United States
*brmT"M\ Environmental Protection
fm Agency
EPA/690/R-02/006F
Final
5-31-2002
Provisional Peer Reviewed Toxicity Values for
Disulfoton
(CASRN 298-04-4)
Derivation of an Oral Slope Factor
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
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NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(.imol
micromoles
voc
volatile organic compound
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5-31-2002
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DISULFOTON (CASRN 298-04-4)
Derivation of an Oral Slope Factor
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
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5-31-2002
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
An assessment of the carcinogenicity of disulfoton is not available on IRIS (U.S. EPA
2002) or in the HEAST (U.S. EPA, 1997). The Drinking Water Standards and Health Advisories
list (U.S. EPA, 2000a) shows disulfoton in cancer-weight-of-evidence Group E - evidence of
noncarcinogenicity for humans. The origin of this assessment was a 1988 Drinking Water Health
Advisory (U.S. EPA, 1988) that reported no human data and several two-year studies in rodents
that found no evidence of carcinogenicity. The CARA list (U.S. EPA, 1991, 1994) includes a
Health and Environmental Effects Document (U.S. EPA, 1990) that assigned disulfoton to Group
D, not classifiable as to human carcinogenicity, based on these same data. Also based on these
data, the Office of Pesticide Programs classified disulfoton in Group E (U.S. EPA, 2000b,c).
IARC (2001) has not evaluated the carcinogenicity of disulfoton. A Toxicological Profile for
disulfoton (ATSDR, 1995), a recent review article (Storm, 2001), the NTP (2001) status report,
and the WHO (2001) were also consulted for relevant information. Literature searches were
conducted from 1989 to November 2001 for studies relevant to the derivation of an oral slope
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5-31-2002
factor for disulfoton. The databases searched were: TOXLINE, MEDLINE, CANCERLIT,
RTECS, GENETOX, HSDB, CCRIS, TSCATS, EMIC/EMICBACK and DART/ETICBACK.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding cancer in humans exposed to disulfoton.
Animal Studies
The available carcinogenicity studies for disulfoton have been reviewed previously (U.S.
EPA, 1988, 1990, 2000b,c; ATSDR, 1995). There was no evidence of carcinogenicity in male
and female Sprague-Dawley rats fed up to 2 ppm (0.1 mg/kg-day) in the diet for 2 years (Carpy et
al., 1975), male and female F344 rats fed up to 13 ppm (0.65 mg/kg-day) in the diet for 2 years
(Hayes, 1985) or male and female CD-I mice fed up to 16 ppm (2.4 mg/kg-day) in the diet for 2
years (Hayes, 1983). One- and two-year studies in dogs, described in the available reviews, also
failed to find evidence of carcinogenicity, but used small numbers of animals, featured short
exposure duration relative to lifetime and were not designed as cancer bioassays. No new
carcinogenicity studies were located in the literature search.
The genotoxicity of disulfoton has been reviewed (U.S. EPA, 1988, 1990, 2000b,c;
ATSDR 1995; Storm, 2001; Woo et al., 1996). Results were primarily negative in numerous
tests for reverse mutation and differential toxicity in bacteria, with or without activation. Assays
for mutation, gene conversion, mitotic crossing over, and DNA damage in the yeast
Saccharomyces cerevisiae were uniformly negative with or without activation, while assays for
genetic recombinants and chromosomal aberrations in barley seeds were all positive without
activation. In mammalian cells, the test results were mixed. Results were positive for mutation
in mouse lymphoma cells without, but not with, activation. With or without activation, results
were negative for mutation in Chinese hamster ovary cells. Some positive and some negative
results were reported for sister chromatid exchange in Chinese hamster ovary cells. There was
no evidence of chromosomal aberrations in various human cell lines. Unscheduled DNA
synthesis was observed in human lung fibroblasts when tested without, but not with, activation.
In vivo studies found no effects on induction of micronuclei or dominant lethal mutations in
mice, or sex-linked recessive lethal mutations in Drosophila. An epidemiological study in
Morelos State, Mexico, observed evidence of genotoxicity in a group of 22 female and 8 male
floriculturists that reportedly used disulfoton occupationally (in addition to organochlorines,
carbamates, other organophosphates, and other chemicals). In comparison to unexposed
controls, the floriculturists had statistically significant increases in peripheral blood lymphocyte
sister chromatid exchange, cell proliferation kinetics and mitotic index (Gomez-Arroyo et al.,
2000). However, it is not clear that the findings in this study can be attributed to disulfoton
exposure. Overall, the data suggest that disulfoton has little genotoxic potency.
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5-31-2002
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR
FOR DISULFOTON
A provisional oral slope factor for disulfoton cannot be derived because human oral
cancer data are lacking and the available animal data provide no evidence of carcinogenicity.
REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological Profile for
Disulfoton. U.S. Department of Health and Human Services, Public Health Service, Atlanta,
GA.
Carpy, S., C. Klotzsche and A. Cerioli. 1975. Disulfoton: 2-year feeding study in rats: AGRO
DOK CBK 1854/74. Report No. 47069. Unpublished study received December 15, 1976 under
3125-58. Prepared by Sandoz, Ltd., Switzerland. Submitted by Mobay Chemical Corp., Kansas
City, MO. CDL:095641-C. MRID 00069966. (Cited in U.S. EPA, 1988, 1990, 2000b)
Gomez-Arroyo, S., Y. Diaz-Sanchez, M.A. Meneses-Perez et al. 2000. Cytogenetic
biomonitoring in a Mexican floriculture worker group exposed to pesticides. Mutat. Res. 466:
117-124.
Hayes, R.H. 1983. Oncogenicity study of disulfoton technical on mice. An unpublished report
of study No. 80-271-04. Mobay Chemical Company. MRID. No. 00129458. (Cited in U.S.
EPA, 1988, 1990, 2000b)
Hayes, R.H. 1985. Chronic feeding/oncogenicity study of technical sulfoton (Di-Syston) with
rats. Unpublished study No. 82-271-01. Mobay Chemical Company. MRID. No. 00129456,
00146873,411115401. (Cited in U.S. EPA, 1988, 1990,2000b)
IARC (International Agency for Research on Cancer). 2001. IARC Agents and Summary
Evaluations. Examined November, 2001. Online.
http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
NTP (National Toxicology Program). 2001. Management Status Report. Examined November,
2001. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
Storm, J.E. 2001. Organophosphorous compounds. In: Patty's Toxicology, 5th ed., E. Bingham,
B. Cohrssen and C.H. Powell, Ed. John Wiley & Sons, Inc. Vol. 5, p.
767-965.
U.S. EPA. 1988. Disulfoton Health Advisory. Office of Drinking Water, Washington, DC.
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U.S. EPA. 1990. Health and Environmental Effects Document for Disulfoton. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables (HEAST). FY-1997 Update.
Prepared by the Office of Research and Development, National Center for Environmental
Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington,
DC. EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000a. Drinking Water Regulations and Health Advisories. Summer 2000. Office
of Water, Washington, DC. Online, http://www.epa. gov/ost/drinking/standards/
U.S. EPA. 2000b. Health Effects Division Toxicity Chapter for Disulfoton for Reregistration
Eligibility Decision (RED) (Revised). 02/07/2000. Office of Prevention, Pesticides, and Toxic
Substances. Online, http://www.epa.gov/pesticides/op/disulfoton/toxicity.pdf
U.S. EPA. 2000c. Disulfoton: Revised (2nd) Report of the Hazard Identification Assessment
Review Committee. 02/03/2000. Office of Prevention, Pesticides, and Toxic Substances.
Online, http://www.epa.gov/pesticides/op/disulfoton/rev hiarc.pdf
U.S. EPA. 2002. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
January, 2002. Online, http://www.epa.gov/iris/
WHO (World Health Organization). 2001. Environmental Health Criteria (EHC) Monographs
International Programme on Chemical Safety, Geneva, Switzerland. Examined November, 2001.
Online, http://www.inchem.org/ehc.html
Woo, Y.T., D.Y. Dai, M.F. Argus et al. 1996. Carcinogenicity of organophosphorus
pesticides/compounds: an analysis of their structure-activity relationships. Environ. Carcino.
Ecotox. Reviews. C14: 1-42.
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