PARAQUAT JMPR 1972
Explanation
This compound was evaluated by the Joint Meeting in 1970 (FAO/WHO,
1971). A temporary acceptable daily intake for man was proposed and
temporary tolerances recommended.
It was noted that no information was available on metabolites formed
by the gut flora and a study of the toxic effects of these was
requested. An additional reproduction study was required on at least
one species as was a detailed comparison of paraquat metabolism and
toxicity in different species to elucidate the reason for the
comparatively high sensitivity of man to the compound. Investigation
of the prophylaxis and treatment of the toxic effects of paraquat was
considered desirable. Since that meeting the results of some
additional experimental work and new data on residues have been
reported.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
When paraquat (50 mg/kg body-weight of 14C-labelled dichloride salt)
was given to rats, 25% of the radioactivity excreted in the faeces
could be attributed to products of metabolism by gut microflora.
Examination of extracts indicated the presence of only one metabolite
in addition to paraquat. Thirty percent of paraquat was broken down
when incubated anaerobically with rat caecal contents; the metabolites
are not yet identified. Urine from rats injected intraperitoneally
with 14C-methyl labelled paraquat contained 87% of administered
radioactivity in 24 hours which was entirely unchanged paraquat.
Experiments in progress on sheep and goats have so far failed to
demonstrate the presence of metabolites in these species (Plant
Protection Ltd., 1972a).
Following intravenous administration of 14C-paraquat, the initial and
secondary half-lives in plasma were 23 min and 56 h. The concentration
in kidney, lung and muscle declined at the same rate as plasma
initially, but the rapid phase in lung ended after 20 min (compared
with 1-4 h in other organs), after which it declined with a 50 h
half-life. The lung became the organ of highest concentration after 4
h, and between this time and 10 days the lung paraquat concentration
was 30 - 80 times that of plasma (Sharp et al., 1972).
TOXICOLOGICAL STUDIES
Special studies on reproduction
Groups of 12 male and 24 female rats were fed on diets containing 0,
30 and 100 ppm paraquat ion from 35 days of age. Three generations
bred from these animals received the same diets during the whole
period under test.
Two litters were bred from each generation, and the effects on growth,
food intake, fertility, fecundity, neonatal morbidity and mortality
noted. No evidence was seen of damage to germ cell production or of
structural and functional damage in these animals, and pregnant and
young animals did not appear from this study to be more vulnerable to
paraquat than adults. However, the incidence of renal hydropic
degeneration in 3-4 week-old offspring was slightly increased in the
100 ppm group (Fletcher et al., 1972a).
Special studies on teratogenicity
On the second day after mating, groups of 10, 10, 6 and 5 female
rabbits received, respectively, control diet, diet providing 1
mg/kg/day paraquat ion, 2.4 mg/kg/day paraquat ion for 8 days
intravenously followed by 1.2 mg/kg/day to term, or 1.2 mg/kg/day
paraquat ion intravenously for ten days followed by approximately 4
mg/kg/day orally in drinking water to term. Offspring were examined
for congenital abnormalities. Fertility and litter sizes were similar
in the control and the orally dosed groups. Only one and three animals
of the third and fourth groups respectively survived treatment but
these produced litters of normal size. No congenital abnormalities
were detected (McElligott, 1966).
Short-term studies
Mouse
Four groups of eight A/He strain mice 9 to 15 weeks old were
administered 50, 100, 200 or 300 ppm paraquat in drinking water for up
to 16 weeks. Mice were killed at intervals during the study, and the
kidneys were examined by light and electron microscopy. Induction of
smooth endoplasmic reticulum and the presence of lipidic lamellate
cytosomes in the proximal convoluted tubule cells were observed in the
kidneys of all paraquat treated animals (Fowler and Brooks, 1971).
Long-term studies
Mouse
In order to investigate the carcinogenic potential of paraquat ion in
mice, 4 groups of 70 males and 50 females received diets containing 0,
25, 50 and 75 ppm of paraquat ion for 80 weeks. All levels caused a
slight to moderate reduction in body-weight increments, and these
paralleled a reduced food intake. Twelve to 24 males and 12 to 23
females survived treatments for 80 weeks, the majority of deaths
before this time being associated, in all groups, with respiratory
disease and, in males, with the results of fighting. Thirty to 38
males and 31 to 38 females were subjected to histological examination.
The incidence and types of tumours and other pathological changes in
animals dying or killed at or before 80 weeks were similar in control
and experimental groups. (Fletcher et al., 1972b).
OBSERVATIONS IN MAN
Paraquat is irritant particularly to mucous membranes. Splashes of
concentrate left in contact with skin cause irritation, inflammation
and even blistering, and prolonged contact with nails leads to
shedding. Contact with wounds delays healing. Inhalation of spray mist
or dust will cause nosebleed. Contact of solid with mucous membranes
causes soreness, and splashes of liquid concentrate in the eye lead to
severe inflammation which develops gradually, reaching its maximum
after 12-24 hours. There may be extensive stripping of superficial
areas of corneal and conjunctival epithelium and healing may be slow,
but even in severe cases is complete, given proper medical care. The
immediate effects of ingestion are due to the local irritant action:
vomiting, abdominal discomfort and diarrhoea and soreness of mouth and
throat. Signs of severe kidney damage may appear in 2-3 days if large
doses are absorbed. Large doses also cause tremors and convulsions.
Signs of pulmonary injury may develop gradually after a few days, and
these may lead on to dyspnoea and pulmonary oedema and fibrosis with
death from respiratory insufficiency (D.H.S.S., 1972).
The exact dose which is fatal to man is uncertain. The smallest dose
known to cause death is 1 g, taken in the form of "Weedol" by a woman
of 23. One man has survived 3 g of paraquat, again as "Weedol" (Plant
Protection, 1972), and one man recovered after swallowing 10 ml of 20%
paraquat solution, despite being untreated for six days (Fisher
et al., 1971). From such evidence the lethal dose in man would seem
to be approximately 30 mg/kg; estimates lower than this are based on
accounts of subjects allegedly spitting out all of a dose, a process
difficult to quantify.
Between 1963 and the present time, no deaths have occurred in persons
occupationally exposed to paraquat in the U.K., and only a few trivial
cases of dermal exposure are reported each year (M.A.F.F., 1965). The
only deaths from paraquat poisoning that have occurred in the United
Kingdom, where it is widely used, have been from suicide or accidental
ingestion of concentrate from unlabelled or mislabelled bottles
(Hansard, 1971 - 1972).
Paraquat has been shown to be passively reabsorbed by the kidney
(Ferguson, 1971), and thus an increased urine flow should increase the
renal clearance of this substance. Forced diuresis is thus advocated
in treatment as is oral administration of Fuller's Earth which
strongly adsorbs paraquat (Clark, 1972; D.H.S.S., 1972).
COMMENT
Additional data as requested by the 1970 Joint Meeting was presented.
Paraquat is not readily absorbed from the gastrointestinal tract. It
is excreted mainly in faeces when administered orally and in urine
when administered by I.V. injection. Metabolic studies are incomplete,
but paraquat appears to concentrate in lung tissue.
The initial signs and symptoms of paraquat poisoning are due to local
irritant effects, but rapid progressive fibrosis of the lung then
occurs in many species. Renal failure may also occur. Significant
variation occurs in species sensitivity to paraquat, man being amongst
the most sensitive.
Two-year studies in rats and dogs indicate no-effect levels at 250 and
50 ppm, respectively, with lung damage at 75 ppm in the dogs. In the
rat, a study indicates no evidence of effects on reproduction,
although kidney hydropic degeneration was observed at 100 ppm, and 30
ppm is considered to be the no-effect level in this species. A
teratogenicity study in rabbits and a carcinogenicity study in mice
were negative.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 30 ppm in the diet, equivalent to 1.5 mg/kg
body-weight/day
Dog: 50 ppm in the diet, equivalent to 1.25 mg/kg
body-weight/day
ESTIMATION OF ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.002 mg/kg body-weight (equivalent to 0 - 0.0014 mg/kg
body-weight, expressed as paraquat ion).
RESIDUES IN FOOD AND THEIR EVALUATION
USE PATTERN
Paraquat has been registered as an effective soybean harvest aid
(Kirby, 1971). The uses and chemical characteristics of paraquat,
together with its mode of action and toxicity, have been reviewed by
Wheeler (1971). Intensive work on the mechanism of the action of the
bipyridyls has also been published (Baldwin, 1969).
RESIDUES RESULTING FROM SUPERVISED TRIALS
Table 1 presents additional data on residues of paraquat in a variety
of crops (Plant Protection Ltd., 1972b).
TABLE 1 Paraquat residues in various crops following desiccant usage
Crop Rate of Interval Samples Paraquat found
application to harvest (no.) range mean
(g a.i./ha) (days) (ppm)
Maize 600 4 - 10 24 ND1 - 0.08 0.05
Olives 400 - 600 3 - 5 8 ND - 0.87 0.24
Potatoes 600 - 1 000 4 - 10 43 ND - 0.27 0.08
Rice (in 200 - 600 3 - 10 25 ND - 9.00 4.00
husk
Rice 200 - 600 3 - 10 21 ND - 0.40 0.16
(polished)
Sorghum 600 - 1 000 4 - 10 21 ND - 1.20 0.34
Soybean 600 4 - 10 5 ND ND
1 ND = not detected (0.01 ppm potatoes and olives; 0.05 ppm others)
Some information regarding the fate and extent of residues of paraquat
occurring in animal tissues resulting from grazing on treated pastures
or feeding with treated fodder was reviewed in 1970 (FAO/WHO, 1971).
In one of the tests, the cows were allowed to graze on grasses
containing up to 1 000 ppm at the start of the test. It was estimated
that they ingested approximately one half of the LD50 daily for the
first two weeks. In other tests cows were dosed at 8 mg/kg of
body-weight with 14C-labelled paraquat (both ring and methyl); this
level was approximately one fifth of the cow LD50. Even at these very
high dosage levels residues of 14C observed in the milk were very
low, ranging from 0.009 to 0.046 ppm (as paraquat) and disappeared
very rapidly after dosing ceased. There were no detectable residues in
meat.
Two additional experiments were reported which fully corroborated the
results of this earlier work. In the first (Daniel et al., 1971),
two cows were dosed for three consecutive weeks at 8 mg/kg. Again, in
each case the total 14C detected in the milk (expressed as paraquat)
was less than 0.01 ppm. This would have included paraquat and all its
metabolites. The average percentage of the applied dose excreted in
the milk was 0.004, regardless of whether methyl or ring-labelled
paraquat was used or whether single or multiple doses were given.
The second report (Leakey et al., 1972) described a successful
attempt to identify the nature of the compounds responsible for the
radioactivity observed in the milk in these trials (less than 0.01 ppm
as paraquat). Eighty percent of the radioactivity was accounted for as
paraquat, monoquat (i.e. paraquat minus one methyl group),
monopyridone and general incorporation (as lactose). Both monoquat and
monopyridone have been shown to be acutely less toxic than paraquat to
rats by oral dosing.
FATE OF RESIDUES
In plants
Paraquat is a contact herbicide that kills or severely scorches all
green herbage with which it comes into contact. It is translocated to
a minor degree, mainly under conditions of low light intensity at the
time of application. Furthermore, it is quickly rendered biologically
inactive by adsorption onto clay minerals in the soil and is thus
immobile and unavailable for root uptake. When paraquat is used for
weed control after crop emergence, there are usually no detectable
residues in the crop harvested one to four months later. Plants may
receive an initial scorch, from which they soon recover. Small
residues have very occasionally been found in certain crops following
this use, e.g., 0.09 ppm in cabbage harvested 51 days after an
application of 2.2 kg paraquat/ha and 0.2 ppm in maize 49 days after
an application of 1.1 kg/ha. Such residues are exceptional. The only
exception to the rule that residues are non-detectable in crops
following the use of paraquat for pre-planting weed control occurs
when new growth picks up traces of the chemical from dead plant debris
that it pushes through. This can lead to low residues in the harvested
crop. In kale, 0.02 - 0.05 ppm paraquat have been found. Small amounts
of paraquat (less than 0.2 ppm) can often be detected in the foliage
of certain crops, e.g., sugar beet and cereal, but there are
invariably no detectable residues in the edible portions at harvest
(Plant Protection Ltd., 1972b).
In soil
The degradation of paraquat in soil by Lipomyces starkeyi was
investigated by Burns and Audus (1970). They found that degradation
only occurred in cultures containing organic components of the soil.
Over a period of time, transfer to the inorganic constituents renders
it unavailable for microbiological degradation. The adsorption and
mobility of paraquat on different soils and soil constituents has been
studied (Damanakis et al., 1970). Adsorption decreased as the ratio
of the soil to water increased, while temperature had little effect.
Giardina et al. (1970) studied the effect on the proteolytic urease
and cellulose activity of soil microflora together with the influence
on total bacterial flora and oxygen consumption of the soil. Paraquat
was degraded to an extent of approximately 50% after ten days in soil.
Watkin and Sagar (1971a,b) when investigating persistence factors,
suggested that paraquat phytotoxicity is a surface, rather than a
solution, phenomenon. The direct relationship between the germination
inhibitory capacity of a paraquat treated soil and the amount of
paraquat extracted by a 50-fold volume of 0.2 N NH4Cl was found by
Radaelli and Martelli (1971). No inhibition was observed with soils
having an extractable value of less than 20 mg/100 g, partial
inhibition was associated with values of 20-85 mg/100 g and complete
suppression of germination was observed at levels greater than 85
mg/100 g. The phytotoxicity of various soils after spraying with
paraquat was determined by the inhibition Lolium perenne (ryegrass)
germination (Watkin and Sagar 1971a,b). Applied amounts of 0.05 and
0.38 kg/ha respectively inhibited germination on sphagnum and peat
soils, but higher doses of 0.75 and 1.5 kg/ha were necessary on
compost and loam soils to obtain the same effect. On all soils,
residual activity increased rapidly with dose once the minimum
phytotoxic dose was reached.
In water
Earnest (1971) treated a pond with paraquat to give an initial
concentration of 1.14 ppm; Chara and Spirogyra were found to
contain 2 300 and 1 300 ppm of paraquat, respectively. Residues in the
water were not detected after 16 days, and the amounts present in the
mud were 1.13 ppm after 3 hours and 3.25 ppm after 99 days.
The use of paraquat as an aquatic herbicide has been reviewed by
Calderbank (1970). The effective concentration was found to be 1 ppm
which was accumulated by plants and adsorbed on to suspended soil
particles causing a decline to 0.1 ppm in 4-7 days. Under these
conditions it was neither toxic to fish nor did they accumulate it,
but death could occur if the herbicidal action caused a greatly
decreased oxygen concentration.
Evidence of residues in food in commerce or at consumption
The great majority of crops treated for weed control showed no
detectable residues (<0.05 ppm) when subsequently harvested (Plant
Protection Ltd., 1972b).
METHODS OF RESIDUE ANALYSIS
Paraquat type herbicides were determined in aqueous solutions by the
colorimetric measurement of the complex formed with a-dipicrylamine
hexanitrodiphenylmethane (Zhemchuzin, 1970). An ion exchange and
colorimetric method has been used by Berry and Grove (1971) for the
determination of paraquat in urine; the method was rapid with a
detection limit of 0.01 µg ion/ml in 250 ml aliquots. Mueller and
Worseck (1970) used a semi-quantitative thin-layer chromatographic
method for the determination of paraquat in bees. The polarographic
response of paraquat in five supporting electrolytes has been reported
(Hance, 1970). Modified versions of Calderbank and Yuen's method
(1965) were applied in a poisoning case for the analysis of body
fluids, urine, blood and gastric aspirates (Tompsett, 1970). The
method of Calderbank and Yuen (1965) is suitable for regulatory
purposes.
APPRAISAL
Since the evaluation of paraquat in 1970 (FAO/WHO, 1971) further
residue data have become available. These have indicated the need to
revise some of the earlier recommendations and allowed the proposal of
tolerances for some additional crops.
RECOMMENDATIONS
TOLERANCES
The following tolerances are recommended to replace the temporary ones
proposed in 1970:
paraquat ion
ppm
Rice (in husk) 10
Olives 1
Sorghum, rice (polished) 0.5
Cottonseed, potatoes 0.2
Maize, soybeans 0.1
Cottonseed oil (refined) 0.05
Other vegetables 0.05*
Milk 0.01*
* at or about the limit of determination
FURTHER WORK OR INFORMATION
DESIRABLE
1. Detailed comparative toxicity and metabolism studies in order to
elucidate the reason for the comparatively high sensitivity of
man to this compound.
2. Comparative studies on the relationship between lung
concentration and toxicity.
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See Also:
Toxicological Abbreviations
Paraquat (HSG 51, 1991)
Paraquat (PIM 399)
Paraquat (JMPR Evaluations 2003 Part II Toxicological)
Paraquat (AGP:1970/M/12/1)
Paraquat (Pesticide residues in food: 1976 evaluations)
Paraquat (Pesticide residues in food: 1978 evaluations)
Paraquat (Pesticide residues in food: 1981 evaluations)
Paraquat (Pesticide residues in food: 1982 evaluations)
Paraquat (Pesticide residues in food: 1986 evaluations Part II Toxicology)