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    DIQUAT

    First draft prepared by
    T.C. Marrs
    Department of Health, London, United Kingdom

    EXPLANATION

         Diquat was previously evaluated by the Joint Meeting in 1970,
    1972 and 1977 (Annex 1, references 14, 18 and 28).  An ADI of 0-
    0.008 mg diquat ion/kg bw was allocated in 1977.  This monograph
    summarizes new or not previously reviewed data on diquat, as well as
    relevant data from previous monographs and monograph addenda on this
    pesticide.

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

         Using unlabelled diquat or 14C-labelled diquat, Daniel &
    Henson (1960) demonstrated that diquat was absorbed to a small
    extent when administered to rats orally in aqueous solution.  In all
    species examined, diquat was poorly absorbed from the
    gastrointestinal tract, the small part absorbed being principally
    eliminated via the urine.

         In a study in rats, 14C-labelled diquat dibromide (5 or 10 mg
    ion/kg bw) or dichloride (22 or 24 mg ion/kg bw) was administered by
    gavage; the dibromide was also administered subcutaneously at doses
    of 5 or 6 mg ion/kg bw.  Most of the radioactivity appeared in the
    excreta within 48 hours, irrespective of the route of
    administration.  After oral administration, most of the diquat was
    found in urine.  Measurements of diquat in excreta suggested that
    biotransformation had occurred after oral adminstration, presumably
    by gut flora, as little evidence of biliary excretion was observed
    (Daniel & Gage, 1966).

         In another study in Wistar rats, 14C-diquat was administered
    as a single oral dose (45 mg ion/kg bw) in aqueous solution by
    gavage; 6% and 89% were excreted in urine and faeces, respectively,
    over 4 days but mainly in the first 24 hours.  After subcutaneous
    administration of 10 mg ion/kg bw, 87% and 5% were excreted in the
    urine and faeces respectively within 4 days (Mills, 1976).

         14C-Diquat as the dibromide was administered orally to Wistar
    to rats at a dose of 1 mg ion/kg bw.  A mean of 90% and 94% of the
    administered radioactivity was recovered in the faeces within 24
    hours and 168 hours, respectively.  Urinary excretion after 168
    hours was 3% of the administered dose (Johnston  et al., 1990a). 
    In another study, a single oral dose of 14C-labelled diquat
    dibromide (> 97% purity) was administered to Wistar rats at a dose
    of 100 mg diquat ion/kg bw.  About 73% of the radioactivity was
    recovered in faeces by 48 hours and 86% by 168 hours.  Urinary
    excretion was 5% of the dose over 168 hours.  There was no evidence
    of retention of label in tissues at 168 hours (Johnston  et al.,
    1990b).

         In a study using animals with cannulated bile ducts, 15 mg
    ion/kg bw diquat dichloride was injected i.p. in rats and 5 mg
    ion/kg bw in guinea-pigs and rabbits.  Some of the 14C-labelled
    dose of diquat was excreted in the bile (1.4% in the rat, 4.8% in
    the guinea-pig and 2.9% in the rabbit) (Hughes  et al., 1973).

         In lactating cows, very little (< 2%) radioactivity occurred
    in milk after administration of 14C-diquat and < 5% was found in
    the urine (Stevens & Walley, 1966).  In a further study in a cow,
    14C-diquat was administered in the diet at a concentration of 30
    ppm for 7 days.  Faeces contained 91% of the dose mostly as
    unchanged diquat.  Only 0.4% was excreted in urine.  Traces (0.004%)
    of label were found in milk (Leahy  et al., 1976).  In a further
    study in cows, 14C-labelled diquat and its photodegradation
    products were fed with barley.  The vast majority of the dose was
    excreted in the faeces within 10 days, 0.4% in urine and a low level
    in milk (Hemingway  et al., 1974).

         In a single goat, 96% of the label from a single oral dose of
    14C-diquat (7 mg/kg bw) was excreted within 7 days.  The vast
    majority of the label was found in faeces (94%).  Only 0.0175% was
    detected in milk (Griggs & Davis, 1975).

         Diquat is poorly absorbed through human skin  in vitro (Scott
    & Corrigan, 1990; Scott  et al., 1991) but skin of rats, mice,
    rabbits and guinea-pigs are more permeable (Scott & Corrigan, 1990). 
    Diquat is also very poorly absorbed through human skin  in vivo
    (Feldmann & Maibach, 1974).  Unlike paraquat, diquat is not
    selectively taken up by the lungs (see below).

    Biotransformation

         Results obtained by Daniel & Gage (1966) led to the conclusion
    that a substantial proportion of orally administered diquat was
    metabolized by gut flora.  However this was based on poor recovery
    of diquat from the faeces and it is probable that gut flora
    metabolism was overestimated.

         After administration of 14C-diquat to Wistar rats in aqueous
    solution by gavage (45 mg ion/kg bw), the major excreted product was
    diquat in both urine (5% of dose) and faeces (> 57% of dose). 
    Diquat monopyridone was the main metabolite mainly in faeces (5% of
    dose), but a minor one in the urine.  Following subcutaneous
    injection (10 mg ion/kg bw), 75% of the dose was present in the
    urine as diquat, about 3% as diquat monopyridone and 6% as the
    dipyridone.  Studies  in vitro suggested that the caecal microflora
    of the rat can metabolize diquat to the monopyridone (Mills, 1976).

         After oral administration of 14C-diquat to rats (strain not
    stated) at 100 mg/kg bw, the major excreted component was diquat in
    both urine and faeces.  In urine, diquat comprised 75-80% of the
    radioactivity, while about 1% (collectively) was picolinic acid,
    diquat dipyridone and diquat monopyridone.  In faeces, only diquat
    was observed except in females where another small component was
    found (Williams  et al., 1991).

         In another study in Wistar rats, in which a single oral dose of
    14C-labelled diquat dibromide (> 97% purity) was administered at
    100 mg ion/kg bw.  The major labelled component in both faeces and
    urine was diquat (Johnston  et al., 1991).

         Hughes  et al. (1973) showed that rabbits metabolized 18% of
    an i.p. 14C-labelled dose of diquat.  Approximately 3% of the dose
    was excreted in the bile as an unidentified metabolite.

         In lactating cows fed 14C-labelled diquat, most of the small
    amount of diquat in the milk appeared as metabolites (Stevens &
    Walley, 1966).  Urine also largely contained breakdown products.  In
    another study in a cow fed straw containing 14C-diquat and its
    degradation products, residues present at low levels in the milk
    were diquat, diquat monopyridone, 1,2,3,4-tetrahydro-1-oxo-pyrido
    (1,2a)-5-pyrizinium salt (TOPPS), picolinic acid and picolinamide
    (Hemingway  et al., 1974).

         In a goat, diquat was the major component in the faeces. 
    Diquat monopyridone was also detected.  The main compounds observed
    in urine in the first day were diquat monopyridone (2-4%) and diquat
    (20%).  In milk, 22% of the radioactivity was present as diquat, 13%
    as TOPPS and 7% as diquat monopyridone (Griggs & Davis, 1975).  In
    another study, straw containing diquat and its degradation products
    was fed to goats.  The main residues present in the milk were diquat
    and TOPPS, but both were present at extremely low levels (Hemingway
     et al., 1973).  In studies in sheep and cattle fed silage
    containing diquat, residues were not detected in meat or milk: 40-
    45% of the ingested diquat was excreted in the faeces and less than
    10% in the urine (Black  et al., 1966).  The authors hypothesized
    that the balance was biotransformed in the gut.

         The metabolism of diquat in animals is presented in Figure 1
    where I = diquat ion, II = diquat monopyridone, III = 1,2,3,4-
    tetrahydro-1-oxo-pyrido (1,2a)-5-pyrizinium salt (TOPPS); IV =
    picolinamide, V = picolinic acid and VI = diquat dipyridone.

    Effects on enzymes and other biochemical parameters

         Unlike paraquat, diquat is not actively taken up by lung slices
    (Rose  et al., 1975; Kurisaki & Sato, 1979), and higher
    concentrations of diquat are necessary for stimulating production of
    CO2 from glucose in rat lung slices (Rose  et al., 1976).  The
    difference in accumulation of diquat and paraquat by lungs is
    responsible for the major difference in toxicity between the two
    compounds (Rose & Smith 1977, Sharp  et al., 1972).  Lung toxicity
    is not characteristic of diquat poisoning (Smith & Rose, 1977). 
    However, there are analogies between the two compounds at the
    cellular level and it is likely that the cytotoxicity of diquat is
    caused by radical formation (Baldwin  et al., 1975).  Hepatocytes

    from old rats were reported to be more susceptible to diquat-induced
    cytotoxicity than those from young rats (Rikans & Cai, 1993; Rikans
     et al., 1993).  Diquat is readily reduced to form a green-coloured
    free radical which, in aerobic environments, is oxidized by
    molecular oxygen generating the superoxide anion radical and diquat.

         Rose  et al. (1974) reported that diquat (and paraquat)
    increased the response of the rat adrenal cortex to ACTH.  However
    it was later reported, on the basis of studies  in vitro in the rat
    adrenal and  in vivo in rats, that increased adrenal
    steroidogenesis was caused by ACTH release from the adenohypophysis
    (Crabtree & Rose, 1976).

         In rats treated orally with diquat at 540 mol/kg bw, decreased
    clearance of inulin, aminohippuric acid and N-methyl nicotinamide
    were noted.  A haemoconcentration was also observed and Lock (1979)
    hypothesized that this resulted from redistribution of fluid into
    the gut lumen, consequent alteration in renal haemodynamics and
    reduction in renal excretory function.  Diquat was also toxic to
    renal tubular cells, producing proteinuria and glycosuria in the rat
    (Lock & Ishmael, 1979)

         In some long-term studies with diquat, cataractogenesis was
    observed.  The mechanism is not clear since despite low levels of
    ascorbic acid in the lens, feeding ascorbic acid did not prevent
    cataract formation (Pirie & Rees, 1970).  Diquat free radicals may
    be formed in the lens under certain circumstances.  The role of OH
    and H202 produced by reaction of diquat free radical with 02 may
    be important in generating cataracts (Bhuyan & Bhuyan, 1991).

    Toxicological studies

    Acute toxicity studies

         The results of acute toxicity studies of diquat are presented
    in Table 1.  Diquat has been classified by WHO as moderately
    hazardous (WHO, 1992).

    Short-term toxicity studies

    Rats

         A 90-day feeding study in rats was carried out using groups of
    12 male and 12 female Alpk:APfSD rats and technical diquat
    dibromide, containing 26.9% (w/v) diquat ion.  The rats received 0,
    20, 100 or 500 ppm diquat.  The clinical condition of the animals,
    including body-weight gain and food consumption were monitored
    during the study and the eyes were examined ophthalmoscopically.  

    FIGURE 01


        Table 1.  Acute toxicity of diquat (dibromide unless otherwise stated)
                                                                                                                
    Species        Strain              Sex      Route    LD50/LC50 (mg ion/kg          References
                                                              bw)/(mg ion/l)
                                                                                                                

    Mouse          Alderley Park       M        p.o.                125                Clark & Hurst (1970)
                                                                 (106-146)
                                                p.o.                170                WHO (1984)

    Rat            Alderley Park       F        p.o.                231                Clark & Hurst (1970)
                                                                 (194-274)

                   Wistar              M        p.o.                231                Pritchard (1986)
                   Alpk:AP                                      (211-254.5)

                   Wistar              M        p.o.                214                McCall & Robinson (1990a)
                   Alpk:APfSD                                    (180-271)

                   Wistar              F        p.o.                222                McCall & Robinson (1990a)
                   Alpk: APfSD                                   (203-241)

                   Alderley Park       M        s.c.1               11                 Clark & Hurst (1970)
                                                                  (5-15)

                   Alderley Park       F        s.c.1               10                 Clark & Hurst (1970)
                                                                  (6-14)

                   Alderley Park       F        s.c.                11                 Clark & Hurst (1970)
                                                                  (9-12)

                   Wistar (Alpk:AP)    M        p.c.2              > 400               Southwood (1987a)

                   Wistar Alpk:AP      F        p.c.2              > 400               Southwood (1987a)

                                                                                                                

    Table 1 (contd)
                                                                                                                
    Species        Strain              Sex      Route    LD50/LC50 (mg ion/kg          References
                                                              bw)/(mg ion/l)
                                                                                                                

                   Wistar              M        p.c.2             > 1070               McCall & Robinson (1990b)
                   Alpk:APfSD

                   Wistar              M        p.c.2             > 1070               McCall & Robinson (1990b)
                   Alpk:APfSD

                   Alderley Park       ?        p.c.              50-100               Parkinson (1974a)
                   albino

                   Sprague-Dawley      M        inh3             121 g/l              Bruce (1985)
                   CD                                          (0.3-63 300)

                   Sprague-Dawley      F        inh3             132 g/l              Bruce (1985)
                   CD                                          (0.3-141 560)

    Rabbit         ?                   F        p.o.                101                Clark & Hurst (1970)
                                                                 (72-138)

                   ?                   F        p.c.               > 400               Clark & Hurst (1970)

                   New Zealand         ?        p.c.              50-100               Parkinson (1974b)
                   White

    Guinea-pig     ?                   F        p.o.                100                Clark & Hurst (1970)

    Dogs           ?                   F        p.o.              100-200              Clark & Hurst (1970)

    Hens           ?                   F        p.o.              200-400              Clark & Hurst (1970)

    Cattle         ?                   ?        p.o.                30                 Walley (1987)

                                                                                                                

    Table 1 (contd)
                                                                                                                
    Species        Strain              Sex      Route    LD50/LC50 (mg ion/kg          References
                                                              bw)/(mg ion/l)
                                                                                                                
    Cattle         ?                   F        p.o.                30                 Clark & Hurst (1970)

    Monkey         Cynomolgus          ?        p.o.1             100-300              Cobb & Grimshaw (1979)

                                                                                                                

    Notes

    1)   diquat dichloride
    2)   administered as 21.2% diquat ion
    3)   whole body 240 min exposure to aerosol
    

    Urine and blood were examined during the study.  At autopsy, blood
    was taken for clinical chemistry and haematology and selected organs
    weighed and examined histologically.  Animals receiving diquat at a
    concentration of 500 ppm showed a marked reduction in weight gain,
    food consumption and utilization.  Cataract formation was also
    observed at this dose at 8 weeks and at autopsy, corneal opacity was
    observed in 7/12 males and 4/12 females; at histological
    examination, cataract was seen in 12/12 males and 11/12 females. 
    Additionally, a low incidence of focal inflammation of the tongue
    and epithelium of the palate was observed.  Reduced plasma protein
    was seen at 500 ppm, possibly caused by low food intake.  Absolute,
    but not relative, organ weights were reduced, almost certainly a
    reflection of poor food intake.  Treatment-related effects were not
    seen at 100 ppm.  The NOAEL was 100 ppm, equal to 8.5 and 9.2 mg
    ion/kg bw/day in males and females, respectively (Hodge, 1989a).

    Dogs

         A one-year study in dogs was carried out using diquat dibromide
    technical (26.7 w/v ion) added to the feed.  Groups of 4 male and 4
    female beagles received diquat at doses of 0, 0.5, 2.5 or 12.5 mg
    ion/kg bw/day.  Clinical condition, body weight and food consumption
    were monitored throughout.  Ophthalmoscopy, haematology and clinical
    chemistry were carried out.  The animals were sacrificed and
    autopsied at 52 weeks and a range of organs examined and processed
    for histological examination.  There was a small but statistically
    significant decrease in body-weight gain in the high-dose groups of
    both sexes, somewhat greater in the females.  No such decrease was
    seen at the lower doses.  There was a statistically significant
    decrease in WBC and neutrophil count in males of all treatment
    groups at a single time point (week 4) which was ascribed to raised
    counts in one control.  There were decreased platelet counts in top
    dose females at 4, 26 and 52 weeks.  Raised plasma chloride levels
    observed in the top dose animals were attributed to bromide ion
    interference.  Plasma triglyceride in the males given 12.5 mg ion/kg
    bw/day were higher than in the controls throughout the study; at 4
    and 26 weeks these increases were statistically significant. 
    Statistically significant increases in relative and absolute kidney
    weight were observed in both sexes at 12.5 mg ion/kg bw/day.  There
    were decreases in absolute and relative adrenal weight in all
    treatment groups in the males, which were statistically significant
    only in the case of relative weights.  Additionally, there was a
    decrease in the absolute and relative weight of the epididymides in
    all test groups compared to the controls; this finding was only
    statistically significant for absolute weights in the 2.5 mg ion/kg
    bw/day group and for relative weights in the top dose group. 
    Changes in organ weights did not correspond to any histopathological
    changes.  Cataract was seen in all the top dose animals by the end
    of the study, both by ophthalmoscopy and histologically and in 2/4
    females receiving diquat at a dose of 2.5 mg ion/kg bw/day; however

    in the latter group only one was confirmed by histopathological
    examination.  Inflammatory changes were seen at the top dose in the
    large intestine, consisting of reduction in mucosal thickness, loss
    and abnormality of mucosal glands, epithelial hyperplasia in crypts
    and increased goblet cell activity.  The NOAEL was 0.5 mg ion/kg
    bw/day based upon lens opacity in females at the next dose (Hopkins,
    1990).

    Long-term toxicity/carcinogenicity studies

    Mice

         In an 80-week feeding study, groups of CD-1 mice (60/sex) were
    fed diquat dibromide (98.5% pure) at dietary concentrations of 30,
    150 or 500 ppm.  The highest dietary concentration was reduced to
    400 ppm after 3 weeks and to 300 ppm after 5 weeks; these changes
    were made because of lethal toxicity and the decedent mice were
    replaced.  Not all groups were started simultaneously: one control
    group and the two lower test groups were started about three months
    before the other control groups and the highest dosage group.  In
    general the test material had little clinical effect, except that
    marked toxicity, evidenced by huddling, hypoactivity, and an
    ungroomed appearance, were observed for the first few weeks at 500
    ppm.  Clinical recovery appeared complete by the eighth week. 
    Survival was not affected by treatment.  Growth rates were reduced
    at the highest dietary concentration and at 150 ppm.  At 30 ppm,
    there were no effects on body-weight gain.  There was an increased
    frequency of hepatic vacuolation in livers at 150 ppm (males) and at
    the highest dose in both sexes.  The NOAEL was 30 ppm, equivalent to
    4.5 mg ion/kg bw/day (Ashby, 1987).

         In a 2-year study, groups of 60 male and 60 female mice
    (C57BL/10JfCD-1/Alpk) were fed a diet containing 0, 30, 100 or 300
    ppm diquat.  The test material was technical grade diquat dibromide,
    containing 26.7% diquat ion w/v.  Haematological examination of tail
    vein blood samples was carried out on all animals at 53 and 79
    weeks.  Fuller haematology was carried out on blood obtained by
    cardiac puncture at 104 weeks.  Various tissues were taken at
    autopsy and processed for histological examination.  There was
    marked toxicity at the highest dose, shown by statistically
    significant reductions in body-weight gain in both sexes, small and
    sometimes statistically significant reductions in food consumption,
    eye discharge and mild nephropathy.  Changes in certain
    haematological parameters at 300 ppm were also seen, namely
    statistically significantly decreased neutrophil count and increased
    lymphocyte count in both sexes at weeks 53 and 79.  There was also a
    significant increase in total WBC at 2 years in males.  Relative
    kidney weights were increased significantly in males and females. 
    At 100 ppm there were statistically significant reductions in body-
    weight gain in both sexes, particularly in the males later in the

    study; there were also some changes in haematology (lymphocytosis
    and neutropenia) which, although statistically significant were
    probably unimportant, and relative kidney weights were increased
    significantly in males.  No treatment-related carcinogenic effects
    were seen in the study (there were reductions in certain tumour
    incidences at 300 ppm) and the incidence of cataract was not related
    to the test material.  The NOAEL was 30 ppm, equal to 3.6 mg ion/kg
    bw/day (males) and 4.8 mg ion/kg bw/day (females) (Hodge, 1992).

    Rats

         In a two-year feeding study, groups of Wistar-derived rats
    (35/sex) received diquat dibromide (100% pure = 53.6% ion) at
    dietary concentrations of 0, 15, 25 or 75 ppm.  Weight gain and food
    consumption did not differ significantly between groups.  A
    significantly increased incidence of cataracts was observed at 75
    ppm.  The NOAEL was 25 ppm, equivalent to 1.3 mg ion/kg bw/day
    (Rogerson & Broad, 1978).

         In another 2-year study, diquat dibromide (technical grade) was
    administered in the diet to groups of Sprague-Dawley rats (60/sex)
    at dietary concentrations of 0, 5, 15, 75 or 375 ppm.  Additionally,
    satellite groups of 10 males and 10 females received diquat at the
    same dietary concentrations and were killed at 1 year. 
    Ophthalmoscopy was carried out before dosing and periodically during
    the study.  Haematological and biochemical variables were measured
    on 10 animals from each main group before dosing, and at 26, 52, 78
    and 104 weeks, and in five satellite animals at week 52.  A
    reduction in food consumption and utilization efficacy was observed
    at 375 ppm.  After 26 weeks, there was a reduction in MCV and in
    haemoglobin in females and males, respectively.  Minimal reductions
    in red blood cell parameters were observed in males at 15 ppm and
    above, at 52 and 78 weeks.  Other changes were prolonged activated
    partial thromboplastin times at 75 and 375 ppm in females at 52 and
    104 weeks and at 52 weeks in the 15 ppm females.  Blood urea
    nitrogen (BUN) was elevated at 52 weeks at 75 and 375 ppm and at 78
    weeks in the 375 ppm females.  At 52 weeks, the 75 and 375 ppm
    groups exhibited lower total protein and albumen levels.  On
    ophthalmoscopic examination, lenticular opacities were seen in the
    75 and 375 ppm groups at 13 weeks and the findings progressed at
    subsequent examinations.  Ophthalmoscopy at 104 weeks showed severe
    lens opacities at 375 ppm in all surviving rats, while less severe
    ones were seen at 75 ppm.  At 15 ppm, a single instance of cataract
    was seen in each sex.  Histological examination of the eyes
    postmortem, showed advanced cataractogenesis in all animals at 375
    ppm and in about 80% of the 75 ppm group.  There was a low
    prevalence of cataract at 15 ppm: cataract-type changes being seen
    in 0/22 controls and 3/22 at 15 ppm (males) and 0/22 controls and
    2/20 at 15 ppm (females).  Small differences were seen in
    nephropathy in arteritis and in aneurism formation in males at the

    highest dose.  Elevations reported as statistically significant were
    seen in the incidence of benign phenochromocytomas at 75 ppm with no
    real evidence of a trend and in combined thyroid parafollicular cell
    adenomas and carcinomas at 5 ppm, both in males but numbers were
    very small.  There was evidence of a trend for thyroid follicular
    cell adenoma; however these figures appear to have been much
    influenced by the frequency of the tumour at 375 ppm (in males the
    number of tumours out of the number of thyroid glands examined in
    each groups were 2/24, 1/32, 1/25, 0/25 and 3/32 for the control, 5,
    15, 75 and 375 ppm groups respectively; none were observed in
    females).  There was a significant increase in the number of females
    with multiple neoplasia and with malignant neoplasms at 5 and 75
    ppm.  No other change attributable to the test material was seen. 
    The LOAEL was 15 ppm (equal to 0.58 and 0.72 mg ion/kg bw/day for
    males and females) based upon cataractogenesis.  The NOAEL was 5
    ppm, equal to 0.19 mg ion/kg bw/day (males) and 0.24 mg ion/kg
    bw/day (females) (Colley  et al., 1985).

    Reproduction studies

    Rats

         A three-generation study was conducted in rats by Fletcher  et
     al. (1972) using diquat dibromide monohydrate (100% pure). 
    Wistar-derived rats were divided into 3 groups, each containing 12
    males and 24 females.  One group received standard diet while the
    other two groups received diquat dibromide in aqueous solution at
    dietary concentrations of 0, 125 or 500 ppm when they were
    approximately 35-days old.  Thereafter the three groups and their
    progeny remained on the diet throughout the study.  Body weights and
    food consumption were recorded weekly and the animals physically
    examined daily.  The F0 animals were mated after 100-days feeding,
    one male and two females being housed together for this purpose. 
    Where pregnancy had not occurred in three weeks, the male was
    replaced by another from the same group.  Litters were examined
    within 20 hours of delivery (F1a).  At 21 days, each litter was
    counted, weighed sexed and subjected to autopsy.  Second matings
    were arranged after a 10-day rest period.  From the progeny (F1b),
    12 males and 24 females were reared and continued on the diet from
    weaning, the remainder being killed and examined.  At 100 days, the
    F1b animals were mated for the production of the second generation
    (F2).  The F2 generation was treated in the same way as the F1,
    the F2a litters being examined and autopsied at 21 days and the F2b
    providing the breeders for production of the F3 generation.  The
    F3a litters were treated as before and the F3b animals were also
    autopsied at 21 days and detailed examination, including
    histological examination was carried out postmortem.  Rats treated
    with diquat (500 ppm) developed lens opacity from about 125 days. 
    The proportion exhibiting this abnormality increased and at 300 days
    about 50% were affected.  Opacity was not seen at the lower dose. 

    There was also a statistically significant reduction in weight gain
    at 500 ppm, at 15 weeks in both sexes of F0 parents.  Similar
    reductions (after weaning) were found in the subsequent generations. 
    In the second generation, significantly reduced body weights were
    seen in the 125 ppm females at weaning and the final week before
    mating but not at other weighings.  There were 6 fewer pregnancies
    in the 500 ppm group of F1 animals.  Atrophy of the seminiferous
    tubules was observed in parents and progeny of each generation. 
    Although more common in the 500 ppm groups, there was no clear dose-
    response relationship.  This study did not exhibit an NOAEL since
    there was decreased weight gain in F0 and F1 animals at the lowest
    dose, but the effects observed at this dose (125 ppm, equivalent to
    6.3 mg ion/kg bw/day) were trivial (Fletcher  et al., 1972).

         A multigeneration study was conducted using technical grade
    diquat dibromide, containing diquat ion 26.7% w/v.  Groups of
    Alpk:APfSD rats (30/sex) were fed diets containing 0, 16, 80 or 400
    ppm diquat.  After 12 weeks the animals were mated and allowed to
    rear the litters that resulted (F1a).  The process was repeated
    with 30 male and 30 female parents/group selected from the F1a
    litter, these F1 parents being mated 11 weeks after selection.  The
    dose received by the top dose F1 rats was reduced after 4 weeks to
    240 ppm.  The animals were examined daily and mouths examined
    weekly.  Animals were weighed weekly in the premating period.  After
    mating the males were weighed monthly and the females were weighed
    on days 1, 8, 15 and 20 of pregnancy and days 1, 5, 11, 16 and 22 of
    lactation.  All animals were weighed at the terminal kill.  Food
    consumption was recorded weekly until mating, and weekly in the
    females during pregnancy and lactation.  Ophthalmoscopic examination
    of the eyes was carried out on the controls and top dose group at 12
    weeks and on all the F0 animals at termination (24 weeks).  A
    similar examination was carried out on the F1 rats 4 weeks after
    selection, at 11 weeks before mating and at termination (21 weeks). 
    Diquat had no effect on fertility in either sex.  Decreased body-
    weight gain was seen at the top dose in both adults (F0 and F1)
    and pups.  Inflammatory lesions in the mouth, particularly
    ulceration of the hard palate was observed at 400 ppm in F0 rats
    and F1 pups and adults.  Cataracts, first seen at week 12 in F0
    females and at week 13 in males and 2 weeks earlier in each sex in
    the F1a and F1b, were also observed in the F1 adults.  Although
    cataract formation was mostly confined to the 240 ppm group, a low
    incidence was seen at 80 ppm in the F1 female parents (3/30 at
    premating ophthalmoscopic examination and 4/30 at examination before
    termination of the study).  At the terminal histopathological
    examination, cataract was seen in the highest dose group only of F0
    and F1 parents.  There was an increase in pathological changes in
    the renal tract in the F1 and F2 pups.  Reproductive toxicity
    (reduced pup weight gain) was observed at 400 ppm.  The NOAEL was 16
    ppm (equivalent to 0.8 mg/kg bw/day) based upon a low incidence of
    partial cataract formation at 80 ppm (Hodge, 1990).

    Other studies on reproduction parameters

         An antifertility effect on male mice was noted during the
    dominant lethal study of Pasi  et al. (1974).  Diquat at doses up
    to 10 ppm in the diet of hens for 6 weeks did not affect food
    consumption, egg production and hatchability.  Residues of diquat
    were not found in eggs or in hens' tissues (Edwards & Smith, 1975).

    Special studies on embryo/fetotoxicity

    Mice

         In a study in Swiss-Webster and Sprague-Dawley (CD) mice, a
    single dose of 15 mg/kg bw diquat was given i.p. to groups of three
    animals at day 7-21 of gestation.  Nine maternal deaths out of 45
    animals occurred.  The percentage dead plus resorbed fetuses was
    57%.  A NOAEL could not be determined in this study (Bus  et al.,
    1975).

         Groups of 20 female CFLP mice were administered diquat i.p. (11
    mg/kg bw Reglone) on day 9 of gestation or diquat (2.7 mg/kg bw/day
    Reglone) on days 9-12 of gestation.  Both groups showed increased
    fetal loss or resorption compared to controls.  Skeletal
    abnormalities were observed in the test group embryos.  A NOAEL
    could not be determined in this study (Selypes  et al., 1980).

    Rats

         Diquat was administered in the diet to pregnant Sprague-Dawley
    rats, from days 1-20 of pregnancy at 0, 125 or 500 ppm diquat ion. 
    There were 18 control rats, and 20 in each of the test groups. 
    Animals were killed at day 20, fetuses removed and the uteri
    examined.  All rats remained in good condition throughout the study
    but food consumption and body-weight gain were reduced significantly
    at 500 ppm.  There was no adverse effect on implantations, mean
    number of fetuses, litter weight or sex ratio.  Mean fetal weight
    was significantly lower in the 500 ppm group.  A dose-related
    increase in subcutaneous fetal haemorrhages compared to the controls
    was observed.  A NOAEL could not be determined in this study (Moore
    & Wilson, 1973).

         Diquat containing 26.2 % ion w/v was administered by gavage to
    groups of 8 female rats (Wistar derived Alpk:APfSD) at doses of 0,
    4, 12, 24 or 40 mg ion/kg bw/day in deionized water from days 7-16
    of gestation.  Controls received deionized water.  On day 22 the
    females were killed and the uteri examined for live fetuses and
    intrauterine deaths.  At a dose of 40 mg ion/kg bw/day the mothers
    showed reduced weight gain and changes in clinical condition
    (piloerection, urinary incontinence and gasping) and 4/24 animals at
    24 mg ion/kg bw/day showed milder signs.  Some fetotoxicity was seen

    at 40 mg ion/kg bw/day (reduced fetal weight gain), but not at the
    lower doses, whereas maternal toxicity, as indicated by dose-related
    reduced food consumption and body-weight gain, was observed at all
    doses.  Although there was a statistically non-significant increase
    in pre- and post-implantation loss at 24 mg ion/kg bw/day, this was
    not observed at the other three doses.  No fetal abnormality was
    observed.  For fetal toxicity, the LOAEL was 40 mg ion/kg bw/day and
    the NOAEL 24 mg ion/kg bw/day.  The NOAEL for maternal toxicity
    could not be determined in this study (Milburn, 1989).

         Groups of 24 female rats were given diquat by gavage in
    deionized water (26.2 % ion w/v) at doses of 4, 12 or 40 mg ion/kg
    bw/day from days 7-16 of gestation.  Maternal toxicity was seen at
    40 mg ion/kg bw/day as reduced weight gain and food consumption. 
    Significant reductions in fetal weight, litter weight and gravid
    uterine weight as well as fetal defects in ossification were seen at
    40 mg ion/kg bw/day.  Minor evidence of reduced ossification were
    seen at the lower doses but these were considered not to be of
    biological significance.  For both maternal and fetotoxicity the
    LOAEL was 40 mg ion/kg bw/day and the NOAEL 12 mg ion/kg bw/day
    (Wickramatne, 1989).

    Rabbits

         Groups of up to 20 female mated Dutch rabbits were dosed orally
    with diquat dibromide (100% pure = 53.6% ion) at levels of 1.3, 2.5
    or 5.0 mg ion/kg bw/day from days 1-28 of gestation (day of mating =
    day 0).  The material was administered in "Dispersol OG" (a 10%
    solution of ricinoleic glycerides with glycerol and polyglycerols),
    which was also used as control.  An additional 4 does were allowed
    to litter and the eyes of the offspring examined for cataracts.  The
    rabbits were sacrificed at day 29 and the uteri examined for live
    fetuses and intrauterine deaths.  The fetuses were weighed and
    examined for gross abnormality and about half processed for skeletal
    examination and half for soft tissue examination.  There was a
    reduction in maternal weight gain at 5.0 mg ion/kg bw/day, which was
    not statistically significant.  There was no evidence of any effect
    on embryonic or fetal development.  The NOAEL was 2.5 mg ion/kg
    bw/day based on mild maternal toxicity at the highest dose (Hodge,
    1987).  A feature of this study was the poor pregnancy rate in all
    groups which necessitated mating of extra animals to achieve
    acceptable numbers of pregnancies per group.

         In a second study, groups of 7 or 8 female New Zeeland white
    rabbits were administered diquat dibromide technical by gavage in
    deionized water (26.2% ion w/v) at doses of 0, 1, 3, 7 or 10 mg
    ion/kg bw/day from days 7-19 of gestation.  Controls received water. 
    On day 30 of gestation, the females were killed and the uteri
    examined for live fetuses and intrauterine deaths.  Doses of 3 mg
    ion/kg bw/day or above were associated with maternal toxicity as

    manifested by weight loss or reduced weight gain and reduced food
    intake.  No evidence of fetotoxicity was observed.  The NOAEL was 1
    mg ion/kg bw/day based upon maternal toxicity (Hodge, 1989b).

         In a third study, groups of 20 New Zeeland white rabbits were
    administered by gavage diquat dibromide technical (26.2% ion w/v) in
    deionized water, at doses of 0, 1, 3 or 10 mg ion/kg bw/day from
    days 7-19 of gestation.  On day 30 of gestation the females were
    killed and the uteri examined for live fetuses and intrauterine
    deaths.  The fetuses were weighed, examined externally and for
    visceral abnormalities, eviscerated and stained for skeletal
    abnormalities.  Doses of 10 mg ion/kg bw/day caused maternal
    toxicity as shown by weight loss and reduced food intake; five
    animals from this group were sacrificed early  in extremis.  
    Effects on body weight and food consumption, although less severe,
    were also present at 3 mg ion/kg bw/day.  Some evidence of
    fetotoxicity was observed at 10 mg/kg bw/day (mottled and friable
    livers and small increase in minor skeletal defects at 3 and 10 mg
    ion/kg bw/day, in the form of partially ossified sternabrae).  The
    elevation in the proportion of fetuses with minor skeletal defect
    was significant at 3 and 10 mg ion/kg bw/day; there was a non-
    significant increase at the lowest dose group.  The NOAEL was 1 mg
    ion/kg bw/day based on maternal toxicity (reduced weight gain and
    food consumption) and skeletal effects in the fetuses at doses of 3
    mg ion/kg bw/day (Hodge, 1989c).

    Special studies on genotoxicity

         Based on the results of the genotoxicity assays given in Table
    2, the Meeting concluded that diquat was not genotoxic.

    Toxicity of metabolites

         In Wistar-derived rats, diquat dipyridone and monopyridine were
    less toxic than diquat when given subcutaneously (Parkinson, 1974b;
    Crabtree, 1976).

         The results of acute and genotoxicity studies with TOPPS are
    given in Tables 3 and 4, respectively.

    Other animal studies

         Diquat dichloride and dibromide are both moderate skin
    irritants to the skin of the rat and mildly irritant to the rabbit
    eye (Parkinson, 1974).  Orally administered diquat increases
    secretion into the gut lumen (Crabtree  et al., 1977; Rawlings  et
     al., 1992).  In a study to detect any other major actions of
    diquat in laboratory animals, single doses of up to 280 mg/kg bw
    were administered orally to rats.  Effects such as CNS depression
    and increased gut motility were observed at perilethal doses only
    (Allen & Brammer, 1990).


        Table 2.  Results of genotoxicity assays on diquat
                                                                                                                              
    Test system    Test object              Concentration of diquat     Purity          Results    Reference
                                                                                                                              

     In vitro

    Ames test      S. typhimurium           0.01-50                      100%           -ve        Shirasu et al. (1979)
    (5)            (strains TA1535,         g/plate
                   1537, 1538, 98, 100)

    Ames test      S. typhimurium           0.00256-100                  100%           -ve        Callander (1986a)
    (5)            (strains TA1535,         g/plate
                   1537, 1538, 98,           S9
                   100

    Ames test      S. typhimurium           0.5-100 g/plate           25.8% w/w        -ve        Callander (1986b)
    (5)            (strains TA1535,         with S9,                ion (technical)
                   1537, 1538               0.1-50 g/plate
                   98, 100)                 without S9

    Reverse        E. coli WP2 hcr          0.01-50 g/plate             100%           -ve        Shirasu et al. (1979)
    mutation (5)

    Reverse        E. coli WP2              0.5-100 g/plate           25.8% w/w        -ve        Callander (1986b)
    mutation (5)   uvrA pKM101              with S9,                ion (technical)
                                            0.1-50 g/plate
                                            without S9

    Mammalian      Mouse lymphoma           6.25-100 g/ml               100%           -ve        Cross (1986a)
    cell (5)       L5178Y TK+/-

    Mammalian      Mouse lymphoma           6.25-100 g/ml             25.8% w/w        -ve        Cross (1986b)
    cell (5)       L5178Y TK+/-                                     ion (technical)

                                                                                                                              

    Table 2 (contd)
                                                                                                                              
    Test system    Test object              Concentration of diquat     Purity          Results    Reference
                                                                                                                              

    Cytogenetics   Human lymphocytes        26.7, 107, 267(2),           100%           +ve (4)    Wildgoose et al. (1986)
    (1)                                     534.8(3) g/ml as ion

    Cytogenetics   Human lymphocytes        12.9-129 g/ml             25.8% w/w        +ve (4)    Richardson et al. (1986)
    (1)                                                             ion (technical)

    Rec-assay      B. subtilis              2-200 g/disc                100%           -ve        Shirasu et al. (1979)
                   H17, M45

     In vivo

    Cytogenetics   Rat bone marrow          4.4, 9.5, 14,                100%           -ve        Anderson et al. (1980)
                   (Wistar-derived          mg/kg bw/day
                   Alderley Park)           for 5 days orally

    Cytogenetics   Mouse bone marrow        0.73, 3.6, 7.3, 22           100%           -ve        Selypes et al. (1980)
                   (CFLP)                   mg/kg bw ip
                                            90 mg/kg/bw/po

    Micro-nucleus  Mouse bone marrow        0, 62.5, 100 mg/kg         25.8% w/w        -ve        Sheldon et al. (1986)
                   C57BL/6J/Alpk            bw                      ion (technical)

    Dominant       Mouse (CD-1)             0.1-10 mg ion/kg           28.6% w/w        -ve        Anderson et al. (1976)
    Lethal Test                             bw/day for 5 days       ion (technical)     

    UDS            Rat hepatocyte           225, 450, 900              25.8% w/w        -ve        Trueman et al. (1987)
                   in vivo                  mg/kg ion               ion (technical)

                                                                                                                              
    1)    S9
    2)   Donor 1 MTD
    3)   Donor 2 MTD
    4)   Clastogenic only at doses causing cytotoxicity
    5)   with and without metabolic activation

    Table 3.  Acute toxicity of TOPPS
                                                                                             
    Species     Strain            Sex       Route      LD50 (mg/kg bw)       References
                                                                                             

    Rat         Wistar Alpk:A     M         PO               2449            Southwood (1987b)
                                                          (2000-3000)

                Wistar Alpk:A     F         PO               2942            Southwood (1987b)
                                                          (2000-5000)

                                                                                             



    Table 4. Results of genotoxicity assays on TOPPS
                                                                                                             
    Test system    Test object              Concentration of TOPPS      Purity          Results    Reference
                                                                                                             

    Ames (1)       S. typhimurium           0.1-5 mg/plate                98%           -ve        Ohta (1987)
                   TA1535, TA1537,
                   98, 100

                   E. coli                  0.1-5 mg/plate                98%           -ve        Ohta (1987)
                   WP uvrA

    Rec Assay (1)  B. subtilis              0.2-10 mg/disc                98%           -ve        Ohta (1987)

                                                                                                             

    (1)  With or without metabolic activation.
    

    Special studies on cataractogenesis

         Pirie & Rees (1970) fed Wistar albino rats a diet containing
    0.05 or 0.075% diquat dibromide.  Lens opacity was produced after 4-
    8 months at both doses.  Ascorbic acid content of the lens, but
    unusually not GSH content, decreased during development of cataract. 
    Radioactivity appeared in the lens after intraperitoneal injection
    of 14C-labelled diquat.  Pirie  et al. (1970) suggested that free-
    radical formation might be responsible for cataract formation.

    Observations in humans

         Vanholder  et al. (1981) reviewed several cases of poisoning
    with diquat.  In one case, initial signs and symptoms were
    abdominal.  Later oliguria and coma developed.  Shock supervened
    followed by cardiac arrest.  In another case progression was slower
    but renal failure occurred and eventually led to anuria.  Despite
    haemodialysis, death occurred from ventricular fibrillation, and
    renal failure was observed.  Unlike poisoning with paraquat, diquat
    does not cause lung fibrosis.  Cataracts have not been observed in
    humans (IPCS, 1984) and more recent investigations have not shown
    cataract formation in those engaged in diquat manufacture or
    formulation (Bonsall, 1990).

         Two patients were splashed in the eyes with a preparation
    containing both paraquat and diquat.  In both cases the corneal
    epithelium was damaged and healing was slow (Nirei  et al., 1993).

         In a recent report, a child survived what was initially
    believed to be a fatal dose of diquat, apparently with no sequelae
    (Buckley & MacKiernan, 1991, 1992).  A recent case report describes
    a patient who developed Parkinsonism a few days after exposure to
    diquat (Sechi  et al., 1992).  The extent of exposure of the
    patient to the pesticide was not known and thus the significance of
    this isolated observation in a 72-year old man is questionable.

    COMMENTS

         When administered orally 14C-diquat is poorly absorbed from
    the gastrointestinal tract of rats, cows and goats and mainly
    eliminated vis the faeces during the first 24 hours, the small part
    absorbed being principally eliminated via the urine.  The total
    percentages of administered doses eliminated via the faeces were 94,
    91 and 94 for the rat, cow and goat, respectively; 3.1% and 0.4%
    were eliminated in the urine of the rat and the cow, respectively,
    and very small percentages of radioactivity were found in cow's and
    goat's milk (0.004% and 0.0175%), respectively.

         After oral administration of 14C-diquat to rats (45 mg ion/kg
    bw), the major excreted product was diquat in both urine (5% of
    dose) and faeces (> 57% of dose): diquat monopyridone was the main
    metabolite in the faeces (5% of dose), but a minor one in the urine. 
    In another oral study in rats (100 mg ion/kg bw), a small amount of
    diquat dipyridone and picolinic acid was found in addition to the
    monopyridone.  After subcutaneous injection (10 mg ion/kg bw) in the
    rat, 75% of the dose was present in the urine as diquat, about 3% as
    the monopyridone and 6% as the dipyridone.

         Unlike paraquat, diquat is not actively taken up by lung
    slices, and lung toxicity is not characteristic of diquat poisoning.

         The acute oral toxicity of diquat varies with species, but is
    between 125 and 250 mg ion/kg bw in rodents.  It is classified by
    WHO as moderately hazardous.

         In a 90-day feeding study in rats, using dietary concentrations
    of 0, 20, 100 or 500 ppm, the NOAEL was 100 ppm, equal to 8.5 mg
    ion/kg bw/day, based upon reduction in body-weight gain, food
    consumption and reduced plasma protein at the next higher dose.

         In a one-year feeding study, dogs received doses of 0, 0.5, 2.5
    or 12.5 mg/kg bw/day.  The NOAEL was 0.5 mg ion/kg bw/day based upon
    lens opacity in females at the next dose.

         Two long-term toxicity/carcinogenicity studies were conducted
    in mice.  The first (80 weeks) used dietary concentrations of diquat
    ion of 0, 30, 150 or 500 ppm.  The NOAEL was 30 ppm, equivalent to
    4.5 mg ion/kg bw/day, based upon reduced growth rates at the next
    higher dose together with hepatic vacuolation in males.  In a 2-year
    study in mice, in which dietary concentrations of 0, 30, 100 or 300
    ppm were used, the NOAEL was 30 ppm, equal to 3.6 mg ion/kg bw/day,
    based on reduction in body-weight gain and increased relative kidney
    weights at the next higher dose.  There was no evidence of
    carcinogenicity in mice.

         Two 2-year feeding studies in rats have been conducted.  In the
    first study, diquat dibromide was administered in the diet at
    concentrations of 0, 5, 15, 75 or 375 ppm.  The NOAEL was 5 ppm,
    equal to 0.19 mg ion/kg bw/day, based upon cataract formation in the
    15 ppm group.  In the second study, dietary concentrations of 0, 15,
    25 or 75 ppm diquat ion were used.  The NOAEL was 25 ppm (equivalent
    to 1.3 mg ion/kg bw/day), based on cataract formation at the next
    higher dose.  There was no evidence of carcinogenicity in rats.

         Numerous teratogenicity studies have been conducted.  NOAELs
    could not be determined in two mouse studies.  There were three
    teratogenicity studies in rats; in the first study dietary
    concentrations of 0, 125 or 500 ppm diquat ion were used.  A dose-
    related increase in subcutaneous fetal haemorrhages compared to the
    controls was observed.  A NOAEL could not be derived from this
    study.  In the second study, diquat was administered at oral doses
    of 0, 4, 12, 24 or 40 mg ion/kg bw/day.  For fetal toxicity, the
    NOAEL was 24 mg ion/kg bw/day, but maternal toxicity was observed in
    all test groups (reduced weight gain and food consumption).  In the
    third study, diquat was administered by gavage at doses of 0, 4, 12
    or 40 mg ion/kg bw/day.  The NOAEL for both maternal and fetal
    toxicity was 12 mg ion/kg bw/day, based in the case of the dams on
    reduced body weight and food consumption and in the case of the
    fetuses on reduced fetal weight and defects in fetal ossification at
    the highest dose.

         In a study in rabbits, diquat was given orally at doses of 0,
    1.3, 2.5 or 5.0 mg ion/kg bw/day.  There was no evidence of any
    effects on embryonic or fetal development.  The NOAEL was 2.5 mg
    ion/kg bw/day based on mild maternal toxicity at the highest dose. 
    In a second study in rabbits, doses of 0, 1, 3, 7 or 10 mg ion/kg
    bw/day were administered by gavage.  Doses of 3 mg ion/kg bw/day or
    above were associated with maternal toxicity as manifested by weight
    loss or reduced weight gain and reduced food intake.  No evidence of
    fetotoxicity was observed.  The NOAEL was 1 mg ion/kg bw/day based
    upon maternal toxicity.  In a third study in rabbits, doses of 0, 1,
    3 or 10 mg ion/kg bw/day diquat were given by gavage.  The NOAEL was
    1 mg ion/kg bw/day based upon maternal toxicity (reduced weight gain
    and food consumption) and skeletal effects in the fetuses at doses
    of 3 mg ion/kg bw/day.

         Two multigeneration reproduction studies were conducted in
    rats.  In the first study, diquat was given at dietary
    concentrations of 0, 125 or 500 ppm.  This study did not exhibit an
    NOAEL, since there was decreased weight gain in F0 and F1 animals
    at the lowest dose, but the effects observed at this dose (125 ppm,
    equivalent to 6.3 mg ion/kg bw/day) were trivial.  In the second
    study, rats were fed diquat at dietary concentrations of 0, 16, 80
    or 400 ppm.  The NOAEL was 16 ppm (equivalent to 0.8 mg/kg bw/day)
    based upon a low incidence of partial cataract formation at 80 ppm.

         Diquat has been adequately tested in a series of genotoxicity
    assays  in vitro and  in vivo.  Chromosomal aberrations were
    induced  in vitro but there was no other evidence of genotoxicity. 
    The Meeting concluded that diquat was not genotoxic.

         An ADI of 0-0.002 mg/kg bw was established based upon a NOAEL
    of 0.19 mg ion/kg bw/day identified in a two-year study in rats,
    using a safety factor of 100.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effects

         Mouse:    30 ppm, equal to 3.6 mg ion/kg bw/day 
                   (two-year study)

         Rat:      5 ppm, equal to 0.19 mg ion/kg bw/day 
                   (two-year study)
                   12 mg ion/kg bw/day (teratogenicity study)
                   16 ppm, equivalent to 1.6 mg ion/kg bw/day
                   (multigeneration reproduction study)

         Rabbit:   1 mg/kg bw/day (teratogenicity study)

         Dog:      0.5 mg ion/kg bw/day (one-year study)

    Estimate of acceptable daily intake for humans

         0-0.002 mg ion/kg bw

    Studies which will provide information in the continued evaluation
    of the compound

         Observations in humans.

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    dietary administration to rats. Report ICI 406/83763. Huntingdon
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    to WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Crabtree, H.C. (1976). Unpublished report. Comparison of the
    subcutaneous toxicity of diquat, diquat monopyridone and diquat
    dipyridone. Report CTL/P/351. Imperial Chemical Industries PLC,
    Alderley Park, Macclesfield, Cheshire, England. Supplied to WHO by
    Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Crabtree, H.C. & Rose, M.S. (1976). Unpublished report. Early
    effects of diquat on plasma corticosteroid concentrations in rats.
    Report CTL/R/380. Imperial Chemical Industries PLC, Alderley Park,
    Macclesfield, Cheshire, England. Supplied to WHO by Zeneca
    Agrochemicals, Fernhurst, Surrey, England.

    Crabtree, H.C., Lock, E.A. & Rose, M.S. (1977). Effects of diquat on
    the gastrointestinal tract of rats.  Toxicology Appl Pharmacol., 
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    Cross, M.F. (1986a). Unpublished report. Diquat dibromide:
    assessment of mutagenic potential using L5178Y mouse lymphoma cells.
    Report CTL/P/1554. Imperial Chemical Industries PLC, Alderley Park,
    Macclesfield, Cheshire, England. Supplied to WHO by Zeneca
    Agrochemicals, Fernhurst, Surrey, England.

    Cross, M.F. (1986b). Unpublished report. Diquat dibromide
    (technical): assessment of mutagenic potential using L5178Y mouse
    lymphoma cells. Report CTL/P/1602. Imperial Chemical Industries PLC,
    Alderley Park, Macclesfield, Cheshire, England. Supplied to WHO by
    Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Daniel, J.W. & Gage, J.C. (1966). Absorption and excretion of diquat
    and paraquat in rats.  Brit J Industr Med., 23: 133-136. 

    Daniel, J.W. & Henson, A.F. (1960). Unpublished report. The
    absorption and excretion of the herbicide K.8483 in rats. Report
    IHR/137. Industrial Hygiene Research Laboratories and Akers Research
    Laboratories. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    Edwards, M.J. & Smith, D.C. (1975). Unpublished report. Diquat:
    residue transfer and hatchability study in laying hens. ICI Plant
    Protection Ltd. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    Feldmann, K.J. & Maibach, H.I. (1974). Percutaneous penetration of
    some pesticides and herbicides in man.  Toxicol appl Pharmacol,, 
    28: 126-132.

    Fletcher, K., Griffiths, D. & Kinch, D.A. (1972). Unpublished
    report. Diquat dibromide: three-generation reproduction study in
    rats. Report HO/IH/R/331A. Imperial Chemical Industries Ltd
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    Agrochemicals, Fernhurst, Surrey, England. 

    Griggs, R.E. & Davis, J.A. (1975). Unpublished report. Diquat:
    excretion and metabolism in a goat. Report AR 2585 A. ICI Plant
    Protection Ltd. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    Hemingway, R.J., Leahey, J.P., Davis, J.A. & Griggs, R.E. (1973).
    Unpublished report. Metabolism of diquat and its photoproducts in
    goats. Report AR 2448 B. ICI Plant Protection Ltd. Supplied to WHO
    by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hemingway, R.J., Leahey, J.P., Davis, J.A. & Burgess (1974).
    Unpublished report. Diquat: metabolism of diquat and its
    photoproducts in a cow. Report AR 2448 B. ICI Plant Protection Ltd.
    Supplied to WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hodge, M.C.E. (1987). Unpublished report. Diquat dibromide:
    teratogenic studies in the rabbit. Report OH/CTL/P114B. Imperial
    Chemical Industries PLC, Alderley Park, Macclesfield, Cheshire, UK.
    Supplied to WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hodge, M.C.E. (1989a). Unpublished report. Diquat: 90 day feeding
    study in the rat. Report no CTL/P/1832 (revised). Imperial Chemical
    Industries PLC, Alderley Park, Macclesfield, Cheshire, UK. Supplied
    to WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hodge, M.C.E. (1989b). Unpublished report. Diquat: embryotoxicity
    study in the rabbit. Report CTL/P/2196. ICI Central Toxicology
    Laboratory, Alderley Park, Macclesfield, Cheshire, UK. Supplied to
    WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hodge, M.C.E. (1989c). Unpublished report. Diquat: embryotoxicity
    study in the rabbit. Report CTL/P/2379. ICI Central Toxicology
    Laboratory, Alderley Park, Macclesfield, Cheshire, UK. Supplied to
    WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hodge, M.C.E. (1990). Unpublished report. Diquat: multigeneration
    study in the rat. Report CTL/P/2462. ICI Central Toxicology
    Laboratory, Alderley Park, Macclesfield, Cheshire, UK. Supplied to
    WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Hodge, M.C.E. (1992). Unpublished report. Diquat: two year feeding
    study in mice. Report CTL/P/3409. ICI Central Toxicology Laboratory,
    Alderley Park, Macclesfield, Cheshire, UK. Supplied to WHO by Zeneca
    Agrochemicals, Fernhurst, Surrey, England.

    Hopkins, M.N. (1990). Unpublished report. Diquat: 1 year feeding
    study in dogs. Report CTL/P/2596. ICI Central Toxicology Laboratory,
    Alderley Park, Macclesfield, Cheshire, UK. Supplied to WHO by Zeneca
    Agrochemicals, Fernhurst, Surrey, England.

    Hughes, R.D., Millburn, P. & Williams, R.T. (1973). Biliary
    excretion of some diquaternary ammonium cations in the rat, guinea-
    pig and rabbit.  Biochem J., 136: 979-984. 

    IPCS (1984). Environmental Health Criteria 39 paraquat and diquat.
    International Programme on Chemical Safety, WHO, Geneva.

    Johnston, A.M., Jones, C., McCullum, J., Mutch, P.J. & Scott, G.
    (1990a). The elimination of 14C-diquat in the rat following single
    dose oral administration (low level). Report no CTL/C/2554. Inveresk
    Research International, Tranent, EH33 2NE, Scotland. Supplied to WHO
    by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Johnston, A.M., Mutch, P.J. & Scott, G. (1990b). The elimination of
    14C-diquat in the rat following single dose oral administration
    (high dose level). Report CTL/C/2555. Inveresk Research
    International, Tranent, EH33 2NE, Scotland. Supplied to WHO by
    Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Johnston, A.M., Jones, C., McCallam, J. & Scott, G. (1991).
    Unpublished report. The disposition of 14C-diquat in the rat.
    Report CTL/C/2553. Inveresk Research International, Tranent, EH33
    2NE, Scotland. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    Kurisaki, E. & Sato, H. (1979). Tissue distribution of paraquat and
    diquat after oral administration in rats.  Forensic Science, 14:
    165-170.

    Leahy, J.P., Gatehouse, D.M., Carpenter, P.K. & Benwell, M. (1976).
    Diquat: metabolism and residue in a cow. ICI Plant Protection
    Division. Report No. AR2698A. Supplied to WHO by Zeneca
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    Lock, E.A. (1979). The effect of paraquat and diquat on renal
    function in the rat.  Toxicol Appl Pharmacol., 48: 327-336.

    Lock, E.A. & Ishmael, J. (1979). The acute toxic effects of paraquat
    and diquat on the rat kidney.  Toxicol Appl Pharmacol., 50: 67-76.

    McCall, J.C. & Robinson, P. (1990a). Unpublished report. Diquat
    dibromide: acute oral toxicity to the rat. Report CTL/P/2999. ICI
    Central Toxicology Laboratory, Alderley Park, Macclesfield,
    Cheshire, UK. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    McCall, J.C. & Robinson, P. (1990b). Unpublished report. Diquat
    dibromide: acute dermal toxicity to the rat. Report CTL/P/2982. ICI
    Central Toxicology Laboratory, Alderley Park, Macclesfield,
    Cheshire, UK. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    Milburn, G.M. (1989). Diquat: embryotoxicity study in the rat.
    Unpublished report CTL/P/2275. ICI Central Toxicology Laboratory.
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    Mills, I.H. (1976). Unpublished report. Diquat: disposition and
    metabolism in the rat.Report CTL/P/214. Imperial Chemical Industries
    PLC, Alderley Park, Macclesfield, Cheshire, England. Supplied to WHO
    by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Moore, S. & Wilson, G.J. (1973). Unpublished report. Diquat
    dibromide: teratogenicity studies in the rat. Report No HO/IH/P/82B.
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    Nirei, M., Hayasaka, S., Nagata, M., Tamai, A. & Tawara, T. (1993).
    Ocular injury caused by preeglox-l, a herbicide contained paraquat,
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    Ohta, T. (1987). Unpublished report. TOPPS: microbial mutagenicity
    study. Report CTL/P/253A. Institute of Environmental Toxicology,
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    Parkinson, G.R. (1974a). Unpublished report. Diquat dichloride and
    dibromide: comparison of dermal toxicity and local irritancy. Report
    No HO/IH/P/116. Supplied to WHO by Zeneca Agrochemicals, Fernhurst,
    Surrey, England.

    Parkinson, G.R. (1974b). Unpublished report. Diquat monopyridone:
    acute and subacute oral toxicity. Report No CTL/P/12213. ICI Central
    Toxicology Laboratory, Macclesfield. Supplied to WHO by Zeneca
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    Pirie, A. & Rees, J.R. (1970). Diquat cataract in the rat.  Exptl.
     Eye Research, 9: 198-203.

    Pirie, A., Rees, J.R. & Holmberg, N.J. (1970). Diquat cataract:
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    Pritchard, V.K. (1986). Unpublished report. Diquat: acute oral
    toxicity to the rat of a 200 g/l formulation ("Reglox"). Report
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    Agrochemicals, Fernhurst, Surrey, England.

    Rawlings, J.M., Foster, J.R. & Heylings, J.R. (1992). Diquat-induced
    intestinal secretion in the anaesthetized rat.  Human Exp Toxicol.,
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    Richardson, C.R., Howerd, C.A., Wildgoose, J. (1986). Unpublished
    report. Diquat dibromide (technical): a cytogenetic study in human
    lymphocytes  in vitro. Report CTL/P/1561. Imperial Chemical
    Industries PLC, Alderley Park, Macclesfield, Cheshire, England.
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    Rikans, L.E. & Cai, Y. (1993). Diquat - induced oxidative damage in
    BCNU - pretreated hepatocytes of mature and old rats.  Tox Appl.
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    Rikans, L.E., Cai, Y., Kosanke, S.D., Venkataraman, P.S. (1993).
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    dibromide: 2 year feeding study in rats - amended report. Report
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    accumulation by tissues. In: Autor PA Ed. Biochemical Mechanisms of
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    report. Paraquat accumulation: tissue and species specificity.
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    Rose, M.S., Smith, L.L. & Wyatt, I. (1976). The relevance of pentose
    phosphate pathway stimulation in rat lung to the mechanism of
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    Rose, M.S., Crabtree, H.C., Fletcher, K. & Wyatt, I. (1974).
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    138: 437-443.

    Scott, R.C. & Corrigan, M.A. (1990). The  in vitro percutaneous
    absorption of diquat: a species comparison.  Toxicol in vitro, 4:
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    Scott, R.C., Walker, M. & Mawdesley, S.J. (1991). Unpublished
    report. Diquat dibromide:  in vitro absorption from technical
    concentrate ('Reglone 40') and spray strength solution through human
    skin. ICI Central Toxicology Laboratory, Alderley Park,
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    Agrochemicals, Fernhurst, Surrey, England.

    Sechi, G.P., Agnetti, V., Piredda, M., Canu, M., Deserra, F., Omar,
    H.A., Rosati, G. (1992). Acute and persistent parkinsonism after use
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    paraquat toxicity with tissue concentrations and weight loss in the
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    Sheldon, T., Richardson, C.R. & Shaw, J. (1986). Unpublished report.
    Diquat dibromide (technical): an evaluation in the mouse
    micronucleus test. No ICI Central Toxicology Laboratory, Alderley
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    Shirasu, Y., Moriya, M. & Toshihiro, T. (1979). Unpublished report.
    Mutagenicity testing on diquat in microbial systems. Institute of
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    Smith, L.L. & Rose, M.S. (1977). A comparison of the effect of
    paraquat and diquat on the water content of rat lung and the
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    toxicity to the rat of a 200 g/l formulation. Report CTL/P/1881.
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    Southwood, J.(1987b). Unpublished report. Topps acute oral toxicity
    to the rat. Report CTL/P/1788. Imperial Chemical Industries PLC,
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    Stevens, M.A. & Walley, J.K. (1966). Tissue and milk residues
    arising from the ingestion of single doses of diquat and paraquat by
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    Trueman, R.W., Elliot, B.M. & Barber, G. (1987). Unpublished report.
    Diquat dibromide (technical): assessment for the induction of
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    CTL/P/1814. Imperial Chemical Industries PLC, Alderley Park,
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    Vanholder, R., Colardyn, F., de Reuck, J., Praet, M., Lameire, N.&
    Ringoir. S. (1981). Diquat intoxication: report of two cases and
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    Walley, J.K. (1987). Unpublished report.Diquat toxicity in cattle.
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    WHO (1992). The WHO recommended classification of pesticides by
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    study in the rat. Report CTL/P/2331. Imperial Chemical Industries
    PLC, Alderley Park, Macclesfield, Cheshire, England. Supplied to WHO
    by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Wildgoose, J., Braithwaite, I., Howerd, C.A., Richardson, C.R.
    (1986). Unpublished report. Diquat dibromide: a cytogenetic study in
    human lymphocytes  in vitro. Report CTL/P/1469. Imperial Chemical
    Industries PLC, Alderley Park, Macclesfield, Cheshire, England.
    Supplied to WHO by Zeneca Agrochemicals, Fernhurst, Surrey, England.

    Williams, S.G., Cameron, B.D. & McGuire, G.M. (1991). Unpublished
    report. Identification of the major radioactive components in urine
    and faeces from rats following single oral administration of [14C]-
    diquat. Report CTL/C/2523. Inveresk Research International, Tranent,
    EH33 2NE, Scotland. Supplied to WHO by Zeneca Agrochemicals,
    Fernhurst, Surrey, England.


    See Also:
       Toxicological Abbreviations
       Diquat (HSG 52, 1991)
       Diquat (PIM 580F, French)
       Diquat (AGP:1970/M/12/1)
       Diquat (WHO Pesticide Residues Series 2)
       Diquat (Pesticide residues in food: 1976 evaluations)
       Diquat (Pesticide residues in food: 1977 evaluations)
       Diquat (Pesticide residues in food: 1978 evaluations)