820K88120 DRAFT
August, 1987
DISULFOTON
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 AMD PROPERTIES
CAS No. 298-04-4
Structural Formula
- S-C,H5
0,0-Diethyl-S-[2-(ethylthio)-ethyl], phosphorodithioate
Synonyms
• Disulfoton; Disyston; Disystox; Dithiodemeton; Bayer 19639; Di-syston;
Ethyl thiometon; Frumin AL; M-74 (Meister, 1983).
Uses
0 Systemic insecticide-acaricide (Meister, 1983).
Properties (Meister, 1983; Windholz et al., 1983)
Chemical Formula
Molecular Weight 274.38
Physical State (at 25°C) Pale yellow liquid
Boiling Point 108eC (0.01 mm Hg); 132 to 133°C (1.5 mm Hg)
Melting Point
Density (20«C) 1.144
Vapor Pressure (at 20°C) 1.8 x 10-4 mn Hg
Water Solubility (at 23°C) 25 mg/L
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor ~
Occurrence
* Disulfoton has been found in only 1 of the surface water samples
and none of the ground water samples analyzed from 835 samples
taken at 764 locations. (STORET, 1987).
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Environmental Fate
0 Disulfoton has a low mobility in Hugo sandy loam soil; 28% of the
pesticide applied to a 6-inch-high soil column was eluted with a
total of 110 feet of dilute buffer (McCarty and King, 1966). In
another study, disulfoton sulfoxide and disulfoton sulfone were more
mobile in sandy loam, clay loam and silty clay loam soils than the
parent compound. Aging 32p-
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III. PHARMACOKINETICS
Absorption
0 Puhl and Fredrickson (1975) administered by gavage single oral
doses of disulfoton-o-ethyl-1-14c (99% purity) to Sprague-Dawley
rats (12/sex/dose). Males received 1.2 mg/kg and females received
0.2 mg/kg. In the 10 days following dosing, an average of 81.6,
7.0 and 9.2% of the dose was recovered in the urine, feces and
expired air, respectively. Males excreted 50% of the administered
dose in the urine in the first 4 to 6 hours; females required
30 to 32 hours. These data indicate that disulfoton is absorbed
readily from the gastrointestinal tract.
Distribution
0 In the study by Puhl and Fredrickson (1975), described above,
4.1 and 16.1% of the administered dose was detected in the livers of
males and females, respectively, and 0.4 and 1.2% of the dose was
detected in the kidneys of males and females, respectively, 48 hours
postdosing.
Metabolism
0 March et al. (1957) studied the metabolism of disulfoton in vivo and
in vitro in mice (strain not specified). In the in vivo portion of
the study, mice received radiolabeled disulfoton intraperitoneally
(dose not specified). Results indicated that unspecified urinary
metabolites consisted mainly of hydrolysis products. In vitro
metabolism data indicated the presence of dithio-systox sulfoxide
and sulfone, and the thiol analog sulfoxide and sulfone. The dithio-
systox sulfoxide was present in the greatest quantity followed by
thiol analog sulfoxide, dithio-systox sulfone and thiol analog
sulfone. Based on a review of these data (U.S. EPA, 1984a), it was
concluded that the metabolism of disulfoton in mice involves at least
two reactions: (1) the sequential oxidation of the thioether sulfur
and/or oxidative desulfuration; and (2) hydrolytic cleavage of the
ester, producing phosphoric acid, thiophosphoric acid and dithio-
phosphoric acid.
0 In the above study by Puhl and Fredrickson (1975), the major urinary
metabolites detected in both sexes were diethylphosphate (DEP) and
diethylphosphorothioate (DEPT). These products were formed from
hydrolysis of disulfoton and/or its oxidation products. Minor urinary
metabolites included the oxygen analog sulfoxide, oxygen analog
sulfone and disulfoton sulfoxide.
Excretion
In the above study by Puhl and Fredrickson (1975), 96 to 99% of the
administered dose was recovered (81.6% in urine, 7.0% in feces and
9.2% as expired carbon dioxide during a 10-day postdosing period.
Excretory pathways were similar for males and females, but the rate
of excretion was slower for females.
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IV. HEALTH EFFECTS
Humans
Short-term Exposure
0 No significant anticholinesterase effects were observed in human
subjects (five test subjects, two controls) who received disulfoton
in doses of 0.75 mg/day (orally) for 30 days (Rider et al., 1972).
0 Quinby (1977) reported that three carpenters were sprayed accidentally
with disulfoton while the compound was being applied by airplane to
a wheat field adjacent to their work site. The individuals were
reexposed as they handled contaminated building materials in the
days following spraying. Exposure levels were not identified. The
older two carpenters experienced coronary attacks and one had at
least two severe cerebral vascular effects subsequent to exposure.
The author postulated that the effects may have been due to disturbances
of clotting mechanisms.
Long-term Exposure
0 No Long-term human studies were identified for disulfoton.
Animals
Short-term Exposure
0 Reported acute oral LD50 values for adult rats administered disulfoton
(approximately 94 to 96% purity when identified) ranged from 1.9 to
2.6 mg/kg for females and 6.2 to 12.5 mg/kg for males (Crawford and
Anderson, 1973b; Bombinski and DuBois, 1957); a value of 5.4 mg/kg was
reported for weanling male rats (Brodeur and Dubois, 1963).
In guinea pigs, acute oral LD^g values ranged from 8.9 to 12.7 mg/kg
(Bombinski and Dubois, 1957; Crawford and Anderson, 1973a).
Mihail (1978) reported acute oral LD50 values of 7.0 mg/kg and 8.2
mg/kg in male and female NMRI mice, respectively.
Hixson (1982) reported that the acute oral LD5Q of disulfoton (98%
pure) in white Leghorn hens was 27.5 mg/kg. Hixson (1983) reported
the results of an acute delayed neurotoxicity study in which 20 white
Leghorn hens were administered technical disulfoton (97.8% pure) by
gavage at a dose level of 30 mg/kg on two occasions, 21 days apart.
The study also employed live animals for each of the negative controls,
antidote controls and positive controls. Disulfoton did not produce
acute delayed neurotoxicity under the conditions of this study.
Based on this information, a No-Observed-Adverse-Effect-Level (NOAEL)
of 30 mg/kg (the only dose tested) was identified in this study.
Taylor (1965) reported the results of a demyelination study in which
white Leghorn hens (six/dose) were administered disulfoton in the diet
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Disulfoton August, 1987
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for 30 days at concentrations of 0, 2, 10 or 25 ppm. Assuming that
1 ppm in the diet of hens is equivalent to 0.06 mg/kg/day (Lehman,
1959), these dietary levels correspond to doses of about 0, 0.1, 0.6
and 1.5 mg/kg/day. The author indicated that no evidence of demyelina-
tion was observed in any of the tissues examined. Based on this
information, a NOAEL of 1.5 mg/kg/day (the highest dose tested) was
identified.
Dermal/Ocular Effects
0 DuBois (1957) reported that the acute dermal LD5Q of technical
disulfoton in male Sprague-Dawley rats was 20 mg/kg. Mihail (1976)
reported acute dermal 1.050 values of 15.9 mg/kg and 3.6 mg/kg in male
and female Wistar rats, respectively.
0 No information was found in the available literature on the effects
of ocular exposure to disulfoton.
Long-term Exposure
6 Hayes (1983) presented the results of a 23-month feeding study in
which CD-1 mice (50/sex/dose) were administered disulfoton (98.2%
pure) at dietary concentrations of 0, 1, 4 or 16 ppm. Assuming that
1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day (Lehman,
1959), these dietary levels correspond to doses of about 0, 0.15, 0.6
and 2.4 mg/kg/day. No treatment-related effects were observed in
terms of body weight, food consumption or hematology. A statistically
significant increase in mean kidney weight and kidney-to-body weight
ratio was noted in high-dose females; this increase may have been
associated with a nonsignificant increase in the incidence of malignant
lymphomas of kidneys in this group. Plasma, red blood cell and brain
cholinesterase (ChE) activity was decreased significantly in both
sexes at the highest dose tested (16 ppm). However, since ChE activity
was measured only in the control and high-dose groups, a NOAEL for
this effect could not be determined.
0 In a study by Hoffman et al. (1975), beagle dogs (four/sex/dose) were
administered disulfoton (95.7% pure) at dietary concentrations of 0,
0.5 or 1.0 ppm for 2 years. Assuming that 1 ppm in the diet of dogs
is equivalent to 0.025 mg/kg/day (Lehman, 1959), these dietary levels
correspond to doses of about 0, 0.0125 and 0.025 mg/kg/day. A fourth
group of animals received disulfoton in the diet at 2 ppm for 69
weeks, then 5 ppm for weeks 70 to 72, and finally 8 ppm from week 73
until termination (104 weeks); these doses correpond to 0.05, 0.125 and
0.2 mg/kg/day, respectively. No treatment-related effects were observed
in terms of general appearance, behavior, ophthalmoscopic examinations,
food consumption, body weight, organ weight, hematology, clinical
chemistry or histopathology. Additionally, no effects on ChE activity
were observed in animals that received 0.5 or 1.0 ppm (0.0125 or
0.025 mg/kg/day). However, exposure at 2.0 ppm (0.05 mg/kg/day)
for 69 weeks caused ChE inhibition in plasma and red blood cells in
both sexes. Maximum inhibition occurred at week 40, when males
exhibited 50% and 33% inhibition of Che in red blood cells and plasma;
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Disulfoton August, 1987
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respectively; females exhibited 22 and 36% inhibition of ChE in red
blood cells and plasma, respectively. At a dose level of 8 ppm
(0.2 mg/kg/day), males exhibited 56 to 66% and 63 to 70% inhibition
of red blood cell and plasma ChE, respectively; females exhibited 46
to 53% and 54 to 64% inhibition of red blood cell and plasma ChE,
respectively. Based on these data, a NOAEL of U0 ppm (0.025 mg/kg/day)
was identified.
0 Carpy et al. (1975) presented the results of a 2-year feeding study
in which Sprague-Dawley rats (60/sex/dose) were administered disulfoton
(95.7% pure) at dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm.
Based on data presented by the authors, these dietary levels correspond
to doses of about 0, 0.02, 0.05 and 0.1 mg/kg/day for males and 0,
0.03, 0.04 and 0.1 mg/kg/day for females. At week 81 of the study,
the 0.5-ppm dose was increased to 5.0 ppm (0.2 and 0.3 mg/kg/day for
males and females, respectively) since no adverse effects were observed
in the 1.0-ppm dose group. No treatment-related effects were observed
in terms of food consumption, body weight, hematology, clinical
chemistry, urinalysis and histopathology. A trend was observed at
all dose levels toward increased absolute and relative spleen, liver,
kidney and pituitary weights in males and toward decreased weights of
these organs in females. In males receiving 5 ppm, the increases
were statistically significant (p <0.05) for absolute spleen and
liver weights. In females receiving 5 ppm, the decrease in absolute
and relative kidney weights was statistically significant (p <0.05).
At all levels tested, the brain showed a trend toward decreased
absolute and relative weights in males and increased weights in
females. Additionally, statistically significant inhibition of
plasma, red blood cell and brain ChE was observed in both sexes at
2.0 and 5.0 ppm. At 1.0 ppm brain ChE in females was inhibited 11%
(p <0.01). Based on this information, a Lowest-Observed-Adverse-
Effect-Level (LOAEL) of 1.0 ppm (0.04 ing/kg/day for females) was
identified for ChE inhibition. It was concluded (U.S. EPA, 1984a)
that a NOAEL for systemic toxicity could not be identified due to the
inadequacy of histopathology and necropsy data.
0 Hayes (1985) presented the results of a 2-year feeding study in
which Fischer 344 rats (60/sex/dose) were administered disulfoton
(98.1% pure) at dietary concentrations of 0, 0.8, 3.3 or 13 ppm.
Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
(Lehman, 1959), these dietary levels correspond to doses of about
0, 0.04, 0.17 and 0.65 mg/kg/day. Mortality was generally low for
all groups with the exception of increased mortality in high-dose
females during the last week of the study. No compound-rela ted
effects were observed in terms of clinical chemistry, hematology or
urinalysis. A dose-related trend in ChE inhibition was observed in
both sexes at all dose levels. Statistically significant inhibition
of plasma, red blood cell and brain ChE occurred in all dose groups
throughout the study. Histopathologically, a statistically significant
increase (p <0.05) in corneal neovascularization was observed in both
sexes at 13 ppm (0.65 mg/kg/day). A dose-related increase in the
incidence of optic nerve degeneration was also observed. This effect
was statistically significant (p <0.05) in mid-dose males and in mid-
and high-dose females. Additionally, a significantly (p <0.05)
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Disulfoton August, 1987
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higher incidence of cystic degeneration of the Harderian gland was
observed in females at all doses and in mid-dose males. A significantly
(p <0.05) increased incidence of atrophy of the pancreas also was
observed in high-dose males. On the basis of ChE inhibition, this
study identified a LOAEL of 0.8 ppm (0.04 mg/kg/day) (lowest dose
tested).
Reproductive Effects
0 Taylor (1966) conducted a three-generation reproduction study in
which albino Holtzman rats (20 females and 10 males) were administered
disulfoton (98.5% pure) at dietary concentrations of 0, 2, 5 or 10 ppnu
Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
(Lehman, 1959), these dietary levels correspond to doses of about
0, 0.1, 0.25 and 0.5 mg/kg/day. At 10 ppm (0.5 mg/kg/day), litter
size was reduced by 21% in the Pa and 33% in the Fb in both the first
and third generations. Also in these generations, a 10 to 25% lower
pregnancy rate was noted for Fa matings. Histopathologically, ?3b
litters at 10 ppm (0.5 mg/kg/day) exhibited cloudy swelling and fatty
infiltration of the liver (both sexes), mild nephropathy in kidneys
(females) and juvenile hypoplasia of the testes. No histopathological
examinations were conducted on the 2- and 5-ppm dose groups.
Cholinesterase determinations revealed a 60 to 70% inhibition of red
blood cell ChE in F^b litters and their parents at 5 and 10 ppm (0.25
and 0.5 mg/kg/day). At 2 ppm (0.1 mg/kg/day), the inhibition was
insignificant in males and moderate (30 to 40%) in females. Based on
these data, a LOAEL of 2 ppm (0.1 mg/kg/day) was identified for ChE
inhibition. It was concluded (U.S. EPA, 1984a) that a reproductive
NOAEL could not be determined due to deficiencies in data reporting
(e.g., insufficient data on reproductive parameters, no statistical
analyses, incomplete necropsy report and insufficient histopathology
data).
Developmental Effects
0 Lamb and Hixson (1983) conducted a study in which CD rats (25/dose)
were administered disulfoton (98.2% pure) by gavage at levels of 0,
0.1, 0.3 or 1 mg/kg/day on days 6 through 15 of gestation. Mean
plasma and red blood cell ChE activities were decreased significantly
in dams receiving 0.3 and 1 mg/kg/day. Examination of the fetuses
after Cesarean section reflected no increases in the incidence of
soft tissue, external or skeletal abnormalities. However, at the
1.0-mg/kg/day dose level, increased incidences of incompletely ossified
parietal bones and sternebrae were observed. This is considered a
fetotoxic effect, since it is indicative of retarded development.
Based on the information presented in this study, a developmental
NOAEL of 0.3 mg/kg/day was identified based on fetotoxic effects. A
NOAEL of 0.1 mg/kg/day was identified for ChE inhibition in treated dams,
0 Tesh et al. (1982) conducted a teratogenicity study in which New
Zealand White rabbits were administered disulfoton (97.3% pure) at
initial doses of 0, 0.3, 1.0 or 3.0 mg/kg on days 6 through 18 of
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Disulfoton August, 1987
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gestation. Due to mortality and signs of toxicity, the high dose was
reduced to 2.0 mg/kg/day and finally to 1.5 mg/kg/day. The control
group consisted of 15 animals, the low- and mid-dose groups consisted
of 14 does each and the high-dose group contained 22 animals. No
signs of maternal toxicity were observed in the low- or mid-dose
groups. In the high-dose group, signs of maternal toxicity included ,
muscular tremors, unsteadiness and incoordination, increased respiratory
rate and increased mortality. No compound-related effects on maternal
body weight or fetal survival, growth and development were observed.
Based on this information, a NOAEL of 1.0 mg/kg/day was identified for
maternal toxicity. The NOAEL for teratogenic and fetotoxic effects was
1.5 mg/kg/day (the highest dose tested).
Mutagenicity
0 Hanna and Dyer (1975) reported that disulfoton (99.3% pure) was
mutagenic in Salmonella typhimurium strains C 117, G 46, TA 1530 and
TA 1535, and in Escherichia coli strains WP 2, WP 2uvrA, CM 571,
CM 611, WP 67 and WP 12. These tests were performed without metabolic
activation; however, demeton, the major metabolite of disulfoton,
was also mutagenic in these microbial tests (U.S. EPA, 1984a).
0 Simmon (1979) presented the results of an unscheduled DNA synthesis
assay using human fibroblasts (W 138). Disulfoton (purity not specified)
was positive in this assay only in the absence of metabolic activation.
Carcinogenic!ty
8 Carpy et al. (1975) presented the results of a 2-year feeding study
in which Sprague-Dawley rats (60/sex/dose) were administered disulfoton
(95.7% pure) at dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm.
Based on data presented by the authors, these dietary levels correspond
to doses of about 0, 0.02, 0.05 and 0.1 mg/kg/day for males and 0,
0.03, 0.04 and 0.1 mg/kg/day for females. At week 81 of the study,
the 0.5-ppm dose was increased to 5.0 ppm (reported to be equivalent
to 0.2 and 0.3 mg/kg/day for males and females, respectively) since
no adverse effects were observed in the 1.0-ppm dose group. The
number of tumor-bearing animals at all dose levels was comparable to
that of controls suggesting that, under the conditions of this study,
disulfoton is not oncogenic. However, a review of this study (U.S.
EPA, 1984a) concluded that due to numerous deficiencies (e.g., invalid
high dose, insufficient necropsy data, insufficient histology data),
the data presented were inadequate for an oncogenic evaluation.
0 Hayes (1983) presented the results of a 23-month feeding study in
which CD-1 mice (50/sex/dose) were administered disulfoton (98.2%
pure) at dietary concentrations of 0,- 1, 4 or 16 ppm. Assuming that
1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day (Lehman,
1959), these dietary levels correspond.to doses of about 0, 0.15, 0.6
and 2.4 mg/kg/day. The incidence of specific neoplasms was similar
among treated and control animals. There, was an increased incidence
of malignant lymphoma (the most frequently observed neoplastic lesion)
in both males and females at 16 ppm (2.4 mg/kg/day) when compared with
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Disulfoton August, 1987
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controls, but this change was not statistically significant. Therefore,
under the conditions of this study, disulfoton was not oncogenic in
mice at dietary concentrations up to 16 ppm (2.4 mg/kg/day).
0 Hayes (1985) presented the results of a 2-year feeding study in
which Fischer 344 rats (60/sex/dose) were administered disulfoton
(98.1% pure) at dietary concentrations of 0, 0.8, 3.3 or 13 ppm,
corresponding doses of about 0, 0.04, 0.17 and 0.65 mg/kg/day (Lehman,
1959). The most commonly occurring neoplastic lesions included
leukemia, adenoma of the adrenal cortex, pheochromocytoma, fibroadenoma
of the mammary glands, adenoma and carcinoma of the pituitary glands,
interstitial cell adenoma of the testes, and uterine stromal polyps.
The incidences of these lesions showed no dose-related trend and were
not significantly different in treated versus control animals.
Therefore, under the conditions of this assay, disulfoton was not
oncogenic in male or female Fischer 344 rats at dietary concentrations
up to 13 ppm (0.65 mg/kg/day).
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 = (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 suitable information was found in the available literature for the
determination of a One-day HA value for disulfoton. It is, therefore,
recommended that the Ten-day HA value for a 10-kg child of 0.01 mg/L (10 ug/L),
calulated below, be used at this time as a conservative estimate of the One-day
HA value.
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Disulfoton August, 1987
Ten-day Health Advisory
The developmental toxicity study by Lamb and Hixson (1983) has been
selected to serve as the basis for the Ten-day HA value for disulfoton.
In this study, CD rats were administered disulfoton (98.2% pure) by gavage
at doses of 0, 0.1, 0.3 or 1 mg/kg/day on days 6 through 1 5 of gestation.
Mean plasma and red blood cell ChE activities were decreased significantly
in dams receiving 0.3 and 1 mg/kg/day. Based on this information, a NOAEL of
0.1 mg/kg/day was identified. The only other study of comparable duration
was a rabbit teratology study (Tesh et al., 1982). This study identified
NOAELs of 1.0 mg/kg/day for maternal toxicity and 1.5 mg/kg/day (the highest
dose tested) for developmental toxicity. The rabbit appeared to be less
sensitive to disulfoton than the rat, therefore the rat study was selected
for this calculation.
Using a NOAEL of 0.1 mg/kg/day, the Ten-day HA for a 1 0-kg child is
calculated as follows:
Ten-day HA = (0-1 mg/kq/day) (10 kg) . 0.01 mg/L (10 ug/L)
(100) (1 L/day)
where:
0.1 mg/kg/day « NOAEL, based on the absence of ChE effects in female
rats administered disulfoton by gavage on days 6
through 1 5 of gestation.
1 0 kg * assumed body weight of a child.
1 00 = 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 by a child.
Longer-term Health Advisory
The 2-year dog feeding study by Hoffman et al. (1975) has been selected
to serve as the basis for the Longer-term HA values for disulfoton. In this
study, beagle dogs were administered disulfoton (95.7% pure)
at dietary concentrations of 0, 0.5 or 1.0 ppm (0, 0.0125 and 0.025 mg/kg/day).
A fourth group of dogs received disulfoton at 2.0
ppm (0.05 mg/kg/day) for 69 weeks, then 5.0 ppm (0.125 mg/kg/day) for weeks
70 to 72, and finally 8.0 ppm (0.2 mg/kg/day) from weeks 73 to 104. Exposure
to 2.0 ppm (0.05 mg/kg/day) for 69 weeks caused plasma and red blood cell ChE
inhibition in both sexes. Brain ChE inhibition was also noted at termination
in this group. Based on this information, a NOAEL of 1.0 ppm (0.025 mg/kg/day)
was identified. No other suitable studies were available for consideration
for the Longer-term HA. Since the effects in the study by Hoffman et al. (1975)
were observed following 69 weeks of exposure, the study is considered to be
of appropriate duration for derivation of a Longer-term HA.
Using a NOAEL of 0.025 mg/kg/day, the Longer-term HA for a 1 0-kg child
is calculated as follows:
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Disulfoton August, 1987
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Longer-term HA - (0.025 mg/kg/day) (10 kg) „ 0.0025 mg/L (3 ug/L)
(100) (1 L/day)
where:
0.025 ing/kg/day = NOAEL, based on the absence of ChE effects in dogs
administered disulfoton in the diet; ChE effects
were noted at the higher dose during the first 40
to 69 weeks of exposure and thereafter.
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.
Using a NOAEL of 0.025 mg/kg/days, the Longer-term HA for a 70-kg
adult is calculated as follows:
Longer-term HA = (0-025 mg/kg/day) (70 kg) = 0.0088 mg/L (9 ug/L)
(100) (2 L/day)
where:
0.025 mg/kg/day » NOAEL, based on the absence of ChE effects in dogs
administered disulfoton in the diet; ChE effects
were noted at the higher dose during the first 40
to 69 weeks of exposure and thereafter.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with
NAS/ODW guidelines for use with a NOAEL from an
animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime 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. 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.
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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, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The studies by Hayes (1985) and Carpy et al. (1975) have been selected
to serve as the bases for the Lifetime HA values for disulfoton. Each of
these studies identifies a LOAEL of 0.04 mg/kg/day. In the Hayes (1985)
study, Fischer 344 rats were administered disulfoton (98.1% pure) at dietary
concentrations of 0, 0.8, 3.3 or 13 ppm (0, 0.04, 0.17 and 0.65 mg/kg/day)
for 2 years. Dose-related, statistically significant inhibition of ChE in
plasma, red blood cell and brain was observed in both sexes at all doses;
also, a dose-related optic nerve degeneration was observed in females. Based
on this information, a LOAEL of 0.04 mg/kg/day was identified. In the Carpy
et al. (1975) 2-year study, Sprague-Dawley rats were administered disulfoton
(95.7% pure) at dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm (0, 0.02,
0.05 and 0.1 mg/kg/day for males and 0, 0.03, 0.04 and 0.1 mg/kg/day for
females). At week 81 of the study, the 0.5 ppm dose was increased to 5.0 ppm
(equivalent to 0.2 and 0.3 mg/kg/day for males and females, respectively).
Statistically significant inhibition of plasma and red blood cell ChE was
observed in both sexes at 2.0 and 5.0 ppm. Additionally, at 1 ppm (0.04
mg/kg/day), brain ChE was inhibited significantly (p <0.01) in females.
Since the initial low dose used in the study (0.5 ppm) was raised to 5.0 ppm,
the 1.0-ppm dose is the lowest dose tested and represents the study LOAEL.
Using a LOAEL of 0.04 mg/kg/day, the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (0.04 mg/kg/day) = 0.00004 mg/kg/day
(1,000)
where:
0.04 mg/kg/day = LOAEL, based on ChE inhibition anf optic nerve
degeneration in rats exposed to disulfoton in the
diet for 2 years.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.00004 mg/kg/day) (70 kg) = Q.0014 mg/L (1 ug/L)
(2 L/day)
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Disulfoton August, 1987
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where:
0.00004 mg/kg/day * RfD.
70 kg = assumed body weight of an adult.
2 L/day - assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory (HA)
Lifetime HA - (0.0014 mg/L)(20%) = 0.0003 mg/L (0.3 ug/L)
where:
0.0014 mg/L * DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 Three studies were available on the carcinogenicity of disulfoton.
The chronic study in rats by Carpy et al. (1975) was inadequate for
an oncogenic evaluation. The remaining two studies presented results
indicating that disulfoton was not carcinogenic in mice (Hayes, 1983)
or in rats (Hayes, 1985).
e The International Agency for Research on Cancer has not evaluated the
carcinogenicity of disulfoton.
* Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986a), disulfoton may be classified in
Group E: no evidence of carcinogenicity in humans. This category is
used for substances that show no evidence of carcinogenicity in at least
two adequate animal tests or in both epidemiologic and animal studies.
However, disulfoton and its metabolites are mutagenic compounds (see
section on Mutagenicity).
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The National Academy of Sciences (NAS, 1977) has calculated an ADI of
0.0001 mg/kg/day, based on a NOAEL of 0.01 mg/kg/day from a subchronic
dog feeding study on phorate (a closely related organophosphorus
insecticide) and an uncertainty factor of 100, with a Suggested-No-
Adverse-Response-Level (SNARL) of 0.0007 mg/L.
• The World Health Organization (WHO, 1976) has identified an ADI of
0.002 mg/kg/day based on chronic data from a 2-year chronic feeding
study in dogs (Hoffman et al., 1975) with a NOAEL of 0.025 mg/kg/day.
0 U.S. EPA Office of Pesticide Programs (OPP) has established residue
tolerances for disulfoton at 0.1 to 0.75 ppm in or on a variety of
raw agricultural commodities (U.S. EPA, 1985). At the present time,
these tolerances are based on a Provisional ADI (PADI) of 0.00004
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Disulfoton August, 1987
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mg/kg/day. As for the RfD calculation, this PADI is calculated based
on a LOAEL of 0.8 ppm (0.04 mg/kg/day) for both ChE inhibition and
optic nerve degeneration that were identified in the 2-year rat
feeding study by Hayes (1985) and using a safety factor of 1,000.
VII. ANALYTICAL METHODS
0 Analysis of disulfoton is by a gas chromatographic (GC) method appli-
cable to the determination of certain nitrogen-phosphorus-containing
pesticides in water samples (U.S. EPA, 1986b). In this method,
approximately 1 L of sample is extracted with methylene chloride.
The extract is concentrated and the compounds are separated using
capillary column GC. Measurement is made using a nitrogen-phosphorus
detector. The method detection limit has not been determined for
disulfoton, but it is estimated that the detection limits for
analytes included in this method are in the range of 0.1 to 2 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 No information was found in the available literature regarding treat-
ment technologies used to remove disulfoton from contaminated water.
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Disulfoton August, 1987
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•Confidential Business Information submitted to the Office of Pesticide
Programs
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