-------
DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented.based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genlclty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxldty and cardno-
genldty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer based RQs are defined In U.S.
EPA, 1984a and 1986b, respectively.
111
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EXECUTIVE SUMMARY
Dlsulfoton Is the common name for the chemical referenced by CAS as
0,0-diethyl S-[2-(ethylthio)ethy1 JphosphorodHhioate (BCPC, 1983). Pure
dlsulfoton has been described as a colorless oil (BCPC, 1983; Wlndholz,
1983) with a characteristic odor (BCPC, 1983) or as a yellow liquid (Hawley,
1983). The technical compound is a brown liquid (Hawley, 1981). Dlsulfoton
is readily soluble In most organic solvents (BCPC, 1983). Dlsulfoton is
synthesized commercially by reaction of 0,0-dlethylhydrogen phosphoro-
dithloate with 2-(2-ethylthio)ethylchloride (BCPC, 1977). Mobay Corp.,
subsidiary, Agricultural Division In Kansas City, MO, is the only current
domestic manufacturer of dlsulfoton (SRI, 1987). Dlsulfoton Is a systemic
insecticlde/acaMclde used primarily for treatment of seeds and application
to soils or plants In the form of granules (BCPC, 1983).
In the atmosphere, dlsulfoton is expected to exist primarily In the
vapor phase (Elsenrelch et al., 1981). The dominant removal mechanism is
the vapor phase reaction with photochemlcally produced hydroxyl radicals.
The reaction half-life was estimated to be 3 hours (Atkinson, 1987), which
suggests that the lifetime of dlsulfoton In the atmosphere may be short.
Dlsulfoton 1s not susceptible to direct photolysis. In water, dlsulfoton
will oxidize rapidly to Us sulfoxide and sulfone by reaction with singlet
oxygen (Gohre and Miller, 1986). It will not be subject to direct
photolysis; however, humlc substances In soil and water have been reported
to photosensitize oxidation of dlsulfoton, with reported half-lives In
natural water ranging from 5 hours In the summer to 12 hours In the winter
(Zepp et al., 1981). Dlsulfoton Is expected to adsorb strongly to suspended
solids and sediments, but will hydrolyze very slowly. Dlsulfoton may
1v
-------
volatilize significantly; the estimated volatilization half-life In a model
river 1 m deep, flowing at a speed of 1 m/sec, with a wind velocity of 3
m/sec was calculated to be 23 days (Thomas, 1982). Adsorption to sediment
and suspended solids may considerably retard the rate of dlsulfoton loss
from evaporation of water. Based on the results of degradation studies In
soil, It appears that dlsulfoton may be susceptible to blodegradatlon In
natural waters and sediments. In soil, It will oxidize to Its sulfoxlde and
sulfone. Studies using sterilized and nonsterlUzed soils have led to con-
flicting results regarding differentiation between chemical and biological
degradation of dlsulfoton In soil (Sanborn et al., 1977). Although rapid
degradation of dlsulfoton to Us sulfoxlde and sulfone has been reported In
certain soil experiments, these degradation products appear to be more
stable than dlsulfoton Itself and they retain Insectlddal activity (Takase
et al., 1972). Estimates of persistence of dlsulfoton residues In soil have
been reported. Some of these estimates, however, do not pertain to dlsulfo-
ton Itself but pertain to total residues that might Include dlsulfoton sulf-
oxlde and sulfone as well as oxygen analogs of dlsulfoton. The estimated
persistence of the parent dlsulfoton ranges from 32-42 days and that of
dlsulfoton sulfone ranges from 60-147 days or longer. Dlsulfoton In near
surface soil Is subject to photosensitized oxidation, mainly to Us
sulfoxlde. Dlsulfoton and Us residues are not expected to be significantly
mobile In soil and therefore will not be expected to leach to groundwater.
Dlsulfoton Is not expected to volatilize significantly from near surface
soil, although evaporation from wet soil surfaces and soil under flooded
(paddy) conditions may be substantially greater than from relatively dry
soil (Gohre and Miller, 1986).
v
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Monitoring data for dlsulfoton are limited. Dlsulfoton has been
detected In groundwater, Irrigation runoff collection pits, certain foods,
and In the atmosphere. In general, dlsulfoton was detected only In a small
percentage of the samples tested and those dlsulfoton residues found usually
were not quantified.
The acute toxldty (96-hour LC5Q) of dlsulfoton (D1-syston») to
freshwater fish ranged from <1 mg/l for largemouth bass and bluegill
sunflsh (Mayer and Ellersleck, 1986; Henderson et al., 1959; Pickering et
al., 1962) to 7.2 ppm for goldfish (Pickering et al., 1962). Butler (1964)
reported a 24-hour EC5fl of 0.74 ppm for sheepshead minnow. Bass and an
air-breathing fish exposed to D1-syston« had reductions 1n brain and
muscle AChE activity (Weiss, 1961; Bakthavathsalam and Reddy, 1983).
Stonefly larvae were very sensitive to exposure to dlsulfoton. Jensen
and Gaufln (1964a,b) and Sanders and Cope (1968) reported 96-hour TLm$ and
LC5Qs ranging from 0.005-0.024 mg/l. The 30-day LC5Qs for stonefly
larvae were 1.4 and 1.9 yg/l. ECcns and TLms for ovsters and clams
ranged from -1-6 ppm (Butler, 1963; Davis and H1du, 1969). Marine and
freshwater shrimp were more sensitive than molluscs to exposure to
D1-syston. Butler (1964) and Sanders (1972) reported ECg-s and TLms of
0.025 and 0.038 mg/l. Freshwater scud were also very sensitive to
dlsulfoton, with 96-hour LC5Qs ranging from 0.021-0.052 mg/l (Sanders,
1969, 1972).
BCF values estimated from the K and water solubility of dlsulfoton
were 669 and 101. respectively, suggesting that dlsulfoton may bloaccumulate
to a certain degree In- aquatic organisms. Experimentally derived BCFs are
comparable with the estimated BCFs ranging from -300-2500 In fish
v1
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(Tomlzawa, 1980; Takase and Oyama, 1985). Despite the potential for
b1oaccumulat1on, depuration appears to be rapid once exposure of fish to
dlsulfoton Is terminated.
The oral toxlclty of dlsulfoton to birds was reported by several
Investigators. The acute per os LD s of dlsulfoton to starlings and
red-winged blackbirds were >32 and 3.2 mg/kg, respectively (Schafer, 1972).
Hill et al. (1975) reported LC s of 715, 333, 634 and 510 ppm for bob-
white, quail, pheasant and mallard, respectively. The acute oral toxlclty
of D1-syston® to bobwhHes was significantly affected by formulation.
Hill and Camardese (1984) reported LD5Qs (and 95% confidence Intervals) of
12 (7-19) and 29 (24-34) mg/kg bw for the technical grade and a granular
formulation, respectively.
The gastrointestinal absorption of d1sulfoton-o-ethyl-l-14C (99%
purity) 1s almost complete. When administered to rats, 90.8% of the admin-
istered dose was recovered In the urine and expired air, with only 7.0% of
the dose being excreted In the feces (Puhl and Fredrlckson, 1975).
After oral administration to rats, the highest concentrations of
dlsulfoton appear in the liver, with lesser amounts found In the kidneys,
fat, blood, muscle and brain (Puhl and Fredrlckson, 1975). Dlsulfoton has
also been found In the kidney, serum, liver, bile and brain of dogs after
oral treatment (Hlklta et al., 1973).
Dlsulfoton undergoes oxldatlve and hydrolytlc reactions 1n rats (Puhl
and Fredrlckson, 1975) and mice (March et al., 1957). The main urinary
metabolites of rats are d1ethylphosphoroth1onate and dlethylphosphate. The
sulfoxlde and sulfone of dlsulfoton and Us oxygen analog are relatively
minor metabolites. Metabolites produced by oxidation may.be responsible for
the chollnesterase Inhibition associated with dlsulfoton (Bomb1nsk1 and
DuBols, 1958; WHO, 1974).
-------
Excretion of dlsulfoton In rats occurs mainly from the kidneys (81.6% In
urine) and to a lesser extent by the gastrointestinal tract (7.0% In the
feces) and lungs (9.2% 1n the expired air) (Puhl and FredMckson, 1975).
Urinary excretion occurs more rapidly In male rats than In female rats.
The presence of dlsulfoton In the bile of dogs treated orally Indicates that
biliary excretion also occurs (H1k1ta et al., 1973).
Chollnesterase Inhibition Is a widely reported effect of chronic,
subchronlc or acute oral exposure to dlsulfoton In humans, rats, mice and
dogs (U.S. EPA, 1984b, 1987; WHO, 1974; WHO, 1976). Chollnesterase Inhibi-
tion has occurred at dietary concentrations as low as 0.8 ppm In a 2-year
dietary study In rats (Hayes, 1985).
Lesions of the optic nerves of rats and dogs and extra-ocular muscles of
dogs have been reported In long-term dietary studies by Hayes (1985), Tokoro
et al. (1973), Ishlkawa (1973) and Uga et al. (1977). Swelling and
demyellnlzatlon of nerve bundles and bullous and Irregular dilation of the
junctlonal folds of the neuromuscular junctions In the extra-ocular muscles
of dogs have been reported at 0.5-1.5 mg/kg/day dlsulfoton (Mukuno and Ima1,
1973). In addition, the occurrence of myopia, Impaired vision, central
scotomas, narrowed peripheral vision, necrosis of the retinal and Muller
cells, rule astigmatism and fluctuations In opthalmk pressure have been
reported 1n chronic studies In dogs (Ishlkawa, 1973; Uga et al., 1977;
Tokoro et al., 1973; Ishlkawa and Mlyata, 1980). Dietary concentrations
ranging from 0.5-1.5 ppm were used In these studies; however, the exact
concentrations at which these symptoms occurred were not given. Corneal
neovascularlzatlon occurred at dietary concentrations of 3.3 and 3.3-13 ppm
1n male and female mice, respectively.
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In addition, chronic effects of altered absolute and relative spleen,
liver, kidney, pituitary and brain weights have occurred In rats at dietary
concentrations from 1-5 ppm In rats. Statistically significant Increased
absolute spleen and liver weights 1n male rats and decreased absolute and
relative kidney weights In female rats occurred in groups that received a
dietary concentration of 5 ppm (Carpy et al., 1975), as well as atrophy of
the pancreas In male rats that received a chronic dietary concentration of
13 ppm (Hayes, 1985).
Altered brain tissue permeability has been reported in rats that
received subchronlc dietary administration of 50-150 ppm dlsulfoton (Clark
and Stavlnova, 1971). In addition, Increased exploratory activity was
observed in rats that received subchronlc dietary administration of 150-200
ppm dlsulfoton (Clark et al., 1971).
Altered glycogen levels, RNA, DNA and protein were also observed In rats
given oral subchronlc doses of >22 yg dlsulfoton (Glurgea, 1979).
Altered activities of ethylmorphlne N-demethylase, NADPH cytochrome C
reductase and NAOP oxldase were observed In acute oral administration of
29.2-35.1 wmol dlsulfoton. Also, Increased levels of adrenaline and
noradrenallne have been observed In rats after acute administration of
dlsulfoton (Stevens et al., 1973).
Oral LDrQs of 6.8 ppm In male rats and 2.3 mg/kg In female rats has
been reported by Galnes (1969). Oral ID,.* 1n rats, mice and guinea pigs
of 2, 4.8 and 10.8 mg/kg, respectively, were also reported (NIOSH, 1988).
Female rats appear to be more sensitive than males; guinea pigs appear to be
slightly less sensitive than rats and mice.
Ix
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No evidence of dlsulfoton-related- carcinogenic!ty was found In two
2-year dietary studies using rats (Hayes, 1985; Carpy et al., 1975) and one
2-year dietary study using mice (Hayes, 1983). Results of mutagenlclty
tests were generally negative; positive results were only observed at high
concentrations 1n base-pair reversion strains of S. typhlmurlum and E_. col 1.
Oral developmental toxldty tests In rabbits revealed no evidence of
fetotoxlclty or teratogenlclty at dosages up to 1.5 mg/kg/day during organo-
genesls (Tesh et al., 1982). Dosages of 1.5-3.0 mg/kg/day were associated
with chollnerglc signs In the dams. In rats treated by gavage during
organogenesls, 0.3 mg/kg/day was a NOAEL and 1.0 mg/kg/day was a LOAEL for
fetotoxlclty (Lamb and Hlxson, 1983).
When treated male and female rats were mated In a 3-generat1on repro-
ductive studies, a dietary concentration of 10 ppm dlsulfoton resulted In
reduced Utter sizes and pregnancy rate (Taylor, 1966). Also, renal
lesions, hepatic lesions, testlcular hypoplasla and chollnesterase Inhibi-
tion occurred In the offspring. In another reproduction study (Ryan et al.,
1970), 10 ppm dlsulfoton In the diet of rats of either or both sexes
resulted 1n reduced fertility.
Dlsulfoton was assigned to EPA Group D; not classifiable as to human
carclnogenldty, based on an absence of cancer data In humans and the lack
of adequate testing and peer reviewed studies In animal models. Cancer
potency factors and a cancer-based RQ were not derived.
An RfD of 0.0003 mg/kg/day was derived for subchronlc oral exposure
based on a NOAEL of 0.025 mg/kg/day In a 2-year study using dogs (Hoffman et
al., 1975). An RfD of 4xlO"s mg/kg/day was derived for chronic oral
exposure based on a LOAEL of 0.04 mg/kg/day for chollnesterase Inhibition In
-------
a 2-year study using rats (Hayes, 1985). An RQ of 10 based on chronic
toxldty ws derived from mortality In rats In the 2-year dietary study
using rats (Hayes, 1985).
x1
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Chemical Reactions 5
2.1.2. Photolysis 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 6
2.2.3. Photolysis 6
2.2.4. Mlcroblal Degradation 6
2.2.5. Volatilization 7
2.2.6. Adsorption 7
2.3. SOIL 7
2.3.1. Hydrolysis 7
2.3.2. Oxidation 7
2.3.3. Photolysis 8
2.3.4. Mlcroblal Degradation 8
2.3.5. Adsorption 11
2.3.6. Volatilization 11
2.4. SUMMARY 12
3. EXPOSURE 14
3.1. HATER 14
3.2. FOOD 14
3.3. INHALATION 15
3.4. DERMAL 15
3.5. SUMMARY 15
4. ENVIRONMENTAL TOXICOLOGY 16
4.1. AQUATIC TOXICOLOGY 16
4.1.1. Acute Toxic Effects on Fauna ' 16
4.1.2. Chronic Effects on Fauna 22
4.1.3. Effects on Flora 23
4.1.4. Effects on Bacteria 24
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TABLE OF CONTENTS (cont.)
Page
4.2. TERRESTRIAL TOXICOLOGY 24
4.2.1. Effects on Fauna 24
4.2.2. Effects on Flora 25
4.3. FIELD STUDIES 25
4.4. AQUATIC RISK ASSESSMENT 25
4.5. SUMMARY 27
5. PHARMACOKINETCS 30
5.1. ABSORPTION 30
5.2. DISTRIBUTION 30
5.3. METABOLISM 30
5.4. EXCRETION 33
5.5. SUMMARY 33
6. EFFECTS 35
6.1. SYSTEMIC TOXICITY 35
6.1.1. Inhalation Exposure 35
6.1.2. Oral Exposure 35
6.1.3. Other Relevant Information 43
6.2. CARCINOGENICITY 46
6.2.1. Inhalation 46
6.2.2. Oral 46
6.3. M.UTAGENICITY 47
6.4. TERATOGENICITY 50
6.5. OTHER REPRODUCTIVE EFFECTS 50
6.6. SUMMARY 52
7. EXISTING GUIDELINES AND STANDARDS 56
7.1. HUMAN 56
7.2. AQUATIC 57
8. RISK ASSESSMENT 58
8.1. CARCINOGENICITY 58
8.1.1. Inhalation 58
8.1.2. Oral 58
8.1.3. Weight of Evidence 58
8.1.4. Quantitative Risk Estimates 59
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TABLE OF CONTENTS (cont.)
Page
8.2. SYSTEMIC TOXICITY 59
8.2.1. Inhalation Exposure 59
8.2.2. Oral Exposure 59
9. REPORTABLE QUANTITIES 62
9.1. BASED ON SYSTEMIC TOXICITY 62
9.2. BASED ON CARCINOGENICITY 65
10. REFERENCES 68
APPENDIX A: LITERATURE SEARCHED 88
APPENDIX B: SUMMARY TABLE FOR DISULFOTON 91
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
DISULFOTON 92
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LIST OF TABLES
No. Title Page
1-1 Dlsulfoton Use Data for 1976 and 1982 From the USDA
Crop and Livestock Pesticide Usage Survey 3
6-1 Acute Oral Toxlclty of Dlsulfoton 45
6-2 Mutagenldty Data for Dlsulfoton 48
9-1 Summary of Oral Toxlclty Data for Dlsulfoton 63
9-2 Oral Composite Scores for Dlsulfoton 66
9-3 Dlsulfoton: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 67
LIST OF FIGURES
No. Title Page
4-1 Organization Chart for Listing GMAVs, GMCVs and BCFs
Required to Derive Numerical Water Quality Criteria by
the Method of U.S. EPA/OWRS (1986) for the Protection of
Freshwater Aquatic Life from Exposure to Dlsulfoton 26
4-2 Organization Chart for Listing GMAVs, GMCVs and BCFs
Required to Derive Numerical Water Quality Criteria by
the Method of U.S. EPA/OWRS (1986) for the Protection of
Saltwater Aquatic Life from Exposure to Dlsulfoton 28
5-1 Proposed Pathways for Metabolism of Dlsulfoton by Rats. ... 31
xv
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LIST OF ABBREVIATIONS
AChE AcetylcholInesterase
ADI Acceptable dally Intake
BCF Bloconcentratlon factor
CAS Chemical Abstract Service
CNS Central nervous system
DMA Deoxyrlbonuclelc acid
DWEl Drinking water exposure level
ECgQ Median effective concentration
EEG Electroencephalogram
EM Ecological magnification
ERG Electroretlnogram
F344 Fischer 344
GC Gas chromatography
GMAV Genus mean acute value
GMCV Genus mean chronic value
HA Health advisory
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kom Sorptlon coefficient standardized
with respect to soil organic matter
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate
(reduced form)
NOAEL No-observed-adverse-effect level
xv1
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Dlsulfoton 1s the common name for the chemical referenced by the
Chemical Abstract Service as 0,0-d1ethyl S-[2-(ethylth1o)ethylJphosphoro-
dlthloate (BCPC, 1983). Other common names Include ethylthlodemeton and
thlodemeton (BCPC, 1983). It has been marketed under many trade names
Including Dlsyston* (D1-Syston In the United States), D1th1osystox«,
Frumin AL* and Solvlrex* (BCPC, 1983). The structure, molecular weight,
empirical formula and CAS Registry number for this compound are as follows:
CH3CH20 S
Ml
P-S-CH2-CH2-S-CH2-CH3
/
CH3CH20
Molecular weight: 274.38
Empirical formula: CQH1Q00PS0
o i y i j
CAS Registry number: 298-04-4
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Pure dlsulfoton has been described as a colorless oil (BCPC, 1983;
Mlndholz, 1983) with a characteristic odor (BCPC, 1983) or as a yellow
liquid (Hawley. 1981). The technical compound 1s a brown liquid (Hawley,
1981). Dlsulfoton Is readily soluble 1n most organic solvents (BCPC, 1983).
Selected physical properties are as follows:
Boiling point (0.01 mmHg): 62°C BCPC, 1983
Vapor pressure (20°C): 1.8x10"* mm Hg Royal Society of
Chemistry, 1983
Log Kow: 4.02 Hansch and Leo, 1985
Water solubility (22°C): 25 ppm BCPC, 1983
0172d -1- 04/21/89
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Specific gravity (20/4°C): 1.144 BCPC, 1983
20
Refractive Index, njj : 1.5348 Wlndholz, 1983
Conversion factor In air: 1 mg/m3 = 0.0891 ppm
1.3. PRODUCTION DATA
Dlsulfoton Is synthesized commercially by reaction of 0,0-dlethyl-
hydrogen phosphorodlthloate with 2-(2-ethylth1o)ethylchlor1de (BCPC, 1977).
According to SRI (1987) and USITC (1986), Bayer U.S.A. Inc., Mobay Corp.,
subsidiary, Agricultural Division 1n Kansas City, MO, Is the only current
domestic manufacturer of dlsulfoton.
1.4. USE DATA
Dlsulfoton Is a systemic Insectldde/acarldde used primarily for treat-
ment of seeds and application to soils or plants In the form of granules
(BCPC, 1983). Dlsulfoton protects young plants from attack by leafhoppers,
aphlds, thrlps and mites by treatment of the seeds of cotton, alfalfa or
sugar beets before planting with a 50% mixture of dlsulfoton In charcoal
powder, by treatment with granules at time of transplanting, or by granular
side-dressing treatment at time of planting (Metcalf, 1981). Dlsulfoton Is
also used for the control of aphlds In brasslcas, beans, carrots, coriander,
mangolds, marrows, parsnips, parsley, peas, potatoes, transplanted celery,
strawberries and beet crops; the control of early generation carrot fly In
transplanted celery, parsnips and carrots; and control of red spider mites
1n strawberries and potato leaf roll and cucumber mosaic viruses (Royal
Society of Chemistry, 1983).
Data for dlsulfoton use on several crops In 1976 and 1982 are listed In
Table 1-1.
0172d -2- 04/21/89
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TABLE 1-1
Dlsulfoton Use Data for 1976 and 1982 from the USDA
Crop and Livestock Pesticide Usage Survey3
Crop
Soybeans
Cotton
Grain sorghum
Tobacco
Wheat
Acres
1976
0.2
1.4
1.5
0.2
3.7
Treated
1982
Million
0.1
b/
&/
b/
b/
Pounds (Active
1976
0.2
1.8
1.1
0.2
1.8
Ingredient)
1982
0.1
b/
b/
0.1
b/
aSource: USDA, 1983
b<50,000 acres or pounds (active Ingredient)
0172d -3- 04/17/89
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1.5. SUMMARY
Dlsulfoton Is the common name for the chemical referenced by CAS as
0,0-dlethyl S-[2-(ethylth1o)ethyl]phosphorod1thioate (BCPC, 1983). Pure
dlsulfoton has been described as a colorless oil (BCPC, 1983; Windholz,
1983) with a characteristic odor (BCPC, 1983) or as a yellow liquid (Hawley,
1981). The technical compound is a brown liquid (Hawley, 1981). Dlsulfoton
Is readily soluble in most organic solvents (BCPC, 1983). Dlsulfoton is
synthesized commercially by reaction of 0,0-d1ethylhydrogen
phosphorodHhloate with 2-(2-ethylth1o)ethylchloride (BCPC, 1977). Mobay
Corp., subsidiary, Agricultural Division In Kansas City, MO, is the only
current domestic manufacturer of dlsulfoton (SRI, 1987). Dlsulfoton 1s a
systemic insectlclde/acarlclde used primarily for treatment of seeds and
application to soils or plants In the form of granules (BCPC, 1983).
0172d -4- 04/21/89
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Given Us vapor pressure of l.SxlO"4 mm Hg at 25°C, dlsulfoton Is
expected to exist primarily In the vapor phase In the atmosphere (E1senre1ch
et al., 1981).
2.1.1. Chemical Reactions. Using the method of Atkinson (1987), the rate
constant for the vapor phase reaction of dlsulfoton with photochemically
produced hydroxyl radicals was estimated to be 1.32xlO"10 cmVmolecule-
sec at 25°C. Based on this value and assuming an average ambient hydroxyl
radical concentration of 5xl05 hydroxyl radicals/cm3, the half-life for
this reaction was estimated to be ~3 hours, suggesting that the residence
time of dlsulfoton In the ambient atmosphere Is rather short.
2.1.2. Photolysis. Dlsulfoton does not absorb UV light 1n the environ-
mentally significant range (wavelengths >290 nm) and does not appear to be
susceptible to direct photolysis 1n sunlight (Gohre and Miller, 1986).
2.2. WATER
2.2.1. Hydrolysis. Dlsulfoton Is hydrolyzed slowly In aqueous, addle
and alkaline media (Royal Society of Chemistry, 1983). Data regarding
hydrolysis rates of dlsulfoton In aqueous solution at environmentally
significant temperatures and pH were not located In the available literature
cited In Appendix A. The reported half-lives for hydrolysis of dlsulfoton
In aqueous solution at 70°C at pH 1.0. 3.0, 5.0, 7.0 and 9.0 are 62, 62, 60,
27.6 and 7.2 hours, respectively (Faust and Gomaa, 1972; Muhlmann and
Schrader, 1957). The reported half-life for hydrolysis of dlsulfoton In
aqueous solution at pH 1-5 at 30°C Is 289 days (Muhlmann and Schrader,
1957). Hydrolysis products are dlethylthlophosphorlc acid and B-ethyl-
mercaptothlo ether (Muhlmann and Schrader, 1957).
0172d -5- 04/17/89
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2.2.2. Oxidation. Dlsulfoton Is oxidized rapidly to Us sulfoxlde and
sulfone by reaction with singlet oxygen (Gohre and Miller, 1986). Indirect
photooxldatlon of dlsulfoton occurs In the presence of humlc substances and
hydrogen peroxide (Section 2.2.3.) (Zepp et al., 1981; Szeto et a!., 1983;
Draper and Crosby, 1984). Chemical oxidation may be a significant factor In
the oxidation of dlsulfoton observed 1n degradation studies In soil (Section
2.3.4.).
2.2.3. Photolysis. Dlsulfoton does not absorb UV light In the environ-
mentally significant range (wavelengths >290 nm) and does not appear to be
susceptible to direct photolysis In sunlight (Gohre and Miller, 1986).
Humlc substances In water have been reported to photosensitize oxidation of
dlsulfoton (Zepp et al., 1981). The half-lives for photosensitized (by
humlc substances) oxidation of dlsulfoton to dlsulfoton sulfoxlde In Audlla
River water (colored water) samples exposed to midday sunlight were experi-
mentally determined to range from -5 hours during summer to 12 hours during
winter (Zepp et al., 1981). After 125 hours In the dark or under sunlit
conditions, 18 and 53% of dlsulfoton In dilute (100 pM) hydrogen peroxide
solution was removed, respectively; 1n distilled water, 11X removal was
observed after 125 hours under sunlit conditions, possibly due to auto-
oxidation (Draper and Crosby, 1984).
2.2.4. M1crob1al Degradation. Pertinent data regarding the blodegrada-
tlon of dlsulfoton 1n water were not located 1n the available literature
cited 1n Appendix A. Based on the results of degradation studies In soil,
It appears that dlsulfoton may be susceptible to blodegradatlon In natural
waters and sediments (Section 2.3.4.); however, none of the data regarding
the fate of dlsulfoton 1n soil clearly Indicate the percentage of degrada-
tion that occurs through mlcroblal degradation pathways (Section 2.3.4.).
0172d -6- 04/17/89
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2.2.5. Volatilization. No experimental data concerning the volatiliza-
tion of dlsulfoton from water were located In the available literature cited
In Appendix A. A Henry's Law constant of 2.6xlO~6 atm-mVmol was
estimated for dlsulfoton using the water solubility at 22°C and the vapor
pressure at 20°C (Thomas, 1982). Based on this Henry's Law constant, the
estimated volatilization half-life for dlsulfoton In a model river 1 m deep,
flowing at a speed of 1 m/sec, with a wind velocity of 3 m/sec was calcu-
lated to be 23 days (Thomas, 1982). Adsorption to sediment and suspended
solids may considerably retard the rate of dlsulfoton loss from evaporation
of water.
2.2.6. Adsorption. Pertinent data regarding the adsorption of dlsulfoton
to sediments or partlculates 1n water were not located In the available
literature cited In Appendix A. Based on a K of 642-8720 1n soils
(Section 2.3.5.), dlsulfoton Is expected to adsorb strongly to suspended
solids and sediments.
2.3. SOIL
2.3.1. Hydrolysis. Pertinent data regarding the hydrolysis of dlsulfoton
In soil were not located In the available literature dted In Appendix A.
Based on the slow hydrolysis rates observed 1n water (Section 2.2.1.),
hydrolysis of dlsulfoton In soil 1s not expected to be a significant fate
process.
2.3.2. Oxidation. Chemical oxidation may be a significant factor In the
oxidation of dlsulfoton observed 1n degradation studies 1n soil (Section
2.3.4.); however, none of the data regarding the fate of dlsulfoton In soil
clearly define the percentage of degradation that occurs through mlcroblal
and chemical degradation pathways (Section 2.3.4.). Humlc substances found
In soil and water have been reported to photosensitize oxidation of
0172d -7- 04/21/89
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dlsulfoton, and the half-life for this process In natural water ranges from
5 hours In summer to 12 hours 1n winter (Zepp et al., 1981) (Section 2.2.3.).
2.3.3. Photolysis. Dlsulfoton does not absorb UV light In the environ-
mentally significant range (wavelengths >290 nm) and does not appear to be
susceptible to direct photolysis In sunlight (Gohre and MUler, 1986).
Dlsulfoton adsorbed on soil surfaces undergoes photosensitized oxidation to
Its corresponding sulfoxlde (major product) and sulfone (trace amounts) when
exposed to sunlight (observed half-life was -1-4 days), probably by reaction
with singlet oxygen (Gohre and Miller, 1986). Humlc substances found 1n
soil have been reported to photosensitize oxidation of dlsulfoton (Zepp et
al., 1981).
2.3.4. M1crob1al Degradation. None of the data regarding the fate of
dlsulfoton In soil clearly Indicate the percentage of degradation that
occurs through mlcroblal degradation pathways. Studies using sterilized and
nonsteMUzed soils have led to conflicting conclusions regarding differen-
tiation between chemical and biological degradation of dlsulfoton 1n soil
(Sanborn et al., 1977).
In a study of the degradation of dlsulfoton In autoclaved and nonauto-
claved sandy loam soil at 10, 25 and 45°C, Yadav et al. (1980) reported that
the dissipation of dlsulfoton concentrations was slower In autoclaved soil
at all temperatures. The difference 1n rates was not great, however, and
the rate of dlsulfoton dissipation decreased with time so that the overall
amount of degradation was similar In both cases. The amounts of dissipation
In nonautoclaved and autoclaved soil were 17 and 9% after 2 days, 24 and 22%
after 5 days, and 64 and 61X after 100 days, respectively. These results
suggest that chemical degradation may play a major role In the dissipation
of dlsulfoton 1n soil.
0172d -8- 04/17/89
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Takase et al. (1972) reported that In upland soils (clay loam, sandy
loam and sandy soil) dlsulfoton Is converted rapidly to Us sulfoxlde and
sulfone. These products are stable and retain Insectlddal activity. In
flooded (anaerobic) soils, oxidation was much more rapid than In the upland
(aerobic) soils. Olsulfoton was degraded only slightly In sterilized soil,
suggesting that blodegradatlon was responsible for the observed loss of
dlsulfoton (Takase et al., 1972). Takase and Nakamura (1974), however,
reported that results of later experiments conducted In sterile and glucose-
amended soil under paddy conditions (flooded, anaerobic soil) suggest that
the rapid oxidation of dlsulfoton observed under the conditions used in
these experiments Is not due to blodegradatlon. Olsulfoton and Its five
oxldatlve metabolites persisted 1n the paddy soil for >12 weeks; their
half-lives were -50 days (Takase and Nakamura, 1974).
Although blodegradatlon has not been conclusively shown to be a major
removal mechanism for dlsulfoton 1n soil, certain soil microorganisms have
been reported to be capable of converting thloethers to the corresponding
sulfoxldes and sulfones (Gohre and MUler, 1986). A majority of the fung!
and actlnomycete microbe Isolates tested by Bhaskaran et al. (1973) utilized
dlsulfoton as a phosphorus source, but only poorly utilized dlsulfoton as a
sole carbon source. A marked Inhibition of growth of the fungi and microbes
occurred In the presence of the Insecticide when compared with controls
(Bhaskaran et al., 1973). In another study, Gohre and MUler (1986) deter-
mined that mlcroblal metabolism was not Involved 1n the dlsulfoton loss and
resulting sulfoxlde production 1n tests of the photosensitized oxidation of
dlsulfoton In sterilized and unsteMllzed soils In closed Klmax volumetric
flasks under sunlight conditions for 7 days (see Section 2.3.3.).
0172d -9- 04/17/89
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Estimates of dlsulfoton persistence and half-life for dlsulfoton
residues 1n soil have been reported. Some of these estimates, however, do
not pertain to dlsulfoton itself but pertain to total residues that might
Include dlsulfoton sulfoxlde and sulfone, as well as oxygen analogs of
dlsulfoton. Furthermore, It 1s not certain whether most of the degradation
observed Is due to blodegradatlon or chemical degradation. Szeto et al.
(1983) studied the degradation of granular dlsulfoton applied as a side-
dressing to asparagus grown 1n sandy loam soil. Oxidation to the sulfoxlde
and sulfone was rapid, with the parent dlsulfoton being detected In the soil
for -42 days at 0.16 ppm. Dlsulfoton was no longer detectable (<0.01 ppm)
at 91 days. Total residues [dlsulfoton, sulfoxlde, sulfone (and minor
amounts of the oxygen analogs of the sulfoxide and sulfone}] were still
detected after 147 days (Szeto et al., 1983).
Clapp et al. (1976) reported results of a laboratory study which
indicated that the half-life of dlsulfoton in Portneuf silt loam soil was -2
days and varied slightly with temperature and moisture content of the soil.
The degradation process was described as being approximately a first-order
phenomenon. Dlsulfoton sulfone was the only degradation product that
persisted 1n soil; the sulfone persisted for >64 days, whereas dlsulfoton
and the sulfoxide persisted for <32 days (Clapp et al., 1976).
Menzer et al. (1970) reported results of a field study which indicated
that although no dissipation of total dlsulfoton residues was observed
during the summer In Chillum silt loam after 60 days, significant degrada-
tion occurred during the winter in Evesboro loamy sand. Large amounts of
dlsulfoton sulfone and Us oxygen analog were present but only minute
amounts of the parent dlsulfoton and the sulfoxlde (and their oxygen
analogs) were found (Menzer et al., 1970).
0172d -10- 04/17/89
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Tomizawa (1975) reported that dlsulfoton sulfoxlde Is partially reduced
to dlsulfoton In flooded alluvial clay loam soil Incubated for 5 days at
30°C In the presence of glucose but not when sodium azlde also was present.
Only partial oxidation of dlsulfoton sulfoxlde to the sulfone occurred In
flooded or unflooded soil In the absence of glucose and no reduction of
dlsulfoton sulfone (to dlsulfoton or dlsulfoton sulfoxlde) occurred In
flooded soil In the presence of glucose (Tomizawa, 1975).
Kearney et al. (1969) reported the persistence of dlsulfoton to be ~4
weeks where persistence represented the time required to observe a 75-100%
loss of the pesticide or for the biological activity to drop to a level of
75-100% below that of the control. While It was not reported whether "loss
of the pesticide" referred to dlsulfoton Itself or to total dlsulfoton
residues, loss of biological activity would apparently Indicate total
dlsulfoton residues.
2.3.5. Adsorption. The reported K values for dlsulfoton are 1780
(Kenaga, 1980), 5217, 1104 and 642 (Hamaker and Thompson, 1972). A reported
range of KQm values of 470-5060 (Mlngelgrln and Gerstl, 1983) can be con-
verted to a range of K values of 810-8720 by multiplying by a conversion
factor of 1.724 (Lyman et al., 1982). Soil TLC has been used to determine
an R, value of 0.01 In Hagerstown sllty loam soil (Helling et al., 1974).
The K and R, values Indicate that dlsulfoton mobility In soil ranges
from low to Immobile (Swann et al., 1983). In laboratory soil piling
experiments, dlsulfoton residues (mostly the oxldatlve metabolites, the
sulfoxlde and sulfone) moved slightly to the layers above (top 2 cm) and
below (5-10 cm) from the level of application (3-4 cm) (Takase et al., 1972).
2.3.6. Volatilization. Pertinent data regarding the . volatilization of
dlsulfoton from soil were not located 1n the available literature dted In
0172d -11- 04/17/89
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Appendix A. Because of Its strong adsorption to soil, dlsulfoton Is not
expected to volatilize significantly from near surface soil. Evaporation of
dlsulfoton from wet soil surfaces and soil under flooded (paddy) conditions
may be substantially greater than from relatively dry soil (Gohre and
Miller, 1986).
2.4. SUMMARY
In the atmosphere, dlsulfoton Is expected to exist primarily In the
vapor phase (Eisenreich et al., 1981). The dominant removal mechanism is
the vapor phase reaction with photochemlcally produced hydroxyl radicals.
The reaction half-life was estimated to be 3 hours (Atkinson, 1987), which
suggests that the lifetime of dlsulfoton 1n the atmosphere may be short.
Dlsulfoton is not susceptible to direct photolysis. In water, dlsulfoton
will oxidize rapidly to Us sulfoxlde and sulfone by reaction with singlet
oxygen (Gohre and Miller, 1986). It will not be subject to direct photoly-
sis; however, humlc substances In soil and water have been reported to
photosensitize oxidation of dlsulfoton, with reported half-lives 1n natural
water ranging from 5 hours 1n the summer to 12 hours 1n the winter (Zepp et
al., 1981). Dlsulfoton Is expected to adsorb strongly to suspended solids
and sediments, but will hydrolyze very slowly. Dlsulfoton may volatilize
significantly; the estimated volatilization half-life In a model river 1 m
deep, flowing at a speed of 1 m/sec, with a wind velocity of 3 m/sec was
calculated to be 23 days (Thomas. 1982). Adsorption to sediment and
suspended solids may considerably retard the rate of dlsulfoton loss from
evaporation of water. Based on the results of degradation studies In soil,
It appears that dlsulfoton may be susceptible to blodegradatlon in natural
waters and sediments. In soil, it will oxidize to Its sulfoxlde and
0172d -12- 04/21/89
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sulfone. Studies using sterilized and nonsterl1Ized soils have led to con-
flicting results regarding differentiation between chemical and biological
degradation of dlsulfoton In soil (Sanborn et al., 1977). Although rapid
degradation of dlsulfoton to Us sulfoxlde and sulfone has been reported In
certain soil experiments, these degradation products appear to be more
stable than dlsulfoton Itself and they retain Insectlddal activity (Takase
et al., 1972). Estimates of persistence of dlsulfoton residues In soil have
been reported. Some of these estimates, however, do not pertain to dlsulfo-
ton Itself but pertain to total residues that might Include dlsulfoton
sulfoxlde and sulfone as well as oxygen analogs of dlsulfoton. The
estimated persistence of the parent dlsulfoton ranges from 32-42 days and
that of dlsulfoton sulfone ranges from 60-147 days or longer. Dlsulfoton In
near surface soil Is subject to photosensitized oxidation, mainly to Us
sulfoxlde. Dlsulfoton and Us residues are not expected to be significantly
mobile 1n soil and therefore will not be expected to leach to groundwater.
Dlsulfoton Is not expected to volatilize significantly from near surface
soil, although evaporation from wet soil surfaces and soil under flooded
(paddy) conditions may be substantially greater than from relatively dry
soil (Gohre and Miller, 1986).
0172d -13- 04/17/89
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3. EXPOSURE
General population exposure to dlsulfoton probably occurs by Ingestlon
of contaminated foods and Inhalation of contaminated ambient air (HSDB,
1988). Workers Involved 1n the manufacture, handling or application of this
Insecticide may be exposed by dermal contact or by Inhalation (HSBD, 1988).
More recent monitoring data, which are not available, are needed to estimate
present potential for exposure to dlsulfoton. Furthermore, data concerning
total dlsulfoton residues, which Includes dlsulfoton sulfoxlde and sulfone,
are needed to Indicate the total potential for potentially harmful human
exposure due to dlsulfoton use.
3.1. HATER
Dlsulfoton was detected, but not quantified, 1n groundwater supplies In
6/28 California counties tested (Cohen, 1986). Dlsulfoton was not detected
'(0.1 ppb detection limit) In 48 municipal and 6 private California ground-
water supply systems (Maddy et al., 1982). Dlsulfoton was not detected In
1508 samples from 358 groundwater wells In Wisconsin through June 1984
(Krill and Sonzognl, 1986).
Dlsulfoton was detected In 5/6 samples of bottom soil from tallwater
pits used to collect Irrigation runoff from corn fields at median, mean and
maximum concentrations of 11.4, 13.8 and 32.7 ppb, respectively, and at 11
ppb In the 1 sample of Irrigation runoff collected from both corn and
sorghum fields (Kadoum and Hock, 1978).
3.2. FOOD
During fiscal year 1976, the Food and Drug Administration Identified
dlsulfoton In cereal by-products (one sample), leaf and stem vegetables (one
sample), grains (one sample), oilseed by-products (four samples) and
miscellaneous animal feed (four samples) (Duggan et al., 1983).
0172d -14- 04/21/89
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Disulfoton was detected in 1/360 food class composites collected from 30
markets in 24 U.S. cities from June, 1968 to April, 1969 (Cornel lussen,
1970). The positive sample was one of six composite samples of leafy
vegetables collected In Boston, MA, and was reported to contain 2 ppb
disulfoton. Disulfoton and residues were not detected (detection limit, 5
ppb) in 258 vegetable samples collected In Ontario, Canada, from 1980-1985
(Frank et al., 1987).
3.3. INHALATION
Disulfoton was detected at a concentration of 4.7 ng/m3 in 1/123
ambient air samples collected at 10 U.S. locations In 1980 (Carey and Kutz,
1985).
3.4. DERMAL
Pertinent data regarding dermal exposure to disulfoton were not located
In the available literature cited In Appendix A.
3.5. SUMMARY
Monitoring data for disulfoton are limited. Disulfoton has been
detected In groundwater, Irrigation runoff collection pits, certain foods,
and In the atmosphere. In general, disulfoton was detected only In a small
percentage of the samples tested and those disulfoton residues found usually
were not quantified.
0172d -15- 04/17/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Henderson et al. (1959) assessed
the acute toxlclty of D1-syston® (90% active Ingredient 1n acetone), a
commercial formulation of dlsulfoton, to fathead minnows, Plmephales
promelas. and blueglll sunflsh, Lepomls macrochlrus. Tests were static and
were conducted at 25°C In 10 l of test solution prepared with either
natural or reconstituted water In 5-gallon glass bottles. Soft water was
prepared by mixing 95 parts distilled water with 5 parts natural spring
water; hard water was obtained directly from a natural limestone spring.
The respective water hardnesses were 20 and 400 ppm. The Investigators
reported 24-, 48- and 96-hour TL s for minnows In hard water of 3.9, 3.9
and 2.9 mg/i, respectively. Toxldty of D1-syston» to minnows In soft
water was not significantly different, with respective values of 6.8, 4.4
and 4.1 mg/i. Toxldty of D1syston« to bluegllls In soft water was
significantly greater than that to minnows, with respective TL s of 0.090,
0.070 and 0.070 mg/i. Pesticide formulation did not appreciably alter the
toxlclty of D1-syston» to sunflsh. The Investigators reported 96-hour
TL s of 0.064 and 0.077 mg/l for tests with an acetone based solution
m
and an emulslf1able concentrate, respectively.
Pickering et al. (1962) assessed the acute toxlclty of technical grade
(90%) and an emulslble concentrate (20%) of 01-syston« to goldfish,
Carraslus auratus. gupples, Leblstes retlculatus. and sunflsh, L,. macro-
chlrus. Test conditions were comparable with those described by Henderson
et al. (1959). When necessary, test solutions were aerated to maintain a
dissolved oxygen level of 4-8 ppm In test containers. The Investigators
reported 24-, 48- and 96-hour TL s for goldfish exposed to technical grade
0172d -16- 04/21/89
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D1-syston« in soft water of 7.5, 7.2 and 7.2 ppm, respectively, and TL s
for gupples of 0.32, 0.32 and 0.28 ppm, respectively. An emulslble concen-
trate of D1-syston« in soft water with 20% active Ingredient generated
Tl_m values with sunflsh of 0.098, 0.082 and 0.082 ppm for exposure periods
of 24, 48 and 96 hours. A summary of toxldty test results presented by
Pickering et al. (1962) revealed that for 96-hour exposure durations the
order of tolerance for four species of warmwater fish to D1-syston» at
25°C was goldfish > fathead minnows > gupples > bluegllls (TL s = 6.5,
3.7, 0.25 and 0.063 ppm, respectively).
Butler (1964) reported a 24-hour EC5Q of 0.74 ppm for juvenile sheeps-
head minnow Cyprinldon varlegatus exposed to D1-syston under flowthrough
conditions at 25°C. Mortality was used as the test endpolnt.
Holcombe et al. (1982) conducted flowthrough toxldty tests exposing
rainbow trout. Salmo qalrdneM. and fathead minnows, P. promelas. to
dlsulfoton. Tests were conducted with proportional dlluters delivering a
flow rate of 81 mi/m1n, producing a 90% turnover of test solution every 8
hours. Mater with a hardness of 45.3 ppm (as CaCO_) was obtained directly
from Lake Superior and was used as diluent. Tests with trout were conducted
at 15.6±1.8°C, while those with minnows were conducted at 25.U1.3°C.
Olsulfoton concentrations 1n exposure chambers were determined dally by GC.
Minnows were 31-32 days old (average we1ght=0.2 g) at the start of the test,
while trout were simply described as juveniles (average weight = 4.3 g).
Investigators reported 24-, 48-, 72- and 96-hour LC5Qs (and 95X confidence
limits) of 4.41 (4.22-4.61), 4.05 (3.85-4.25), 4.03 (3.83-4.23) and 4.00
mg/i (3.81-4.21) for fathead minnows, respectively, and 4.32 (4.32-4.32),
3.88 (3.47-4.35), 3.02 (2.58-3.55) and 3.02 mg/l (2.58-3.55), respec-
tively, for rainbow trout.
0172d -17- 04/17/89
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Weiss (1961) assessed the effects of Di-syston» on brain AChE activity
In largemouth bass, Micropterus salmoldes. and fathead minnows, P. promelas.
Fish were exposed to D1-syston® In 5-gallon wide-mouth Jars containing 15
a. of solution prepared with dechlorInated tap water. Tests were conducted
at 20-21°C. Fish were exposed to 0.5 mg/i of D1-syston® until -50% had
died. The Investigators reported that surviving largemouth bass revealed a
reduction in AChE activity to 16.754 of that observed in control fish after
24 hours. Brain AChE activity of dead bass was only 13.7% of that observed
in control fish. Brain AChE activity in fathead minnows was reduced to
45.2% of normal after 24 hours and 37.7% of normal after 72 hours. There
were no mortalities among fathead minnows exposed to 0.5 mg/i Di-syston«
after 72 hours.
Subsequently, Bakthavathsalam and Reddy (1983) assessed the effects of
exposure to 4.0 and 10.5 mg/i D1-syston» on brain and muscle AChE
activity In an air-breathing fish, Anabas testudlneus. F1sh were exposed to
Olsyston In aquaria containing 200 i of solution at 28^1°C, test solutions
were renewed dally. The Investigators reported decreases In brain and
muscle AChE activity levels of 77 and 27.2%, respectively, after 24 hours
and a decrease of 82.1% In brain AChE activity after 120 hours of exposure
for fish exposed to 4 mg/i. Muscle AChE activity of fish exposed to 4
mg/i D1-syston« for 48-120 hours was Increased from 43.2-18.1% relative
to controls. Muscle and brain AChE activity declined from 17-78.7% in fish
exposed to 10.5 mg/i D1-syston» for 1-6 hours. The Investigators specu-
lated that significant reductions In brain AChE activity Induced behavioral
and physiological modifications that reduce the survival fitness of the
organism In the environment.
0172d -18- 04/17/89
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Devlllers et al. (1985) estimated that the LC5Q for zebra fish.
Brachyodanlo rerlg. exposed to dlsulfoton at 24°C was >100 mg/a. after an
exposure period <4 hours, and ranged from 10-35 mg/i for exposure periods
of 6-24 hours.
Mayer and Ellersieck (1986) reported the results of studies assessing
the acute toxldty of dlsulfoton to rainbow trout, S. galrdnerl. fathead
minnow, P. promelas. channel catfish, Ictalurus punctatus. blueglll sunflsh,
L. machrochlrus. and largemouth bass, M. salmoldes. All tests were static.
Tests with trout were conducted at 13°C, while those with blueglll were at
24°C. All others were conducted at 18°C. All tests were conducted In soft
water (hardness=44 mg/l) except for those with bass (hardness=272 mg/i).
The 24-hour LC5Qs for trout, minnow, catfish, sunflsh and bass were 2.45,
5.6, 6.0, 0.65 and 0.27 mg/l, respectively. The 96-hour LC5Qs were
1.85, 4.3, 4.7, 0.30 and 0.060, respectively.
Butler (1963) reported an EC,-Q of 0.90 ppm for oysters, Crassostrea
vlrglnlca, exposed to D1-syston for 96 hours under flowthrough conditions at
20°C. A 50% decrease In shell growth was used as the test endpolnt. Butler
(1964) reported 24- and 48-hour EC5Qs of 0.05 and 0.025 ppm for adult
brown shrimp, Penaeus aztecus. exposed to D1-syston« under flowthrough
conditions at 25°C. Mortality and loss of equilibrium were used as test
endpolnts.
Jensen and GauMn (1964a) assessed the acute toxldty of D1-syston (89%
active 1n acetone) to naiads of two species of stonefly, Pteronarcys
callfornlca and Acroneurla padf 1ca. Tests were conducted In 2-gallon glass
aquaria at temperatures of 11-12°C. Creek water with a hardness of 122-210
ppm was used as diluent. Small granitic stones were, provided In each
0172d -19- 04/17/89
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chamber as a place of attachment for the naiads. Test solutions were
aerated during the assays. The Investigators reported 48-, 72- and 96-hour
TL s of 0.048, 0.023 and 0.0082 ppm, respectively for A. paclflea. The
72- and 96-hour TL s for £. callfornlca were 0.056 and 0.0285 ppm, respec-
tively. According to Jensen and Gaufin (1964b), flowthrough design did not
Influence the outcome of 4-day assays with stonefly naiads; the reported
96-hour TL s were 0.0094 and 0.0240 ppm in flowthrough studies with A.
padflea and P. callfornlca. respectively.
Sanders and Cope (1968) assessed the acute toxldty of dlsulfoton to
naiads of the stonefly, £. callfornlca. later reported In Mayer and
Ellersieck (1986). Test specimens were collected from mountain streams and
were maintained In aerated water at 15.5°C, with driftwood as a source of
food and attachment for the naiads for a minimum of 48 hours. Tests were
conducted In 5.7 I glass aquaria containing 4 i of reconstituted water
with a methyl orange alkalinity of 35 ppm. Test solutions were not renewed
and aeration was not provided during the 96-hour study. The 24-, 48- and
96-hour LC5Qs (and 95% confidence limits) were 40 (31-52), 18 (13-25) and
5.0 yg/l (3.7-6.7), respectively.
Davis and H1du (1969) assessed the effects of D1-syston» on develop-
ment of embryos and survival and growth of larvae of the hard clam,
Mercenarla mercenarla. and the oyster, C. vlrqlnlca. Exposure of embryos
was Initiated shortly after release and fertilization. The percentages of
fertilized eggs that reached the normal straight-hinge vellger larvae were
determined after 48 hours. The effects on growth of larvae were assessed by
exposing 2-day-old larvae that had been reared under normal conditions.
Exposure duration was 12 days; larvae were fed live flagellates each day.
0172d -20- 04/17/89
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Tests were conducted at 24°C, and test solutions were renewed every other
day. The Investigators reported 48-hour TL s of 5.86 and 5.28 ppm for
oysters and clams, respectively, and 14-day TL s of 3.67 and 1.39 ppm for
oysters and clams, respectively.
Sanders (1969) determined the toxlclty of dlsulfoton to scud, Gammarus
fasdatus. In a static acute study at 70°F. Tests were conducted in 4 a.
of reconstituted water with a total alkalinity of 30 ppm. Test organisms
were 60-day-old Immature* reared 1n the laboratory from field-captured
specimens. The 24-, 48- and 96-hour LC5Qs (and 95% confidence limits)
were 110 (81-148), 70 (52-94) and 52 vg/l (49-58), respectively.
Results were also reported 1n Mayer and Ellersleck (1986).
Subsequently, Sanders (1972) assessed the static acute toxlclty of
dlsulfoton to scud, G. fasdatus. and glass shrimp, Palaemonetes kadla-
kensls. Tests were conducted In glass aquaria containing 4 i of test
solution and maintained at 21°C. Test organisms were collected from the
field and held In laboratory aquaria until mortality was <10% among the
prospective test organisms for the 4 days before the Initiation of testing.
The reported 24- and 96-hour TL5Qs (and 95X confidence Intervals) were 110
(70-160) and 27 yg/4, (24-30), respectively, for tests conducted with
scud 1n reconstituted water (alRallnlty = 35 ppm as CaCO.) and 100
(60-170) and 21 vq/l (17-27), respectively, for tests conducted In well
water (alkalinity = 260 ppm as CaCO«). Static acute testing with shrimp
-------
maqna. Tests were conducted at 27°C for 24 hours. The Investigators
reported estimated L05Q ranges of 0.0029-0.0030 ppm for mosquito larvae
and 0.0004-0.0009 ppm for 0. maqna.
Devlllers et al. (1985) estimated that the median Inhibitory concentra-
tion for 0. maqna exposed to dlsulfoton at 20°C ranged from 1-3.5 mg/i
after a 2-hour exposure period and was <1 mg/i after exposure periods
ranging from 4-24 hours.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY --Jensen and Gaufln (19645) assessed the toxldty
of D1-syston« (89% active In acetone) to naiads of the stoneflles, P.
callfornlca and A. paclflea. Flowthrough tests were conducted in stainless
steel aquaria at a temperature of 12.8^0.6°C. Toxicant solutions were
delivered to test chambers by metering pumps. Diluent water possessed a
total alkalinity of 165-225 ppm during the tests. Test solutions were not
aerated during the assays. The Investigators reported 5-, 10-, 15-, 20-,
25- and 30-day TLms of 0.0094, 0.0048, 0.0045, 0.00225, 0.0014 and 0.0014
ppm, respectively, for £. callfornlca and 0.024, 0.0034, 0.0025, 0.0025,
0.0024 and 0.0019 ppm, respectively, for A. padflca.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION — A BCF value of 669 Is
estimated for this compound based on Equation 4-1 and a log K value of
4.02 (see Section 1.2.).
log BCF * 0.76 log KQW - 0.23 (Lyman et al., 1982) (4-1)
log BCF = 2.791 - 0.564 log S (Lyman et al., 1982) (4-2)
Based on Equation 4-2 and a water solubility value of 25 mg/l (see Section
1.2.), a BCF value of 101 1s estimated for this compound. These values
suggest that dlsulfoton may bloaccumulate to a certain degree In aquatic
organisms.
0172d -22- 04/17/89
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Tomlzawa (1980) reported EM values (parent compound In organism/parent
compound In water) that bracketed the estimated BCF values. A microcosm
with sweet potato, tobacco cutworm, algae, red snail, Indoplanorbls exustus.
Daphnla. mosquito larvae, Culex plplens and gupples, Leblstes retIculatus.
was used to assess the accumulation of dlsulfoton 1n a simulated rice paddy
system over a 33-day study period. EM values of 9 and 2487 for snails and
fish, respectively, were reported.
Takase and Oyama (1985) assessed the accumulation of dlsulfoton from
water by carp, CypMnus carplo. exposed to a variety of treatments contain-
ing 1 ppm dlsulfoton or 1 and 10 ppm mixtures of dlsulfoton and Us oxida-
tion products In flowthrough tests. Tests were conducted at 25jt2°C for 56
days. A 4-day period for depuration of dlsulfoton following termination of
the test was Incorporated Into the experimental design. The Investigators
reported BCF values for dlsulfoton ranging from 369-525 for fish exposed to
0.01 ppm dlsulfoton for 56 days and 333-646 for fish exposed to 0.001 and
0.01 ppm dlsulfoton for 56 days. Tissue levels of dlsulfoton dropped
rapidly from 3.66 ppm at the end of the exposure period to 0.19 ppm after a
4-day depuration period.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY ~ Butler (1963) reported a 55.2X decrease In the
productivity of estuarlne phytoplankton exposed to 1 ppm D1-syston« for 4
hours. Productivity was assessed by adding known amounts of 14C to the
sample.
4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bloconcen-
tratlon potential of dlsulfoton 1n aquatic flora were not located In the
available literature cited 1n Appendix A.
0172d -23- 04/17/89
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4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to dlsulfoton were not located In the available
literature cited In Appendix A.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Schafer (1972) reported the results of studies
In which wild-trapped birds were dosed by gavage with solutions of dlsulfo-
ton after a 2- to 6-week conditioning period. The acute per os L0pns to
starlings, Sturnus vulgarls, and red-winged blackbirds, Agelalus phoenlceus.
were >32 and 3.2 mg/kg, respectively.
Hill et al. (1975) reported the results of studies In which the oral
toxlclty of dlsulfoton was assessed In bobwhHes, Collnus vlrglnlanus.
Japanese quail, Coturnlx c. japonlca. ring-necked pheasants, Phaslanus
colchlcus. and mallards, Anas platyrhynchos. All test birds were Incubator-
hatched. Age of birds at the start of the tests were 14, 12, 10 and 10 days
for bobwhHes, quail, pheasant and mallard, respectively. Toxicant was
blended Into commercial starter mash for testing of birds. Birds were given
dlsulfoton-contamlnated feed each day at midday for 5 days and monitored for
3 days after cessation of treatment. The Investigators reported LCcgS of
715, 333, 634 and 510 ppm for bobwhHe, quail, pheasant and mallard,
respectively.
Hill and Camardese (1984) compared the acute oral toxldtles of tech-
nical grade and a granular formulation of dlsulfoton 1n adult bobwhHes, C.
vlrglnlanus. BobwhHes were 16-20 weeks of age at the time of the test.
Birds were fasted overnight and then given encapsulated technical grade and
granular dlsulfoton; capsules were deposited Into the proventrlculus with
stainless steel forceps. Technical grade and granular formulation
treatments each contained equivalent levels of active Ingredient. Feed was
0172d -24- 04/17/89
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provided Immediately after treatment. Survival among treated birds was
monitored dally for 1 week following treatment. The Investigators reported
LD5Qs (and 95% confidence Intervals) of 12 (7-19) and 29 (24-34) mg/kg bw
for technical grade and granular formulation, respectively. The granular
formulation was found to be significantly more toxic than the technical
grade form.
Balcomb et al. (1984) assessed the acute oral toxlclty of Dl-syston, a
product with a 15% active Ingredient level of dlsulfoton, to house sparrows,
Passer domestlcus. and red-winged blackbirds, Agelalus phoenlceus. Birds
were wild caught and conditioned to captivity for 2 weeks before the Initia-
tion of testing. Toxicant was orally administered In capsules to birds with
forceps and survival was monitored dally for 1 week. The Investigators
reported 20% mortality among house sparrows given capsules with 10 and 20
granules each (mean granule weight = 0.083 mg, resulting In 0.83 and 1.66 mg
treatments) and 20% mortality among blackbirds given 20 grain capsules (1.66
mg). These results did not permit the calculation of L05Q values.
4.2.2. Effects on Flora. Pertinent data regarding the effects of expo-
sure of terrestrial flora to dlsulfoton were not located In the available
literature cited 1n Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of dlsulfoton on flora and fauna In
the field were not located 1n the available literature cited 1n Appendix A.
4.4. AQUATIC RISK ASSESSMENT
Insufficient data precluded the development of criteria for the protec-
tion of freshwater life exposed to dlsulfoton (Figure 4-1). Development of
a freshwater criterion requires the results of an acute assay with a species
0172d -25- 04/17/89
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TEST TYPE
Family
#1
Chordate (Salmonid-f ish)
#2
Chordate (warmwater fish)
#3
Chordate (fish or amphibian)
#4
Crustacean (planktonic)
#5
Crustacean (benthic)
#6
Insectan
#7
non-Arthropod/-Chordate
GMAVa
2.36b
0.060C
3.765d
0.0386
0.0375f
0.01519
NA
GMCVa
NA
NA
NA
NA
NA
0.0014*
NA
BCFa
NA
NA
NA
NA
.NA
NA
NA
#8
New Insectan or phylum
representative
0.00881
#9
algae
NA
#10
Vascular plant
NA
0.00193
NA
NA
NA
NA
NA
aNA=Not Available b96-hour LC50 in mg/L for rainbow trout Salmo
oairdneri c96-hour LC50 in mg/L for largemouth bass Mierooterus
salmoides d96-hour TL^ and LC50 in mg/L for fathead minnows Promelas
pimephales e9 6-hour LC50 in mg/L for shrimp Palaemonetes kadiakensis
^96-hour LC50 in mg/1 for the scud Gammarus faseiatus 996-hour TI^, in
mg/L for the stonefly Pteronarcvs c^alj-fornica n96-hour TI^ in ppm for
^-
the stonefly Acroneuria pacifiea ^OO-day TLn in mg/L for the stonefly
£. ealifornica 330-dav TL,,, in ppm for the stonefly A- pacifiea
FIGURE 4-1
Organization Chart for Listing GMAVs, GMCVs and BCFs Required
to Derive Numerical Water Quality Criteria by the Method
of U.S. EPA/OHRS (1986) for the Protection of Freshwater
Aquatic Life from Exposure to Olsulfoton
0172d
-26-
04/17/89
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of non-Arthropod/Chordate. Results from chronic assays required for the
development of a freshwater criterion Include assays with one species of
fauna or flora and at least one bloconcentratlon study.
Insufficient data also precluded the development of criteria for the
protection of marine life exposed to dlsulfoton (Figure 4-2). Development
of a saltwater criterion requires the results of acute assays with a second
chordate species, a representative from a nonchordate family and a species
from a family not represented previously. Results from chronic assays
required for the development of a saltwater criterion Include assays with
one species of fauna and one species of algae, and at least one bloconcen-
tratlon study.
4.5. SUMMARY
The acute toxldty (96-hour LC5Q) of dlsulfoton (D1-syston«) to
freshwater fish ranged from <1 mg/i for largemouth bass and blueglll
sunHsh (Mayer and Ellersleck, 1986; Henderson et al., 1959; Pickering et
al., 1962) to 7.2 ppm for goldfish (Pickering et al., 1962). Butler (1964)
reported a 24-hour EC™ of 0.74 ppm for sheepshead minnow. Bass and an
air-breathing fish exposed to D1-syston« had reductions 1n brain and
muscle AChE activity (Weiss, 1961; Bakthavathsalam and Reddy, 1983).
Stonefly larvae were very sensitive to exposure to dlsulfoton. Jensen
and Gaufin (1964a,b) and Sanders and Cope (1968) reported 96-hour Tl_ms and
LC5Qs ranging from 0.005-0.024 mg/l. The 30-day LC5Qs for stonefly
larvae were 1.4 and 1.9 vq/l. ECcns and TL s for oysters and clams
ranged from -1-6 ppm (Butler, 1963; Davis and Hldu, 1969). Marine and
freshwater shrimp were more sensitive than molluscs to exposure to
D1-syston. Butler (1964) and Sanders (1972) reported EC5Qs and TLm$ of
0172d -27- 04/21/89
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Family
#1
Chordate
#2
Chordate
#3
non-Arthropod/-Chordate
#4
Crustacean (Mysid/Panaeid)
#5
non-Chordate
#6
non-Chordate
#7
non-Chordate
#8
other
#9
algae
GMAVa
0.74b
NA
0.90°
0.025d
5.86e
5.28f
NA
NA
NA
TEST TYPE
GMCVa
NA
NA
NA
NA
3.679
1.39h
NA
NA
NA
BCFa
NA
NA
NA
NA
NA
NA
NA
NA
NA
#10
Vascular plant
NA
NA
NA
aNA=Not Available b24-hour EC50 in ppm for sheepshead minnow Cyprinidon
variegatus c96-hour ECe0 (shell growth) in ppm for American oysters
Crassostrea virainica d48-hour ECc0 in ppm for brown shrimp Penaeus
aztecus e4S-hour TLj,, (larval survival) in ppm for American oysters £.
virginica f48-hour TLjj, (larval survival) in ppm for hard clams
Mercenaria mercenaria 9l4-dav TLj, (larval growth) in ppm for American
oysters £. virainica n!4-day TLm (larval growth) in ppm for hard clams
- mercenaria
FIGURE 4-2
Organization Chart for Listing GMAVs. GMCVs and BCFs Required to
Derive Numerical Water Quality Criteria by the Method of
U.S. EPA/OURS (1986) for the Protection of Saltwater
Aquatic Life from Exposure to Dlsulfoton
0172d
-28-
04/17/89
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0.025 and 0.038 mg/l. Freshwater scud were also very sensitive to
dlsulfoton, with 96-hour LC s ranging from 0.021-0.052 mg/i (Sanders,
1969, 1972).
BCF values estimated from the K and water solubility of dlsulfoton
ow J
were 669 and 101, respectively, suggesting that dlsulfoton may bloaccumulate
to a certain degree In aquatic organisms. Experimentally derived BCFs are
comparable with the estimated BCFs ranging from -300-2500 In fish
(Tomlzawa, 1980; Takase and Oyama, 1985). Despite the potential for
bloaccumulatlon, depuration appears to be rapid once exposure of fish to
dlsulfoton Is terminated.
The oral toxlclty of dlsulfoton to birds was reported by several
Investigators. The acute per os LD5Qs of dlsulfoton to starlings and
red-winged blackbirds were >32 and 3.2 mg/kg, respectively (Schafer, 1972).
H111 et al. (1975) reported LC^s of 715, 333, 634 and 510 ppm for bob-
•whlte, quail, pheasant and mallard, respectively. The acute oral toxldty
of 01-syston» to bobwhHes was significantly affected by formulation.
H111 and Camardese (1984) reported LD5_s (and 95% confidence Intervals) of
12 (7-19) and 29 (24-34) mg/kg bw for the technical grade and a granular
formulation, respectively.
0172d . -29- 04/21/89
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5. PHARMACOKINETICS
5.1. ABSORPTION
Puhl and FredMckson (1975) Investigated the gastrointestinal absorption
of a single orally administered dose of dlsulfoton-o-ethyl-1-14C (99%
purity) In Sprague-Dawley rats. Groups of 12 males received a single gavage
dose of 1.2 mg/kg and 12 females received 0.2 mg/kg. Over a 10-day period,
an average of 81.6, 7.0 and 9.2% of the administered dose of radioactivity
was recovered In the urine, feces and expired air, respectively. Urinary
excretion appeared to be rapid; 50% of the administered dose was eliminated
within 4-6 hours In males and within 30-32 hours In females. Gastrointesti-
nal absorption of dlsulfoton 1n rats appears to be rapid and nearly complete.
5.2. DISTRIBUTION
In the study described above, peak levels of radioactivity were observed
In tissues and blood 6 hours after treatment (Puhl and FredMckson, 1975).
Highest levels of radioactivity occurred In the liver, followed In order of
decreasing concentrations by the kidney, plasma, fat, whole blood, skin,
muscle and brain. At 48 hours after dosing, male rats had 4.1 and 0.4% of
the administered dose of radioactivity In the liver and kidneys, respec-
tively. In female rats, 16.1 and 1.2% of the administered dose of radio-
activity was detected 1n the liver and kidneys, respectively, at 48 hours.
In beagle dogs given oral doses of dlsulfoton, residues of dlsulfoton
were found (listed from the highest to the lowest concentration) In the
kidneys, urine, serum, liver, bile and brain (H1k1ta et al., 1973).
5.3. METABOLISM
WHO (1976) proposed the scheme for the metabolism of dlsulfoton 1n rats
presented 1n Figure 5-1. This scheme Is constructed around three different
pathways: 1) oxidation of the thloether sulfur to produce sulfoxldes and
0172d -30- 04/21/89
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"'MI
r . n
H,0
l
P-
P-OH
EtO s
Nil
P-S-CHjCHjSCHjCHj
EtO/
01sulfo ton
CO]
EtO ° 0
Ml t
P-S-CHjCHjSCHgCHj
• /
EtO 0*j$t" antloj ful'enat
co:
C03
"°MI
P-SCHjCH2SCH;CHj
EtO/ Qiiulfoton tul'an*
to:
EtO
Nil \f
P-SCHjCHjSCHjCH,
Oijrjtn «n«lo) sal font
14,
Position of "C-Ubel
FIGURE 5-1
Proposed Pathways for Metabolism of Dlsulfoton by Rats
Source: WHO, 1976
0172d
-31-
04/17/89
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sulfones; 2) oxidation of the thlono sulfur to produce the oxygen analog;
and 3) hydrolysis of the P-S-C linkage to produce the corresponding phos-
phorothlonate or phosphate. WHO (1974) hypothesized that oxidation produced
metabolites that were active as cholInesterase Inhibitors. Greatest support
for this scheme comes from the study by Puhl and Fredrlckson (1975)
described above. Together, d!ethylphosphoroth1onate and Its oxygen analog
dlethylphosphate constituted 93% of the radioactivity recovered, presumably
from the urine. Chloroform-soluble metabolites In the liver and urine were
Identified as dlsulfoton sulfoxlde and the sulfoxlde and sulfone of the
oxygen analog. In addition, 9.2X of the dose was recovered as radlolabeled
carbon dioxide, suggesting that hydrolysis of the P-O-C bond had occurred.
There appeared to be no gender-related differences In metabolism of
dlsulfoton by rats.
Iji vivo and j_n vitro studies In mice support the pathways suggested for
rats. March et al. (1957) administered 32P-labeled dlsulfoton to mice by
1ntraper1toneal Injection (animal strain and dose not reported) and
recovered mainly (unspecified) hydrolysis products from the urine. Metabo-
lites Identified In j£ vitro studies were the sulfoxlde and sulfone of
dlsulfoton and Us oxygen analog.
Rapid oxldatlve metabolism of dlsulfoton has been demonstrated In liver
homogenates from rats, guinea pigs and monkeys (Rao and McKlnley, 1969). In
this study, no formation of esterase Inhibitors was detected. This sug-
gested that the oxldatlve metabolites of dlsulfoton either were not active
or that they underwent rapid degradation after formation. Bomblnsk! and
DuBols (1958) reported that dlsulfoton Is metabolized to Us oxygen analog
and that this oxygen analog 1s the active antlchollnesterase metabolite In
rats, mice and guinea pigs.
0172d -32- 04/17/89
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5.4. EXCRETION
Radioactivity recovered from urine, feces and as 14CO_ from expired
air accounted for 84.3, 6.1 and 9.2% of the administered dose In male rats
(total of 99.6%), and 78.9, 7.8 and 9.2% (total of 95.9%) of the adminis-
tered dose In female rats within 10 days of oral treatment In the study by
Puhl and Fredrkkson (1975). The primary route of excretion was through the
urine. The Investigators noted that urinary excretion In males was markedly
more rapid than In females; within 8 hours of treatment, urinary excretion
had accounted for 60.9% of the dose 1n males but only 11.2% of the dose 1n
females. Total urinary excretion at the end of the 10-day collection period
was similar for both sexes. The presence of dlsulfoton 1n the bile of dogs
Indicates that biliary excretion also occurs, although neither biliary nor
fecal excretion was quantified (Hlklta et al.. 1973).
5.5. SUMMARY
The gastrointestinal absorption of d1sulfoton-o-ethyl-l-l4C (99%
purity) Is almost complete. When administered to rats, 90.8% of the
administered dose was recovered In the urine and expired air, with only 7.0%
of the dose being excreted In the feces (Puhl and FredMckson, 1975).
After oral administration to rats, the highest concentrations of
dlsulfoton appear In the liver, with lesser amounts found In the kidneys,
fat, blood, muscle and brain (Puhl and Fredrlckson, 1975). Dlsulfoton has
also been found In the kidney, serum, liver, bile and brain of dogs after
oral treatment (H1k1ta et al., 1973).
Dlsulfoton undergoes oxldatlve and hydrolytlc reactions In rats (Puhl
and Fredrkkson, 1975) and mice (March et al., 1957). The main urinary
metabolites of rats are d1ethylphosphoroth1onate and dlethylphosphate. The
0172d -33- 04/21/89
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sulfoxide and sulfone of dlsulfoton and Its oxygen analog are relatively
minor metabolites. Metabolites produced by oxidation may be responsible for
the cholinesterase Inhibition associated with dlsulfoton (Bomblnskl and
DuBois, 1958; WHO, 1974).
Excretion of dlsulfoton 1n rats occurs mainly from the kidneys (81.6% 1n
urine) and to a lesser extent by the gastrointestinal tract (7.0% in the
feces) and lungs (9.2% In the expired air) (Puhl and Fredrlckson, 1975).
Urinary excretion occurs more rapidly in male rats than in female rats.
The presence of dlsulfoton In the bile of dogs treated orally Indicates that
biliary excretion also occurs (Hlkita et al., 1973).
0172d -34- 04/21/89
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Pertinent data regarding the subchronic and
chronic toxlclty of dlsulfoton as a result of Inhalation exposure were not
located 1n the available literature dted In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC — Schwab and Murphy (1981) fed groups of 50
female Holtzman rats 0, 7.5 or 20 ppm dietary dlsulfoton (97% pure) for 62
days. Overt signs of chollnesterase Inhibition observed among rats In the
20 ppm group Included diarrhea, polyurla and tremors. These symptoms became
less severe as the experiment neared completion. Overt signs of chollnes-
terase Inhibition were not observed at 7.5 ppm. Acetylchollnesterase
activity of the brain and diaphragm was depressed In a dose-related manner
In both treatment groups from day 6 through completion of the experiment.
Acetylchollnesterase activity depression reached steady-state by day 9 of
treatment. A dose-related depression of body weight occurred after ~2 weeks
of treatment that was statistically significant at the lower dietary
concentration at some time points during the study.
Vaughn et al. (1958) fed four groups of one male and one female mongrel
dogs dlsulfoton In dietary concentrations of 0, 1, 2 and 10 ppm for 12
weeks. Plasma and red blood cell chollnesterase activity was reduced
significantly In the 2 and 10 ppm groups. Plasma chollnesterase activity
rapidly returned to control levels after discontinuing treatment; however
red blood cell chollnesterase activity remained depressed for at least 4
weeks after treatment was discontinued. No antkhoHnesterase activity was
observed In the 1 ppm group. In addition, no effect on weight change or
behavior occurred.
0172d -35- 04/17/89
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Five groups of 13 male and 13 female rats were fed dlsulfoton In dietary
concentrations of 0, 1, 2, 5 and 10 ppm for 16 weeks (Ooull and Vaughn,
1958). At weeks 8 and 16, brain and erythrocyte cholInesterase levels were
depressed In male and female rats receiving a dietary concentration of >2
ppm. As noted In other studies, the females were more sensitive than males
to the antlcholInesterase activity of dlsulfoton. No antlcholInesterase
activity occurred at 1 ppm. Also, no treatment-related effects were
observed during extensive gross and microscopic analysis of tissues. Food
consumption, growth, behavior and mortality were also unaffected by
treatment.
In a similar study, groups of 12 male and 12 female CF-LP mice were fed
dietary concentration of 0, 0.2, 1.0 and 5.0 ppm dlsulfoton for 13 weeks
(Rlvett et al., 1972). Chollnesterase activity was reduced In all tissues
(not specified) 1n male and female mice In the 5 ppm group, with female mice
showing a greater sensitivity to antlchollnesterase activity. Also, female
mice 1n the 5 ppm group had slightly Increased liver weights. Growth,
urlnalysls, hematology, blood chemistry and hlstopathology were not affected
by dlsulfoton administration.
No significant antlchollnesterase activity was observed In the plasma
and red blood cells of five humans treated orally with 0.75 mg/kg/day of
dlsulfoton for 30 days (Rider et al., 1972). Two humans served as controls.
No further details were provided.
Clark and Stavlnova (1971) reported reduced brain acetylchollnesterase
and altered brain tissue permeability In mice and rats fed diets containing
150 and 50 ppm dlsulfoton for >2 months, respectively. Brain acetylcholln-
esterase was reduced by 2554 when compared with control animals. The purpose
0172d -36- 04/21/89
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of this study was to examine staining techniques for studying permeability
changes In CNS tissue. Further details of the results or the study design
were not given.
Clark et al. (1971) studied the exploratory behavior of Charles River
mice. One group of male mice (unspecified number) and one group of 25
female mice were fed diets containing 200 ppm dlsulfoton. One group of male
mice and one group of female mice served as controls. The authors stated
that there were four groups of 10-12 male mice and four groups of 10-12
female mice; however, H Is unclear when these groups were divided and how
they were treated or examined. Because of excessive mortality among females
(5/25) during the first 4 weeks of treatment, the dietary concentration of
dlsulfoton was decreased to 150 ppm; no further deaths occurred. Explora-
tory activity, examined after 8 weeks of treatment, was Increased signifi-
cantly (p<0.05) In dlsulfoton treated mice when compared with control mice.
There was no apparent difference between the exploratory activity of male
and female mice. The authors did not Interpret the significance of these
results.
No neuroses or discrimination deficits were reported 1n an abstract of a
study 1n which Long-Evans rats were fed diets containing 50 ppm dlsulfoton
for 2 months (Clark and Pearson, 1972). Control rats were fed an untreated
diet. Brain acetylchollnesterase activity In treated rats was "-25% that of
control activity. Tremors and convulsions occurred In a few of the treated
rats and a few died from treatment.
An abstract of a study by Glurgea (1979) reported the effects of
dlsulfoton on thymus weight and thymus concentrations of RNA, ONA, total
protein and glycogen among rats. Adult female Wlstar rats were given orally
administered doses of 22 or 110 wg/kg/day dlsulfoton In milk for 3 or 6
0172d -37- 04/21/89
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months. At 3 months, glycogen levels were altered significantly In rats
given 22 pg/kg/day, and RNA, ONA, total protein and glycogen were altered
significantly 1n rats given 110 pg/kg/day. After 6 months, all of the
parameters were within control ranges in the 22 yg/kg/day group. In rats
given 110 yg/kg/day, RNA, DMA and glycogen levels were significantly
different from controls after 6 months. It was postulated that the toxic
effects of dlsulfoton were due to RNA polymerase inhibition.
6.1.2.2. CHRONIC — Four groups of 60 male and 60 female F344 rats
were given dietary concentrations of 0, 0.8, 3.3 or 13 ppm dlsulfoton (98.1%
pure) for 2 years (Hayes, 1985). Increased mortality occurred In females In
the 13 ppm group during the last week of the study. Dose-related and
statistically significant decreases 1n chollnesterase activity occurred In
the plasma, red blood cells and brain tissue of male and female rats 1n all
treated groups throughout the study. A statistically significant (p<0.05)
Increased Incidence of cornea! neovascularlzatlon occurred In male and
female rats 1n the 13 ppm group. Also, a dose-related Increased Incidence
of optic nerve degeneration occurred In all treated groups, which became
statistically significant In males fed 3.3 ppm and In females fed 3.3 and 13
ppm. Statistically significant (p<0.05) cystic degeneration of the
HardeMan gland occurred 1n female rats from all of the treatment groups and
in male rats In the 3.3 ppm group. Atrophy of the pancreas also occurred at
a significantly (p<0.05) Increased Incidence In high-dose males. It Is not
clear why chollnesterase Inhibition occurred throughout this study In rats
at a dietary concentration as low as 0.8 ppm, but did not occur at 1.0 ppm
1n a 16-week study (Doull and Vaughn, 1958) discussed 1n Section 6.1.2.1.
Dietary concentrations of 0, 1, 4 or 16 ppm dlsulfoton (98.2% pure) were
administered to four groups of 50 male and 50 female CD-I mice for 23 months
0172d -38- 04/21/89
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(Hayes, 1983). Female mice In the 16 ppm group had a significantly higher
mean kidney-to-body weight ratio, which may have been due to a nonsignifi-
cant Increased Incidence of malignant renal lymphomas In this group.
Significant ant1chol1nesterase activity occurred In the plasma, red blood
cells and brain tissue of both males and females In the 16 ppm group. The
chollnesterase levels of animals In the 1 and 4 ppm dose groups were not
measured. No dlsulfoton-related effects were noted on the body weight, food
consumption or hematology of the treated mice.
Dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm dlsulfoton (95.7% pure)
were administered to groups of 60 male and 60 female Sprague-Dawley rats for
2 years (Carpy et al., 1975). The 0.5 ppm dose was Increased to 5.0 ppm at
week 81 of the study period. A dose-related trend toward Increased absolute
and relative spleen, liver, kidney and pituitary weights occurred In male
rats treated with 1-5 ppm dlsulfoton. A trend toward decreased absolute and
relative brain weights occurred In male rats and Increased brain weights
occurred In female rats at concentrations of 1-5 ppm. A trend toward
decreased spleen, liver, kidney and pituitary weights were observed In
female rats from all treatment groups. Statistically significant (p<0.05)
Increased absolute spleen and liver weights occurred In male rats from the 5
ppm group. Statistically significant (p<0.05) decreased absolute and
relative kidney weights occurred In female rats from the 5 ppm group.
Statistically significant antlchollnesterase activity In the plasma, red
blood cells and brain tissue occurred In male and female rats In the 2.0 and
5.0 ppm groups. Female rats In the 1 ppm group also had statistically
significant (p<0.01) antlchollnesterase activity In the brain. No
dlsulfoton-related effects were reported on food consumption, body weight,
hematology, clinical chemistry, urlnalysls and hlstopathology. In a review
0172d -39- 04/17/89
-------
of this study, U.S. EPA (1984b) concluded that the hlstopathologkal evalua-
tion was Inadequate. A less detailed review of this study (Klotzsche, 1975)
Indicated that cholInesterase Inhibition occurred at 2.0 ppm but not at 1.0
ppm.
Dietary concentrations of 0, 0.5 or 1.0 ppm dlsulfoton (95.7% pure) were
administered to groups of four male and four female beagle dogs for 2 years
(Hoffman et al., 1975). A fourth group of beagle dogs received 2.0 ppm
dietary dlsulfoton for 69 weeks, 5 ppm for an additional 3 weeks and 8 ppm
for an additional 32 weeks. Chollnesterase activity In male dogs from the
2.0 ppm group was depressed by 50 and 33% 1n the red blood cells and plasma,
respectively. Similarly, female dogs 1n this group had red blood cell and
plasma Chollnesterase activities that were depressed by 22 and 36%, respec-
tively. The antlchollnesterase activity In this group decreased somewhat,
but was still present by week 69. When the dose was Increased to 5 ppm
there was an even more pronounced decrease In the Chollnesterase activity.
There were no dlsulfoton-related effects on general appearance, behavior,
ophthalmoscoplc examinations, food consumption, body weight, organ weight.
hematology, clinical chemistry or hlstopathology.
Four groups of beagle dogs (10 total) were given orally administered
gelatin capsules containing 0, 0.5, 1.0 or 1.5 mg/kg dlsulfoton, 5 days/week
for 2 years (Uga et al., 1977). The number per group and sex of the dogs
was unspecified. Dose-related reductions 1n the number of nerve fibers and
Increased numbers of gllal cells 1n the optic nerve occurred at each dose.
Infrequent occurrences of myelln sheath necrosis were also observed at 0.5
mg/kg/day. Severe destruction of the optic nerve and thinning of the myelln
sheaths of surviving axons were observed among dogs In the 1.0 and 1.5
mg/kg/day groups. Concentric lamellae were observed on the surviving axons,
0172d -40- 04/17/89
-------
which Indicates a degenerative process. Necrosis of the retinal epithelial
and Muller cells was observed In all treated dogs. The necrosis of the
epithelial cells only occurred In a small area of the retina and probably
does not represent a toxic effect of dlsulfoton. These data were not
quantified and statistical analyses were not presented.
Ishlkawa (1973) compared the symptoms of Saku disease (chronic optic
neuropathy) In humans with signs observed In beagle dogs given oral doses of
dlsulfoton of 0.5 and 1.5 mg/kg/day for 2 years. The dogs showed many of
the signs of Saku disease, which has been characterized (In humans) by
Impaired vision, central scotomas, narrowed peripheral vision* myopia
(sometimes associated with severe vertical corneal astigmatism), pyramidal
signs, reduced propMoceptlve sense, disturbed balance, dizziness, vomiting,
diarrhea, constipation, perspiration, numbness, polydlpsla, Impotency,
organophosphates In the blood or urine (>0.01 ppm), swelling or degeneration
of the optic nerve, Impaired movement of the ocular muscles, abnormal ERG,
reduced chollnesterase activity. Impaired liver function, loss of tactile
sensitivity 1n hands and feet, foot drop and abnormal EEGs.
An abstract of a Japanese study by Mukuno and Ima1 (1973) reported the
results of a study In which dogs were treated orally with dlsulfoton at
doses of 0, 0.5 or 1.5 mg/kg/day 2 years. Swelling or demyellnatlon of
nerve bundles and mild axonal change occurred In the extra-ocular muscles.
Also, the chollnesterase activity was significantly reduced (no statistical
analysis was performed) In the erythrocytes; however, the chollnesterase
activity of the neuromuscular Junctions was within normal limits. Bullous
and Irregular dilation of the Junctlonal folds of the neuromuscular junc-
tions was observed. In addition, atrophy of some Junctlonal folds, marked
by shorter and fewer folds, occurred. A reduction 1n the numbers of
0172d -41- 04/21/89
-------
mitochondria in the sole plate area also occurred and swelling of some
mitochondria were observed in the muscle fibers. These effects were not
observed In control dogs. No further details of this study were provided.
An abstract of a Japanese study by Tokoro et al. (1973) reported myopia
and rule astigmatism, and a correlation between AChe inhibition and the
occurrence of myopia and axial nerve elongation in beagle dogs given
dlsulfoton at oral doses of 0, 5, 10 or 15 mg/kg/day for 2 years. There
were six, two, two and one dogs In the control, low, middle and high dose
groups, respectively. No further details were provided.
Ocular effects were observed In groups of 10 beagle dogs that were given
oral doses of dlsulfoton at 0, 5, 10 and 15 mg/kg/day for 2 years (Suzuki
and Ishlkawa, 1974). Measures of refraction revealed that myopia occurred
after 12 months of dlsulfoton administration, with the greatest occurrence
In the 10 and 15 mg/kg/day groups. As the dogs Increased In age, myopia was
also observed In control animals. Incidence data for this effect were not
given. Structural changes to the ciliary muscle cells of treated dogs also
occurred in dogs from the 10-15 mg/kg/day groups, and were characterized by
the presence of unique membranous structures In the cytoplasm of these cells
and cystic enlargement of the cell's outer space. The rich chollnergic
Innervatlon of these cells may Induce oxidation of dlsulfoton to Us toxic
metabolite. Myopia seen In the dlsulfoton-treated dogs was attributed to
the structural changes found 1n the ciliary muscles.
An abstract of a Japanese study by Ishlkawa and Mlyata (1980) reported
that myopia occurred simultaneously with the reduction of acetylchollnes-
terase activity In all beagle dogs treated with 5, 10 or 15 mg of dlsulfo-
ton, 5 days/week for 2 years (route of exposure not reported). Widespread
destruction of the ciliary muscle occurred 1n dogs receiving the 15 mg dose.
0172d -42- 04/17/89
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Myopia (after 18 months), astigmatism (after 4 months), abnormal refrac-
tion associated with decreased acetylchollnesterase activity (from 4-12
months) and an Increase followed by a subsequent decrease in ophthalmic
pressure were reported 1n beagle dogs that received oral doses of 0.5, 1.0
or 1.5 mg/kg/day of dlsulfoton for 2 years (Otsuka and Tokoro, 1976).
Hlklta et al. (1973) measured acetylchollnesterase activities In several
organs and tissues of beagle dogs that received low (unspecified) doses of
dlsulfoton orally for 2 years. Tissues with the highest to lowest acetyl-
chollnesterase activities were the retina, uvea, mldbraln, spinal cord and
Intestine. Inhibition of chollnesterase activity occurred In a dose-related
manner.
6.1.3. Other Relevant Information. The activities of ethylmorphlne
N-demethylase and NADPH cytochrome C reductase were significantly lower
(p<0.05) In three mice given single oral doses of 35.1 ymol/kg (9.6 mg/kg)
dlsulfoton 1 hour before sacrifice when compared with control mice (Stevens
et al., 1973). In contrast, the activity of NADPH cytochrome C reductase
was not significantly different from controls 1n three mice given oral doses
of 35.1 ymol/kg dlsulfoton for 3 days. In these treated mice, the activi-
ties of ethylmorphlne N-demethylase and NADP oxldase were significantly
different (p<0.05) from controls. In three mice given 29.2 ymol/kg (8.0
mg/kg) dlsulfoton orally for 5 days, activities of ethylmorphlne N-demethyl-
ase and NADPH oxldase were significantly different (p<0.05) from controls.
In addition the P-450 content of these treated mice was significantly higher
(p<0.05) than that of control mice. These data suggest that dlsulfoton
affects the activities of various drug metabolizing enzymes In the body.
Pretreatment with phenobarbltal to Induce liver mlcrosomal oxidizing
enzyme activity protected adult rats and mice against the lethality of acute
1ntraper1toneal doses of dlsulfoton (DuBols and KlnoshHa, 1968).
0172d -43- 04/17/89
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Acute toxldty data for dlsulfoton are presented in Table 6-1. The
acute toxldty of dlsulfoton appears to be similar In rats and mice by
either oral or Intraperltoneal administration, but female rats appear
markedly more sensitive than male rats. Guinea pigs appear to be somewhat
less sensitive than rats or mice. An Inhalation LC,n 1n rats of 200
mg/m3 was also reported, but the duration of exposure was not specified
(NIOSH, 1988). Crawford and Anderson (1974) reported oral LD5Q values for
the oxygen analog of dlsulfoton, the sulfoxldes and sulfones of disulfoton,
and Us oxygen analog of 1.1-1.24 mg/kg In female rats, suggesting that the
acute toxldty of the metabolites 1s similar to that of the parent compound.
Groups of six white leghorn hens were fed concentrations of 0, 2, 10 or
25 ppm dlsulfoton 1n their diet for 30 days (Taylor, 1966). No evidence of
demyelInatlon was observed In any tissues examined.
Hlxson (1982) also evaluated dlsulfoton for delayed neurotoxlclty In
white leghorn hens. Groups of 20 hens were given 30 mg/kg (97.8X pure) In
two doses, 21 days apart. Negative, positive and antidote controls were
maintained and responded appropriately. There were no Indications of
delayed neurotoxlclty 1n dlsulfoton-treated hens. A similar study was
performed by Fletcher et al. (1971), 1n which hens were treated with a 26
mg/kg oral dose on each of 2 days separated by 21 days. No evidence of
delayed neurotoxlclty was reported after an additional 21-day observation
period. Hens treated with a positive control responded appropriately.
WHO (1974) reviewed several Investigations of the Interaction of
dlsulfoton In combination with other organophosphates and a carbamate
compound 1n acute toxldty tests. Interactions were described as slightly
less than or slightly more than additive, but potentlatlon .was not observed.
0172d -44- 04/17/89
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TABLE 6-1
Acute Toxlclty of Dlsulfoton
Route Species
Oral rat
rat
rat
rat
rat
rat
guinea pig
mouse
mouse
Intraperltoneal rat
mouse
guinea pig
Dermal rat
Sex
M
M
M
F
F
F
M
M
F
NR
M
F
M
F
M
M
F
L050
(mg/kg)
12.5
>2.0
6.8
2.6
2.0
2.3
27
7.0
8.2
4.8
10.5
2.0
5.5
6.5
30
25
6.0
Reference
Bomblnskl and DuBols,
Crawford and Anderson,
Galnes, 1969
Bomblnskl and DuBols,
Crawford and Anderson,
Galnes, 1969
Bomblnskl and DuBols,
M1ha1l, 1978
NIOSH, 1988
Bomblnskl and DuBols,
Bomblnskl and DuBols,
Bomblnskl and DuBols,
NIOSH, 1988
1958
1974
1958
1974
1958
1958
1958
1958
NR = Not reported
0172d
-45-
04/17/89
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6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the Inhalation carclnogen-
Iclty of dlsulfoton were not located In the available literature cited In
Appendix A.
6.2.2. Oral. Dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm dlsulfoton
(95.7% pure) were administered to four groups of 60 male and 60 female
Sprague-Dawley rats for 2 years (Carpy et al., 1975). The 0.5 ppm dose was
Increased to 5.0 ppm at week 81 of the study. In terms of food consumption,
body weight, hematology, clinical chemistry, urlnalysls and hlstopathology,
no treatment-related effects were noted. Females receiving 5.0 ppm had a
significant (p<0.05) decrease In absolute and relative kidney weights. A
significant (p<0.01) decrease In brain AChE (11%) was observed 1n females at
1.0 ppm and In both sexes at 2.0 and 5.0 ppm. No evidence of dlsulfoton-
related cardnogenlcKy was observed under the conditions of this study.
In another study, four groups of 60 male and 60 female F344 rats were
fed dietary concentrations of 0, 0.8, 3.3 or 13 ppm dlsulfoton (98.154 pure)
for 2 years (Hayes, 1985). Nonneoplastlc effects Included a significant
(p<0.05) dose-related Inhibition of AChE In all dose groups and a signifi-
cant (p<0.05) Increase 1n corneal neovascularlzatlon In both sexes at 13
ppm. Leukemia, adenoma of the adrenal cortex, pheochromocytoma, flbro-
adenoma of the mammary glands, adenoma and carcinoma of the pituitary
glands, adenoma of the testes and uterine stromal polyps were observed but
the Incidence was not reported. These neoplastlc lesions, however, did not
occur In a dose-related pattern, and there was no statistically significant
difference In their Incidence between treated and control rats.
In a study by Hayes (1983), dietary concentrations of 0, 1, 4 or 16 ppm
dlsulfoton (98.2% pure) were administered to groups of 50 male and 50 female
CD-I mice for 23 months. An Increased Incidence of malignant lymphoma
0172d -46- 03/21/90
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occurred In male (20%, 18%, 24%, 30%) and female (54%, 44%, 52%, 68%) rats
at 0, 1, 4 and 16 ppm, respectively; however, this Incidence was not
statistically significant when compared with control rats. Furthermore,
these Incidences were within normal limits reported 1n the literature. AChE
activity was tested 1n the high-dose group (16 ppm) and the controls. The
AChE activity was significantly depressed In the treated mice. A
significantly (p<0.05) Increased mean kidney weight and kidney-to-body
weight ratio In high-dose females may have been related to the
nonsignificant Increase In the Incidence of malignant lymphomas of the
kidneys In this group. The occurrence of other neoplasms was only
equivocally different between the control and treated rats. Therefore,
although these studies are suggestive, the evidence of dlsulfoton-lnduced
carclnogenklty 1s mixed and no clear conclusions are possible.
6.3. MUTAGENICITY
Several tests for the mutagenlc activity of dlsulfoton have been
performed (Table 6-2) and show generally negative results. Confirmation of
positive responses have only been observed 1n base-pair reversion strains of
Salmonella typhlmurlum (Hanna and Dyer, 1975; Morlya et al., 1983) and E..
coll (Hanna and Dyer, 1975). In Salmonella, the mutagenlc activity 1s not
observed 1n TA100 and the response seen 1n TA1535 was only slightly greater
than 2-fold above controls and at high concentrations. Dlsulfoton did not
Increase gene conversion or mltotlc recombination 1n yeast (Simmon, 1979;
Rlcdo et al., 1981), sister chromatld exchange In V79 Chinese hamster cells
(Chen et al., 1981), chromosome aberration In cultured human cells (Huang,
1973) or dominant lethals 1n male mice (Arnold, 1971). Dlsulfoton did
Increase unscheduled DMA synthesis In WI38 human flbroblasts In one experi-
ment without S9 activation, but the response was not reproducible and was
clearly negative 1n two replicates with S9 activation (Simmon, 1979).
0172d -47- 03/21/90
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TABLE 62
Hutagenlclty Data.for Dlsulfoton
CO
i
o
co
ro
co
co
VO
Assay
Reverse mutation
Relative toxlclty
Nilotic crossing-over;
gene conversion;
Indicator Organism
Salmonella typhlmurlum
TA1535
S. typhlmurlum TA100.
TA98. TA1537. TA1538;
Escherlchla coll WP?hvr
S. typhlmurlum
several strains
S. typhlmurlum
S. typhlmurlum TA1535.
TA1S37. TA1S38. TA98.
TA100
Bacillus subtins;
S. typhlmurlum
E . coll MP2
E. colt UP?. HP? uvrA.
CM 571. CM 611. UP67.
MP12
E . coll CH 561
|. subtllls
L- coll
Saccharomyces cerevlslae
Purity
NR
NR
NR
NR
technical
grade
NR
technical
grade
NR
NR
technical
grade
technical
grade
NR
Application
plate
Incorporation
plate
Incorporation
spot test
NR
plate
Incorporation
NR
plate
Incorporation
spot test
spot test
plate
Incorporation
plate
Incorporation
liquid
suspension
Concentration/
Dose
0 to >5000
tig/plate
0 to >5000
pg/plate
5-10 ut/plate
NR
10-5000
pg/plate
NR
10-5000
pg/plate
5-10 pt/plate
5-10 pi/plate
10-5000
pg/plate
10-5000
pg/plate
NR
Activating
System
• S-9
iS-9
none
t Aroclor
l?54-1nduced
rat liver
homogenate
»S-9/Aroclor
T?54
NR
•S-9
none
none
• S-9
*S-9
«S 9
Response Reference
•/» Horlya
et al.. 1983
-/- Norlya
et al.. 1963
« Hanna and
Dyer. 1975
Qulnto
et al.. 1980
-/- Simmon. 1979
Jeang and
LI. 1978
-/- Simmon. 1979
» Hanna and
Dyer. 1975
Hanna and
Dyer. 1975
-/- Simmon. 1979
-/- Simmon. 19/9
./- Rlcclo
et al.. 1981
reverse mutation
-------
TABLE 6-? (cont.)
Assay
Hltotlc recomblnants
Sister chroma t Id
exchange
Unscheduled ONA
synthesis
Chromosomal aberration
Dominant lethal
Indicator Organism
S. cercvlslae 03
Chinese hamster V79
cell line
human flbroblast
HI -38 cells
human cells
mouse
Purity
technical
grade
9B.6X
technical
grade
NR
NR
Application Concentration/ Activating
Dose System
liquid 1-5X v/v .59
suspension
cell culture 10-80 \>q/ml none
cell culture 0-1000 ng/tnl »S-9
cell culture NR NR
Intraperltoneal 0-0.5 mg/kg NA
Injection
Response Reference
-/- Simmon,
Chen et
1981
-A Simmon.
Huang,
Arnold
et a)..
1979
al..
1979
1973
1971
NR •= Not reported; NA = not applicable
o
CD
CD
CD
10
-------
6.4. TERATOGENICITY
Tesh et al. (1982) administered 97.3% pure dlsulfoton by gavage to
groups of 14-22 pregnant New Zealand white rabbits at dosages of 0, 0.3, 1.0
or 3.0 mg/kg/day on days 6-18 of gestation. No signs of maternal toxIcHy
were observed at 0.3 or 1.0 mg/kg/day, but signs of toxlclty (muscular
tremors, unsteadiness, 1ncoord1nat1on, Increased respiratory rate) and
mortality In the high dose group led to reduction of the dosage first to 2.0
mg/kg/day and then to 1.5 mg/kg/day. There were no compound-related effects
on maternal body weight or on fetal survival, growth or development.
Although the study has not been peer -reviewed, the 1.5 mg/kg/day dosage was
considered a NOAEL for developmental toxldty In this study (U.S. EPA, 1987).
Lamb and Hlxson (1983) treated groups of 25 pregnant CO rats by gavage
with dlsulfoton (98.2% pure) at dosages of 0, 0.1, 0.3 or 1 mg/kg/day on
gestation days 6-15. Maternal plasma and RBC chollnesterase activities were
Inhibited at 0.3 and 1 mg/kg/day; no other parameters of maternal toxlclty
were reported. Examination of the fetuses delivered by Caesarean section
revealed no evidence of compound-related skeletal or soft tissue malforma-
tions. Fetal body weights were not reported, but retarded ossification of
the parietal bones and sternebrae, manifestations of fetotoxldty, were
reported at 1.0 mg/kg/day. U.S. EPA (1987) judged 0.3 mg/kg/day a NOAEL and
1.0 mg/kg/day a LOAEL for fetotoxldty In this study.
6.5. OTHER REPRODUCTIVE EFFECTS.
Groups of 20 female and 10 male albino Holtzman rats were given dietary
concentrations of 0, 2, 5 or 10 ppm dlsulfoton (98.5% pure) during a
3-generat1on reproduction study (Taylor, 1966). In the first and third
generations, a 21 and 33% reduction 1n Utter size occurred 1n the F
la+b
and F rats receiving 10 ppm dlsulfoton. A 10-25% reduction In
pregnancy rate also occurred In the F ma tings In these generations.
O
0172d -50- 08/28/89
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Hepatic lesions characterized by cloudy swelling and fatty Infiltration
occurred In both sexes of the F_. litters at 10 ppm. In these Utters,
nephropathy occurred In females and juvenile testlcular hypoplasla occurred
In the males. Hlstopathologkal examinations of the lower dose groups were
not performed. A 60-70X Inhibition of chollnesterase activity In RBCs of
rats 1n the F Utters and their parents was observed at >5 ppm. A
30-40X Inhibition of RBC chollnesterase occurred In females of this genera-
tion at a dietary concentration of 2 ppm. The U.S. EPA (1987) stated that
because of Incomplete necropsy and hlstopathologlcal data and a failure to
perform statistical analysis 1n this study, which has not undergone peer
review, a reproductive NOAEL could not be Identified.
The reproductive effects of dlsulfoton were examined 1n a study by Ryan
et al. (1970), 1n which 15 male and 10 female albino rats (unspecified
strain) received a diet containing 10 ppm dlsulfoton for 60 days. Controls
consisted of 10 males and 15 females given untreated feed for 60 days.
After this period, the rats were divided Into five groups of five males and
five females per group. The first group consisted of male and female rats
that had both received dlsulfoton before mating and continued to receive It
throughout the mating period (8 days). The second group consisted of males
that had received dlsulfoton before mating and females that were untreated;
neither sex In this group received dlsulfoton during the mating period. The
third group consisted of male and female rats that were untreated before
mating and remained untreated during the mating period. The fourth group
consisted of females that were untreated and males that were treated with
dlsulfoton before mating; both sexes In this group received dlsulfoton
during the mating period. The fifth group consisted of untreated males and
treated females that did receive dlsulfoton before mating; both sexes
0172d -51- 08/28/89
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received dlsulfoton during the mating period. All of the rats that were
treated with dlsulfoton before mating received dlsulfoton during the
gestation period.
The inhibition of cholInesterase activity In the brain associated with
dlsulfoton treatment was more pronounced In female rats than In male rats.
In group 1 male and female rats that received dlsulfoton throughout the
study period (95 days), percent cholInesterase activity was 48.4 (males) and
18.7% (females) compared with controls. Pups born to group 1 dams treated
with dlsulfoton throughout the study (95 days) had brain chollnesterase
activity of only 67.9X of chollnesterase activity measured 1n control group
pups. The number of pregnancies was also decreased among all groups of
dlsulfoton-treated rats when compared with controls (group 3). Among
control rats (group 3), 5/5 females became pregnant. In group 2, In which
only the male rats received the treated diet before but not during mating,
4/5 females became pregnant. In group 1, In which both sexes received
dlsulfoton before and during mating, only 3/5 females became pregnant. In
group 4, In which males were treated and females were untreated before
mating and both sexes were treated during mating, only 3/5 females became
pregnant. In group 5, where females were treated and males were untreated
before mating and both sexes were treated during mating, only 3/5 females
became pregnant. The cause of the decrease In pregnancies was not deter-
mined in this study. No further details were provided. It appears that
dlsulfoton Impaired both male and female reproduction In this study. The
small number of animals, however, makes meaningful conclusions difficult.
6.6. SUMMARY
Chollnesterase Inhibition Is a widely reported effect of chronic, sub-
chronic or acute oral exposure to dlsulfoton 1n humans, rats, mice and dogs
0172d -52- 08/28/89
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(U.S. EPA, 1984b, 1987; WHO, 1974; WHO, 1976). ChoiInesterase Inhibition
has occurred at dietary concentrations as low as 0.8 ppm 1n a 2-year dietary
study In rats (Hayes, 1985).
Lesions of the optic nerves of rats and dogs and extra-ocular muscles of
dogs have been reported 1n long-term dietary studies by Hayes (1985), Tokoro
et al. (1973), Ishlkawa (1973) and Uga et al. (1977). Swelling and
demyelInlzatlon of nerve bundles and bullous and Irregular dilation of the
junctlonal folds of the neuromuscular Junctions In the extra-ocular muscles
of dogs have been reported at 0.5-1.5 mg/kg/day dlsulfoton (Mukuno and Ima1,
1973). In addition, the occurrence of myopia, Impaired vision, central
scotomas, narrowed peripheral vision, necrosis of the retinal and Muller
cells, rule astigmatism and fluctuations In opthalmlc pressure have been
reported In chronic studies In dogs (Ishlkawa, 1973; Uga et al., 1977;
Tokoro et al., 1973; Ishlkawa and Mlyata, 1980). Dietary concentrations
ranging from 0.5-1.5 ppm were used In these studies; however, the exact
concentrations at which these symptoms occurred were not given. Cornea!
neovascularlzatlon occurred at dietary concentrations of 3.3 and 3.3-13 ppm
In male and female mice, respectively.
In addition, chronic effects of altered absolute and relative spleen,
liver, kidney, pituitary and brain weights have occurred 1n rats at dietary
concentrations from 1-5 ppm In rats. Statistically significant Increased
absolute spleen and liver weights In male rats and decreased absolute and
relative kidney weights In female rats occurred 1n groups that received a
dietary concentration of 5 ppm (Carpy et al., 1975), as well as atrophy of
the pancreas In male rats that received a chronic dietary concentration of
13 ppm (Hayes, 1985).
0172d -53- 08/28/89
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Altered brain tissue permeability has been reported In rats that
received subchronlc dietary administration of 50-150 ppm dlsulfoton (Clark
and Stavlnova, 1971). In addition, Increased exploratory activity was
observed 1n rats that received subchronlc dietary administration of 150-200
ppm dlsulfoton (Clark et al., 1971).
Altered glycogen levels, RNA, DNA and protein were also observed In rats
given oral subchronlc doses of >22 yg dlsulfoton (Glurgea, 1979).
Altered activities of ethylmorphlne N-demethylase, NADPH cytochrome C
reductase and NADP oxldase were observed 1n acute oral administration of
29.2-35.1 ymol dlsulfoton. Also, Increased levels of adrenaline and
noradrenallne have been observed In rats after acute administration of
dlsulfoton (Stevens et al., 1973).
Oral lD50s of 6.8 ppm In male rats and 2.3 mg/kg In female rats has
been reported by Galnes (1969). Oral LD5_s 1n rats, mice and guinea pigs
of 2, 4.8 and 10.8 mg/kg, respectively, were also reported (NIOSH, 1988).
Female rats appear to be more sensitive than males; guinea pigs appear to be
slightly less sensitive than rats and mice.
No clear evidence of dlsulfoton-related carc1nogen1dty was found In two
2-year dietary studies using rats (Hayes, 1985; Carpy et al., 1975) while
the 2-year dietary study using mice Is equivocal (Hayes, 1983). Results of
mutagenldty tests were generally negative; positive results were only
observed at high concentrations In base-pair reversion strains of S.
typhlmurlum and E.. coll.
Oral developmental toxldty tests In rabbits revealed no evidence of
fetotoxUUy or teratogenldty at dosages up to 1.5 mg/kg/day during organo-
s
'genesis (Tesh et al., 1982). Dosages of 1.5-3.0 mg/kg/day were associated
0172d -54- 03/21/90
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with chollnerglc signs In the dams. In rats treated by gavage during
organogenesls, 0.3 mg/kg/day was a NOAEL and 1.0 mg/kg/day was a LOAEL for
fetotoxUHy (Lamb and Hlxson, 1983).
When treated male and female rats were mated In a 3-generaUon repro-
ductive studies, a dietary concentration of 10 ppm dlsulfoton resulted In
reduced Utter sizes and pregnancy rate (Taylor, 1966). Also, renal
lesions, hepatic lesions, testlcular hypoplasla and chollnesterase Inhibi-
tion occurred In the offspring. In another reproduction study (Ryan et al.,
1970), 10 ppm dlsulfoton In the diet of rats of either or both sexes
resulted 1n reduced fertility.
0172d -55- 03/21/90
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1988) recommended a 1HA-TLV for dlsulfoton of 0.1 mg/m3, based
largely on Its similarity 1n LD values and mode of action to parathlon
(ACGIH, 1986). ACGIH (1986) considers dermal exposure to be more signifi-
cant than Inhalation exposure under most conditions of use. There Is no
OSHA standard for dlsulfoton.
NAS (1977) suggested a SNARL for dlsulfoton In drinking water of 0.7
yg/l, based on an ADI of 0.1 vg/kg/day. The ADI was based on a NOAEL
of 0.01 mg/kg/day for chollnesterase Inhibition 1n dogs fed diets containing
phorate, a structurally similar organic phosphate pesticide. Long-term
studies with dlsulfoton were not yet available.
U.S. EPA (1987) recommended 1- and 10-day HAs for dlsulfoton In drinking
water for a 10 kg child of 10 w9/t> based on the NOAEL for maternal
chollnesterase Inhibition of 0.1 mg/kg/day 1n the rat developmental toxldty
study by Lamb and Hlxson (1983). Longer-term HAs of 3 vq/l for a 10 kg
child and 9 ng/i, for a 70 kg adult were based on the NOAEL for cholln-
esterase Inhibition of 1 ppm (0.25 mg/kg/day) In the 2-year dog study by
Hoffman et al. (1975). A DHEL of 1 vq/l and a lifetime HA of 0.3
ug/l were derived from the RfD of 4x10"" mg/kg/ddy, based on the
2-year dietary study In rats by Hayes (1985). This RfD has been verified
and 1s currently on IRIS (U.S. EPA, 1986a); Us derivation Is discussed In
Section 8.2.2.2.
WHO (1976) and U.S. EPA (1984b) derived an ADI for dlsulfoton of 0.02
mg/kg/day based on a NOAEL of 0.025 mg/kg/day In the subchronlc dietary
study 1n dogs by Vaughn et al. (1958). U.S. EPA (1984b) listed tolerances
0172d -56- 08/28/89
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In or on several raw agricultural commodities ranging from 0.1-0.75 ppm for
commodities used as human food, and as high as 12 ppm for forages used for
livestock feeding.
U.S. EPA (1988) reported a final RQ for dlsulfoton of 1, based on
aquatic toxlclty.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to dlsulfoton were not located 1n the available literature cited In
Appendix A.
0172d -57- 08/28/89
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8. RISK ASSESSMENT
Statements concerning available literature 1n this document refer to
published, quotable sources and are 1n no way meant to Imply that confiden-
tial business Information (CBI), which this document could not address, are
not in existence. From examination of the bibliographies of the CBI data,
however, U was determined that CBI data that would alter the approach to
risk assessment or the risk assessment values presented herein do not exist.
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the Inhalation carclnogen-
Idty of dlsulfoton were not located In the available literature cited 1n
Appendix A.
8.1.2. Oral. Two studies have been conducted 1n which 60 male and 60
female Sprague-Dawley rats were given dietary concentrations of dlsulfoton
of 0, 0.5, 1 or 2-5 ppm (Carpy et al., 1975) or 0, 0.8, 3.3 or 13 ppm
(Hayes, 1985) for 2 years. In another 2-year study (Hayes, 1983), CD-I mice
were given dietary concentrations of dlsulfoton of 0, 1, 4 or 16 ppm. Under
the conditions of these studies, the evidence Is viewed as Inadequate to
demonstrate or refute a carcinogenic potential. NTP (1988) has not
scheduled dlsulfoton for further cancer testing.
8.1.3. Height of Evidence. No data were located regarding the carcino-
genic potential of dlsulfoton In humans. Only synopses of the studies by
Hayes (1983) and Hayes (1985) were available for review; therefore, their
adequacy for evaluation of the carcinogenic potential of dlsulfoton could
not be assessed. In a draft document, the U.S. EPA (1987) evaluated these
animal studies and assigned dlsulfoton to EPA Group E, using guidelines for
carcinogen risk assessment established by the Agency (U.S. EPA, 1986b).
0172d -58- 05/23/90
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These studies, however, have been reevaluated In this assessment. It was
concluded that the data are not totally negative nor reported In full
detail. Therefore, dlsulfoton 1s assigned to EPA Group D - not classifiable
as to human cardnogenldty.
8.1.4. Quantitative Risk Estimates. The lack of adequate positive data
precludes estimation of carcinogenic potencies for dlsulfoton for either
Inhalation or oral exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Data regarding chronic or subchronlc Inhala-
tion exposure to dlsulfoton were not located In the available literature
dted In Appendix A; hence, Inhalation RfDs cannot be derived.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — Several
subchronlc oral studies with dlsulfoton were discussed 1n Section 6.1.2.1.
Three dietary studies were considered suitable for derivation of an RfD for
subchronlc oral exposure because they Identified LOAELs and NOAELs for
chollnesterase Inhibition, the critical effect for subchronlc exposure to
organophosphorous Insecticides, 1n three species. In a 12-week study using
dogs (Vaughn et al.. 1958) and a 16-week study using rats (Doull and Vaughn,
1958), chollnesterase Inhibition was observed at 2 ppm but not at 1 ppm. In
mice fed dlsulfoton In the diet for 13 weeks, chollnesterase Inhibition
occurred at 5.0 but not at 1.0 ppm (Rlvett et al., 1972). In addition to
these studies, Hoffman et al. (1975) reported chollnesterase Inhibition at
>2 ppm but not at 1.0 ppm In dogs fed dlsulfoton for 2 years.
The longer-term dog study (Hoffman et al., 1975) seems to be the most
appropriate from which to derive an RfD for subchronlc oral exposure to
dlsulfoton. The NOAEL of 1.0 ppm, equivalent to 0.025 mg/kg/day [assuming a
food factor for dogs of 0.025 (U.S. EPA, 1986c)], may be divided by an
0172d -59- 03/21/90
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uncertainty factor of 100 (10 for Interspedes extrapolation and 10 to
provide additional protection for unusually sensitive humans) to obtain a
subchronlc oral RfD of 0.0003 mg/kg/day. Confidence In the RfD Is high;
confidence In the study Is high [based on U.S. EPA (1987) analysis] and
confidence In the data base Is medium. This derivation Is consistent with
that In U.S. EPA (1987), In which the dog NOAEL of 0.025 mg/kg/day (Hoffman
et al., 1975) served as the basis for the longer-term HAs.
8.2.2.2. CHRONIC EXPOSURE — Several chronic oral studies are
available for consideration In deriving an RfD for chronic oral exposure.
When Hayes (1983) fed mice diets containing dlsulfoton for 23 months,
Increased relative kidney weight and chollnesterase Inhibition were observed
at 16 ppm, but not at 1 or 4 ppm.
Rats appear to be more sensitive than mice to chollnesterase Inhibition
associated with dietary dlsulfoton. an observation that was not apparent
from the subchronlc studies. In rats exposed to diets containing dlsulfoton
at 1.0, 2.0 or 5 ppm for <2 years, chollnesterase Inhibition In the plasma,
RBC and brain was observed In both sexes at >2.0 ppm. and 1n the brain In
females at 1..0 ppm (Carpy et al., 1975). Hlstopathologlc examination was
Inadequate, however, and the 2-year dietary study using rats by Hayes (1985)
Is a better basis for the RfD (U.S. EPA, 1986a). In this study,
chollnesterase Inhibition In both sexes and cystic degeneration of the
Harderlan gland In females occurred at 0.8 ppm. the lowest dietary
concentration tested. In addition, a dose-related Increase In the Incidence
of optic nerve degeneration was also observed and attributed to exposure to
dlsulfoton, although statistical significance was reached only at >3.3 ppm,
the next higher dietary concentration. The lowest dietary concentration
(0.8 ppm), equivalent to 0.04 mg/kg/day assuming a food factor for rats of
0.05 (U.S. EPA, 1986c), Is a LOAEL.
0172d -60- 08/28/89
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In addition, abstracts of several Japanese studies associate oral expo-
sure to dlsulfoton with damage to the optic nerve and extra-ocular muscles
and adverse effects effects on vision (Uga et al., 1977; Ishlkawa, 1973;
Mukuno and Ima1, 1973; Tokoro et al., 1973). Some of the effects persisted
at 0.5 mg/kg/day, the lowest dosage tested. The studies do not Identify a
threshold for these effects, but similar effects were not reported In the
2-year (Hoffman et al., 1975) dietary study In dogs at 1-8 ppm.
U.S. EPA (1986a) derived an RfO for chronic oral exposure of 4xlO"5
mg/kg/day by application of an uncertainty factor of 1000 (10 for Inter-
species extrapolation, 10 for Intraspecles variation and 10 to estimate a
NOAEL from a LOAEL) to the LOAEL of 0.04 mg/kg/day. In the U.S. EPA (1986a)
analysis, the key study Is referenced as Mobay Chemical Company (1985),
which Is the source of the Hayes (1985) report. U.S. EPA (1986a) placed
high confidence In the study and medium confidence In the RfD and data base.
This derivation 1s consistent with the RfD derived by U.S. EPA (1987) that
served as the basis for the DWEL and lifetime HA. Data have not been
located that would challenge this RfD.
The chronic oral RfD 1s smaller than the subchronlc oral RfD by >1 order
of magnitude. This observation 1s probably an artifact of the data base
rather than an Indication of marked differences In the toxic potency of
chronic compared with subchronlc exposure. The chronic rat studies (Carpy
et al., 1975; Hayes, 1985) suggest that rats are slightly more sensitive
than dogs, an observation that was not apparent from the subchronlc rat
studies.
0172d -61- 08/28/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Effects associated with dlsulfoton exposure are discussed In Chapter 6.
Subchronk data were not used In determining the RQ because adequate chronic
toxldty studies are available. While not reported In chronic studies,
Increased exploratory behavior was reported In an oral subchronlc study In
mice (Clark et al., 1971). This effect occurred at a relatively high
dietary concentration (>150 ppm), however, and Us biological significance
Is uncertain. Another subchronlc study by Glurgea (1979) reported altered
glycogen levels and altered DNA, RNA and total protein concentration.
Although these effects occurred at doses of dlsulfoton (0.022-0.11 mg/kg/
day) lower than those used 1n chronic experiments, the biological signifi-
cance of these effects 1s unclear. These effects are not scored for use In
the derivation of a CS. Other effects observed In the subchronlc studies
occurred at comparable or lower doses In the chronic studies.
The chronic, reproductive and teratogenlc effects of dlsulfoton
considered for derivation for an RQ are summarized In Table 9-1. The most
serious chronic effects were mortality, optic nerve degeneration, altered
brain and organ weights, cystic degeneration of the Harderlan gland and
chollnesterase Inhibition. These effects occurred In rats at doses of 0.65,
0.17, 0.05, 0.04 and 0.04 mg/kg/day, respectively (Hayes, 1983, 1985; Carpy
et al., 1975). In addition, various CNS effects and various effects on the
eye and vision were reported In abstracts of several Japanese studies In
dogs (Suzuki and Ishlkawa, 1974; HlkUa et al., 1973; Uga et al., 1977;
Ishlkawa, 1973; Mukuno and Ima1, 1973; Tokoro et al., 1973). Although the
complete reports were not available for evaluation, at least some of these
effects occurred at 0.5 mg/kg/day, the lowest dosage reported. A fetotoxlc
0172d -62- 08/28/89
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1ABIE 9-1
Summary of Oral Toxtclty Data for Olsulfolon
V '
. 3 ' ~~ •
-«J
•si Average
°- Species/ No. at Body Vehicle/
Strain Sex Start Height* Physical Purity Exposure
(kg) State
Oog/beagle NR NR 12.7 NR NR 0.5-10 mg/kg/day
for 2 years
N.F 5/sex 12.7 food 95. 7X 2 ppm dietary
concentration
for 69 weeks
Rat/Sprague- N.F 60 0.35 food 95. 7X 1 ppm dietary
er> Oawley concentration
w for 2 years
Rat/F344 F 60 0.35 food 98. IX 0.8 ppm dietary
concentration
for 2 years
F 60 0.35 food 98. IX 3.3 ppm dietary
concentration
for 2 years
F 60 0.35 food 98. IX 13 ppm dietary
concentration
for 2 years
House/NR F 50 0.03 food 98. 2X 16 ppm dietary
concentration
for 23 months
o
00
CD
CD
transformed Transformed
Animal Dose Human Doseb Response
(mg/kg/day) (mg/kg/day)
0.5-10 0.28-5.7 Various effects on the
eye and vision. CMS
effects
0.05C 0.03 Decreased chollnes-
terase activity
0.05C 0.009 Decreased chollnester-
ase activity, altered
brain and organ weights
0.04C 0.007 Decreased chollnester-
ase activity, cystic
degenerat Ion of the
Harder Ian gland
0.17C 0.028 Optic nerve degenera-
tion
0.65C 0.11 Mortality, corneal
neovasculartratlon.
atrophy of the pancreas
2.1C 0.16 Decreased chollnester-
ase act Ivlty, altered
kidney/body weight ratio.
Reference
Suzuki and
Ishlkawa. 19/4,
Hlklta el al. .
19/3; Uga
et al.. I97/;
Ishlkawa. 19/3,
Hukuno and
Imal. 1973;
lokoro et a 1 . .
1973
Hoffman et al. ,
1975
Carpy et al . .
1975
Hayes. 1985
Hayes. 1985
Hayes. 1985
Hayes. 1983
-------
1ABII 91 (coot )
Average
Species/ No. at Body
Strain Sex Start Weight*
(kg)
Rats /MR H.f 10 H. 0.35
10 r
F 25 0.35
Vehicle/
Physical Purity Exposure
State
food NR 10 ppm
NR 98. nt 1.0 mg/kg/day
Transformed
Animal Dose
(mg/kg/day)
0.5C
1.0C
Transformed
Human Doseb
(mg/kg/day)
0.09
0.17
Response
Reduced litter sl/e.
reduced pregnancy rate
Retarded ossification
of the parietal bones
and sternebral (feto-
toxlclty)
Reference
laylor. 1966
lamb and
Hlxson. 1983
'Reference body weights (U.S. EPA. 1986a)
''Calculated by multiplying the animal transformed dose by the cube root of the ratio of the animal body weight to the human body weight (70 kg)
C0ose conversions from ppm to mg/kg/day were obtained by multiplying the ppm dosage by the reference animal food factor (U.S. EPA. 1986a).
NR < Not reported
o
CD
oo
CD
10
-------
effect of retarded ossification of fetal parietal bones and sternebrae
occurred In rats at a dose of 1.0 mg/kg/day (Lamb and Hlxson, 1983). CSs
for these effects are presented In Table 9-2. Mortality among rats receiv-
ing dietary dlsulfoton for 2 years (Hayes, 1985) resulted In the highest CS
of 42, which corresponds to an RQ of 10 (Table 9-3).
9.2. BASED ON CARCINOGENICITY
Three dietary studies have been performed to evaluate the carcinogenic
potential of dlsulfoton (Carpy et al., 1975; Hayes, 1983, 1985). The study
In rats by Carpy et al. (1975) yielded no evidence of carclnogenlcHy. The
study by Hayes (1985) yielded leukemia, adenomas of the adrenal cortex,
pheochromocytoma, Hbroadenoma of the mammany glands, adenoma and carcinoma
of the pituitary glands, adenoma of the testes and uterine stromal polyps.
These neoplastlc lesions, however, did not occur In a dose-related pattern
and. were not significantly different from the untreated control rats. In an
earlier study, Hayes (1983) reported an Increased Incidence of malignant
lymphoma In both male and female rats but the Incidence was not
significantly different from that seen 1n untreated control rats. These
reports are suggestive of cardnogenldty but not conclusive. For this
reason, dlsulfoton Is assigned to the EPA welght-of-evldence Group D - not
classifiable as to human cardnogenldty. This designation precludes an RQ
determination for dlsulfoton based on cardnogenldty.
0172d -65- 03/21/90
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o
--J
ro
1ABIE 9-2
Oral Conposlte Scores for Otsulfoton
Species AntMl Dose
(•g/kg/day)
Dog 0.5
Rat 0.65
0.17
0.05
0.04
0.04
1.0
Chronic
Human HED*
(•g/day)
19.6
7.7
?.o
0.6
0.5
0.5
12
RVd Effect RVe CS
3.6 CMS effects and effects 7 25.?
on the eye and vision
4.2 Mortality 10 42
5 Optic nerve degeneration 6 30
5.8 Altered brain and organ 4 23.2
weights
6.0 Cystic degeneration of 5 30
the Harder Ian gland
6.0 Chollnesterase Inhibition 2 12
3.9 Retarded ossification of 8 31.2
fetal parietal bones and
sternebrae
RQ Reference
100 Suzuki and Ishlkawa,
1974; Otsuka and
Ntyata. I960; Hlklta
el al.. 1973; U
-------
TABLE 9-3
Dlsulfoton
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species:
Dose*:
Duration:
Effect:
RVd:
RVe:
Composite Score:
RQ:
Reference:
oral
rat
7.7 mg/day
2 years
mortality
4.2
10
42
10
Hayes, 1985
*Equ1valent human dose
0172d
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08/28/89
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Fletcher, 0., D.H. Jenkins and M.L. Kepllnger. 1971. Neurotoxlclty study
with D1-Syston technical In chickens. IBT No. 471. Unpublished report from
Industrial B1o-Test laboratories, Inc. (Cited 1n WHO, 1974)
Frank, R., H. Brown and B.D. Rlpley. 1987. Residues of Insecticides,
fungicides and herbicides on Ontario-grown vegetables, 1980-1985. J. Assoc.
Off. Anal. Chem. 70: 1081-1086.
0172d -72- 08/28/89
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Gaaboub, I.A., P.M. El-Gayar and A.A. Abdel-Gawaad. 1973. Comparative
studies on the sensitivity of Culex plplens fatlgans W1ed. mosquito larvae
and the mlcrocrustacean adults of Daphnla magna Straj^s as mlcrobloassay test
organisms for screening certain soil Insecticides applied to cotton cultiva-
tions In Eygpt. Bull. Entomol. Egypt Econ. Ser. 7: 193-199.
Galnes, T.8. 1969. Acute toxldty of pesticides. Toxlcol. Appl.
Pharmacol. 14: 515-534.
Glurgea, R. 1979. Reaction of the thymus of Wlstar rats treated with alar
and dlsulfoton. Rev. Roum. Blol. 24(1): 59-61. (Taken from PESTAB/80/3228)
Gohre, K and G.C. Miller. 1986. Photooxldatlon of thloether pesticides on
soil surfaces. J. Agrlc. Food Chem. 34:709-713.
Hamaker, J.W. and J.M. Thompson. 1972. Adsorption of organic chemicals by
soils. Jji: Organic Chemicals 1n the Soil Environment, C.A.I. Goring and
J.N. Hamaker,. Ed. 1: 74.
Hanna, P.J. and K.F. Oyer. 1975. MutagenlcHy of organophosphorus
compounds In bacteria and DrosophHa. Mutat. Res. 28(3): 405-420.
Hansch, C. and A.J. Leo. 1985. MedChem Project. Issue No. 19. Pomona
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Hawley, G.G. 1981. The Condensed Chemical Dictionary. 10th ed. Van
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0172d -73- 08/28/89
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Hayes, R.H. 1983. Oncogenlclty study of dlsulfoton technical on mice. An
unpublished report of study No. 82-271-01. Prepared by Mobay Chemical Corp.
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Hayes, R.H. 1985. Chronic feedlng/oncogenldty study of technical dlsulfo-
ton (D1-Syston) with rats. Unpublished study No. 82-271-01. Prepared by
Mobay Chemical Corp. Accession No. 258857. (Cited In U.S. EPA, 1987)
Helling, C.S., D.G. Dennlson and D.D. Kaufman. 1974. Fungicide movement In
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Henderson, C., Q.H. Pickering and C.M. Tarzwell. 1959. The toxldty of
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Trans. Second Sem. Blol. Problems Hater Pollut. U.S. Public Health Service,
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H1k1ta, H., M. Mlyata and S. Ishlkawa. 1973. Experimental study of chronic
organophosphate (OP) Intoxications In the beagle dogs. Activities of
chollnesterases and residue of OP. Nippon Ganka Gakkal Zasshl. (Jap.)
77(9): 1254-1265.
Hill, E.F. and N.B. Camardese. 1984. Toxlclty of antlchollnesterase Insec-
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0172d -74- 08/28/89
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Hill, E.F., R.G. Heath, J.W. Spann and J.D. Williams. 1975. Lethal dietary
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unpublished report (No. 341) prepared by the Environmental Health Research
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Oct. 25, 1982. MRID 00000000. (Cited 1n U.S. EPA, 1987)
Hoffman, K., C.H. Welscher, G. Luckhaus, et al. 1975. S 276 (Dlsulfoton)
chronic toxlclty study on dogs (two-year feeding experiment). Report No.
5618; Report No. 45287. Unpublished study received Dec. 15, 1976 under
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1987)
Holcombe, G.W., G.L. Phlpps and O.K. Tanner. 1982. The acute toxlclty of
kelthane, dursban, dlsulfoton, pydrln, and permethrln to fathead minnows
Prlmephales promelas and rainbow trout Salmo galrdneM. Environ. Pollut.
Ser. A. 29(3): 167-178.
HSOB (Hazardous Substances Data Bank). 1988. Report No. 379. Online: May
1988.
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0172d -75- 08/28/89
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Ishlkawa, S. 1973. Chronic optlconeuropathy due to environmental exposure
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Ishlkawa, S. and M. Mlyata. 1980. Development of myopia following chronic
organophosphate pesticide Intoxication: An ep1dm1olog1cal and experimental
study. I_n: Neurotoxldty of the Visual System, H.H. Herlgan and B. Weiss,
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00156275)
Jeang, C. and G. 11. 1978. Screening of mutagenlc pesticides using
mlcroblal systems. K'o Hsueh Fa Chan Yueh K'an. 6(8): 780-788. (CA
090/1985418)
Jensen, L.D. and A.R. Gaufln. 1964a. Effects of ten organic Insecticides
on two species of stonefly naiads. Trans. Am. Fish. Soc. 93(1): 27-34.
Jensen, L.O. and A.R. Gaufln. 19646. Long-term effects of organic Insec-
ticides on two species of stonefly naiads. Trans. Am. F1sh Soc. 93(4):
357-363.
Kadoum. A.N. and D.E. Hock. 1978. Herbicide and Insecticide residues In
tallwater pits: Water and pit bottom soil from Irrigated corn and sorghum
fields. 3. Agrlc. Food Chem. 26: 45-50.
0172d -76- 08/28/89
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Kearney, P.C., R.G. Nash and A.R. Isensee. 1969. Persistence of pesticides
In soil. UK Chemical Fallout: Current Research on Persistent Pesticides,
M.W. Miller and C.G. Berg, Ed. Charles C. Thomas, Springfield, II.
p. 54-67.
Kenaga, E.E. 1980. Predicted bloconcentratlon factors and soil sorptlon
coefficients of pesticides and other chemicals. Ecotoxlcol. Environ. Saf.
4: 26-38.
Klotzsche, C. 1975. Olsulfoton. 2-Year Feeding Study In Rats. Unpub-
lished report from Agrochemlcal Research Department. Submitted to the World
Health Organization by Sandoz, Ltd. (CHed In WHO, 1976}
KM11, R.M. and W.C. Sonzognl. 1986. Chemical monitoring of Wisconsin's
groundwater. J. Am. Water Works Assoc. 78: 70-75.
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dlsulfoton. Unpublished study No. 81-611-02. Prepared by Mobay Chemical
Corp. (Cited In U.S. EPA, 1987)
Lyman. W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. Environmental Behavior of Organic Compounds.
McGraw H111 Book Co., New York. p. 5-4 to 5-5, 5-10 to 5-11.
Maddy, K.T., H.R. .Pong, 3.A. Lowe, et al. 1982. A study of well water In
selected California communities for residues of 1,3-dkhloropropene, chloro-
allyl alcohol and 49 organophosphate or chlorinated hydrocarbon pesticides.
Bull. Environ. Contam. Toxlcol. 29: 354-359.
0172d -77- 08/28/89
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Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer Res. 35: 1379-1386.
March, R.B., T.R. Fukuto and R.L. Metcalf. 1957. Metabolism of P-32-dl-
thlosystox In the white mouse and American cockroach: Submitter 1830.
Unpublished study. MRIO 00083215. (Cited In U.S. EPA, 1987)
Mayer, F.L., Jr. and M.R. Ellersleck. 1986. Manual of Acute Toxlclty:
Interpretation and Data Base for 410 Chemicals and 66 Species of Freshwater
Animals. Fish and Wildlife Service Resource Publ. 160, U.S. Department of
the Interior, Washington, DC. p. 180.
Menzer, R.E., E.L. Fontanllla and L.P. Dlttman. 1970. Degradation of
dlsulfoton and phorate In soil Influenced by environmental factors and soil
types. Bull. Environ. Contam. Toxlcol. 5: 1-5.
Metcalf, R.L. 1981. Insect Control Technology. Klrk-Othmer Encyclopedia
of Chemical .Technology, 3rd ed., Vol. 13. John Wiley & Sons, Inc., New
York, NY. p. 447.
Mlhan, F. 1978. S 276 (Dlsyston active Ingredient) acute toxlclty
studies. Report No. 7602a prepared by A.G. Bayer, Instltut Fur Toxlkologle,
for Mobay Chemical Corp. June 12, 1978. (CHed In U.S. EPA, 1987)
Mlngelgrln, U. and Z. Gerstl. 1983. Reevaluatlon of partitioning as a
mechanism of nonlonlc chemicals adsorption 1n soils. J. Environ. Qual. 12:
1-11.
0172d -78- 08/28/89
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Morlya, M., T. Ohta, K. Watanabe, T. Mlyazawa, K. Kato and Y. Shlrasu.
1983. Further mutagenlclty studies on pesticides In bacterial reversion
assay systems. Mutat. Res. 116(3-4): 185-216.
Muhlmann, R. and G. Schrader. 1957. Hydrolysis of phosphoric acid ester
Insecticides. Z. Naturforschg G. 12: 196-208.
Mukuno, K. and H. Imal. 1973. A study on extraocular muscles of beagles
Intoxicated chronically by an organophosphorus compound - hlstochemlcal and
electron microscopic observation. Nippon Ganka Gakkal Zasshl (J. Jap.
Ophthal. Soc. 77(9): 1246-1253. (In Japanese with English abstract)
NAS (National Academy of Sciences). 1977. Drinking Water and Health. V.I.
Safe Drinking Water Committee. NAS, Washington, DC. p. 612-620.
NIOSH (National Institute for Occupational Safety and Health). 1988. RTECS
(Registry of Toxic Effects of Chemical Substances). Dlsulfoton. CAS
Registry No. .298-24-4. Online.
NTP (National Toxicology Program). 1988. Management Status Report. Dated
05/06/88.
Otsuka, J. and K. Tokoro. 1976. Experimental studies on the occurrence of
myopia Induced by long-term administration of a low toxlclty organophos-
phorus Insecticide and Us prevention. Ganka Rlnshl Iho. (Jap.) 70(6):
669-678. (Taken from PESTAB/76/2561)
0172d -79- 08/28/89
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Pickering, Q.H., C. Henderson and A.E. Lemke. 1962. The toxlclty of
organic phosphorus Insecticides to different species of warmwater fishes.
Trans Am. Fish Soc. 91: 175-184.
Puhl, R.J. and D.R. Fredrlckson. 1975. The metabolism and excretion of
dl-syston by rats. Unpublished report submitted by Mobay Chemical Corp.,
Report No. 44261, prepared by Chemagro Agricultural Division, Mobay Chemical
Corp. Dated May 6, 1975. (Cited In U.S. EPA, 1987; WHO, 1976)
Qulnto et al., 1980
Rao, S.L.N. and W.P. McKlnley. 1969. Metabolism of organophosphorus
Insecticides by liver homogenates from different species. Can. J. Blochem.
47(12): 1155-1159.
Rlcclo, E., G. Shepherd, A. Pomeroy, K. Mortelmans and M.D. Haters. 1981.
Comparative studies between the S. cerevlslae D3 and D7 assays of eleven
pesticides. Environ. Mutagen. 3(3): 327.
Rider, J.A., J. Swader and E.J. Pulettl. 1972. Antlchollnesterase toxlclty
studies with guthlon, phosdrln, d1-syston, and trlthlon In human subjects.
Fed. Proc. Fed. Am. Soc. Exp. B1ol. 31(2): 520. (Abstract only)
Rlvett, K.E., A. Bhatt, A.E. Street and A.J. Newman. 1972. Thlo-Demeton/
Oral Toxldty to Mice/Dietary Administration for Three Months. Unpublished
report from Huntlngton Research Centre, England. (Cited In WHO, 1974)
0172d -80- 08/28/89
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Royal Society of Chemistry. 1983. Dlsulfoton. The Agrochemlcals Handbook.
The Royal Society of Chemistry, Nottingham, England.
Ryan, L.C., B.R. Endecott, G.O. Hanneman and P.M. Smith. 1970. Effects of
an Organophosphorus Pesticide on Reproduction In the Rat. Civil Aeromedkal
Inst., Oklahoma City, OK. Report No. FAA-AM-70-3. NTIS AD 709327.
Sanborn, J.R., 8.M. Francis and R.L. Metcalf. 1977. The degradation of
selected pesticides In soil: A review of published literature. EPA
600/9-77-022. p. 475-487.
Sanders, H.O. 1969. Toxlclty of pesticides to the crustacean Gammarus
lacustrls. JJK Technical Papers of the Bureau of Sport Fisheries and Wild-
life, No. 25. Fish and Wildlife Service, U.S. Department of the Interior,
Washington. DC. p. 1-18.
Sanders, H.O. 1972. Toxlclty of some Insecticides to four species of
malacostracan crustaceans. ln_: Technical Papers of the Bureau of Sport
Fisheries and Wildlife, No. 66. Fish and Wildlife Service, U.S. Department
of the Interior, Washington, DC. p. 1-19.
Sanders, H.O. and O.B. Cope. 1968. The relative toxldtles of several
pesticides to naiads of three species of stonefHes. Llmnol. Oceanogr.
13(1): 112-117.
Schafer, E.W. 1972. Acute oral toxldty of 369 pestlddal, pharmaceutical,
and other chemicals to wild birds. Toxlcol. Appl. Pharmacol. 21(3):
315-330.
0172d -81- 08/28/89
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Schwab, B.W. and S.D. Murphy. 1981. Induction of antkhollnesterase toler-
ance In rats with doses of dlsulfoton that produce no chollnerglc signs. J.
Toxlcol. Environ. Health. 8(1-2): 199-204.
Simmon, V.F. 1979. Iji Vitro Microbiological MutagenlcHy and Unscheduled
DNA Syntehsis Studies of Eighteen Pesticides. Health Effects Research Lab.,
Research Triangle Park, NC. EPA 600/1-79-041. NTIS PB80-133226.
SRI (Stanford Research Instltue). 1987. 1987 Directory of Chemical
Producers. SRI International, Menlo Park, CA. p. 846.
Stevens, J.T., F.E. Greene, R.E. Stltzel and J.J. McPhllllps. 1973.
Effects of antlchollnesterase Insecticides on mouse and rat liver mkrosomal
mixed function oxldase. I_n: Pestle. Environ.: Continuing Controversy, Pap.
8th Inter-Am. Conf. Toxlcol. Occ. Med. p. 489-501.
Suzuki, H. and S. Ishlkawa. 1974. Ultrastructure of the ciliary muscle
treated by organophosphate pesticide In beagle dogs. Br. J. Ophthal. 58:
931.
Swann. R.L., D.A. Laskowskl, P.J. McCall, et al. 1983. A rapid method for
the rapid estimation of the environmental parameters octanol/water partition
coefficient, soil adsorption constant, water to air ratio, and water
solubility. Res. Rev. 85: 17-28.
0172d -82- 08/28/89
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Szeto, S.Y., R.S. Vernon and M.J. Brown. 1983. Degradation of dlsulfoton
In soil and Us translocatlon Into asparagus. J. Agrlc. Food Chem. 31:
217-220.
Takase, I. and H. Nakamura. 1974. The fate of ethylthlometon (0,0-dlethyl-
S-(2-ethylthlo)ethyl) phosphorod!thloate In paddy soil. J. Agrlc. Chem.
Soc. Jap. 48: 29-36. (CA 81:1315362)
Takase, I. and H. Oyama. 1985. Uptake and bloconcentratlon of dlsulfoton
and Its oxidation 1n carp, CypMnus carplo L_. Nippon Noyaku Gakkalshu.
10(1): 47-53.
Takase, I., H. Tsuda and Y. Yoshlmoto. 1972. Fate of dlsyston active
Ingredient In soil. Pflanzenschutz-Nachr. 25: 43-63.
Taylor, R.E. 1966. Letter sent to 0. MacOougall dated May 5, 1966:
D1-Syston, Three Generation Rat Breeding Studies: Submitted 18154. Unpub-
lished study, received March 7, 1977, under 3125-252; prepared by Harris
Laboratories, Inc., submitted by Mobay Chemical Corp., Kansas CHy, MO.
COL:096021-L. MRID 00091104. (CHed 1n U.S. EPA, 1987}
Tesh, J.M., et al. 1982. S 276: Effects of Oral Administration Upon Preg-
nancy In the Rabbit. An unpublished report (Bayer No. R2351) prepared by
Life Science Research, Essex. England, and submitted to A.G. Bayer,
Wuppertal. Germany; dated Dec. 22, 1982. MRID 00000000. (Cited In U.S.
EPA. 1987)
0172d -83- 08/28/89
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Thomas, R.G. 1982. Volatilization from water. In: Handbook of Chemical
Property Estimation Methods, W.J. Lyman, et al., Ed. McGraw-Hill, NY.
p. 15-19 to 15-31.
Tokoro, T., K. Suzuki, N. Hldekl, J. Otsuka and H. Suzuki. 1973. Experi-
mental studies of organic phosphorus pesticide on beagle dogs. Long-term
observation on the refraction and the Intraocular pressure. Nippon Ganka
Gakka! Zasshl. 77(9): 1237-1245. (Jap.)
Tomlzawa, C. 1975. Degradation of organophosphorus pesticides In soils
with special reference to anaerobic soil conditions. Environ. Qua!. Saf.
4: 117-127.
Tomlzawa, C. 1980. Biological accumulation of pesticides In an ecosystem
evaluation of blodegradablllty and ecological magnification of rice pesti-
cides by a model ecosystem. JARQ (Jap. Agrlc. Res. Q.). 14(3): 143-149.
Uga, S., S. Ishlkawa and K. Mukuno. 1977. Hlstopathologlcal study of
canine optic nerve and retina treated by organophosphate Insecticide.
Invest. Ophthalmol. Visual Scl. 16(9): 877-881.
USOA (U.S. Department of Agriculture). 1983. Inputs. Outlook & Situation.
USOA, Washington, DC. p. 9-12.
U.S. EPA. 1980. .Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
0172d -84- 08/28/89
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U.S. EPA. 1984a. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxldty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1984b. Guidance for the Registration of Manufacturing - Use
and Certain End-Use Pesticide Products containing Dlsulfoton (032501) as the
Active Ingredient. Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1986a. Integrated Risk Information System (IRIS). Reference
Dose (RfD) for Oral Exposure for Dlsulfoton. Online. (Revised verification
date 05/14/86.) Office of Health and Environmental Assessment, Environ-
mental Criteria and Assessment Office, Cincinnati. OH.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986c. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC. p. 1-2.
U.S. EPA. 1987. Health Advisory Document for 50 Pesticides: Dlsulfoton.
Draft. Prepared by the Office of Drinking Water, Washington, DC. (Draft)
U.S. EPA. 1988. Integrated Risk Information System (IRIS). Online.
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH.
0172d -85- 08/28/89
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U.S. EPA/OWRS. 1986. Guidelines for Deriving Numerical National Water
Quality Criteria for the Protection of Aquatic Organisms and Their Uses.
PB85-227049/XAB. OWRS, U.S. EPA, Washington DC. p. 22-58, 98.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic Chem-
icals, United States Production and Sales, 1985. U.S. Government Printing
Office, Washington, DC. USITC Publ. 1892. p. 188.
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dietary level of Dl-Syston® for dogs. Unpublished report from The
University of Chicago. (Cited In WHO, 1974)
Weiss, C.M. 1961. Physiological effect of organic phosphorus Insecticides
on severals species of fish. Trans. Am. Fish. Soc. 90(2): 143-152.
WHO (World Health Organization). 1974. 1973 Evaluations of Some Pesticides
Residues In Food. The Monographs. WHO Pesticide Residue Series, No. 3.
WHO, Geneva, Switzerland, p. 199-212.
WHO (World Health Organization). 1976. 1975 Evaluation of Some Pesticide
Residues In Food. The Monographs. Dlsulfoton. WHO Pesticide Residues
Series No. 5. WHO. Geneva. Switzerland, p. 199-212.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 450.
0172d -86- 08/28/89
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Yadav, P.R., A.K. Singh, Z. Singh and O.S. Gupta. 1980. Effect of auto-
clavlng on the degradation of dlsulfoton in soil at different temperature.
Haryana Agrlc. Univ. J. Res. 10: 213-217.
Zepp, R.G., G.L. Baughman and P.P. Schlotzhauer. 1981. Comparison of
photochemical behavior of various humlc substances In water: I. Sunlight
Induced reactions of aquatic pollutants photosensitized by humlc substances.
Chemosphere. 10: 109-117.
0172d -87- 08/28/89
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In May, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons. NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
0172d -88- 08/28/89
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA, 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index. 10th ed. Merck and Co.,
Inc.. Rahway, NJ.
Worthing. C.R. and S.B. Walker. Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0172d -89- 08/28/89
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In addition, approximately 30 compendia of aquatic toxklty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. .Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0172d -90- 08/28/89
-------
APPENDIX 8
SuMMry Table for Olsulfoton
1
«x>
1
o
oo
>^
r\j
CD
^^«
CD
Species
Inhalation Exposure
Subchronlc 10
Chronic 10
Carclnogenlclty 10
Oral Exposure
Subchronlc dog
Chronic rat
Carclnogenlclty 10
REPORTABLE QUANTITIES
Based on chronic toxic Ity:
Based on carctnogenlclty:
10 - Insufficient data; NA = not
Exposure
I»
10
10
1.0 pp« In diet for ?
years (0.025 ag/kg/day)
0.8 pp» In diet for 2
years (0.04 ag/kg/day)
10
10
ID
applicable
Effect RfD or qj* Reference
ID NA NA
10 NA NA
ID NA NA
NOAEl for chollnesterase 3x10 • ag/kg/day Hoffaan
Inhibition et a).. 1975
LOAEl for chollnesterase 4x10'* ag/kg/day Hayes. 1985
Inhibition
10 NA NA
Hayes. 1985
NA
-------
APPENDIX C
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO OISULFOTON
C.I. DISCUSSION
Dose/duration-response graphs for oral exposure to dlsulfoton generated
by the method of Crockett et al. (1985) using the computer software by
Ourkin and Meylan (1988) under contract to ECAO-Clnclnnatl are presented In
Figures C-l and C-2. Data used to generate these graphs are presented In
Section C.2. In the generation of these figures, all responses are classi-
fied as adverse (FEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for
plotting. For oral exposure, the ordlnate expresses dosage as human equiva-
lent dose. The animal dosage In mg/kg/day Is multiplied by the cube root of
the ratio of the animal:human body weight to adjust for species differences
In basal metabolic rate (Mantel and Schnelderman, 1975). The result Is then
multiplied by 70 kg, the reference human body weight, to express the human
equivalent dose as mg/day for a 70 kg human.
The boundary for adverse effects (solid line) Is drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point an Infinite
line Is extended upward, parallel to the dose axis. The starting point Is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process 1s continued
to the lowest adverse effect dose or concentration. From this point a line
Is extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
0172d -92- 08/28/89
-------
ieoe
»i
c
\
t
v
fc
I
»
10 -r
IT
A34
A31
0.0881
•:0ral Exposure)
F36
F37
F12
F45
L35
Fl
•28
A27
b-
L20
F17
nlS
e.ei e.i
HUMAN EQUIU DURATION (fraction
ENVELOP METHOD
1 2
Key: F. . PEL
A . AEL
L . LOAEL
n . NOAEL
N . NOEL
Solid line - Adverse Effects Boundary
Dashed line • No Adverse Effects Boundary
FIGURE C-l
Dose/Duration-Response Graph for Oral Exposure to Dlsulfoton:
Envelope Method
0172d
-93-
08/28/89
-------
1BW«
9
% 100 •
^
(1
c
"
u
0
ft 10 •
5
"
u
z
c « .
I 1
I
a t -
- i i T T T . i i | i i . i , i i t i 1 i . i i , j
- L3^
F36 F12
f \ F37 F45 Ai:
' "'"la^
• III E1
^ L35
^^ Fl
• ~&A
: ~ "^46 L2
' • b L:
t>42
,
A34 \
^30 ]
}
a
:
•F26
•28
L20 _
F17 :
AS0 F48 -
L7 '
>4 A 1 ft
• "• n J. D •
^V^r^C^^^sl^q
Nl^ ^>- =
^ ""^tU — j
'•15
, , , , , , , J
0.0B81
(Oral Exposure>
0.601 6.01 0.1
HUNAN EQUIU DURATION (fraction
CENSORED DATA METHOD
Key: F . PEL
A - AEL
L . LOAEL
n • NOAEL
N - NOEL
Solid line - Adverse Effects Boundary
Dashed line • No Adverse Effects Boundary
FIGURE C-2
Dose/Duration-Response Graph for Oral Exposure to Dlsulfoton-
Censored Data Method
0172d
-94-
08/28/89
-------
Using the envelope method, the boundary for no-adverse effects (dashed
line) is drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point a line parallel to the duration axis Is extended
to the dose or concentration axis. The starting point Is then connected to
the next lower or equal no adverse effect dose or concentration at a longer
duration of exposure. When this process can no longer be continued, a line
Is dropped parallel to the dose or concentration axis to the duration axis.
The region of no-adverse effects lies below the no-adverse effects boundary.
At either ends of the graph between the adverse effects and no-adverse
effects boundaries are regions of ambiguity. The area (If any) resulting
from Intersection of the adverse effects and no-adverse effects boundaries
Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located In the
region of contradiction are dropped from consideration and the no-adverse
effect boundary Is redrawn so that H does not Intersect the Adverse Effects
boundary and no region of contradiction 1s generated. This method results
In the most conservative definition of the no-adverse effects region.
The Adverse Effects Boundary 1n Figures C-l and C-2 Is defined by oral
LD5 values In male guinea pigs (Bomblnsk! and DuBols, 1958, Rec. #41) and
female rats (Crawford and Anderson, 1974, Rec. #39) and LOAEL values for
delayed skeletal ossification In rats (Lamb and Hlxson, 1983, Rec. #46) and
for chollnesterase Inhibition In dogs (Vaughn et al., 1958, Rec. #3; Hoffman
et al., 1975, Rec. #24; Mukuno and Ima1, 1973, Rec. #29) and rats (Ooull and
Vaughn, 1958, Rec. #5). The graphs confirm that chollnesterase Inhibition
Is the critical effect of oral exposure to dlsulfoton. Data points for
ocular effects In dogs (Recs. #26, 27, 28, 30, 31, 32. 33, 34, 35) cluster
above the adverse effects boundary at =0.1 human llfespans, suggesting
0172d -95- 08/28/89
-------
that protection against chollnesterase Inhibition should provide ample
protection against ocular effects. The slope of the graph Indicates that
adverse effects Intensify with continued exposure, at least In rats.
The NOAEL In dogs that served as the basis of the subchronlc oral RfD Is
below the adverse effects boundary at -0.13 human Hfespans (Hoffman et al.,
1975, Rec. #25). The LOAEL In rats that served as the basis of the chronic
oral RfD anchors the adverse effects boundary at 1.0 human llfespans (Hayes,
1985, Rec. #19).
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Oral Exposure
Chemical Name: Dlsulfoton
CAS Number: 298-04-4
Document Title: Health and Environmental Effects Document on Dlsulfoton
Document Number: SRC-TR-88-165
Document Date: 1/16/89
Document Type: HEED
RECORD #1:
Comment:
Citation:
Species: Rats
Sex: Female
Effect: PEL
Route: Food
Number Exposed: 50
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: CNS
Severity Effect: 6
20 ppm In diet; chollnerglc
In brain, diaphragm.
Schwab and Murphy, 1981.
Dose:
Duration Exposure:
Duration Observation:
50
NR
UGTDC
BODY
4
signs, reduced bw, ChE
1.000
62.0 days
62.0 days
Inhibition
0172d
-96-
08/28/89
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RECORD #2:
Species:
Sex:
Effect:
Route:
Rats
F ema1e
LOAEl
Food
Dose:
Duration Exposure:
Duration Observation:
0.375
62.0 days
62.0 days
Comment:
Citation:
Number Exposed: 50
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: CNS
Severity Effect: 6
50
NR
WGTDC
BODY
4
7.5 ppm In diet, ChE Inhibition of brain, diaphragm, body
weight depression.
Schwab and Murphy, 1981
RECORD #3:
Species:
Sex:
Effect:
Route:
Dogs
Both
LOAEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
0.050
12.0 weeks
12.0 weeks
Number Exposed: 2
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BLOOD
Severity Effect: 2
Comment :
Citation:
RECORD #4:
2 ppm 1n diet; ChE Inhibition 1n RBC and plasma.
Vaughn et al., 1958
. Species:
Sex:
Effect:
Route:
Dogs
Both
NOEL
Food
Dose:
Duration Exposure:
Duration Observation:
0.025
12.0 weeks
12.0 weeks
Comment:
Citation:
Number Exposed: 2
Number Responses: NR
Type of Effect: ENZYM
SHe of Effect: BLOOD
Severity Effect: 2
1 ppm In diet, no ChE Inhibition In RBC or plasma.
Vaughn et al., 1958
0172d
-97-
08/28/89
-------
RECORD #5:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose:
Duration Exposure:
Duration Observation:
0.100
16.0 weeks
16.0 weeks
Number Exposed: 26
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BRAIN
Severity Effect: 2
2 ppm 1n diet; ChE Inhibition 1n brain, RBC. No effect on
food consumption, growth, gross or hlstopathologlcal
appearance of wide range of tissues.
Doull and Vaughn, 1958
RECORD #6:
Comment:
Citation:
RECORD |7:
Species: Rats
Sex: Both
Effect: NOEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1 ppm In diet; no
Doull and Vaughn,
Species: Mice
Sex: Both
Effect: LOAE'L
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
26
NR
ENZYM
BRAIN
2
ChE Inhlbl
1958
24
NR
ENZYM
NR
2
Dose:
Duration Exposure:
Duration Observation:
tlon.
Dose:
Duration Exposure:
Duration Observation:
24
NR
WGTIN
LIVER
4
0.050
16.0 weeks
16.0 weeks
0.650
13.0 weeks
13.0 weeks
Comment: 5 ppm In diet; ChE Inhibition In unspecified tissues; no
effects on growth, urinalysis, hematology, blood chemistry,
hlstopath.
Citation: Rlvett et al., 1972
0172d
-98-
08/28/89
-------
RECORD #8:
Comment:
Citation:
RECORD #9:
Species: Mice
Sex: Both
Effect: NOEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1 ppm In diet.
Rlvett et al., 1972
Species: Humans
Sex: NR
Effect: NOAEL
Route: Oral (NO!
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
24
NR
ENZYM
NR
2
5)
5
NR
ENZYM
BLOOD
2
Dose:
Duration Exposure:
Duration Observation:
24
NR
MG1IN
LIVER
4
Dose:
Duration Exposure:
Duration Observation:
0.130
13.0 weeks
13.0 weeks
0.750
30.0 days
30.0 days
Comment: No ChE Inhibition In plasma or RBC.
Citation: Rider et al., 1972
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
NR
LOAEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
2.500
2.0 months
2.0 months
Comment:
Citation:
Number Exposed: 0
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BRAIN
Severity Effect: 2
50 ppm In diet; brain ChE Inhibition; no other data available.
Clark and Stavlnova, 1971
0172d
-99-
08/28/89
-------
RECORD #11:
Comment:
Citation:
RECORD #12:
Comment:
Citation:
RECORD #13:
Comment:
Citation:
Species: Rats
Sex: NR
Effect: LOAEL
Route: Food
Number Exposed: 0
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BRAIN
Severity Effect: 2
150 ppm In diet; brain ChE
Clark and Stavlnova, 1971
Species: Mice
Sex: Female
Effect: PEL
Route: Food
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
200 ppm In diet; deaths of
Clark et al.. 1971
Species: Mice
Sex: Female
Effect: AEL
Route: Food
Number Exposed: NR
Number Responses: NR
Type of Effect: FUNS
Site of Effect: BODY
Severity Effect: 6
150 ppm In diet; Increased
significance unknown.
Clark et al.. 1971
Dose: 19.500
Duration Exposure: 2.0 months
Duration Observation: 2.0 months
Inhibition; no other data provided.
Dose: 26.000
Duration Exposure: 4.0 weeks
Duration Observation: 4.0 weeks
females at 4 weeks.
Dose: 19.500
Duration Exposure: 8.0 weeks
Duration Observation: 8.0 weeks
exploratory activity, toxlcologlcal
0172d
-100-
08/28/89
-------
RECORD |14:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
PEL
Food
Dose: 2.500
Duration Exposure:
Duration Observation:
NR
NR
DEATH
BODY
9
NR
NR
FUND
CNS
6
NR
NR
ENZYM
BRAIN
2
2.0 months
2.0 months
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
50 ppm In diet; mortality, tremors, convulsions, Inhibited
brain ChE; no neuroses or discrimination deficits.
Clark and Pearson, 1972
RECORD #15:
Species: Rats
Sex: NR
Effect: NOAEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
(NOS)
NR
: NR
ENZYM
THYRD
1
Dose: 0.022
Duration Exposure: 6.0 months
Duration Observation: 6.0 months
Comment: Altered thyroid glycogen levels after 3 but not after 6
months; toxkologlcal significance unclear.
Citation: Glurgea, 1979
RECORD #16: Species:
Sex:
Effect:
Route:
Rats
NR
LOAEL
Oral (NOS)
Dose:
Duration Exposure:
Duration Observation:
0.110
6.0 months
6.0 months
Comment:
Citation:
Number Exposed: NR
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: THYRO
Severity Effect: 3
Altered thyroid glycogen, RNA, DNA levels (hypothesized
Inhibited RNA polymerase activity).
Glurgea, 1979
0172d
-101-
08/28/89
-------
RECORD #17:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Food
Dose: 0.650
Duration Exposure: 2.0 years
Duration Observation: 2.0 years
Number Exposed: 120
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
13 ppm diet; Increased mortality In females; cornea!
vascularlzatlon In both sexes; pancreatic atrophy In males
Hayes, 1985
RECORD #18:
Species:
Sex:
Effect:
Route:
Rats
Both
AEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
0.165
2.0 years
2.0 years
Comment:
Citation:
Number Exposed: 120
Number Responses: NR
Type of Effect: DEGEN
Site of Effect: PNS
Severity Effect: 7
3.3 ppm In diet; degeneration of optic nerve In both sexes;
degeneration of Harderlan gland 1n males.
Hayes, 1985
RECORD #19: Species: Rats
Sex: Both
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
120
NR
ENZYH
BRAIN
2
Dose:
Duration Exposure:
Duration Observation:
120
NR
ENZYM
BLOOD
1
0.040
2.0 years
2.0 years
Comment: 0.8 ppm In diet; ChE Inhibition In brain, plasma, RBC 1n both
sexes; degeneration of Harderlan gland 1n females.
Citation: Hayes, 1985
0172d
-102-
08/28/89
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RECORD #20:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Both
LOAEL
Food
Dose:
Duration Exposure:
Duration Observation:
2.080
23.0 months
23.0 months
100
NR
WGTIN
KIONY
3
100
NR
ENZYM
BRAIN
2
100
NR
ENZYM
BLOOD
1
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
16 ppm In diet; Increased relative kidney weight In females;
ChE Inhibition In plasma, RBC, brain of both sexes.
Hayes, 1983
RECORD #21: Species: Mice
Sex: Both
Effect: NOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
100
NR
WGTIN
KIDNY
3
Dose:
Duration
Duration
100
NR
ENZYM
BRAIN
2
Exposure:
Observation:
100
NR
ENZYM
BLOOD
1
0.520
23.0 months
23.0 months
Comment: 4 ppm In diet; no effect on kidney weight; ChE activity not
measured.
Citation: Hayes, 1983
RECORD #22: Species:
Sex:
Effect:
Route:
Rats
Both
AEL
Food
Dose:
Duration Exposure:
Duration Observation:
0.250
2.0 years
2.0 years
Comment:
Citation:
120
NR
WGTIN
LIVER
3
120
NR
WGTIN
SPLEN
3
120
NR
ENZYM
BRAIN
2
120
NR
ENZYM
BLOOD
1
Number Exposed:
Number Responses:
Type of Effect:
SUe of Effect:
Severity Effect:
5.0 ppm In diet; Increased liver and spleen weight In males;
decreased kidney weight 1n females; ChE Inhibition In plasma,
RBC; brain.
Carpy et al., 1975
0172d
-103-
08/28/89
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RECORD #23:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose: 0.050
Duration Exposure: 2.0 years
Duration Observation: 2.0 years
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1 ppm In diet; ChE Inhibition In brain In females.
Carpy et al., 1975
120
NR
WGT1N
LIVER
3
120
NR
WGT1N
SPLEN
3
120
NR
ENZYM
BRAIN
2
120
NR
ENZYM
BLOOD
1
RECORD #24:
Species:
Sex:
Effect:
Route:
Dogs
Both
LOAEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
0.050
69.0 weeks
69.0 weeks
Comment:
Citation:
Number Exposed: 8
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BLOOD
Severity Effect: 1
Comment:
Citation:
RECORD #25:
2.0 ppm 1n
Hoffman et
Species:
Sex:
Effect:
Route:
diet; ChE Inhibition In RBC, plasma of both sexes.
al., 1975
Dogs
Both
NOAEL
Food
Dose:
Duration Exposure:
Duration Observation:
0.025
2.0 years
2.0 years
Number Exposed: 8
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BLOOD
Severity Effect: 1
1.0 ppm In diet; apparently no ChE Inhibition In plasma or
RBC.
Hoffman et al., 1975
0172d
-104-
08/28/89
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RECORD #26:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Dogs
NR
PEL
Capsul
Dose: 0.710
Duration Exposure: 2.0 years
Duration Observation: 2.0 years
Number Exposed: NR
Number Responses: NR
Type of Effect: OEGEN
Site of Effect: PNS
Severity Effect: 5
Comment:
Citation:
RECORD #27:
1 mg/kg/day
Uga et al.,
Species:
Sex:
Effect:
Route:
5 days/week;
1977
Dogs
NR
AEL
Capsul
optic nerve
Dose:
Duration
Duration
degeneration.
Exposure:
Observation:
0
2
2
.357
.0 years
.0 years
Number Exposed: NR
Number Responses: NR
Type of Effect: DEGEN
Site of Effect: PNS
Severity Effect: 5
0.5 mg/kg/day 5 days/week; degeneration of optic nerve, less
severe than 1.0 mg/kg dose group (see previous record).
Uga et al., 1977
RECORD #28:
Comment:
Citation:
Species: Dogs
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:
Impaired vision
Ishlkawa. 1973
(NOS)
NR
: NR
FUND
EYE
7
and ocular
Dose: 0.500
Duration Exposure: 2.0 years
Duration Observation: 2.0 years
lesions and other CNS signs.
0172d
-105-
08/28/89
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RECORD #29:
Comment:
Citation:
RECORD #30:
Comment:
Citation:
RECORD #31:
Comment:
Citation:
Species: Dogs
Sex: NR
Effect: AEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BLOOD
Severity Effect: 1
RBC ChE Inhibition; effects
Hukuno and Imal , 1973
Species: Dogs
Sex: NR
Effect: AEL
Route: Oral (NOS)
Number Exposed: 2
Number Responses: NR
Type of Effect: FUND
Site of Effect: EYE
Severity Effect: 7
Myopia, rule astigmatism and
Tokoro et al., 1973
Species: Dogs
Sex: NR
Effect: AEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: FUND
Site of Effect: EYE
Severity Effect: 7
Dose:
Duration Exposure:
Duration Observation:
NR
NR
DEGEN
EYE
5
on the extra-ocular muse
Dose:
Duration Exposure:
Duration Observation:
axial nerve elongation.
Dose:
Duration Exposure:
Duration Observation:
0.500
2.0 years
2.0 years
les.
5.000
2.0 years
2.0 years
10.000
2.0 years
2.0 years
Myopia and structural changes 1n the ciliary muscles.
Suzuki and Ishlkawa, 1974
0172d
-106-
08/28/89
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RECORD #32:
Comment:
Citation:
RECORD #33:
Comment :
Citation:
RECORD #34:
Comment:
Citation:
Species: Dogs Dose:
Sex: NR Duration
Effect: LOAEL Duration
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: FUND
Site of Effect: EYE
Severity Effect: 7
Myopia after exposure for 12 months 1i
Suzuki and IsMkawa, 1974
Species: Dogs Dose:
Sex: NR Duration
Effect: LOAEL Duration
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: FUNS
Site of Effect: EYE
Severity Effect: 6
Myopia and ChE Inhibition 1n unspeclf
Ishlkawa and Mlyata, 1980
Species: Dogs Dose:
Sex: NR Duration
Effect: AEL . Duration
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: FUNS
Site of Effect: EYE
Severity Effect: 6
Myopia and widespread destruction of
Ishlkawa and Mlyata, 1980
5.000
Exposure: 12.0 months
Observation: 12.0 months
n 2-year study.
5.000
Exposure: 2.0 years
Observation: 2.0 years
led tissues.
15.000
Exposure: 2.0 years
Observation: 2.0 years
ciliary muscles.
0172d
-107-
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RECORD #35:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Dogs
NR
LOAEL
Oral (NOS)
Dose:
Duration Exposure:
Duration Observation:
0.500
4.0 months
4.0 months
Number Exposed: NR
Number Responses: NR
Type of Effect: FUNS
Site of Effect: EYE
Severity Effect: 6
Astigmatism and abnormal refraction with ChE Inhibition (In
unspecified tissues).
Otsuka and Tokoro, 1976
RECORD #36:
Comment:
Citation:
RECORD #37:
Comment:
Citation:
Species: Rats
Sex: Male
Effect: FEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral LD5Q In male rats.
Bomblnskl and DuBols, 1958
Species: Rats
Sex: Male
Effect: FEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral LD5Q 1n male rats.
Games, 1969
Dose: 12.500
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Dose: 6.800
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
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RECORD #38:
Comment:
Citation:
RECORD #39:
Comment:
Citation:
RECORD #40:
Comment:
Citation:
Species: Rats Dose: 2.600
Sex: Female Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral LDso In female rats.
Bomblnskl and DuBols, 1958
Species: Rats Dose: 2.000
Sex: Female Duration Exposure: 1.0 days
Effect: FEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral 1050 1n female rats.
Crawford and Anderson, 1974
Species: Rats Dose: 2.300
Sex: Female Duration Exposure: 1.0 days
Effect: FEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 9
Oral 1050 In female rats.
Galnes, 1969
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RECORD |41:
Comment:
Citation:
RECORD #42:
Comment:
Citation:
RECORD #43:
Comment:
Citation:
Species: Guinea pigs Dose: 27.000
Sex: Male Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral 1050 In male guinea pigs.
Bomblnskl and DuBols, 1958
Species: Mice Dose: 7.000
Sex: Male Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral LDso In male mice.
Mlhall, 1978
Species: Mice Dose: 8.200
Sex: Female Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Oral 1050 In female mice.
Mlhall, 1978
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RECORD #44:
Species:
Sex:
Effect:
Route:
Rabbits
F ema1e
NOAEL
Capsul
Dose: 0.200
Duration Exposure: 13.0 days
Duration Observation: 13.0 days
Number Exposed: 15
Number Responses: NR
Type of Effect: REPRO
Site of Effect: FETUS
Severity Effect: 8
Comment:
Citation:
RECORD #45:
No maternal or fetal effects
Ladd et al.. 1971
Species: Rabbits
Sex: Female
Effect: FEL
Route: Oral (NOS)
Number Exposed: 14
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
In teratogenlclty
Dose:
Duration Exposure
Duration Observat
FETUS
study.
3.000
: 13.0 days
Ion: 13.0 days
Comment: Maternal toxlclty (chollnerglc signs and mortality) but no
evidence of fetotoxldty In this teratogenlclty study.
Citation: Tesh et al.. 1982
RECORD #46:
Species: Rats
Sex: Femal
Effect: LOAEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
e
(NOS)
25
: NR
ENZYM
BLOOD
1
Dose:
Duration Exposure:
Duration Observation:
25
NR
OTHER
FETUS
7
0.300
10.0 days
10.0 days
Comment: Teratogenlclty study; ChE Inhibition In plasma, RBC of dams;
delayed skeletal ossification In fetuses.
Citation: Lamb and Hlxson, 1983
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RECORD |47;
Comment:
Citation:
Species: Rats
Sex: Female
Effect: NOAEL
Route: Oral (NOS)
Number Exposed:
Number Responses
Type of Effect:
SUe of Effect:
Severity Effect:
25
: NR
ENZYM
BLOOD
1
Dose:
Durat
Durat
25
NR
OTHER
FETUS
7
Exposure:
Observation:
0.100
10.0 days
10.0 days
TeratogenkHy study; no effects
no evidence of fetotoxkHy.
Lamb and Hlxson, 1983
on maternal ChE activities
RECORD |48: Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Food
Dose:
Duration Exposure:
Duration Observation:
0.500
200.0 days
200.0 days
Number Exposed: 30
Number Responses: NR
Type of Effect: REPRO
Site of Effect: OTHER
Severity Effect: 8
Comment: 10 ppm In diet; effects on repro., hepatic and kidney lesions
In offspring. Other diet cone. 1n this study: 0, 2, 5 ppm.
Study Inadequate to Identify reproductive NOAEL. Duration
crude estimate.
Citation: Taylor, 1966
RECORD #49:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose:
Duration
Duration
Exposure:
Observation:
0.100
200.0 days
200.0 days
Comment:
Citation:
Number Exposed: 30
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BLOOD
Severity Effect: 1
2 ppm In diet, see previous record. ChE Inhibition In RBC.
Taylor, 1966
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RECORD #50:
Comment:
Citation:
Species: Rats
Sex: Both
Effect: AEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 0.500
Duration Exposure: 90.0 days
Duration Observation: 90.0 days
10
NR
REPRO
OTHER
8
10 ppm In diet; Impaired reproduction and ChE Inhibition In
brain of offspring.
Ryan et al., 1970
NR = Not reported
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