August, 1987
820K88100
CHLOROTHALONIL
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-
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 1897-45-6
Structural Formula
2,4,5,6-Tetrachloro-1,3-benzenedicarbonitrile
Synonyms
e Tetrachloroisophthalonitrile; Bravo? Chloroalonil; Chlorthalonil;
Daconil; Exothern; Forturf; Nopcocide N96; Sweep; Termil; TPN; DAC-2787.
Uses (Meister, 1986)
0 Broad-spectrum fungicide.
Properties (Meister, 1986; CHEMLAB, 1985; Meister, 1983; Windholz et al., 1983T
Chemical Formula CgN2Cl4
Molecular Weight 265.89
Physical State (25°C) White, crystalline solid
Boiling Point 350°C
Melting Point 250 to 251°C
Density —
Vapor Pressure (40°C) <0.01 mm Hg
Specific Gravity ~
Water Solubility (25°C) 0.6 mg/L
Octanol/Water Partition 1.32 (calculated)
Coefficient
Taste Threshold
Odor Threshold —
Conversion Factor —
Occurrence
0 Chlorothalonil has been found in the 1 surface water sample analyzed
and in none of the 560 ground water samples (STORET, 1987). Samples
were collected at 1 surface water location and 556 ground water
locations; and the 1 location where it was found in Michigan, the
concentration was 6,500 ug/L.
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Environmental Fate
0 Ring-labeled !4C-chlorothalonil, at 0.5 to 1.5 ppm, was stable to
hydrolysis for up to 72 days in aqueous solutions buffered at pH 5
and 7 (Szalkowski, 1976b). At pH 9, chlorothalonil hydrolyzed with
half-lives of 33 to 43 days and 28 to 72 days in solutions to which
ring-labeled 14C-chlorothalonil was added at 0.52 and 1.5 ppm,
respectively. After 72 days of incubation, pH 9-buffered solutions
treated with chlorothalonil at 1.5 ppm contained 36.4% chlorothalonil,
48.9% 3-cyano-2,4,5,6-tetrachlorobenzamide (DS-19211) and 11.3% 4-
hydroxy-2,5,6-trichloroisophthalonitrile (DAC-3701).
0 The degradate 14C-DAC-3701, at 1°00 PPm» was not hydrolysed in aqueous
solutions buffered at pH 5, 7, and 9 after 72 days of incubation
(Szalkowski, 1976b).
0 Ring-labeled 14c-chlorothalonil and its major degradate, ring-labeled
14C-DAC-3701, were stable to photolysis on two silt loam and three
silty clay loam soils, after UV irradiation for the equivalent of 168
12-hour days of sunlight (Szalkowski, 19??).
0 14c-Chlorothalonil is degraded with half-lives of 1 to 16, 8 to 31,
and 7 to 16 days in nonsterile aerobic sandy loam, silt loam and peat
loam soils, respectively, at 77 to 95°F and 80% of field moisture
capacity (Szalkowski, 1976a). When chlorothalonil (WP) was applied
to nonsterile soils ranging in texture from sand to silty clay loam,
at 76 to 100°F and 6% soil moisture, it was degraded with half-lives
of 4 to more than 40 days; increasing either soil moisture content
(0.6 to 8.9%) or incubation temperature (76 to 100°F) enhanced
chlorothalonil degradation (Stallard and Wolfe, 1967). Soil pH
(6.5 to 8) does not appear to influence or only negligibly influences
the degradation rate of chlorothalonil; however, soil sterilization
greatly reduced the degradation rate. The major degradate identified
in nonsterile aerobic soil was DAC-3701, representing up to 69% of the
applied radioactivity. Other identified degradates included DS-19221,
trichloro-3-carboxybenzanu.de, 3-cyanotrichlorohydroxybenzamide, and
3-cyanotrichlorobenzamide (Stallard and Wolfe, 1967; Szalkowski, 1976a;
Szalkowski et al., 1979).
0 14C-Chlorothalonil was immobile (Rf 0.0) and the degradate 14C-DAC-3701
was found to have low to intermediate mobility (Rf 0.25 to 0.43) in
two silt loam and three silty clay loam soils, as evaluated using soil
thin-layer chromotography (TLC) (Szalkowski, 19??). Based on batch
equilibrium tests, chlorothalonil has a relatively low mobility (high
adsorption) in silty clay loam (K = 26), silt (K = 29), and sandy
loam (K = 20) soils but is intermediately mobile (low adsorption) in
a sand (K » 3) (Capps et al., 1982). Soil organic matter content did
not appear to influence the mobility of chlorothalonil in soil.
0 The chlorothalonil degradate DAC-3701 is mobile in sand, loam, silty
clay loam and clay soils (Wolfe and Stallard, I968a). After eluting
a 6-in soil column with the equivalent of 5 inches of water, approxi-
mately 57, 84, 10 and 84% of the applied DAC-3701 was recovered in
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Chlorothalonil August, 1987
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the leach ate of the sand, loam, silty clay loam and clay soil columns,
respectively.
e Chlorothalonil (4.17 Ib/gal F1C) was degraded with a half-life of
1 to 3 months in sandy loam and silt loam soils when applied alone at
8.34 Ib ai/A or in combination with benomyl (50% wettable powder) at
1.35 Ib ai/A (Johnston, 1981). The treated soils were maintained at
80% of moisture capacity in a greenhouse.
0 Under field conditions, the half-life of Chlorothalonil (75% wettable
powder) in a sandy loam soil was between 1 and 2 months following the
last of five consecutive weekly applications totaling 15 Ib ai/A
(Stallard et al., 1972). Little movement of Chlorothalonil (0.01 to
0.17 ppm) below the 0- to 3-inch depth occurred throughout the 8-month
study. Small amounts (0.01 to 0.21 ppm) of the degradate DAC-3701
were found in soil samples collected up to 5 months post-treatment.
No Chlorothalonil or DAC-3701 was detected (less than 1 ppb) in a
nearby stream up to 7 months post-treatment, or in ground water
samples (10-foot depth) up to 8 months post-treatment. Cumulative
rainfall over the study period was 26.22 inches.
III. PHARMACOKINETICS
Absorption
0 Ryer (1966) administered 14C-chlorothalonil (dose not specified)
orally to albino rats (3/sex; strain not specified). In 48 hours
post-treatment, 60.21% of the radioactivity was detected in the
feces, indicating that at least 40% of the oral dose was absorbed.
0 Skinner and Stallard (1967) reported that rats receiving 1.54 mg of
14c-chlorothalonil in a 500 mg/kg dose (route not specified)
eliminated 88% of the administered dose unchanged in the feces over
264 hours, indicating that 12% was absorbed.
0 Skinner and Stallard (1967) reported that mongrel dogs receiving
a single oral dose (by capsule) of 500 mg/kg of Chlorothalonil,
eliminated 85% of the administered dose as the parent compound
within 24 hours post-treatment, indicating that 15% was absorbed.
Distribution
e Ryer (1966) administered 14c-chlorothalonil (dose not specified) to
albino rats (3/sex; strain not specified) by oral intubation. After
11 days, the carcasses retained 0.44% of the dose while 0.05% of the
dose remained in the gastrointestinal tract. The highest residues
occurred in the kidneys, which averaged 0.01% of the dose for the six
rats. Lesser amounts were detected in the eyes, brain, heart, lungs,
liver, thyroid and spleen.
0 Ribovich et al. (1983) administered single doses of 14C-chlorothalonil
by oral intubation to CD-1 mice at levels of 0, 1.5, 15 or 105 mg/kg.
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Chlorothalonil August, 1987
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Twenty-four hours post-treatment, the stomach, liver, kidneys, fat,
small intestine, large intestine, lungs and heart accounted for less
than 3% of the administered dose. The stomach and kidneys had the
highest concentration at all doses tested. The compound was
eliminated from the stomach and kidneys by 168 hours post-treatment.
0 Wolfe and Stallard (1968b) reported a study in which dogs and rats
received chlorothalonil in the diet for 2 years at 1,500 to 30,000 ppm.
The amount of the 4-hydroxy-2,5,6-trichloroisophthalonitrile metabolite
that was detected in the kidney tissue of dogs was less than 1.5 ppm;
less than 3.0 ppm was detected in liver tissue from dogs and rats.
The authors concluded that the metabolite was not stored in animal
tissue.
Metabolism
0 In the Wolfe and Stallard (196Sb) study, only a small amount of the
4-hydroxy-2,5,6-trichloroisophthalonitrile metabolite was detected in
the kidney tissue of dogs (<1.5 ppm) and in liver tissue from dogs
and rats (<3 ppm).
0 Marciniszyn et al. (1983) reported that when Osborne-Mendel rats were
administered single oral doses of 1 4C-chlorothalonil by intubation at
levels of 0, 5, 50, 200 or 500 rag/kg, no metabolites of chlorothalonil
were unequivocally identified in urine.
Excretion
The Ryer study (1966) revealed that, at the end of 11 days, an average
of 88.45% of the administered dose was excreted in the feces, 5.14% in
the urine and 0.32% in expired gases as CC^.
The Skinner and Stallard study (1967) presented results that demon-
strated that 88% of a dose (route unspecified) of chlorothalonil was
eliminated unchanged in the feces. Only 5.2% was eliminated via the
urine and negligible amounts were detected in expired air.
Ribovich et al. (1983) administered single doses of 14c-chlorothalonil
by oral intubation to CD-1 mice at levels of 0, 1.5, 15 or 105 mg/kg.
The total recoveries of radioactivity 24 hours post-treatment were
93% for the low dose, 81% for the mid dose and 62% for the high dose.
The major route of elimination was the feces and was complete at 24
hours post-treatment for the low- and mid-dose animals, and by 96
hours for the high dose animals.
Marciniszyn et al. (1981) reported a study in which single doses of
14c-chlorothalonil were administered intraduodenally to male Sprague-
Dawley rats at 0.5, 5, 10, 50, 100 or 200 mg/kg. Biliary excretion
of radioactivity was monitored for 24 hours. Percent recovery of
radioactivity was 27.8, 20.7, 16.8, 6.4, 7.8 and 6% for each dose
level, respectively.
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Marciniszyn et al. (1983a) administered 14C-Chlorothalonil intra-
duodenally to male Sprague-Dawley rats (donor animals) at a dose of
5 mg/kg. Bile was collected for 24 hours following administration.
Some of the collected bile was administered intraduodenally to recipient-
rats; bile was also collected from these animals for 24 hours. Data
from the donor rats indicated that 1 to 6% of the administered radio-
activity was excreted in the bile within 24 hours after dosing.
Approximately 19% of the radioactivity in bile administered to recipient
rats was excreted within 24 hours after dosing. These data suggest
that enterohepatic recirculation plays a role in the metabolism of
Chlorothalonil in rats.
Pollock et al. (1983) administered 14C-chlorothalonil by gavage to
male Sprague-Dawley rats at dose levels of 5, 50 or 200 mg/kg. They
subsequently determined blood concentrations of radioactivity. The
authors hypothesized that, at 200 mg/kg, an elimination mechanism
(urinary, biliary and/or metabolism) was saturated, since the kinetics
were nonlinear at this dose.
IV. HEALTH EFFECTS
0 The purity of the administered Chlorothalonil is assumed to be
>90% for all studies described below, unless otherwise noted.
Humans
Johnsson et al. (1983) reported that Chlorothalonil exposure resulted
in contact dermatitis in 14 of 20 workers involved in woodenware
preservation. The wood preservative used by the workers consisted
mainly of "white spirit," with 0.5% Chlorothalonil as a fungicide.
Workers exhibited erythema and edema of the eyelids, especially the
upper eyelids, and eruptions on the wrist and forearms. Results of
a patch test conducted with 0.1% Chlorothalonil in acetone were posi-
tive in 7 of 14 subjects. Reactions ranged from a few erythematous
papules to marked papular erythema with a brownish hue without
infiltration.
Animals
Short-term Exposure
0 Powers (1965) reported that the acute oral LD^Q of Chlorothalonil
(75% wettable powder) in Sprague-Dawley rats was >10 g/kg.
0 Doyle and Elsea (1963) reported that the acute oral LD50 of Chloro-
thalonil in Sprague-Dawley rats was >10 g/kg.
0 Rittenhouse and Narcisse (1974) reported that the acute ocal LD50 of
Chlorothalonil in Sprague-Dawley rats was >17.4 g/kg.
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Dermal/Ocular Effects
0 Doyle and Elsea (1963) reported that the dermal LD50 of DAC-2787
(technical chlorothalonil) in albino rabbits was >10 gAg« At dermal
concentrations of 1, 2.15, 4.64 or 10 g/kg (24-hour exposure), the
compound produced mild to moderate skin irritation characterized by
erythema, edema, atonia and desquamation.
0 Doyle and Elsea (1963) reported that when 3 mg of DAC-2787 (technical
chlorothalonil) was applied to the eyes of albino rabbits, eye
irritation was limited to mild conjunctivitis that subsided largely
or completely within 7 days.
0 Auletta and Rubin (1981) reported the results of eye irritation
studies in cynomologus monkeys and New Zealand White rabbits using a
formulation containing 96% chlorothalonil. In both species, 0.1 mL
of the test substance was instilled into the conjunctival sac of one
eye. Each species displayed mild and transient ocular irritation as
evidenced by corneal opacities that were reversed by 4 days post-
instillation. The animals also showed slight to moderate iridial
and conjunctival effects which were also reversible. Rinsing reduced
conjunctival and iridial effects and prevented formation of corneal
opacities.
Long-term Exposure
0 Blackmore and Shott (1968) administered technical grade DAC 2787
(chlorothalonil) to Charles River rats for 90 days at dietary levels
of 0, 4, 10, 20, 30, 40 or 60 ppm (approximately 0, 0.2, 0.5, 1.0,
1.5, 2.0 or 3.0 mg/kg/day; Lehman, 1959). No compound-related effects
were reported regarding physical appearance, growth, survival, terminal
clinical values, organ weights or organ-to-body weight ratios.
Microscopically, the kidneys exhibited occasional vacuolation and
swelling of the epithelial cells lining the deeper proximal convoluted
tubules. These changes were more numerous and more severe in the two
highest dose groups. The authors stated that the difference between
the two highest dose groups (2.0 and 3.0 mg/kg/day) and the controls
was distinct, but the difference between the lower dose groups and
controls was not clear. Based on this information, a NOAEL of 30 ppm
(1.5 mg/kg/day) is identified.
0 Wilson et al. (1981) administered chlorothalonil in the diet to
Charles River CD rats (20/sex/dose) for 90 days at doses of 0, 40,
80, 175, 375, 750 or 1,500 mg/kg/day. At doses of 375 mg/kg/day or
higher, significant decreases in body weight were reported. Decreases
in glucose levels, blood urea nitrogen and serum thyroxine were
attributed by the investigators to body weight effects. A dose-related
decrease in serum glutamic-pyruvic transaminase (SGPT) was noted in all
test groups. Significant increases in kidney weights were also noted
in males at 40, 80, 175 and 375 mg/kg, while in females increased
kidney weights were noted at 80, 175 and 750 mg/kg. These were
dose-related increases in kidney-to-body weight ratios in both sexes
at all doses. Focal acute gastritis occurred in some rats of both
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Chlorothalonil August, 1987
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sexes at all doses and this effect was inversely related to dose.
A LOAEL of 40 mg/kg/day (the lowest dose tested) is identified in
this study.
Colley et al. (1983) administered technical-grade chlorothalonil in
the diet to Charles River rats (27 males and 28 females per dose) for
13 weeks at concentrations of 0, 1.5, 3.0, 10 or 40 mg/kg/day.
Histopathological examination revealed that at a dose of 3.0 mg/kg/day
or greater, all males displayed an increased number of irregular
intracytoplasmic inclusion bodies in the renal proximal convoluted
tubules. A NOAEL of 1.5 mg/kg/day is identified in this study.
Shults et al. (1983) administered technical-grade chlorothalonil to
CD-1 mice for 90 days at dietary concentrations of 0, 7.5, 15, 50, 275
or 750 ppm (approximately 0, 1.1, 2.3, 7.5, 33.8 or 112.5 mg/kg/day;
Lehman, 1959). No treatment-related effects were noted on survival,
physical condition, body weight, food consumption or gross pathology.
At 750 ppm (112.5 mg/kg/day), an increase in alkaline phosphatase
levels was observed in females only. Increased kidney weight was
reported in males dosed at 750 ppm (112.5 mgAg/day) and in females
dosed at 275 and 750 ppm (33.8 and 112.5 mg/kg/day). Histopatho-
logically, dose-related changes in the forestomach of mice were
characterized by hyperplasia and hyperkeratosis of squamous epithelial
cells. These changes were observed in the 50-, 275- and 750-ppm dose
groups. No other treatment-related histopathological changes were
reported. A NOAEL of 15 ppm (2.3 mg/kg/day) is identified in this
study.
Paynter and Murphy (1967) administered DAC 2787 (chlorothalonil) to
beagle dogs (4/sex/dose) for 16 weeks at dietary concentrations of 0,
250, 500 or 750 ppm (approximately to 0, 6.3. 12.5 or 18.8 mg/kg/day;
Lehman, 1959). No effects attributable to chlorothalonil were noted
in terms of appearance, behavior, appetite, elimination, body weight
changes, gross pathology or organ weights. Hematological, biochemical
and urinalysis values were generally within accepted limits in treated
and control animals, except for slightly elevated protein-bound
iodine values in treated dogs (especially high-dose females). No
compound-related histopathology was noted. Based on this, a minimum
NOAEL of 750 ppm (18.8 mg/kg/day) is identified.
Hastings et al. (1975) administered chlorothalonil to Wistar albino
rats (15/sex/dose for treatment groups, 30/sex for controls) for four
months at dietary concentrations of 0, 1, 2, 4, 15, 30, 60 or 120 ppm
(approximately 0, 0.05, 0.1, 0.2, 0.8, 1.5, 3 or 6 mg/kg/day; Lehman,
1959). No significant differences between treated and control groups
were seen in body weight, food consumption, mortality or gross patho-
logical changes. Histopathological examination of the kidneys
revealed no demonstrable effects at any dose level. A minimum NOAEL
of 120 ppm (6 mg/kg/day) is identified.
Blackmore et al. (1968) administered DAC 2787 (chlorothalonil) to
Charles River rats (35/sex/dose) for 22 weeks at dietary concentrations
of 0, 250, 500, 750 or 1,500 ppm (approximately 0, 12.5, 25, 37.5 or
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75 mg/kg/day; Lehman, 1959). At all dose levels, male rats gained
less weight from weeks 11 to 22. Females gained less weight from
weeks 9 to 22 at 750 and 1,500 ppm (37.5 or 75 mg/kg/day). Food
consumption values were similar for all groups. No differences
between control and test animals were reported for various hematological
parameters, urinalysis and plasma and urine electrolytes. Results of
gross necropsy revealed that livers and kidneys of males treated at
750 or 1,500 ppm (37.5 or 75 mg/kg/day) were larger than controls.
Microscopic examinations demonstrated dose-related compound-induced
alterations in the kidneys of both sexes at all doses. These changes
were characterized by irregular swelling of the tubular epithelium,
epithelial degeneration and tubular dilatation. There was a signifi-
cant increase in renal tubular diameter in males at all dose levels.
Accordingly, a LOAEL of 250 ppm (12.5 mg/kg/day) is identified.
0 Blackmore and Kundzin (1969) administered technical-grade DAC 2787
(chlorothalonil) to rats (strain not specified) (35/sex/dose) for 1
year at dietary concentrations of 0, 4, 10, 20, 30, 40 or 60 ppm.
The authors indicated that these dietary levels correspond to 0, 0.2,
0.5, 1.0, 1.5, 2.0 or 3.0 mg/kg/day. No compound-related effects on
physical appearance, behavior, growth, food consumption, survival,
clinical laboratory values, organ weights or gross pathology were
noted. Microscopically, there were kidney alterations in both sexes
at 40 and 60 ppm (2.0 and 3.0 mg/kg/day). These alterations occurred
primarily in the deeper cortical tubules and consisted of increased
vacuolation of epithelial cells accompanied by swelling or hypertrophy
of the affected cells, often with the deposition of an eosinophilic
droplet material in the cytoplasm of the vacuole. Statistical
significance was not addressed. A NOAEL of 30 ppm (1.5 mg/kg/day)
is identified.
0 Holsing and Voelker (1970) administered technical-grade chlorothalonil
to beagle dogs (eight/sex/dose) for 104 weeks at dietary concentrations
of 0, 60 or 120 ppm (approximately 0, 1.5 or 3 mg/kg/day; Lehman, 1959).
After 2 years of administration, compound-related histopathological
changes were observed in the kidneys of males fed 120 ppm (3 mg/kg/day).
Males fed 60 ppm (1.5 mg/kg/day) and females fed both dose levels
were comparable to controls. The observed changes included increased
vacuolation of the epithelium in both the convoluted and collecting
tubules and increased pigment in the convoluted tubular epithelium.
Clinical findings, terminal body weight, organ-to-body weight ratios
and gross pathology revealed no conclusive compound-related trends.
A NOAEL of 60 ppm (1.5 mg/kg/day) is identified.
0 Tierney et al. (1983) administered technical grade chlorothalonil
to Charles River CD-1 mice (60/sex/dose) for 2 years at dietary
concentrations of 0, 750, 1,500 or 3,000 ppm. The authors indicated
that these dietary levels were approximately 0, 119.4, 251.1 or
517.4 mg/kg/day for males and 0, 133.6, 278.5 or 585.0 mg/kg/day
for females. No treatment-related effects on body weight, food
consumption, physical condition or hematological parameters were noted.
A slightly increased mortality rate was noted in males receiving
3,000 ppm (517.4 mg/kg/day). Also, kidney-to-body weight ratios and
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Chlorothalonil August, 1987
kidney-to-brain weight ratios were increased significantly in all
test groups. Gross necropsy revealed a number of renal effects
including kidney enlargement, discoloration, surface irregularities,
pelvic dilation, cysts, nodules and masses. Effects on the stomach
included an increased incidence in masses or nodules. In the stomach
and esophagus, nonneoplastic histopathological effects were noted at
all dose levels, and included hyperplasia and hyperkeratosis of the
squamous mucosa. This was considered to be indicative of mucosal
irritation. Other changes in the stomach included mucosal and
submucosal inflammation, focal necrosis or ulcers of mucosa and
hyperplasia of glandular mucosa. Reported histopathological effects
on the kidney included an increase in the incidence and severity of
glomerulonephritis, cortical tubular degeneration and cortical cysts.
These changes were not dose-related, but they did occur at higher
incidences in treated animals. Based on the information presented in
this study, a LOAEL of 750 ppm (119.4 mg/kg/day-males; 133.6 mg/kg/day-
females) is identified.
Reproductive Effects
0 In a three-generation reproduction study, Paynter and Kundzin (1967)
administered a mixture containing 93.6% chlorothalonil to Charles River
rats (10 males and 20 females per dose) at dietary concentrations of
0 or 5,000 ppm (approximately 0 or 250 mg/kg/day; Lehman, 1959). At
the dose tested, the test material produced significant growth
suppression in the nursing litters of each generation. Reproductive
performance was not affected and pups showed no malformations attrib-
utable to the test substance. Body weight gains for exposed male and
female rats of each generation were lower than controls.
Developmental Effects
0 Rodwell et al. (1983) administered technical grade chlorothalonil by
gavage at doses of 0, 25, 100 or 400 mg/kg/day to Sprague-Dawley rats
(25/dose level) on days 6 to 15 of gestation. No compound-related
external, internal or skeletal malformations were observed in fetuses.
At 400 mg/kg/day, maternal toxicity was noted (as evidenced by changes
in appearance, three deaths, decreased body weight gain and food con-
sumption). A slight increase in the number of early embryonic deaths
was associated with this maternal toxicity. Ihis study identifies
a NOAEL of 400 mg/kg/day for teratogenic effects and a NOAEL of
100 mg/kg/day for maternal toxicity.
0 Wazeter et al. (1976) administered DTX-75-0016 (chlorothalonil;
purity not specified) by oral intubation at doses of 0, 1, 2.5 or
5 mg/kg to Dutch Belted rabbits (10/dose) on days 6 to 18 of gestation.
No compound-related changes in general behavior or appearance were
reported at the 1 or 2.5 mg/kg dose level. Occasional hypothermia
and hyperactivity were noted at a dose of 5 mg/kg. Maternal body
weight was not affected at any dose. No signs of toxicity were
reported regarding the number of implantation sites, numbers of live
or dead fetuses, live fetal weight, sex ratio or structural development)
However, an increase in the number of females with dead or resorbed
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Chlorothalonil August, 1987
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fetuses (nine) and in the number of females aborting (four, two died
during the study) were seen at 5 mg/kg. Based on this information,
this study identifies a NOAEL of 2.5 mg/*.g/3ay for maternal/fetal
toxicity and a NOAEL of 5 mgAg/day for teratogenic effects.
0 Shirasu and Teramoto (1975) administered chlorothalonil by gavage to
Japanese white rabbits (eight controls, nine per dose) at doses of
0, 5 or 50 mgAg/day on days 6 to 18 of gestation. At 50 mg/kg/day,
four of the nine does aborted. No compound-related growth retardation
or malformations were noted in offspring in any test group. This
study identifies a NOAEL of 50 mg/kg/day for teratogenic effects and
a NOAEL of 5 mgAg/day for maternal toxicity.
Mutagenicity
8 Qiinto et al. (1981) reported that chlorothalonil (concentrations not
specified) was not mutagenic, with or without metabolic activation,
in five tester strains of Salmonella typhimurium.
0 Wei (1982) reported that chlorothalonil, at concentrations up to
764 ug/plate, was not mutagenic in S. typhimurium strains TA 1535,
1537, 1538, 100 or 98, with or without liver or kidney activation
systems.
0 Kouri et al. (1977c) reported that DTX-77-0035 (chlorothalonil) at
concentrations up to 6.6 ug/plate did not induce point mutations in
S. typhimurium strains TA 1535, 100, 1537, 1538 or 98, with or without
S-9 activation.
0 Shirasu et al. (1975) reported the results of a reverse mutation test
using j>. typhimurium strains TA 1535, 1537, 1538, 98 and 100 and
Escherichia coli WP2 hcr+ and WP2 her-. Chlorothalonil failed to pro-
duce an effect without activation at concentrations up to 500 pg/plate;
negative results also were obtained with activation at chlorothalonil
concentrations up to 100 pg/plate.
0 Kouri et al. (1977b) reported the results of a DNA repair assay using
—• typhircurim" strains TA 1978 and 1538. Chlorothalonil, dissolved
in dimethylsulfoxide at 1 mg/mL and tested at 2, 10 and 20 uL of the
stock solution per plate, was found to be active in both strains with
or without metabolic activation.
0 DeBertoldi et al. (1978) reported that chlorothalonil (2,500 ppm) did
not induce mitotic gene conversions in Saccharomyces cerevisiae in the
presence or absence of metabolic activation systems. In tests on
Aspergillus nidulans using both-resting and germinating conidia,
chlorothalonil (up to 200 ppm) did not induce mitotic gene conversions.
0 Shirasu et al. (1975) reported that, at concentrations up to 200
ug/disk, chlorothalonil was negative in a rec-assay using Bacillus
subtilis strains H17 and M45.
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Chlorothalonil August, 1987
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0 Kouri et al. (1977a) exposed Chinese hamster cells (V-79) and mouse
fibroblast cells (BALB/3T3) in vitro to chlorothalonil at concentra-
tions of 0.3 ug/mL (for V-79 cells) or 0.03 ug/mL (for mouse fibroblast
cells). The V-79 cells were tested without metabolic activation; the
BALB/3T3 cells were tested with and without metabolic activation.
Chlorothalonil was not mutagenic in either cell type.
0 Mizens et al. (1983a) reported the results of a micronucleus test in
Wistar rats, Swiss CFLP mice and Chinese hamsters. Rats were dosed at
0, 8, 40, 200, 1,000 or 5,000 rag/kg; mice and hamsters received 0, 4,
20, 100, 500 or 2,500 mg/kg. All animals were dosed by gavage and all
received two doses, 24 hours apart. Chlorothalonil did not induce
bone marrow erythrocyte micronuclei in any of the species tested.
0 Legator (1974) reported the results of an in vivo cytogenetic test on
chlorothalonil in mice (strain not specified) using the micronuclei
procedure. The test compound was administered by gavage for 5 days
at a concentration of 6.5 mg/kg/day. At this concentration,
chlorothalonil did not increase the number of cells with micronuclei.
0 Legator (1974) presented the results of a host-mediated assay using
male Swiss albino mice and S. typhimurium strains G-46, TA1530, C-207,
TA1531, C-3076, TA1700, D-3056 and TA1724. Mice (10/dose) received
chlorothalonil by gavage for 5 days at 6.5 mg/kg/day. The compound
did not produce any measurable mutagenic response when initially
evaluated in vitro against the eight tester strains of S. typhimurium.
When the tester strains were inoculated into treated mice, no increase
in mutation frequency was observed.
0 Legator (1974) presented the results of a dominant lethal assay in
which male mice (strain not specified) were dosed with chlorothalonil
for five days at 6.5 mg/kg/day. These mice were mated with untreated
females, and the number of early fetal deaths and preimplantation
losses were measured. There was no significant difference in the
fertility rates between test and control animals during weeks 1 to 7.
At week 8, there was a significant decrease in fertility in the test
group.
0 Mizens et al. (1983b) presented the results of a chromosomal aberration
test in Chinese hamsters. The test animals received two doses of
chlorothalonil, 24 hours apart, by gavage at concentrations of 0, 8,
40, 200, 1,000 or 5,000 mg/Kg. At 5,000 mg/kg» a statistically
significant increase in bone marrow chromosomal abnormalities was
observed. However, the authors concluded that this effect could not
be attributed to chlorothalonil because the animals exhibited toxic
responses to dosing.
Carcinogenic!ty
0 NCI (1980) reported the results of a study in which technical-grade
chlorothalonil was administered to Osborne-Mendel rats (50/sex/dose)
for 80 weeks at Time-Weighted Average (TWA) dietary doses for both
males and females of 5,063 or 10,126 ppm, respectively. These dietary
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Chlorothalonil August, 1987
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doses have been calculated to correspond to approximately 253 and
506 mgAg/day (Lehman, 1959). Matched controls consisted of groups
of 10 untreated rats of each sex; pooled controls consisted of the
matched controls combined with 55 untreated male or female rats from
other bioassays. An observation period of 30 to 31 weeks followed
dosing. Clinical signs that appeared with increased frequency in
dosed rats included hematuria and, from week 72 on, bright yellow
urine. Adenomas and carcinomas of renal tubular epithelium occurred
with a significant (p = 0.03, males; p = 0.007, females) dose-related
trend. The frequency of renal tumors was statistically greater in
the high-dose males (p * 0.035) and high-dose females (p = 0.016)
than in corresponding controls (males: pooled controls, 0/62; low
dose, 3/46; high dose, 4/49; females: pooled controls, 0/62; low
dose, 1/48; high dose, 5/50). The observed adenomas and carcinomas
were considered to be histogenically related. Results of this study
were interpreted as sufficient evidence of carcinogenic!ty in
Osborne-Mendel rats.
0 NCI (1980) also reported a study in which technical-grade Chlorothalonil
was administered to B6C3F1 mice (50/sex/dose) for 80 weeks at TWA
dietary doses of 2,688 or 5,375 ppm for males and 3,000 or 6,000 ppm
for females. These dietary doses have been calculated to correspond
to approximately 403.2 or 806.3 rag/kg for males and 450 or 900 mg/kg
for females (Lehman, 1959). Matched controls consisted of 10 untrea1?ed
mice of each sex; pooled controls consisted of the matched controls
combined with 50 untreated male or female mice from other bioassays.
An observation period of 11 to 12 weeks followed dosing. Since the
dosed female mice did not show depression in mean body weights or
decreased survival compared with the controls, they may have been
able to tolerate a higher dose. No tumors were found to occur at a
greater incidence among dosed animals than among controls. It was
concluded that, under the conditions of this bioassay, Chlorothalonil
was not carcinogenic in B6C3Fi mice.
0 Tierney et al. (1983) administered technical-grade Chlorothalonil
(97.7% pure) to Charles River CD-I mice (60/sex/control and dose groups)
for 2 years at dietary concentrations of 0, 750, 1,500 or 3,000 ppm.
The authors indicated that these dietary levels were equivalent to
0, 119, 251 or 517 mg/kg/day for males and 0, 133, 278 or 585 mg/kg/day
for females. Increased incidences of squamous cell tumors of the
forestomacb were noted in all treatment groups. These tumors consisted
principally of carcinomas, although papillomas were also seen. This
increased incidence was statistically significant in females dosed
at 1,500 ppm (279 mg/kg/day). No clear dose-related trend in the
incidence of these tumors was observed. A slight increase in the
incidence of tumors of the glandular epithelium of the fundic stomach
was observed in dosed animals; this increase was neither statistically
significant nor dose-related. When the numbers of animals with
epithelial tumors of the fundic or forestomach were combined, the
incidence of these tumors showed a statistically significant increase
in the 1,500- and 3,000-ppm female dose groups (279 and 585 mg/kg/day).
No treatment-related renal neoplasms were seen in any female dose
group. Increased incidences of adenomas and carcinomas in renal
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Chlorothalonil August, 1987
-14-
cortical tubules were noted in all treated groups of male mice.
These changes did not show a dose-response relationship; the increased
incidence was statistically significant only in the 750 ppm (251
mg/kg/day) group. The authors concluded that the administration of
chlorothalonil caused an increase in the incidence of primary gastric
tumors and an increase in the incidence of renal tubular neoplasms.
Wilson et al. (1985) gave chlorothalonil (98.1% pure with less than 0.03s
hexachlorobenzene) to Fischer 344 rats (60/sex/dose) in their diet at
dose levels of 0, 40, 80 or 175 mg/kg/day. Males were treated for
116 weeks, while females received the chemical for 129 weeks. Survive]
among the various groups was comparable. In both sexes, at the high-
dose level, there were significant decreases in body weights. In
addition, there were also significant increases in blood urea nitrogen
and creatinine, while there were decreases in serum glucose and
albumin levels. In both sexes, there were dose-dependent increases
in kidney carcinomas and adenomas at doses above 40 mg/kg/day. In
the high-dose females, there was also a significant increase in
stomach papillomas. The data show that, in the Fischer 344 rat,
chlorothalonil is a carcinogen.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
V
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 = (NOAEL or LOAEL) x (BW) . /L { /L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
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 information was found in the available literature that was suitable
for determination of a One-day HA for chlorothalonil. Accordingly, it is
recommended that the Ten-day HA value (250 ug/L, calculated below) for a
10-kg child be used at this time as a conservative estimate of the One-day
HA value.
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Chlorothalonil « August, 1987
-15-
Ten-day Health Advisory
The rabbit teratology study by Wazeter et al. (1976) has been chosen to
serve as the basis for the calculation of the Ten-day HA. Animals received
0, 1, 2.5 or 5 mg/kg Chlorothalonil by gavage on days 6 through 18 of gestation.
No adverse effects were observed at either of the two lower treatment doses.
At 5 mg/kg, an increase in the number of females with dead or resorbed fetuses
and in the number of females aborting was observed. The NOAEL for maternal/
fetal toxicity is 2.5 mg/kg/day.
The Ten-day HA for the 10-kg child is calculated as follows:
Ten-day HA = (2.5 mg/kg/day) (10 kg) = 0.25 mg/L (250 ug/L)
(100) (1 L/day)
where:
2.5 mg/kg/day » NOAEL, based on absence of maternal or fetal toxicity
in rabbits exposed to Chlorothalonil via gavage on
days 6 to 18 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.
Longer-term Health Advisory
The studies by Colley et al. (1983), Blackmore and Kundzin (1969) and
Blackmore and Shott (1968) have been selected to serve as the basis for the
Longer-term HA for Chlorothalonil. In the study by Colley et al., technical-
grade Chlorothalonil was administered in the diet to Charles River rats for
13 weeks at concentrations of 0, 1.5, 3.0, 10 or 40 mg/kg/day. Histopatho-
logical examinations revealed that at doses of 3.0 mg/kg/day or greater, male
rats displayed an increased number of intracytoplasmic inclusion bodies in
the proximal convoluted renal tubules. Blackmore and Shott (1968), gave
technical-grade Chlorothalonil in the diet to Charles River rats for 90 days
at doses of 0, 0.2, 0.5, 1.0, 1.5, 2.0 or 3.0 mg/kg/day. At the two highest
dose levels, the kidneys exhibited occasional vacuolation and swelling of
the epithelial cells lining the deeper proximal convoluted tubules. In the
Blackmore and Kundzin (1969) study, technical-grade Chlorothalonil was admin-
istered in the diet to rats for 1 year at doses of 0, 0.2, 0.5, 1.0, 1.5, 2.0
or 3.0 mg/kg/day. At the 2 higher doses, there were alterations in the deeper
convoluted renal tubules in both sexes. Each of the studies identified a
NOAEL of 1.5 mg/kg/day.
The Longer-term HA for a 10 kg child is calculated as follows:
Longer-term HA = (1>5 mg/kg/day) (10 kg) = 0.15 mg/L (150 uq/L)
(100) (1 L/day)
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Chlorothalonil , * August, 1987
-16-
where:
1.5 mg/kg/day - NOAEL, based on absence of kidney effects in rats
exposed to Chlorothalonil in the diet for 13 weeks.
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.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (1
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Chlorothalonil August, 1987
-17-
The study by Holsing and Voelker (1970) has been selected to serve as
the basis for the Lifetime HA for chlorothalonil. In this study, technical-
grade Chlorothalonil was administered to beagle dogs (eight/sex/dose) for 104
weeks at dietary concentrations of 0, 60 or 120 ppm (0, 1.5 or 3.0 mg/kg/day).
The results following 2 years of administration revealed compound-related
histopathological changes in the kidneys of males fed 120 ppm (3 mg/kg/day).
Males fed 60 ppm (1.5 mg/kg/day) and females fed both dose levels were
comparable to controls. The observed changes included increased vacuolation
of the epithelium in both the convoluted and collecting tubules and increased
pigment in the convoluted tubule epithelium. From these results, a NOAEL of
1.5 mg/kg was identified.
Using this NOAEL, the Lifetime HA is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (1»5 mg/kg/day) = 0.015 mg/kg/day
(100)
where:
1.5 mg/kg/day = NOAEL, based on absence of histopathological changes
in dogs fed chlorothalonil for one year.
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 = (0-015 mg/kg/day) (70 kg) = 0>525 mg/L (525 /L)
2 L/day
where:
0.015 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determinetion of the Lifetime Health Advisory
The estimated excess cancer risk associated with lifetime exposure to
drinking water containing chlorothalonil at 525 ug/L (the DWEL) is 3.5 x 10~4.
This estimate represents the upper 95% confidence limit from extrapolations
prepared by OPP and ODW using the linearized, multistage model. The actual
risk is unlikely to exceed this value, but there is considerable uncertainty
as to the accuracy of risks calculated by this methodology.
Evaluation of Carcinogenic Potential
a In an NCI bioassay (1980), technical grade chlorothalonil was
administered in the diet at 253 or 506 mg/kg/day to Osborne-Mendel
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Chlorothalonil August, 1987
-18-
rats for 80 weeks. A statistically significant increase in the
frequency of renal tumors was observed in high-dose males and females.
0 NCI (1980) reported that chorothalonil was not carcinogenic in B6C3F-)
mice when administered in the diet, at 403 or 806 mg/kg and 450 or
900 mg/kg for males and females, respectively, for 80 weeks. However,
Tierney et al. (1983) concluded that chlorothalonil was carcinogenic
in Charles River CD-1 which received the compound (0, 119, 251 or
517 mg/kg/day for males and 0, 134, 279 or 585 mg/kg/day for females)
in the diet for 2 years. Increased incidences of squamous cell
papilloma and carcinoma of the forestomach were noted in all treatment
groups. This increase was statistically significant only in the mid-
dose females. Increased incidences of adenoma and carcinoma of the
renal cortical tubules were observed in all treatment groups. Again,
no dose-response was noted, since these increases were statistically
significant only in the mid-dose males.
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of chlorothalonil.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986a), chlorothalonil is classified in
Group B2: probable human carcinogen. This category is for chemicals
for which there is inadequate evidence from human studies and sufficient
evidence from animal studies.
0 From the Wilson et al. (1985) data, OPP calculated a q-| * of 2.4 x
10-2 (mg/kg/day)-1. The 95% upper limit lifetime dose in drinking water
associated with a 10-6 excess risk level is 1.5 ug/L. Corresponding
levels for 10-5 an(j 1 o~4 are 15 and 150 ug/L, respectively. While
recognized as statistically alternative approaches, the range of
risks described by using any of these modelling approaches has little
biological significance unless data can be used to support the selection
of one model over another. In the interest of consistency of approach
and in providing an upper bound on the potential cancer risk, the
Agency has recommended use of the linearized multistage approach.
However, for completeness, the 10"^ risk numbers for other models
will be given. These values, at the 10-6 level, are: multihit -
9 ug/L; one hit - 2 ug/L; probit - 51 ug/L; logit - 0.8 ug/L; and
Weibel - 0.6 ug/L.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 WHO Temporary Acceptable Daily Intake = 0.005 mg/kg/day (Vettorazzi
and Van den Hurk, 1985).
0 EPA/OPP has calculated a PADI of 0.015 mg/kg/day based on the NOAEL
of 1.5 mg/kg/day identified in the 2-year dog study (Holsing and and
Voelker, 1970) and an uncertainty factor of 100 (U.S. EPA, 1984a).
0 U.S. EPA established tolerances in or on raw agricultural commodities
residue levels of 0.1 to 5 ppm (40 CFR 180.275, 1985).
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Chlorothalonil August, 1987
-19-
VII. ANALYTICAL METHODS
0 Analysis of chlorothalonil is by a gas chromatographic (GC) method
applicable to the determination of certain chlorinated pesticides in
water samples (U.S. EPA, 1986b). In this method, approximately
1 liter of sample is extracted with methylene chloride. The extract
is concentrated and the compounds are separated using capillary
column GC. Measurement is made using an electron capture detector.
The method detection limit has not been determined for chlorothalonil,
but it is estimated that the detection limits for analytes included
in this method are in the range of 0.01 to 0.1 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Reverse osmosis (RO) is a promising treatment method for pesticide-
contaminated water. As a general rule, organic compounds with
molecular weights greater than 100 are candidates for removal by RO.
Larson et al. (1982) reported 99% removal efficiency of chlorinated
pesticides by a thin-film composite polyamide membrane operating at
a maximum pressure of 1,000 psi and a maximum temperature of 113°F.
More operational data are required, however, to specifically determine
the effectiveness and feasibility of applying RO for the removal of
chlorothalonil from water. Also, membrane adsorption must beXconsid-
ered when evaluating RO performance in the treatment of chlorothalonil-
contaminated drinking water supplies.
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Chlorothalonil August, 1987
-20-
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