormal fetuses per litter compared to 7% in the litters of 7
    untreated mothers; cleft palates, small-sized kidneys and renal
    agenesis were found only in treated animals (Courtney et al.,

         Placental transfer of HCB was reported by Andrews and
    Courtney, (1976).

    Special study on mutagenicity

         Hexachlorobenzene did not indicate mutagenic activity in
    Saccharomyces cerevisiae (Guerzoni et al., 1976).

    Short term studies


         Groups of 70 male and female rats were maintained on a diet
    with HCB added at does levels of 0, 0.5, 2, 8 and 32 mg/kg b.w.
    over a period of 15 weeks. Part of the animals was observed during
    a recovery period of another 18 weeks. At 32 mg/kg reduction of the
    average body weight of male rats was noted; mortality of 40%
    occurred in females only by the end of treatment. Urinalyses did
    not reveal abnormal findings except for a red color in females at
    32 mg/kg after 9 weeks of feeding, presumably due to the presence

    of high concentrations of uroporphyrins. At 8 and 32 mg/kg the
    relative liver weights were significantly increased compared to
    control. After 16 weeks on the recovery diet only liver weights 
    in females at the highest dose level were still significantly 
    higher than controls. Reversible increase of the relative kidney 
    and spleen weights was found in both sexes at 32 mg/kg. Gross 
    pathological and histopathological changes were found in liver 
    and spleen. The livers were enlarged and an increase in the size 
    of centrilobular heaptocytes was found accompanied by an increase 
    in smooth endoplasmic reticulum. These changes were particularly 
    marked in animals treated with 8 and 32 mg/kg. Spleens of many 
    females at 32 mg/kg were enlarged, sometimes accompanied by 
    hyperplasia. At 8 and 32 mg/kg females developed porphyria with 
    high levels of liver porphyrin (> 800 nmol/g) even during the 
    recovery period. Porphyrin also accumulated in the kidney and 
    the spleen.

         Tissue residues of HCB reached a plateau before 15 weeks and
    were dose-related with concentrations in adipose tissue > liver 
    > brain > serum. Maximum residues of approximately 6000 ppm were
    measured in the adipose tissue of females treated with 32 mg/kg
    HCB. A no effect level of 0.5 mg/kg was established in this study
    (Kuiper-Goodman et al., 1977).

         Similar results with respect to porphyrin accumulation in
    organs were reported by Doss et al., (1976).


         A 90-day toxicity study was carried out with pigs receiving
    the test compound in the diet at concentrations to give dose levels
    of 0, 0.05, 0.5, 5 and 50 mg/kg b.w. Animals treated with 50 mg/kg
    showed porphyria and died before termination of the experiment. A
    dose-related increase in the urinary excretion of coproporphyrin
    was found at does levels of 0.5 mg/kg and above as well as
    induction of microsomal liver enzymes (mixed-function oxidases)
    accompanied by increased liver weight at 5 mg/kg; significant
    increase of kidney and thyroid weights were also found at this dose
    level. Histopathological examination of the liver revealed
    centrilobular hypertrophy of the cells at dose levels of 0.5 mg/kg
    and above. At 50 mg/kg kidneys showed degenerative changes and
    lymph nodes atrophy. HCB residues in the 5 mg/kg group after 12-13
    weeks of feeding were 2.5 ppm in blood, 1300 ppm in fat, 42 ppm in
    the liver and approximately 20 ppm in kidney and brain. Residue
    levels at 50 mg/kg determined after 8 weeks of feeding were 30 ppm
    in blood and 15'000 ppm in fat.

         A no effect level of 0.05 mg/kg was found (Den Tonkelaar,

    Further short term studies:

         - Rats were fed low levels of HCB for 4 weeks; subsequent food
    deprivation enhanced the toxic response, thus indicating
    mobilization of HCB residues from fat (Villeneuve et al., 1977).

         - Immuno-suppression was observed in mice treated with 167 mg
    HCB/kg diet for 6 weeks (Loose et al., 1977).

         - In a 90 day feeding study in Japanese quails using dietary
    concentrations of 0, 1.5, 20 and 80 ppm, the treatment with 80 ppm
    caused mortality, tremors, liver damage consisting of enlargement
    of nuclei and nucleoli, proliferation of bile ductules and necrosis
    of hepatocytes, an well an reduction in egg production and
    hatchability. Increased liver weight, slight liver damage and
    increased faecal excretion of coproporphyrin were already observed
    at the 5 ppm dose level (Vos et al., 1971).

    Observation in Man

    Abnormal high plasma coproporphyrin levels of 3.6 ppb were measured
    in people not exposed occupationally but living near an
    HCB-manufacturing plant. There was no evidence of porphyria (Burns
    and Miller, 1975).


         Carcinogenicity tests in mice and hamsters were available. In
    mice HCB caused an increase in the incidence of hepatomas when fed
    at dose levels of 100 and 200 ppm. In hamsters feeding with 50, 100
    and 200 ppm caused an increase of hepatomas, haemangioendotheliomas
    and thyroid adenomas. No long-term studies in rats are available.

         The Meeting concluded that the maintenance of a conditional
    ADI was no longer justified. The Meeting further stressed the need
    to lower the human exposure to HCB as much as possible. The Meeting
    was aware of the fact that the use of HCB as a acid-dressing has
    declined considerably during recent years. It expressed the hope
    that the use of HCB in agriculture will completely cease in the
    near future.

         The Meeting stressed especially the importance of efforts to
    identify the various agricultural and non-agricultural sources of
    environmental contamination by HCB and of programmes directed to
    its diminution.


         Because the toxicity of HCB is such that the contamination of
    food should be kept as low as possible the previously allocated
    conditional ADI was withdrawn.


    Andrews, J.E. and Courtney, K.D. Inter-and intralitter variation of
    (1976)              Hexachlorobenzene deposition in fetuses.
                        Toxicol. Appl. Pharmacol. 37, 128.

    Burns, J.E. and Miller, F.M. Hexachlorobenzene contamination: its
    (1975)              effects in a Louisiana population. Arch.
                        Env. Health 30 44-48.

    Cabral J.R.P., Shubik, P., Mollner, T. and Raitano, F.
    (1978)              Carcinogenic activity of Hexachlorobenzene in
                        hamsters. Nature (Lond.)269, 510-511.

    Cabral J.R.P., Mollner, T., Raitano, F. and Shubik, P.
    (1978)              Carcinogenesis study in mice with
                        hexachlorobenzene. Toxicol. appl. Pharmacol.
                        44, 323 (Abstract No. 242).

    Courtney, K.D., Copeland, M.F. and Robbins, A. The effects of
    (1976)              pentrachloronitrobenzene, hexachlorobenzene
                        and related compounds on fetal development.
                        Toxicol. Appl. Pharmacol. 35, 239-256.

    Den Toneklaar, E.M., Verschluuren, H.G., Bankovska, J., DeVries, T.,
    (1978)              Kroes, R. and Van Esch, G.J.,
                        Hexachlorobenzene toxicity in pigs. Toxicol.
                        Appl. Pharm. 43, 137-145.

    Doss, M., Schermuly, E and Koss, G. Hexachlorobenzene porphyria
    (1976)              in rats as a model for human chronic heaptic
                        porphyrias. Ann. Clin. Res. 8, 171-181.

    Engst, R., Macholz, R.M. and Kujawa, M. The metabolism of
    (1976)              hexachlorobenzene (HCB) in rats. Bull:
                        environm. Contam. Toxicol. 16, 248-252.

    Fries, G.F. and Marrow, G.S. Hexachlorobenzene retention and
    (1976)              excretion by dairy cows. J. Dairy Sci. 59,

    Grant, D.L., Phillips, W.E.J. and Hatina, G.V. Effect of
    (1977)              hexachlorobenzene on reproduction in the rat.
                        Arch. environm. Contam. Toxicol. 5, 207-216.

    Guerzoni, M.E., Cupolo, L.D. and Ponti, I. Mutagenic activity of
    (1976)              pesticides. Rev. Sci. Technol. Aliment. 6,

    Iatropoulos, M.J., Milling, A., Müller, W.F., Nohynek, G., Rozman,
    (1975)              K., Coulston, F. and Kortey F. Absorption,
                        transport and organotropism of
                        dichlorobiphenyl, dieldrin and
                        hexachlorobenzene in rats. Environm. Res.
                        10, 384-389.

    Koss, G., Koransky, W. and Steinbach, K. Studies on the toxicology
    (1976)              of hexachlorobenzene.  II. Identification and
                        determination of metabolites. Arch. Toxicol.
                        35, 107-114.

    Kuiper-Goodman, T., Grant, D.L., Moddie, C.A., Korsrud, G.O. and
    (1977)              Munro, I.C. Subacute toxicity of
                        hexachlorobenzene in the rat. Toxicol. Appl.
                        Pharmacol.40 529-549.

    Loose, L.D., Pittman, K.A., Benitz, K.F. and Silkworth, J.B.
    (1977)              Polychlorinated biphenyl and hexachlorobenzene
                        induced humoral immunosuppression.
                        J. Reticuloendothel. Soc. 22, 253-271.

    Mehendale, H.M., Fields, M. and Matthews, H.B. Metabolism and
    (1975)              effects of hexachlorobenzene on hepatic
                        microsomal enzymes in the rat. J. Agr. Food
                        Chem. 23, 261-265.

    Mendoza, C.E., Grant, D.L. and Shields, J.B. Env. Phsiol.
    (1975)              Biochem. 5, 460-464.

    Renner G. and Schuster, K.P. 2,4,5-trichlorophenol a new urinary
    (1977)              metabolite of hexachlorobenzene. Toxicol.
                        Appl. Pharmacol. 39, 355-356.

    Rozman K., Mueller, W., Coulston, F. and Korte, F. Long-term
                        feeding study of hexachlorobenzene in rhesus
                        monkeys. Chemosphere 6, 81-84.

    Theiss, J.C., Stoner, G.D., Shimkin, M.B. and Weisburger, E.K.
    (1977)              Tests for carcinogenicity of organic
                        contaminants of United States drinking waters
                        by pulmonary tumor response in strain A mice.
                        Cancer Res. 37, 2717-2720.

    Villeneuve, D.C., Van Logten, M.J., DenTonkelaar, E.M., Greve, P.A.,
    (1977)              Vos, J.G., Speijers, G.J.A. and VanEsch, G.J.
                        Effect of food deprivation on low level
                        hexachlorobenzene exposure in rats. Sci.
                        Total Environm. 3, 179-186.

    Vos, J. G., van der Maas, H.L., Musch, A. and Ram, E. Toxicity
                        of hexachlorobenzene in Japanese quail with
                        special reference to porphyria, liver damage,
                        reproduction and tissue residues. Toxicol.
                        Appl. Pharmacol. 18, 944-957.

    See Also:
       Toxicological Abbreviations
       Guazatine (Pesticide residues in food: 1980 evaluations)
       Guazatine (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)