QUINTOZENE     JMPR 1975


         Earlier Joint Meetings (FAO/WHO, 1970, 1974 and 1975) have dealt
    with this compound and established a number of tolerance
    recommendations on a temporary basis. These tolerances were
    recommended by the 1969 Meeting to include the metabolite
    pentachloroaniline (PCA), while the 1973 Meeting after reconsideration
    noted that "limits for quintozene residues in all commodities include
    not only quintozene but the following impurities and metabolites:
    hexachorobenzene (HCB), pentachloroaniline (PCA), methyl
    pentachlorophenyl sulfide (MPCPS) and pentachlorobenzene (PCB)". At
    the eighth session of the Codex Committee on Pesticide Residues,
    several delegations opposed the inclusion of HCB in the tolerance and
    the Joint Meeting was requested to clarify its position (ALINORM
    76/24, para. 164).

         The 1973 Joint Meeting (FAO/WHO, 1974) listed further work and
    information which was required. In response, some new data on residues
    in poultry tissues and eggs have come forward.



    Special studies on carcinogenicity


         Groups of 100 male and 100 female Swiss random strain mice were
    fed dietary levels of 0, 100, 400 or 1200 ppm of quintozene
    (containing 2.7% HCB) for 80 weeks. Body weight gain was decreased in
    both sexes at 1200 ppm. Organ to body weight ratios of the liver were
    increased in male and female at 400 ppm and 1200 ppm and of the kidney
    at 1200 ppm in females. Microscopic examination revealed a non-dose
    related increase of nodular hyperplasia in the liver in males of all
    treatment groups. The hyperplastic areas have essentially normal
    cell-architecture and are regarded as non-neoplastic. An increased
    incidence of subcutaneous fibrosarcomas was observed in females at
    1200 ppm. All other neoplasms had no apparent relationship to
    treatment and were considered common features for mice of this strain.
    General appearance, behaviour and survival were not affected by
    treatment. Haematological indices were considered to be within normal
    limits (van der Heijden and Til, 1974).


         Groups of 50 male and 50 female Wistar strain rats were fed
    dietary levels of 0, 100, 400 and 1200 ppm quintozene (containing 2.7%
    HCB) for two years. Liver and kidney to body weight ratios were
    increased at 400 and 1200 ppm. Histological examination of the various
    organs revealed dose-related increases in the incidences of single
    cell necrosis and fatty metamorphosis of hepatocytes in both sexes at
    400 and 1200 ppm and the presence of enlarged centrolobular
    hepatocytes at all treatment levels. There was no increase in tumour
    incidence. No adverse effects were observed in general appearance,
    behaviour, body weight gain and food consumption. Haematology, blood
    chemistry and urinalysis values were considered to be within normal
    limits (Sinkeldam et al., 1974).

    Special studies on teratogenicity

         Quintozene (PCNB) was administered by intubation to groups of 20
    pregnant rats from day 6 to 15 of gestation at dosage levels of 0, 50,
    100 or 200 mg/kg body weight. Animals were killed on day 20 of
    pregnancy and foetuses were removed by caesarian section. PCNB
    residues were not detected (limit of detection 0.05 ppm) in either
    maternal or foetal tissues and no foetotoxic consequences were
    observed (Villeneuve et al., 1975). The type and number of skeletal or
    visceral abnormalities observed in the treated groups did not differ
    from that of the controls (Khera et al., 1975).


         Long-term studies on the rat and mouse have shown dose related
    liver abnormalities at dietary levels of 100, 1100 and 1200 ppm. An
    increased incidence in subcutaneous fibrosarcoma was noted in the
    female mouse. Since this lesion was observed in only one sex of one
    species of animal at a very high dosage level it was felt that this
    may be an aberrant observation and quintozene would not appear to have
    carcinogenic potential.

         A temporary ADI was established by the 1973 Joint Meeting based
    on no-effect levels determined in the rat and dog. Although all data
    required by the previous Joint Meeting has not become available it was
    felt that the two long-term studies provided sufficient evidence for
    the estimation of an acceptable daily intake.


    Level causing no toxicological effect

         Rat: 25 ppm in diet equivalent to 1.25 mg/kg bw

         Dog: 30 ppm in diet equivalent to 0.75 mg/kg bw

    Estimation of acceptable daily intake for man

         0-0.007 mg/kg bw


    Purity of quintozene

         The Meeting was informed that manufacturers are making efforts to
    eliminate the technical impurities, especially hexachlorobenzene
    (HCB), from quintozene formulations and that increasing quantities of
    low-HCB products, containing less than 0.1-0.5% HCB, are now
    available. It is noted, however, that this development is unavoidably
    accompanied by a parallel increase in the content of
    pentachlorobenzene (PCB) and there is ample evidence that considerable
    quantities of marketed products still contain varying amounts of both
    HCB and PCB.

         One country, the Netherlands, has already taken advantage of the
    existence of low-HCB formulations and has since July 1974 withdrawn
    all quintozene preparations with more than 0.1% HCB and 1.0% PCB.

    Residues in poultry

         Results of extensive feeding trials with laying hens have been
    presented to the Meeting (Kucher and Griffith, 1975). In these
    studies, which lasted for four months, eggs and tissues were analysed
    for residual quintozene, the impurities HCB and PCB and the
    metabolites PCA and MPCPS. The feeding levels were 0.5, 1, 5, 15, 75,
    and 300 mg of technical quintozene per kg diet. The quintozene
    contained 1.5% HCB, 0.07% PCB and 0.2% tetrachlorobenzene (TCNB).

         A summary of results for residues in egg yolk and chicken fat is
    shown in Table 1 from which it can be seen that residues of both PCB
    and HCB concentrate in proportion to their concentration in the feed
    and with similar concentration factors, namely one to two times in egg
    yolk and four to 10 times in chicken fat. These ratios must be
    considered maximum values, as plateau levels were reached for both
    compounds after three weeks in yolk; and after about seven weeks in

         Quintozene residues were found in yolk and fat, the plateau level
    being reached in less than one week. Both relatively and absolutely,
    residues of quintozene were less than those of the impurities.
    Quintozene was not present in bile, gall-bladder, blood, white meat or

         Residues of quintozene were low and even in those chickens whose
    feed contained 300 mg of technical quintozene per kg they did not
    exceed 1.4 mg/kg in fat and 0.03 mg/kg in egg yolk. This is in
    contrast to the impurity PCB which gave rise to almost identical
    amounts of residue although the PCB content of the technical
    quintozene was only 0.07%.

         The metabolites, PCA and MPCPS were found in eggs and fat, both
    reaching their plateau levels in less than one week, but combined
    levels of the two metabolites did not exceed 0.2 mg/kg in yolk or
    0.4 mg/kg in fat at the 300 mg/kg feeding level.

    TABLE 1.  Average plateau residues in chicken fat and egg yolk after feeding
              with technical quintozene1

          Feeding level (mg/kg)                   Residues found (mg/kg)
    PCNB2        HCB2         PCB2          PCNB2       PCA2        MPCPS2      HCB2        PCB2

    Chicken fat

    0.05         0.00075      0.000035      0.017       0.037       n.d.        0.048       n.d.
    1            0.015        0.0007        0.019       0.026       0.004       0.061       0.008
    5            0.075        0.004         0.027       0.027       0.001       0.364       0.023
    15           0.23         0.01          0.085       0.052       0.023       1.43        0.064
    75           1.1          0.05          0.228       0.106       0.042       6.74        0.334
    300          4.5          0.21          1.40        0.281       0.122       25.9        1.63

    Egg yolk

    0.05         0.00075      0.000035      n.d.        n.d.        n.d.        0.003       n.d.
    1            0.015        0.0007        0.003       n.d.        n.d.        0.012       n.d.
    5            0.075        0.004         0.003       0.008       n.d.        0.078       0.004
    15           0.23         0.01          0.004       0.014       0.001       0.359       0.011
    75           1.1          0.05          0.019       0.084       0.012       2.05        0.072
    300          4.5          0.21          0.024       0.174       0.024       8.14        0.224

    1  Technical product contained PCNB, HCB, PCB and TCNB in the ratio 100:1.5:0.07:0.2.

    2  PCNB = quintozene; HCB = hexachlorobenzene; PCB = pentachlorobenzene;
       PCA = pentachloroaniline; MPCPS = methyl pentachlorophenyl sulfide;
       TCNB = tetrachloronitrobenzene (present in feed, but not found as residue).

         The TCNB which was present as an impurity in the quintozene
    formulation could not be detected either in chicken tissues or in


         During the eighth session of the Codex Committee on Pesticide
    Residues in 1975 several delegations questioned the earlier
    recommendation from the Joint Meeting (FAO/WHO, 1974) that HCB among
    other impurities and metabolites should be included in tolerances for
    quintozene residues in various commodities.

         Considering the question, the Meeting evaluated previously
    available information as well as the results of new chicken feeding
    studies, which illustrate clearly the ability of both HCB and PCB to
    concentrate in fatty tissues, including eggs. Concentration factors of
    one to two and four to 10 from feed to egg yolk and fat, respectively,
    arc found. Because HCB and PCB tend also to be taken up and
    concentrated in plant materials which may become animal feed, the
    Meeting recognizes the unacceptability of the presence of these
    impurities of which HCB is assumed to have the greater persistence. It
    is realized that the accumulation of HCB and PCB in crops and soil may
    restrict, or even in some cases prevent, the use of quintozene treated
    crops for feeding purposes. When quintozene containing substantial
    amounts of HCB and PCB is applied, the persistence of these impurities
    in soil leads to carry-over of residues into subsequent crops
    including forage.

         In discussing the proposal that reference to HCB should be
    excluded from quintozene limits, the Meeting further recognized that
    PCB should logically also be excluded and that steps should be taken
    to provide maximum residue limits for the unavoidable residues of HCB
    and PCB resulting from the use of quintozene. Practical residue limits
    for HCB in individual crops could be established in line with the
    already recommended practical residue limits for HCB in animal
    products, although somewhat more extensive basic information would
    then be needed. However, the available data are not adequate to
    provide a basis for practical residue limits for PCB and the Meeting
    further recognized that the recommendation of maximum residue limits
    for HCB and PCB in crops could be interpreted as encouraging the use
    of unsatisfactory preparations.

         On balance, and in view of the lack of other alternatives, the
    Meeting decided that its position from the 1973 Meeting should be
    maintained until further information became available. HCB and PCB
    residues derived from quintozene treatments of plant material are
    therefore still included as part of the maximum residue limit already
    established. HCB residues in foods of animal origin resulting from the
    contamination of animal feeds or the carry-over from, previous use of
    quintozene as well as from other sources should be regulated according
    to the practical residue limits already recommended for HCB in meat,
    milk and eggs.

         The new data from chicken feeding studies, although derived from
    technical quintozene containing both HCB and PCB, do not realistically
    reflect the situations which may be expected in general practice since
    the composition of the technical quintozene differs from the
    composition of residues in feeds for poultry and will vary
    considerably from one situation to another. A recommendation for
    maximum residue limits in poultry products can therefore not be made
    on that basis.

         The final decision depends to a considerable extent on the
    outcome of investigations being undertaken by a number of quintozene
    manufacturers in order to develop manufacturing processes that reduce
    the HCB and PCB content to the lowest level consistent with
    maintaining acceptable costs and output.

         Meanwhile governments may have to consider limiting the usage of
    quintozene to those situations and regions where the build-up of HCB
    and PCB in soil, plant materials and animals will be minimal and where
    the maximum residue limits for HCB in foods of animal origin will not
    be exceeded.


         Earlier recommendations for temporary tolerances are confirmed as
    no longer temporary and converted to maximum residue limits. Attention
    is drawn to the previous recommendation that every effort should be
    made to encourage manufacturers to reduce the amount of chlorinated
    benzene impurities in quintozene to a minimum.


    REQUIRED (before additional maximum residue limits can be

         1.   Information on the occurrence of hexachlorobenzene (HCB) and
    pentachlorobenzene in plant and animal products, including animal
    feeds, resulting from the use of quintozene as well as from other
    sources, as a basis for making recommendations for practical residue
    limits for pentachlorobenzene as well as for HCB.

         2.   Further studies on the nature and levels of residues in
    animal products following feeding of plant materials containing
    residues typical of those resulting from the use of quintozene in


         1.   Further research to elucidate the formation of subcutaneous
    fibrosarcomas in female mice.


    ALINORM 76/24, (1975) para. 164

    Khera, K. S. and Villeneuve, D. C. (1975) Teratogenicity studies on
    halogenated benzenes (pentachloro-pentachloronitro- and hexabromo-).
    Toxicology 5 in press

    Kuchar, E. J. and Griffith, W. P. (1975) Analytical investigations
    concerned with feeding terraclurR to chickens. Report from Olin
    Corporation, Chemicals Division, Central únalytical Department, New
    Haven, Connecticut, October 30

    Sinkeldam, E. J., van der Heijden, C. A., de Groot, A. P. and Til, H.
    P. (1974) Carcinogenicity study with pentachloronitrobenzene in rat.
    Submitted by Central Institute for Nutrition and Food Research. Report
    R4442 (Unpublished)

    van der Heijden, C. A. and Til, H. P. (1974) Pentachloronitrobenzene
    carcinogenicity study in mice. Submitted by Central Institute for
    Nutrition and Food Research. Report R4365 (Unpublished)

    Villeneuve, D. C. and Khera, K. S. (1975) Placental transfer of
    halogenated benzenes in rats. Environmental Physiol. Biochem. accepted
    for publication

    See Also:
       Toxicological Abbreviations
       Quintozene (EHC 41, 1984)
       Quintozene (HSG 23, 1989)
       Quintozene (ICSC)
       Quintozene (FAO/PL:1969/M/17/1)
       Quintozene (WHO Pesticide Residues Series 3)
       Quintozene (WHO Pesticide Residues Series 4)
       Quintozene (Pesticide residues in food: 1977 evaluations)
       Quintozene (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)