400. Diquat (Pesticide residues in food: 1977 evaluations)

DIQUAT JMPR 1977

Explanation

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.

EVALUATION FOR ACCEPTABLE DAILY INTAKE

BIOCHEMICAL ASPECTS

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).

TOXICOLOGICAL STUDIES

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,
1976).

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).

OBSERVATIONS IN HUMANS

A few cases of human poisoning have been reported following accidental
and suicidal ingestion of diquat in the form of the concentrate,
Reglone^R (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).

COMMENTS

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
diquat.

TOXICOLOGICAL EVALUATION

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

ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR HUMANS

0-0.008 mg/diquat ion/kg bw

RESIDUES IN FOOD AND THEIR EVALUATION

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
Meeting.

REFERENCES

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,
585-595.

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.
AGP:1976/M/14.

    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)