820K88129
August, 1987
PARAQUAT
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the one-hit, Weibull, logit'or probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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II. GENERAL INFORMATION AND PROPERTIES
Paraquat, with a chemical name 1,1 '-dimethyl-4,4'-dipyridinium
ion, is present mostly as the dichloride salt (CAS No. 1910-42-5) or
as the dimethyl sulfate salt (CAS No. 2074-50-2, molecular weight 408.48)
(Meister, 1987). Contents discussed below pertain to paraquat dichloride.
CAS No. 1910-42-5
Structural Formula
CH,-N
N-CH,
2CI
1,1'-Dimethyl-4,4'-bipyridinium-dichloride
Synonyms
o-Paraquat dichloride, Gramixel, Gramonol, Gramoxone, Gramuron,
Pathclear, Totacol, Weedol (Meister, 1985).
Uses
0 Contact herbicide and desiccant used for desiccation of seed crops,
for noncrop and industrial weed control in bearing and nonbearing
fruit orchards, shade trees, and ornamentals, for defoliation and
desiccation of cotton, for harvest aid in soybeans, sugarcane, guar,
and sunflowers, for pasture renovation, for use in "no-till" or before
planting or crop emergence, dormant alfalfa and clover, directed
spray, and for killing potato vines. Paraquat is also effective for
eradication of weeds on rubber plantations and coffee plantations and
against paddy bund (Meister, 1985).
Properties (ACGIH, 1980; Meister, 1985; CHEMLAB, 1985; TDB, 1985)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Vapor Pressure
Specific Gravity
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C12H14N2.2C1
257.18
Colorless to yellow crystalline
solid
175 to 180°C
No measurable vapor pressure
1.24 at 20°C/20°C
Very soluble
2.44 (calculated)
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Occurrence
0 Paraquat was found in only one sample, at a concentration level of
20 ug/L, from 721 ground water samples analyzed (STORET, 1987).
Samples were collected at 715 ground water locations, with paraquat
found in one location in California. No surface water samples were
collected for analysis.
Environmental Fate
0 14c-Paraquat dichloride (>96.5% pure) at 91 mg/L was stable to
hydrolysis at 25 and 40°C at pH 5, 7 and 9 for up to 30 days (Upton
et al., 1985).
0 Uniformly ring-labeled 14c-paraquat (99.7% pure) at approximately
7.0 ppm in sand did not photodegrade when irradiated with natural
sunlight for 24 months (Pack, 1982). No degradation products were
detected at any sampling interval. After 24 months of irradiation,
>84% of the applied radioactivity was extractable and <4% was
unextractable.
0 Paraquat was essentially stable to photolysis in soil (Day and
Hemingway, 1981). Four degradation products, 1-methyl-4,4'-bipyridylium
ion, 4-(1,2-dihydro-1-methyl-2-oxo-4-pyridyl)-1 -methyl pyridylium
ion, 4-carboxy-1-methyl pyridylium ion, and an unknown, individually
constituted <6.0% of the total radioactivity in either irradiated
(undisturbed) or dark control soils.
0 Paraquat (test substance uncharacterized) at 0.05 to 1.0 ppm in water
plus soil declined with a half-life of >2 weeks (Coats et al., 1964).
In water only, paraquat declined with a half-life of approximately
23 weeks.
o 14c-Paraquat (test substance uncharacterized) was immobile in silt
loam and silty clay loam (Rf 0.00), and slightly mobile in sandy loam
(Rf 0.13) soils, based on soil thin-layer chromatography (TLC) tests
(Helling and Turner, 1968).
0 Methyl-labeled 14c-paraquat (test substance uncharacterized) at 1.0
ppm was stable to volatilization at room temperature over a 64-day
period (Coats et al., 1964).
In a pond treated with paraquat (test substance uncharacterized) at
1.14 ppm (Frank and Comes, 1967), paraquat residues (uncharacterized)
declined from 0.55 ppm 1 day after treatment to nondetectable (<0.001
ppm) 18 days after treatment. The dissipation of paraquat residues
(uncharacterized) in water was accompanied by a concomitant increase
of paraquat residues (uncharacterized) in the soil. Paraquat (test
substance uncharacterized) at 0.04 ppm dissipated in pond water with
a half-life of approximately 2 days (Coats et al., 1964). For more
details, see Calderbank's chapter on paraquat in Herbicides
(Calderbank, 1976).
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III. PHARMACOKINETICS
Absorption
0 In Wistar rats given single oral doses of 14c-paraquat dichloride or
dimethyl sulfate by gavage (0.5 to 50 mg/kg, purity not stated),
69 to 96% was excreted unchanged, mostly in feces, and no radioactivity
appeared in bile (Daniel and Gage, 1966). Some systemic absorption of
the degradation products that were produced in the gut was noted.
Approximately 30% of the administered dose appeared in feces in a
degraded form.
0 14C-Methyl-labeled paraquat (99.7% purity) was administered orally
to a cow in a single dose of approximately 8 mg cation/kg (Leahey
et al., 1972). A total of 95.6% of the dose was excreted in feces in
the first 3 days. A small amount, 0.7% of the dose, was excreted in
the urine, 0.56% during the first 2 days. Only 0.0032% of the dose
appeared in the milk.
0 A goat was administered 1 4C-ring-labeled paraquat dichloride (>99%
purity) orally at 1.7 mg/kg for 7 consecutive days (Leahey et al.,
1976a). At sacrifice, 2.4% and 50.3% of the radioactive dose had been
excreted in the urine and feces, respectively, and 33.2% was recovered
in the contents of the stomach and intestines. The radioactivity was
associated with unchanged paraquat.
0 In studies with pigs, 14C-methyl-labeled (Leahey et al., 1976b) and
1^-ring-labeled (Spinks et al., 1976) paraquat (>99% purity) at
dose levels of 1.1 and 100 mg ion/kg/day, respectively, was given
for,up to 7 days. At sacrifice, 69 to 72.5% and 2.8 to 3.4% of the
total radioactive dose had been excreted in the feces and urine,
respectively.
Distribution
0 Pigs were given oral doses of 14C-methyl-labeled (Leahey et al.,
1976b) and 14c-ring-labeled (Spinks et al., 1976) paraquat dichloride
(>99% purity) for up to 7 consecutive days at dose levels of 1.1 and
1 00 mg ion/kg/day, respectively. At sacrifice, radioactivity associated
mostly with unchanged paraquat was identified in the lungs, heart,
liver and kidneys, with trace amounts in the brain, muscle and fat.
0 The distribution of radioactivity was studied in a goat fed 14C-ring-
labeled paraquat dichloride (1.7 mg/kg/day, 99.7% purity) in the
diet for 7 consecutive days (Hendley et ai., 1976). Most of the
radioactivity was found in the lungs, kidneys and liver. The major-
residue was unchanged paraquat.
Metabolism
* Paraquat dichloride or paraquat dimethyl sulfate (radiochemical
purity: 99.3 to 99.8%), labeled with 14C in either methyl groups or
in the ring, was poorly absorbed from the gastrointestinal tract of a
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Paraquat August, 1987
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cow (Leahey et al., 1972), goats (Hendley et al., 1976), pigs (Leahey
et al., 1976b; Spinks et al., 1976) and rats (Daniel and Gage, 1966),
and was excreted in the feces mostly as unchanged paraquat. However,
after an oral dose, there was microbial degradation of paraquat in
the gut. In one study with rats (Daniel and Gage, 1966), 30% of a
dose of paraquat appeared in the feces in a degraded form. A portion
of these microbial degradation products can be absorbed and excreted
in the urine, whereas the remainder is excreted in the feces.
Excretion
In studies with a cow (Leahey et al., 1972) and rats (Daniel and
Gage, 1966), about 96% and 69 to 96%, respectively, of the administered
radioactivity (single oral doses, 14C-labeled) from paraquat was
excreted in the feces within 2 to 3 days as unchanged paraquat.
Goats (Hendley et al., 1976) and pigs (Leahey et al., 1976b; Spinks
et al., 1976) that received single oral doses of 14c-labeled paraquat
(1.7 and 1.1 or 100 mg ion/kg/day, respectively) for up to 7 days
excreted 50 and 69%, respectively, of the total administered dose in
feces unchanged.
IV. HEALTH EFFECTS
s ————————
Humans
Short-term Exposure
0 The Pesticide Incident Monitoring System (U.S. EPA, 1979) indicated
numerous cases of poisoning from deliberate or accidental ingestion
of paraquat or by dermal and inhalation exposure from spraying,
mixing and loading operations. Generally, the concentrations of the
ingested doses or of amounts inhaled or spilled on the skin were not
specified. Symptoms reported following these exposures included
burning of the mouth, throat, eyes and skin. Other effects noted
were nausea, pharyngitis, episcleritis and vomiting. No fatalities
were reported following dermal or inhalation exposure. Deliberate
and accidental ingestion of unspecified concentrations of paraquat
resulted in respiratory distress and subsequent death. See also
Cooke et al. (1973).
Long-term Exposure
0 No information was found in the available literature on long-term
human exposure to paraquat.
Animals
Short-term Exposure
Acute oral LD50 values for paraquat (99.9% purity) were reported as
112, 30, 35 and 262 mg paraquat ion/kg in the rat, guinea pig, cat
and hen (Clark, 1965). Signs of toxicity included respiratory distress
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and cyanosis among rats and guinea pigs, blood-stained droppings
among the hens, and muscular weakness, incoordination and frequent
vomiting.of frothy secretion among the cats.
0 Acute (4-hour) inhalation LC50 values for paraquat ranged from 0.6 to
1.4 mg ion/m3 paraquat (McLean Head et al., 1985).
Dermal/Ocular Effects
0 Acute dermal LD50 values for rabbits (Standard Oil, 1977) were
59.9 mg/kg and 80 to 90 mg paraquat ion/kg for rats (FDA, 1970).
0 Paraquat concentrate 3 (34.4% paraquat ion) was applied (0.5 mL or
172 mg paraquat ion) to intact and abraded skin of six male New
Zealand White rabbits for 24 hours (Bullock, 1977). Very slight,
moderate or severe erythema and slight edema were noted during the
7-day observation period for both intact and abraded skin.
0 Paraquat concentrate 3 (0.1 mL, 34.4% paraquat ion) was instilled
into the conjunctival sac of one eye in each of six male New Zealand
White rabbits (Bullock and MacGregor, 1977). Untreated eyes served
as controls. Unwashed eyes were examined for 14 days. Complete
opacity of the cornea was reported in three of six rabbits. Roughened
corneas, severe pannus, necrosis of the conjunctivae, purulent discharge,
severe chemosis of the conjunctivae and mild iritis were also reported.
Long-term Exposure
0 Beagle dogs (three/sex/dose) were fed technical o-paraquat (32.2%
cation) in the diet for 90 days at dose levels of 0, 7, 20, 60 or
120 ppm (Sheppard, 1981). Assuming that 1 ppm is equivalent to
0.025 mg/kg/day, these levels correspond to doses of 0, 0.18, 0.5,
1.5 or 3 mg paraquat ion/kg/day (Lehman, 1959), respectively.
Increased lung weight, alveolitis and alveolar collapse were observed
at 60 ppm. The No-Observed-Adverse-Effect-Level (NOAEL) identified
for this study was 20 ppm (0.5 mg paraquat ion/kg/day).
0 Alderley Park beagle dogs (six/sex/dose) were fed diets containing
technical paraquat (32.3%) cation daily for 52 weeks at dietary levels
of 0, 15, 30 or 50 ppm (Kalinowski et al., 1983). Based on actual
group mean body weights and food consumption, these values correspond
to doses of 0, 0.45, 0.93 and 1.51 mg/kg/day for male dogs and 0,
0.48, 1.00 or 1.58 for females. Clinical and behavioral abnormali-
ties, food consumption, body weight, hematology, clinical chemistry,
urinalysis, organ weights, gross pathology and histopathology were
comparable for treated animals and controls at 15 ppm (the lowest
dose tested). An increased severity and extent of chronic pneumonitis
occurred at 30 ppm in both sexes, but especially in the males. Based
on the results of this study, the NOAEL identified was 15 ppm (0.45 mg
paraquat cation/kg/day).
0 Technical paraquat dichloride (32.7% paraquat ion) was fed to Alderley
Park mice (60/sex/dose) for 97-99 weeks at levels of 0, 12.5, 37.5
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Paraquat August, 1987
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and 100/125 ppm (100 ppm for the initial 35 weeks and then 125 ppm
until termination of the study) (Litchfield et al., 1981). Based on
the assumption that 1 ppm in the diet of mice is equivalent to 0.15
ing/kg/day (Lehman, 1959), these levels correspond to doses of 0,
1.87, 5.6 and 15/18.75 mg/kg. The animals were observed for toxic
signs, and body weights, food consumption and utilization, urinalysis,
gross pathology and histopathology were evaluated. Renal tubular
degeneration in the males and weight loss and decreased food intake
in the females, were the only effects observed, and occurred in the
37.5-ppm dose group. Based on these findings, a NOAEL of 12.5 ppm
(1.87 mg/kg/day) was identified.
0 Fischer 344 rats (70/sex/dose) were fed diets containing 0, 25, 75
or 150 ppm of technical paraquat (32.69% cation) for 113 to 117 weeks
(males) and 122 to 124 weeks (females) (Woolsgrove et al., 1983). Based
on the assumption that 1 ppm in the diet is equivalent to 0.05 mg/kg/day
(Lehman, 1959), these levels correspond to doses of 0, 1.25, 3.75 or
7.5 mg/kg/day. Clinical signs, food and water consumption, clinical
chemistry, urinalysis, hematology, ophthalmoscopic effects, gross
pathology and histopathology were evaluated. Increased incidences of
slight hydrocephalus were noted in the female rats dying between week
53 and termination of the study; these incidences were 5/60, 8/30,
9/27 and 9/30 rats in the control, low, mid and high dose, respectively.
Also, increased incidences of spinal cord cysts and cystic spaces
were noted in the male rats dying between week 53 and termination of
the study. These incidences were 0/53, 6/36 and 4/35 rats at the
control, low and mid-level doses, respectively; no incidence was
reported at the high dose. Eye opacities, cataracts and nonneoplastic
lung lesions (alveolar macrophages and epithelialization, and slight
peribronchiolar lymphoid hyperplasia) were observed at 75 ppm and
above. Similar eye lesions occurred at 25 ppm (the lowest dose
tested). These effects did not appear to be biologically significant,
since they were either minimal or occurred after 104 weeks of treatment
and appeared, therefore, to be only an acceleration of the normal
aging process. Based on these results, an approximate NOAEL of
25 ppm (1.25 mg/kg/day) was identified.
Reproductive Effects
0 Lindsay et al. (1982) fed Alderley Park rats technical paraquat
dichloride (32.7% cation w/w) in unrestricted diet for three genera-
tions at dose levels of 0, 25, 75 or 150 ppm paraquat ion.
Based on the assumption that 1 ppm in the diet of
rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), these levels
correspond to doses of 0, 1.25, 3.75 or 7.5 mg/kg/day. No adverse
reproductive effects were reported at 150 ppm (the highest dose
tested) or less. An increased incidence of alveolar histiocytosis in
the lungs of male and female parents (Fg, FI and F2) was observed in
the 75- and 150-ppm dose groups. Based on these results, a reproductive
NOAEL of >150 ppm (7.5 mg/kg/day, the highest dose tested) and a
systemic NOAEL of 25 ppm (1.25 mg/kg/day, the lowest dose tested)
were identified.
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Developmental Effects^
0 Young adult Alderley Park mice (number not stated) were administered
paraquat dichloride (100% purity) orally by gavage at dose levels of
0, 1, 5 or 10 mg paraquat ion/kg/day on days 6 through 15 of gestation
(Hodge et al., 1978a). No teratogenic responses were reported at
10 mg ion/kg/day (the highest dose tested) or lower. Partially
ossified sternebrae in 26.3% of the fetuses in the high-dose group
(10 mg ion/kg/day) and decreased maternal weight gain in the 5-mg
ion/kg/day dose group were observed. Based on these results, the
developmental NOAEL identified for this study was 5 mg/kg/day, while
the maternal NOAEL was 1 mg/kg/day.
0 Hodge et al. (1978b) dosed Alderley Park rats (29 or 30/dose) by
gavage with paraquat dichloride (100% purity) on days 6 through
15 of gestation at dose levels of 0, 1, 5 and 10 mg paraquat ion/kg/day.
No teratogenic effects were reported at 10 mg ion/kg/day (the highest
dose tested). Maternal body weight gain was significantly decreased
(p_
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Paraquat August, 1987
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125 ppm until termination of the study) (Litchfield et al., 1981).
Based on the assumption that 1 ppm in food in mice is equivalent to
0.15 mg/kg/day (Lehman, 1959), these levels correspond to doses of 0,
1.87, 5.6 and 15/18.75 mg/kg. The study appeared to have been conducted
properly, except that hematological and organ weight determinations
were not performed. The absence of these parameters do not compromise
the results, since the occurrence of certain toxicological end points
(e.g., leukemia) detected by these tests are rare in mice. The
results, therefore, provide evidence that paraquat is not oncogenic
at the dose levels tested.
0 Woolsgrove et al. (1983) fed Fischer 344 rats (70/sex/dose) diets
containing technical paraquat (32.69%) for 113 to 117 weeks (males)
and 122 to 124 weeks (females) at dietary levels of 0, 25, 75 and
1 50 ppm. Based on the assumption that 1 ppm in the diet of rats is
equivalent to 0.05 mg/kg/day (Lehman, 1959), these levels correspond
to doses of 0, 1.25, 3.75 and 7.5 mg paraquat cation/kg/day. The
predominant tumor types noted in this study were tumors of the lungs,
endocrine glands (pituitary, thyroid and adrenal) and of the skin and
subcutis. Both the lung and endocrine tumors occurred at a frequency
similar to the incidence of these kinds of tumors in the historical
control. Only the squamous cell neoplasia of the skin and subcutis
were determined to be treatment-related. The squamous cell carcinoma
was a predominant tumor in the head region of the male and female
rats. This uncommon tumor occurred in 51.6% of all rats with skin and
subcutis tumors in the head region. The incidence of these tumors in
this study was 2, 4, 0 and 8% in the control, low-, mid- and high-dose
male groups, respectively and 0, 0, 4 and 3% in the control, low-,
mid- and high-dose female groups, respectively. When these incidences
were compared with incidences in historical controls (0 to 2.0% in
males and 1.9 to 4.0% in females) the high-dose male group reflected a
significant increase (p = 0.01). Also when squamous cell carcinoma and
papilloma (including those of the head region) were combined, only
the tumor incidence in the high-dose male group exceeded the historical
and concurrent controls (U.S. EPA, 1985 and 1986a).
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = -ig"«*n or LOAEL) x (BW) = mg/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
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BW » assumed body weight of a child (10 kg) or
an adult (70 kg).
UF * uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
_ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No suitable information was found in the available literature for the
determination of the One-day HA value for paraquat. It is therefore recommended
that the Ten-day HA value for the 1 0-kg child of 0.1 mg/L (100 ug/L), calculated
below, be used at this time as a conservative estimate of the One-day HA value.
Ten-day Health Advisory
The rat developmental study (Hodge et al., 1978b) has been selected to
serve as the basis for the determination of the Ten-day HA value for paraquat.
In this study, Alderley Park rats were administered paraquat (100% purity)
during gestation days 6 through 15 at dose levels of 0, 1, 5 or 10 mg paraquat
ion/kg/day. There was a statistically significant (p^_0.001; p = 0.05)
decrease in maternal and fetal body weight gain at the 5-mg paraquat ion/kg/day
dose; also at 5 mg/kg/day, there was a slight retardation in ossification.
The fetotoxic and maternal NOAEL identified in this study was 1 mg paraquat
ion/kg/day. An adequate study of comparable duration reported a NOAEL that
was higher than that in the study selected for derivation of the Ten-day HA.
A NOAEL of 5 mg/kg/day was identified for developmental effects, while the
maternal NOAEL was similar (1 mg/kg/day) (Hodge et al., 1978a).
Using a NOAEL of 1 mg/kg/day, the Ten-day HA for a 1 0-kg child is
calculated as follows:
where:
Ten-day HA = (1 m?Ag bw/day) (10 kg) _ 0.1 mg/L (100 ug/L)
(100) (1 L/day)
1 mg/kg/day = NOAEL, based on the absence of fetotoxic and maternal
effects in rats exposed to paraquat by gavage on days
6 through 15 of gestation.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW-
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
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Longer-term Health Advisory
No studies were found in the available literature that were suitable for
deriving the Longer-term HA value for paraquat. The 90-day oral study of dogs
(Sheppard, 1981) reported a NOAEL (0.5 mg ion/kg/day) which is similar to the
NOAEL (0.45 mg ion/kg/day) of the 52-week oral dog study (Kalinowski et al.,
1983) used to derive the Lifetime HA. It is, therefore, recommended that the
Drinking Water Equivalent Level (DWEL) of 0.16 mg/L (160 ug/L), calculated below,
be used for the Longer-term HA value for an adult, and that the DWEL adjusted
for a 10-kg child, 0.045 mg/L (45 ug/L), be used for the Longer-term HA value
for a child.
Ldfetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986b), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The study by Kalinowski et al. (1983) has been selected to serve as the
basis for the Lifetime HA value for paraquat. In this 52-week feeding study
in beagle dogs, a NOAEL of 15 ppm (0.45 mg paraquat ion/kg/day) was identified
based on the absence of hematological, biochemical, gross pathological and
histclogical effects as well as the absence of any significant changes in
food consumption, or in body and organ weights for treated and control groups.
Adequate studies of comparable duration reported NOAELs higher than those of
the critical study selected for derivation of the Lifetime HA. A lifetime
oral study in rats (Woolsgrove et al., 1983) reported a NOAEL of 25 ppm
(about 1.25 mg/kg/day); a NOAEL of 12.5 ppm (about 1.87 mg/kg/day) was
identified for mice (Litchfield et al., 1981).
Step 1; Determination of the Reference Dose (RfD)
RfD = JO.45 mc^ion/kg/day) = 0.0045 mg/kg/day
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where:
0.45 mg ionA9/day = NOAEL, based on the absence of biochemical,
hematological, gross pathological and histo-
pathological effects in dogs fed paraquat in
the diet for 52 weeks.
100 * uncertainty factor, chosen in accordance with
NAS/ODW guidelines for use with a NOAEL from
an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.0045 mgAg/day) (70 kg) , 0>16 mg/L (160 ug/L)
(2 L/day)
where:
0.0045 mgAg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Calculation of the Lifetime Health Advisory
Lifetime HA = (0.16 mg/L) (20%) = 0.003 mg/L (3 ug/L)
10
where:
0.16 mg/L = DWEL.
20% = assumed relative source contribution from water.
10 = additional uncertainty factor per ODW policy to account
for possible carcinogenicity.
Evaluation of Carcinogenic Potential
0 In studies with mice, technical paraquat dichloride (32.7% paraquat
ion) did not induce significant oncogenic responses at dose levels of
0, 12.5, 37.5 or 100/125 ppm (0, 1.87, 5.6 or 15/18.75 mgA9» respec-
tively) (Litchfield et al., 1981). The oncogenic potential of paraquat
has been determined in studies in which rats were fed technical
paraquat for 113 to 124 weeks at dose levels of 0, 25, 75 and 150 ppm
(0, 1.25, 3.75 and 7.5 mgAg/day), respectively. The incidences of
pulmonary, thyroid, skin and adrenal tumors were not clearly associated
with treatment; however, the incidence of skin carcinomas was signifi-
cantly increased (p = 0.01) in the high-dose males (Woolsgrove et al.,
1983).
0 The International Agency for Research on Cancer has not evaluated the
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Paraquat i August, 1987
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Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986b), paraquat may be classified in
Group C: possible human carcinogen. This group is used for substances
with limited evidence of carcinogenicity in animals in the absence of
human data.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The Office of Pesticide Programs (OPP) has established tolerances on
raw agricultural commodities for paraquat ion derived from either the
bis(methyl sulfate) or dichloride salt ranging from 0.01 to 5 ppm
(U.S. EPA, 1984). The tolerances are based on an ADI of 0.0045
mg/kg/day derived from a 1-year feeding study in dogs, with a ,NOAEL
of 0.45 mg/kg/day and a safety factor of 100.
0 The National Academy of Sciences (NAS, 1977) has a Suggested-No-
Adverse-Response-Level (SNARL) of 0.06 mg/L. This was calculated-
using an uncertainty factor of 1,000 and a NOAEL of 8.5 mg/kg/day
identified in the 2-year rat study by Chevron Chemical Company (1975),
with an assumed consumption of 2 L/day of water by a 70-kg adult, with
the assumption that 20% of total intake of paraquat was from water.
0 American Conference of Governmental Hygenists has presented a threshold
limit value of 0.1 mg/m^ for paraquat of respirable particle sizes
(ACGIH, 1980).
VII. ANALYTICAL METHODS
There is no standarized method for the determination of paraquat in
water samples. A method has been reported for the estimation of para-
quat residues on various crops (FDA, 1979). In this method, paraquat
is reduced by sodium dithionite to an unstable free radical that has
an intense blue color and also a strong absorption peak at 394 run.
VIII. TREATMENT TECHNOLOGIES
Weber et al. (1986) investigated the adsorption of paraquat and other
compounds by charcoal and cation and anion exchange resins and their
desorption with water. They developed Freundlich adsorption-desorption
isotherms for paraquat on charcoal. When 250 mg of charcoal was added
to paraquat solutions, it exhibited the following adsorptive capacities:
37.3 and 93.2 mg paraquat/g charcoal at concentrations of 0.373 mg/L
and 37.3 mg/L, respectively. Paraquat was also adsorbed by IR-120
exchange resins (H+ and Na+ forms). The IR-120-H resin showed more
affinity towards paraquat than the IR-120-Na resin. When 665 mg of
paraquat in solution was added to 15 mg of resin, IR-120-H adsorbed
70% of paraquat while the IR-120-Na adsorbed 66% of paraquat.
0 MacCarthy and Djebbar (1986) evaluated the use of chemically modified
peat for removing paraquat from aqueous solutions under a variety of
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Paraquat August, 1987
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experimental conditions. Paraquat sorption isotherms on treated
Irish peat were determined by equilibrating 100-mL volumes of 3.66 mg/L
paraquat with 0.1 g of peat at ambient conditions. Tests indicated
that equilibrium for paraquat was achieved after 6 days. Peat exhib-
ited the following paraquat sorption capacities: 40, 55 and 60 mg
paraquat/g peat at concentrations of 2, 4 and 6 mg/L, respectively.
The effects of pH, ionic strength and flow rate on paraquat removal
efficiency were also investigated. When 45 mL of 16-mg/L paraquat
solution was gravity fed to a column with a diameter of 6 mm that had
been packed with 700 mg treated peat, 95 to 99% paraquat removal
efficiency was reported without a significant effect by variations in
pH, ionic strength or flow rate.
In summary, several techniques for the removal of paraquat from water
have been examined. While data are not unequivocal, it appears that
adsorption of paraquat by charcoal, ion exchange and modified peat are
effective treatment techniques. However, selection of individual or
combinations of technologies for paraquat removal from water must be
based on a case-by-case technical evaluation and an assessment of
the economics involved.
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Paraquat August, 1987
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*
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•Confidential Business Information submitted to the Office of Pesticide
Programs.
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