DIQUAT       JMPR 1977


    Diquat has been evaluated previously at the Joint Meeting in 1970,
    1972, and 1976 (FAO/WHO, 1971, 1973, 1977). New data have become
    available on metabolism and excretion following diquat administration
    and a preliminary assessment of the toxicological significance of
    detected metabolites has been made. A new "no effect" level based on
    the oataractopenic activity of chronically administered diquat to rats
    is also presented. Details of additional toxicological studies on the
    cause of death following oral diquat administration to rats and data
    an the toxic effects of this compound to humans following ingestion
    are also included, in the following monograph addendum.

    Questions concerning residues in food and their evaluation were also
    considered and are discussed below.



    Further studies on metabolism and excretion

    Following oral and parenteral administration of diquat to various
    laboratory species, the majority of the administered dose is excreted
    unchanged (Hughes et al., 1973; Mills, 1975).

    Excretion of metabolites in the urine after intraperitoneal injection
    was greater in the rabbit and guinea pig than in the rat (18%, 5% and
    < 1% of the dose respectively). These metabolites were not identified
    but were similar for the three species studies (Hughes et al., 1973).

    After oral administration of 14C-diquat (45 mg/kg b.w.) to rats
    most of the radioactivity was excreted in 4 days (6% of dose in urine, 89%
    of dose in faeces). Chromatography indicated that unchanged diquat was
    the major radioactive component of both the urine (5% of the dose) and
    faeces (at least 57% of the dose). The two metabolites identified were
    diquat monopyridone, (5% of the dose, mainly in the faeces) and diquat
    dipyridone as a minor urinary metabolite (approx. 0.1% of the dose)
    (Mills, 1975).

    Following subcutaneous injection of 14C-diquat (10 mg/kg b.w.) in
    rats, 87% of the administered dose was excreted in the urine and 5% in
    the faeces within 4 days. The urine contained mainly unchanged diquat
    (75% of the dose) together with diquat monopyridone (about 3% of the
    dose) and diquat dipyridone (about 6% of the dose) (Mills, 1975).

    Intestinal bacteria from rat caecal contents caused metabolism of
    about 10% of added diquat in a 24 hr incubation period, with the
    formation of some diquat monopyridone (Mills, 1975).


    Preliminary toxicological study with two metabolites

    Diquat monopyridone was the major metabolite following oral closing
    and could, therefore, be the toxicologically active species following
    administration by this route. However, the oral LD50 of this
    compound to rats was in excess of 4000 mg/kg, (maximum dose
    administered) and oral administration of 1000 mg/kg five days a
    week for two weeks to a group of 10 males and 10 females showed no
    clinical, haematological, biochemical or histopathological
    abnormalities, except for a decreased number of lymphocytes in both
    males and females (Parkinson, 1974).

    Preliminary data also suggest that diquat monopyridone is less toxic
    than diquat when administered subcutaneously. When diquat monopyridone
    and diquat were administered at equivalent doses of 90 µmoles/kg (i.e.
    16 mg active ingredient/kg) to groups of 10 rats, the animals in the
    monopyridone group showed no adverse effects for the entire 14 day
    period studied with no deaths occurring. In the diquat group, however,
    all animals appeared subdued by day 3 and many animals developed
    abdominal distention. Nine animals of the original group of 10 were
    dead by the 14th day after dosing with the remaining animal exhibiting
    abdominal distention. When diquat dipyridone was administered at a
    dose of 90 µmoles/kg (i.e. 16 mg active ingredient/kg) to 10 rats, the
    animals showed no adverse effects for the entire 14 day period studied
    with no deaths occurring. For diquat the equivalent dose is
    approximately the subcutaneous LD50 (Crabtree, 1976),

    Special study on cataractogenesis

    A study was carried out with diquat dibromide monohydrate in which
    special attention was paid to the incidence of eye opacity. Groups of
    35 male and 35 female rats were maintained for up to 2 years on diets
    containing 0, 15, 25 and 75 ppm diquat ion. Body weights, food
    consumption and deaths did not vary significantly in the four groups,
    but a significant increase in the number of cataracts was observed in
    the 75 ppm group when compared with the control group. There was no
    significant difference between the number of cataracts in rats fed at
    dietary levels of 15 and 25 ppm and those on control diets. The first
    eye lesions in animals fed 75 ppm diquat appeared within 9 months. In
    the period 9-18 months there was a further large increase in the
    number of cataracts in this group. The cataracts in the other
    experimental groups, especially in the 25 ppm group, appeared somewhat
    earlier than in the control group (see Table 1) (Rogerson and Broad,

        TABLE 1. No. of cataracts observed at 6, 9, 18 and 24 months.


                   I(male)     I(female)      II(male)       II(female)     III(male)      III(female)    IV(male)       IV(female)
    6 months       0           0              0              0              0              0              2              0

    9 months       0           0              0              1              0              1              12             14

    18 months      3           2              4              3(1)*          4              8              24             19

    2 years        5           6              4              2              5              8              25             21

    * One annual with doubtful cataract at 18 months dead at 2 years.

    Special studies to determine the cause of death following oral
    administration of diquat to rats

    Histological changes in liver, myocardium, brain, kidneys and lung
    have been reported following oral dosing (Verbetskii and Pushkar,
    1968) but none of the changes seen are severe enough to account for
    death (Clark and Hurst, 1970).

    However, recent work indicates that early deaths following
    administration of an oral LD50 are associated with a considerable
    redistribution of body water from the rest of the body into the lumen
    of the gastrointestinal tract. Dehydration of blood and other organs
    and tissues appears to be sufficiently rapid and severe to be
    consistent with development of shock and death due to peripheral
    circulatory failure. The cause of death following subcutaneous
    injection, however, appears to be different. The delayed deaths are
    associated with an increased water retention in the gastrointestinal
    tract, but also in many other tissues. Water accumulation in the
    gastroinstestinal tract was also observed after oral administration of
    paraquat (Crabtree at al., 1977).


    A few cases of human poisoning have been reported following accidental
    and suicidal ingestion of diquat in the form of the concentrate,
    RegloneR (Weirich, 1969; Oreopoulos and McEvoy, 1969; Schönborn et
    al., 1971; Okonek and Hofmann, 1975). Toxic symptoms vary but have
    included vomiting, diarrhoea and impaired kidney function. Changes in
    the brain, liver, kidney, lung and gastrointestinal tract have been
    noted post-mortem and signs of peripheral circulatory failure and
    incidence of shock have also been reported in fatal cases (Schönborn
    et al., 1971; Okonek and Hofmann, 1975). It appeared that
    haemodialysis is not an efficient technique for removing
    toxicologically relevant amounts of diquat from the organism, (Okonek
    and Hofmann, 1975).


    Two metabolites, diquat monopyridone and diquat dipyridone, have been
    identified after oral and subcutaneous administration of diquat to
    rats. The same type of metabolites were found after i.p. injection in
    rabbits, guinea pigs and rats. These metabolites are produced only in
    small amounts and are less toxic than diquat itself. It seems
    therefore that the parent compound is the toxicologically active
    substance. In a new long-term study with rats special attention was
    paid to the cataractogenic action of diquat. A significant increase in
    the number of cataracts was observed in the 75 ppm group. There was no
    significant difference, between the number of cataracts at dietary
    levels of 15 and 25 ppm and those on control diets. In this respect 25
    ppm of diquat ion was found to be the no-effect level. However, the
    cataracts in the experimental groups, especially in the 25 PPM group,
    appeared somewhat earlier than in the control group. Cataracts have

    never been observed in humans following occupational exposure to


    Level causing no toxicological effect

         Rat: 15 mg/kg diquat ion in the diet (fed as dibromide),
              equivalent to 0.75 diquat ion/kg bw

         Dog: 68 mg/kg diquat dichloride in the diet, corresponding to
              1.22 mg diquat ion/kg bw


         0-0.008 mg/diquat ion/kg bw


    Some questions concerning diquat were raised at the 1977 Meeting of
    the Codex Committee on Pesticide Residues (ALINORM 78/24,
    para. 91-93).

    The use pattern and residue information on wheat and barley previously
    considered by the Joint Meeting in 1972 referred only to the
    desiccation of lodged crops leading to the harvesting, of grain which
    would be suitable only for animal feed.

    The meeting was informed that experimental work concerning residues of
    diquat in wheat and barley possibly useful for human consumption was
    still in progress. It was hoped that this work would be completed and
    reported by the middle of 1978 for consideration by the 1978 Joint
    Meeting. Data on residues in brown rice were not available to the


    Clark, D.G. and Hurst, E.W. (1970) The toxicity of diquat. Br. J. Ind.
    Med., 27, 51-55

    Crabtree, H.C. (1976) Comparison of the sub-cutaneous toxicity of
    diquat, diquat monopyridone and diquat dipyridone. ICI Central
    Toxicology Laboratory Data. (Unpublished report).

    Crabtree, H.C., Lock, E.A. and Rose, M.S., (1977) Effects of diquat on
    the gastrointestinal tract of rats. Toxicol. Appl. Pharmacol., 41,

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

    Mills, I.H. (1975) Diquat: disposition and metabolism in the rat. ICI
    Ltd Central Toxicology, Report No. CTL/P/214 (Unpublished report).

    Okonek, S. and Hofmann, A. (1975) On the question of extracorporeal
    hemodialysis in diquat intoxication. Arch. Toxicol., 33. 251-257.

    Oreopoulos, D.G. and McEvoy, K. (1969) Diquat poisoning. Postgrad,
    Med. J., 45, 635-637.

    Parkinson, G.P. (1974) Diquat monopyridone: acute and subacute oral
    toxicity. ICI Ltd Central Toxicology Laboratory, Report No.:
    HO/CTL/P/122B. (Unpublished report).

    Rogerson, A. and Broad, R.D. (1976) Diquat dibromide: 2 year feeding
    study in rats. ICI Ltd. Pharmaceuticals Division, Report No.
    OTL/P/253. (Unpublished report).

    Schönborn H., Schuster, H.P. and Kössling, F.K. (1971) Klinik und
    Morphologie der akuten peroralen diquat Intoxikation (Reglone). Arch.
    Toxikol., 27, 204-216.

    Verbetskii, V.E. and Pushkar, M.S. (1968) Pathological changes in the
    organs of animals on acute poisoning with the herbicide diquat
    (Reglone). In "Some questions concerning human and animal morphology".
    Odessa, 51-52.

    Weirich, J. (1969) Intoxikation mit Diquat (Reglone). Deuts Gesundh.,
    24, 1986-1988.

    FAO/WHO (1971) 1970 evaluations of some pesticide residues in food.
    AGP:1970/M/12/1; WHO Food Add./71.42.

    FAO/WHO (1973) 1972 evaluations of some pesticide residues in food.
    AGP:1972/M/9/1; WHO Pesticide Residues Series, No. 2.

    FAO/WHO (1977) 1976 evaluations of some pesticide residues in food.

    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: 1978 evaluations)
       Diquat (Pesticide residues in food: 1993 evaluations Part II Toxicology)