QUINTOZENE JMPR 1975
Explanation
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.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Mouse
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).
Rat
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).
COMMENTS
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.
TOXICOLOGICAL EVALUATION
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
RESIDUES IN FOOD AND THEIR EVALUATION
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
fat.
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
liver.
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
eggs.
APPRAISAL
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.
RECOMMENDATIONS
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.
FURTHER WORK OR INFORMATION
REQUIRED (before additional maximum residue limits can be
recommended)
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
agriculture.
DESIRABLE
1. Further research to elucidate the formation of subcutaneous
fibrosarcomas in female mice.
REFERENCES
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 œnalytical 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)