v°,EPA EPA/690/R-24/006F | September 2024 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
Dimethyl Sulfide
(CASRN 75-18-3)
PRO1*
supERFU[\|D
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
-------
A mA United States
Environmental Protection
* ^ ^1 M % Agency
EPA 690 R-24-006F
September 2024
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Dimethyl Sulfide
(CASRN 75-18-3)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Laura M. Carlson, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
Kyoungju Choi, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
John Stanek, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
SCIENTIFIC TECHNICAL LEAD
Lucina E. Lizarraga, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Q. Jay Zhao, PhD, MPH, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
in
Dimethyl Sulfide
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 8
2.1. HUMAN STUDIES 13
2.1.1. Oral Exposures 13
2.1.2. Inhalation Exposures 13
2.2. ANIMAL STUDIES 13
2.2.1. Oral Exposures 13
2.2.2. Inhalation Exposures 18
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 18
2.3.1. Supporting Animal Studies 18
2.3.2. Genotoxi city 24
2.3.3. Absorption, Distribution, Metabolism, and Excretion (ADME) Studies 24
3. DERIVATION 01 PROVISIONAL VALUES 27
3.1. DERIVATION OF ORAL REFERENCE DOSES 27
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 27
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 27
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 28
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 29
APPENDIX A. NONCANCER SCREENING PROVISIONAL VALUES 30
APPENDIX B. DATA TABLES 65
APPENDIX C. ANALOGUE STRUCTURES, SOURCE, AND SELECTION CRITERIA 68
APPENDIX D. PARAMETERS OF TOOLS USED FOR READ-ACROSS 75
APPENDIX E. REFERENCES 77
iv
Dimethyl Sulfide
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
7V-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NOAEL
no--observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethyl sulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
g 1 ut a t h i o nc - V-1 ra n s fc ra sc
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL to NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV assessment.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
DIMETHYL SULFIDE (CASRN 75-18-3)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund program. PPRTVs are derived after a review of the relevant
scientific literature using established U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing
toxicologically relevant human-health effects. Questions regarding nomination of chemicals for
update can be sent to the appropriate U.S. EPA eComments Chemical Safety website at
https://ecomments.epa.gov/chemicalsafetv/.
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV assessment
was written with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP),
the QAPP titled Program Quality Assurance Project Plan (POAPP) for the Provisional
Peer-Reviewed Toxicity Values (PPRTVs) and Related Assessments Documents
(L-CPAD-0032718-OP), and the PPRTV assessment development contractor QAPP titled
Quality Assurance Project Plan—Preparation of Provisional Toxicity Value (I'll) Documents
(L-CPAD-0031971-OP). As part of the QA system, a quality product review is done prior to
management clearance. A Technical Systems Audit may be performed at the discretion of the
QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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DISCLAIMERS
The PPRTV assessment provides toxicity values and information about the
toxicologically relevant effects of the chemical and the evidence on which the value is based,
including the strengths and limitations of the data. All users are advised to review the
information provided in this document to ensure that the PPRTV used is appropriate for the types
of exposures and circumstances at the site in question and the risk management decision that
would be supported by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
Dimethyl sulfide, CASRN 75-18-3, is a discrete organosulfur chemical; it consists of a
sulfur atom bonded to two methyl groups. Dimethyl sulfide is produced in nature during
metabolic processes of terrestrial plants and marine bacteria, marine algae, and phytoplankton in
oceans, and during microbial degradation of certain amino acids. Dimethyl sulfide is also
produced endogenously in mammals during metabolism of methionine and related substances
(Blom et al.. 1989; Blom et al.. 1988; A1 Mardini et al.. 1984). and by bacteria in the mammalian
gut and mouth (De Boever et al.. 1994; Hiele et al.. 1991; Yaegaki and Suetaka. 1989). High
levels of dimethyl sulfide were detected in the breath of patients with advanced liver disease
(Tangerman et al.. 1994).
Dimethyl sulfide has been identified as a component of unprocessed natural gas and as a
volatile component of some foods (U.S. EPA. 2024a; NLM. 2022). Dimethyl sulfide is registered
with Europe's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
program (ECHA. 2021) and is listed on the U.S. EPA's Toxic Substances Control Act (TSCA)
public inventory (U.S. EPA. 2024e) and the U.S. EPA's Clean Air Act (CAA) Section 111
(NLM. 2022). Dimethyl sulfide is used as an industrial solvent, catalyst impregnator, and raw
material in chemical manufacturing processes. It is also used as a gas odorant and as a flavor
ingredient in various food products (U.S. EPA. 2024a; NLM. 2022). Dimethyl sulfide can be
produced by thiolation using methanol and hydrogen sulfide, by heating spent liquors from kraft
pulping processes with inorganic sulfur compounds, or by distillation of potassium methyl
sulfate with aqueous potassium sulfide (NLM. 2022).
The empirical formula for dimethyl sulfide is C2H5S. The chemical structure is shown in
Figure 1.
S CH,
/
h3c
Figure 1. Dimethyl Sulfide (CASRN 75-18-3) Structure
The physicochemical properties for dimethyl sulfide are provided in Table 1. Dimethyl
sulfide is a colorless, volatile liquid with an unpleasant odor (U.S. EPA. 2024a; NLM. 2022). Its
high water solubility and high vapor pressure at ambient temperature indicate that this substance
is hydrophilic and volatile and will exist in the vapor phase in air. At normal temperatures,
volatilization from water surfaces or moist soil surfaces is expected to be high based upon an
estimated Henry's law constant of 1.61 x 10 3 atm m3/mole at 25°C. In the atmosphere, dimethyl
sulfide has an estimated half-life of 26.6 hours, calculated from an experimental reaction rate
constant of 4.82 x 10 12 cm3/molecule-second at 25°C for reaction with photochemically-
produced hydroxyl radicals (U.S. EPA. 2024a). The estimated soil adsorption coefficient (Koc)
for dimethyl sulfide indicates minimal potential for sorption to soil (U.S. EPA. 2012b); therefore,
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dimethyl sulfide has the potential for migration into groundwater according to the Food &
Agriculture Organization of the United Nations (FAO) mobility classification based on log Koc
(U.S. EPA. 2009a). Volatilization from dry soil surfaces is expected based on its vapor pressure.
Dimethyl sulfide is not expected to undergo hydrolysis due to its lack of hydrolysable functional
groups. Dimethyl sulfide is considered readily biodegradable based on the Organisation for
Economic Cooperation and Development (OECD) 301D ready biodegradability test results of
77% biodegradation after 28 days; therefore, it is not expected to be persistent (ECHA. 2021).
Table 1. Physicochemical Properties of Dimethyl Sulfide (CASRN 75-18-3)
Property (unit)
Value3
Physical state
Liquidb
Boiling point (°C)
37.8
Melting point (°C)
-92.5
Density (g/cm3 at 20°C)
0.8483b
Vapor pressure (mm Hg at 25°C)
502
pH (unitless)
NA
Acid dissociation constant (pKa) (unitless)
NA
Solubility in water (mg/L at 25°C)
2.2 x 104 (reported as 0.355 mol/L)
Octanol/water partition coefficient (log Kow)
1.05
Henry's law constant (atm-m3/mole at 25°C)
1.61 x 103
Soil adsorption coefficient Koc (L/kg)
12.7 (predicted average)
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
4.82 x 10-12
Atmospheric half-life (h)
26.6 (calculated assuming a 12-h day and
1.5 x 106OH/cm3)
Relative vapor density (air = 1)
2.14b
Molecular weight (g/mol)
62.13
Flash point (°C)
-48 (closed cup)b
aUnless otherwise noted, data were extracted from the U.S. EPA CompTox Chemicals Dashboard, accessed August
27, 2024 (dimethyl sulfide [CASRN 75-18-3]
https://comptox.epa. gov/dashboard/chemical/details/DTXSID90263 98). All values are experimental averages
unless otherwise specified.
bNLM (2022).
NA = not applicable; U.S. EPA = U.S. Enviromnental Protection Agency.
A summary of available toxicity values and qualitative conclusions for dimethyl sulfide
from the U.S. EPA and other agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values and Qualitative Conclusions
Regarding Carcinogenicity for Dimethyl Sulfide (CASRN 75-18-3)
Source/
(parameter)ab
Value (applicability)
Notes
Reference0
Noncancer
IRIS
NV
NA
U.S. EPA (2024c)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018a)
ATSDR
NV
NA
ATSDR (2021)
WHO
NV
NA
WHO (2022); JECFA
(2000)
CalEPA
NV
NA
CalFPA (2022. 2020)
OSHA
NV
NA
OSHA (2021a. 2021b.
2021c)
NIOSH
NV
NA
NIOSH (2018)
ACGIH (TLV-TWA)
10 ppm (25 mg/m3)
Based on upper
respiratory tract irritation
and lack of toxicity in rats
exposed orally for 14 wk
ACGIH (2021. 2004)
AIHA (ERPG)
ERPG-1: 0.5 ppm (1.3 mg/m3)
ERPG-2: 1,000 ppm (2,500 mg/m3)
ERPG-3: 5,000 ppm (13,000 mg/m3)
ERPG-1: odor perception
ERPG-2: CNS impairment
in rats and eye irritation in
humans
ERPG-3: mortality in rats
(>10% LEL and <50%
LEL)
AIHA (2016)
DOE (PAC)
PAC 1: 0.5 ppm (1.3 mg/m3)
PAC 2: 1,000 ppm (2,500 mg/m3)
PAC 3: 5,000 ppm (13,000 mg/m3)
PACs are based on ERPGs
DOE (2018)
USAPHC (air-MEG)
1-H critical: 13,000 mg/m3
1-H marginal: 2,500 mg/m3
1-H negligible: 1.3 mg/m3
8-H negligible: 1.3 mg/m3
14-D negligible: 1.3 mg/m3
1-Yr negligible: 1.3 mg/m3
Based on ERPGs;
negligible values based on
ERPG-1
U.S. APHC (2013)
MI DNR (AAC)
1-Yr: 0.0028 ppm (0.007 mg/m3)
No details provided
U.S. EPA(1993)d
TX ACB (AAC)
30-Min: 0.0012 ppm (0.003 mg/m3)
No details provided
U.S. EPA(1993)d
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Table 2. Summary of Available Toxicity Values and Qualitative Conclusions
Regarding Carcinogenicity for Dimethyl Sulfide (CASRN 75-18-3)
Source/
(parameter)ab
Value (applicability)
Notes
Reference0
Cancer
IRIS
NV
NA
U.S. EPA (2024c)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018a)
NTP
NV
NA
NTP (2021)
IARC
NV
NA
IARC (2021)
CalEPA
NV
NA
CalEPA (2022. 2020)
ACGIH
NV
NA
ACGIH (2021. 2004)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; AIHA = American Industrial
Hygiene Association; ATSDR = Agency for Toxic Substances and Disease Registry; CalEPA = California
Enviromnental Protection Agency; DOE = U.S. Department of Energy; DWSHA = Drinking Water Standards and
Health Advisories; HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for
Research on Cancer; IRIS = Integrated Risk Information System; MI DNR = Michigan Department of Natural
Resources; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; TX ACB = Texas Air Control Board;
USAPHC = U.S Army Public Health Command; WHO = World Health Organization.
Parameters: AAC = Acceptable Ambient Concentration; ERPG = emergency response planning guideline;
LEL = lower explosive limit; MEG = military exposure guideline; PAC = protective action criteria;
TLV = threshold limit value; TWA = time-weighted average.
°Reference date is the publication date for the database and not the date the source was accessed.
dThis document was compiled by the U.S. EPA in 1993. Values from this document may have since been archived
or updated by the state agencies that reported them.
CNS = central nervous system; NA = not applicable; NV = not available.
Literature searches were conducted in June 2019 and updated most recently in July 2024
for studies relevant to the derivation of provisional toxicity values for dimethyl sulfide. Searches
were conducted using U.S. EPA's Health and Environmental Research Online (HERO)
(www.hero.epa.gov) database of scientific literature^HERO searches the following databases:
PubMed, TOXLINE2 (including TSCATS1), Scopus, and Web of Science. The following
resources were searched outside of HERO for health-related values: American Conference of
Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease
Registry (ATSDR), California Environmental Protection Agency (CalEPA), Defense Technical
Information Center (DTIC), European Centre for Ecotoxicology and Toxicology of Chemicals
(ECETOC), European Chemicals Agency (ECHA), the U.S. EPA Chemical Data Access Tool
(CDAT), the U.S. EPA ChemView, the U.S. EPA Integrated Risk Information System (IRIS),
the U.S. EPA Health Effects Assessment Summary Tables (HEAST), the U.S. EPA Office of
Water (OW), International Agency for Research on Cancer (IARC), the U.S. EPA
TSCATS2/TSCATS8e, U.S. EPA High Production Volume (HPV), Chemicals via International
1 Search strings and literature documentation are available from U.S. EPA (2024d).
2TOXLINE was retired in December 2019. Searches of this database were conducted through June 2019.
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Programme on Chemical Safety (IPCS) INCHEM, Japan Existing Chemical Database (JECDB),
Organisation for Economic Cooperation and Development (OECD) Screening Information Data
Sets (SIDS), OECD International Uniform Chemical Information Database (IUCLID), OECD
HPV, National Institute for Occupational Safety and Health (NIOSH), National Toxicology
Program (NTP), Occupational Safety and Health Administration (OSHA), and World Health
Organization (WHO).
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer evidence
bases, respectively, for dimethyl sulfide and include all potentially relevant repeated-dose
short-term, subchronic, and chronic studies, as well as reproductive and developmental toxicity
studies. Principal studies used in the PPRTV assessment for derivation of provisional toxicity
values are identified in bold. The phrase "statistical significance" and term "significant," used
throughout the document, indicate a p-value of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Dimethyl Sulfide (CASRN 75-18-3)
Number of Male/Female,
Strain Species, Study
Type, Reported Doses,
Reference
Category3
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Short-term
5 M/5 F, Wistar rats.
0, 25, 250
Lack of toxicologically relevant
250
NDr
Butterworth et
PR
gavage in corn oil, 7 d/wk.
effects.
al. ("19751
2 wk
(interim
sacrifice group)
Subchronic
5 M/5 F, Wistar rats.
0, 25, 250
Lack of toxicologically relevant effects
250
NDr
Butterworth et
PR
gavage in corn oil, 7 d/wk.
al. ("19751
6 wk
(interim
sacrifice group)
Subchronic
15 M/15 F, Wistar rats,
0, 2.5, 25, 250
Lack of toxicologically relevant effects
250
NDr
Butterworth et
PR, PS
gavage in corn oil, 7 d/wk,
al. ("19751
14 wk
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Table 3A. Summary of Potentially Relevant Noncancer Data for Dimethyl Sulfide (CASRN 75-18-3)
Category3
Number of Male/Female,
Strain Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
10 M/F, NZW rabbits,
drinking water, 7 d/wk,
13 wk
0, 2,000
Decreased relative liver weight and
increased relative lung weight
associated with pulmonary congestion.
NDr
2,000
Wood et al.
(1971)
(focused on
ocular effects;
limited
systemic
endpoints
evaluated)
PR
Chronic
15 rats and 18 total rabbits
(strains not specified),
gavage, 225 d
0,0.0015,0.015,0.6, 15
Based on reporting from a secondary
source, the dose of 0.6 mg/kg-d is an
apparent NOAEL; however, effects
observed at 15 mg/kg-d were not
specified.
NDr
NDr
Koptyaev
(1967) as cited
in EFSA CEF
Panel (2010)
(Russian
language study;
full study not
available)
NPR
Reproductive/
Developmental
8 F/0 M, Sprague Dawley
rats, gavage in corn oil,
GDs 6-19
0, 333, 666, 1,000
No toxicologically relevant effects.
1,000
NDr
ECHA (2004)
(full study
report not
available)
NPR
Reproductive/
Developmental
25 F/0 M, Sprague Dawley
rats, gavage in corn oil,
GDs 6-19
0, 100, 500, 1,000
No toxicologically relevant effects.
1,000
NDr
ECHA (2005)
(full study
report not
available)
NPR
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Table 3A. Summary of Potentially Relevant Noncancer Data for Dimethyl Sulfide (CASRN 75-18-3)
Category3
Number of Male/Female,
Strain Species, Study
Type, Reported Doses,
Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
2. Inhalation (mg/m3)
Short-term
ND
Subchronic
ND
Chronic
5 rats (sex and strain not
specified), 6 mo, 6 li/d
Range: 1-6.3 (exact
concentrations not
reported)
Secondary source reported decreased
body-weight gain increased heart
weight, decreased oxygen
consumption increased serum
cholesterol, and a variety of
biochemical changes in whole blood
and tissue homogenates at unspecified
exposure levels. Transient changes (not
further described) reportedly occurred
at 5 mg/m3 (HEC of 1 mg/m3).
NDr
NDr
Selyuzhitskii
(1972) as cited
in Oodvkc
(1979)
(Russian
language study;
full study not
available)
NPR
Reproductive/
Developmental
ND
"¦Duration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long-term (subchronic) = repeated
exposure for >30 days <10% life span for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% life span for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDosimetry: Doses are presented as ADDs (mg/kg-day) for oral noncancer effects and as HECs (in mg/m3) for inhalation noncancer effects. The HEC from animal
studies was calculated using the equation for extrarespiratory effects from a Category 3 Gas (U.S. EPA. 1994): HECer = continuous concentration in mg/m3 x ratio of
animal:humanblood gas partition coefficients (default value of 1 applied). In contrast to other repeated-exposure studies, values from animal gestational exposure studies
are not adjusted for exposure duration in calculation of the ADD. All NOAELs/LOAELs were identified by the U.S. EPA unless noted otherwise.
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; F = females; GD = gestation day; HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level; M = males;
ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level; NZW = New Zealand White; U.S. EPA = U.S. Enviromnental Protection Agency.
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Table 3B. Summary of Potentially Relevant Cancer Data for Dimethyl Sulfide (CASRN 75-18-3)
Category
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Duration
Dosimetry
Critical Effects
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
ND = no data.
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2.1. HUMAN STUDIES
2.1.1. Oral Exposures
No studies were located regarding cancer or noncancer effects in humans after oral
exposure.
2.1.2. Inhalation Exposures
Information regarding the toxicity of dimethyl sulfide to humans following inhalation
exposure is limited to a case report and a few epidemiological studies involving mixed
exposures. Due to mixed exposures and general lack of quantitative exposure data, these studies
were not considered informative for toxicity value derivation; therefore, they are not included in
Table 3A. However, they are briefly discussed below. The case report involved a man who had
entered a storage tank in a paper manufacturing plant, collapsed immediately, and was dead
when removed (duration of exposure was not specified) (Terazawa et al.. 1991a; Terazawa et al..
1991b). Autopsy revealed congestion of the internal organs and pulmonary edema. Sampling and
analysis of the atmosphere in the tank at an unspecified interval after the accident revealed no
detectable hydrogen sulfide, methyl mercaptan at <10 ppm, dimethyl sulfide at "several ppm,"
and dimethyl disulfide at 1 ppm. Death was attributed to dimethyl sulfide (possibly combined
with hypoxia) because gas chromatographic-mass spectrometric (GC-MS) analysis of headspace
gas from blood and organ samples revealed a single peak identified as dimethyl sulfide. The
samples, however, were taken 27 hours after the accident and were heated to 60°C for
30 minutes prior to analysis of the headspace gas. The delay in obtaining samples and conditions
of analysis may have afforded opportunity for microbial degradation of the cadaver tissue,
releasing dimethyl sulfide.
Several epidemiological studies were conducted on workers in the paper pulp industry
and populations located near pulp mills. Exposure was to a mixture of sulfur compounds,
including dimethyl sulfide, but also hydrogen sulfide, methyl mercaptan, dimethyl disulfide, and
sulfur dioxide. Effects attributed to exposure to the mixed sulfur compounds were headaches in
workers (Kangas et al.. 1984). altered heme synthesis and iron metabolism in workers (Klingberg
et al.. 1988; Tenhunen et al.. 1983). and eye and respiratory symptoms in residents of
communities located near the paper pulp mills (Partti-Pellinen et al.. 1996; Jaakkola et al.. 1990).
A study of symptoms and neuropsychological test results in a small number of former workers
and neighbors located geographically downwind of an oil refinery (who were exposed to
hydrogen sulfide, unspecified mercaptans, ethane, propane, and other chemicals, in addition to
dimethyl sulfide) reported significant differences in the exposed groups, as compared with a
control group consisting of friends and relatives nominated by the exposed group (Kilburn and
Warshaw. 1995). It is not possible to draw any conclusions regarding dimethyl sulfide from these
data, as subjects were exposed in each case to a mixture of chemicals. The studies were also
limited by lack of quantitative exposure assessment and reliance on self-reported symptoms.
2.2. ANIMAL STUDIES
2.2.1. Oral Exposures
Short-Term Study
Butterworth et al. (1975)
In a published, peer-reviewed study, Butterworth et al. (1975) briefly reported results of a
2-week interim sacrifice group from a 90-day gavage study. In this study, Wistar rats
(five/sex/group) were administered dimethyl sulfide at doses of 0, 25, or 250 mg/kg-day via
gavage in corn oil 7 days/week for 2 weeks. Body weights and food and water consumption were
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recorded weekly throughout the study. Rats were sacrificed 24 hours after the final gavage
exposure and subjected to gross necropsy. At sacrifice, blood and urine were collected for
hematology (total red blood cell [RBC] count, hemoglobin, packed cell volume, total and
differential white blood cell [WBC] count), clinical chemistry (aspartate transaminase [AST],
alanine transaminase [ALT], lactic dehydrogenase [LDH]) and urinalysis (appearance, volume,
specific gravity, glucose, ketones, bile salts, blood content). The following organs were removed
and weighed: brain, pituitary, thyroid, heart, liver, stomach, small intestine, cecum, spleen,
kidneys, adrenal glands, and reproductive organs (testes, ovaries). Histopathology was not
performed. The study authors analyzed continuous data using the Student's M:est; however, no
quantitative data were provided in the study report for the 2-week interim sacrifice group.
No clinical signs of toxicity were observed for the 2-week sacrifice group. No exposure-
related changes were observed for body weight, food or water consumption, hematology, clinical
chemistry, or urinalysis. Relative brain weight was significantly increased in female rats at
250 mg/kg-day, compared to control; no difference was observed in absolute brain weight in
females or absolute or relative brain weight in males. No significant, exposure-related changes
were reported for other weighed organs. The study authors noted that gross observations at
necropsy showed occasional pitting of the kidney cortex and pallor of the liver. However,
incidences and doses at which these observations were made were not reported, and it is not clear
if these observations were made after 2 weeks of exposure or only after longer exposure
durations (see Subchronic Studies below).
Based on available data, the highest administered dose of 250 mg/kg-day is identified as
a no-observed-adverse-effect-level (NOAEL) for this study based on the lack of exposure-related
effects. The elevated relative brain weight observed in high-dose females is not considered a
toxicologically relevant effect because brain weight changes were not observed after 6 or
14 weeks of exposure, and histopathological brain lesions were not observed after 14 weeks of
exposure (see Subchronic Studies below). While the 2-week study has limited quantitative data
reporting, the NOAEL is supported by the lack of toxicologically relevant findings from the
associated 6- and 14-week studies discussed below.
Subchronic Studies
Butterworth et al. (1975)
In a published, peer-reviewed study, Wistar rats (15/sex/group) were administered
dimethyl sulfide at doses of 0, 2.5, 25, or 250 mg/kg-day via gavage in corn oil 7 days/week for
14 weeks. Additional rats (five/sex/group) were similarly exposed to 0, 25, or 250 mg/kg-day via
gavage 7 days/week for 6 weeks. Body weights and food and water consumption were recorded
weekly throughout the study. Rats were sacrificed 24 hours after the final gavage exposure (at
6 or 14 weeks) and subjected to gross necropsy. At sacrifice, blood and urine were collected for
hematology (total RBC count, hemoglobin, packed cell volume, total and differential WBC
count), clinical chemistry (AST, ALT, LDH), and urinalysis (appearance, volume, specific
gravity, glucose, ketones, bile salts, blood content). The following organs were removed and
weighed: brain, pituitary, thyroid, heart, liver, stomach, small intestine, cecum, spleen, kidneys,
adrenal glands, and reproductive organs (testes, ovaries). Histopathology was conducted on the
weighed organs as well as the salivary gland, trachea, esophagus, colon, rectum, lymph nodes,
lung, aorta, pancreas, urinary bladder, uterus, and skeletal muscle in all high-dose rats after
14 weeks of exposure and half of the control rats. All gross abnormalities were examined
microscopically after 14 weeks regardless of exposure group; it is unclear if gross abnormalities
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were examined microscopically after 6 weeks. Continuous data were statistically analyzed using
the Student's /-test. Details on statistical analysis of incidence data were not provided.
No mortalities or clinical signs of toxicity were observed after 6 or 14 weeks of exposure.
No exposure-related changes were observed for body weight, food or water consumption,
hematology, or clinical chemistry after 6 or 14 weeks of exposure. Sporadic changes in urinalysis
values were observed at 6 weeks (volume) and 14 weeks (specific gravity); however, findings
did not show clear dose relationships and were not consistent across exposure durations or
sampling time points (see Table B-l). The study authors noted occasional pitting of the kidney
cortex and pallor of the liver at gross autopsy; however, incidences, doses, and exposure duration
at which these observations were made were not reported. After 6 weeks, statistically significant
organ weight changes were limited to sporadic, non-dose-related findings, including increased
absolute spleen weight in males at 25 mg/kg-day, decreased relative stomach weight in males at
25 mg/kg-day, and decreased heart weight in females at 250 mg/kg-day (quantitative data not
reported). A few statistically significant changes in organ weights were also observed in rats
treated for 14 weeks, compared to the control group (see Table B-2). Observed changes in males
included mild increases (9-12%) in absolute and relative small intestine weights in males at
>2.5 and >25 mg/kg-day, respectively. The small intestine weight changes were analyzed by an
F-test by the study authors and reported to have a nonsignificant, dose-response relationship. No
histopathological changes were observed in the intestine (quantitative data not reported). In
addition, there was a 19% increase in relative thyroid weight in males at 250 mg/kg-day and a
23% decrease in both absolute and relative thyroid weight in females at 250 mg/kg-day. Given
that the thyroid weight changes were in opposite directions in the males and females, and there
are no supporting thyroid pathology data available (quantitative data not reported), the biological
significance of these findings is unclear. Histopathological evaluation reported some degree of
liver cell fatty degeneration and some chronic inflammation in lungs and kidneys; however,
incidence and severity of these findings were comparable in the treated and control groups
(quantitative data not reported).
Based on available data, the highest administered dose of 250 mg/kg-day is identified as
a NOAEL for this study due to the observed lack of exposure-related effects. The mild increases
in male small intestine weights were not considered toxicologically relevant in the absence of
histopathological findings. Similarly, the changes in thyroid weights were not considered
toxicologically relevant based on the opposite direction of change between sexes and lack of
supporting histological findings. Histopathological incidence data were not available for
independent review.
Woodet al. (1971)
In a published, peer-reviewed study, groups of 10 New Zealand White (NZW) rabbits
(males and females combined) were administered drinking water containing 0 or 2% dimethyl
sulfide for 13 weeks. The administered dose was the highest possible based on the solubility of
dimethyl sulfide. Using measured daily fluid intake, the study authors estimated the dose of
dimethyl sulfide in the treated group to be 2,000 mg/kg-day. The primary focus of the study was
to evaluate potential changes in the lens of the eye known to occur following oral exposure to
dimethyl sulfoxide (DMSO), which is both a metabolic precursor and a metabolite of dimethyl
sulfide. Baseline measures of body weight and ocular evaluations (retinoscopy, ophthalmoscopy,
biomicroscopy) were performed. Any animals with abnormal findings in the eye or gross
physical findings were excluded from the study. Retinoscopic exams were repeated weekly for at
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least the first 8 weeks of treatment; it is unclear if exams continued for the remaining weeks of
the exposure period. After the exposure period, animals were sacrificed. At necropsy, all animals
were subject to gross necropsy and the following organs were removed and weighed: liver,
kidney, spleen, heart, lungs, and adrenal glands. Eyes were removed and enucleated, and the
lenses were removed posteriorly to be weighed and examined. Histopathological examination of
non-ocular tissue was not performed. Statistical analyses were not reported by the study authors.
No exposure-related changes in body weights were observed (see Table B-3). No
retinoscopic, lenticular, or microscopic changes in the eye occurred with dimethyl sulfide
treatment. Exposure-related organ weight changes included an 18% decrease in relative liver
weights and a 50% increase in relative lung weights in treated rabbits, compared to controls
(males and females combined; see Table B-3); absolute organ weights were not reported.
Observed changes in relative liver and lung weights were statistically significant based on
Student's M:est (conducted for this review)3. All other organ weights were comparable to control.
The study authors reported that gross necropsy showed pulmonary congestion with some
hemorrhagic spots and renal pyelonephritis in the treated rabbits; however, incidence of these
findings was not reported and histological examinations of gross findings were not conducted.
Based on available data, the only administered dose of 2,000 mg/kg-day is identified as a
lowest-observed-adverse-effect level (LOAEL) based on decreased relative liver weights and
increased relative lung weights associated with pulmonary congestion. The toxicological
relevance of renal pyelonephritis cannot be determined in the absence of incidence data or
histopathological evaluation. The confidence in the NOAEL is low due to lack of quantitative
reporting of gross lesions and lack of histopathological examination of non-ocular tissues.
Reproductive/Developmental Studies
ECHA (2004)
The ECHA database summarized findings from a developmental range-finding study
conducted in 2004. The full study report was not available. In this study, mated female
Sprague Dawley rats (eight per group) were administered dimethyl sulfide (reported as pure
active substance) at doses of 0, 333, 666, or 1,000 mg/kg-day via gavage in corn oil on gestation
days (GDs) 6-19. Dams were observed twice daily for mortality and clinical signs of toxicity.
Body weights and food consumption were monitored at "appropriate intervals." Dams were
sacrificed on GD 20 and underwent gross necropsy. The uteri, placenta, and ovaries were
removed for examination. Endpoints evaluated included gravid uterine weight, early and late
resorptions, total implantations, number of corpora lutea, number and weight of fetuses, and
number of external fetal malformations and variations. No quantitative data or details regarding
statistical analysis were reported in the available study summary.
All dams survived until scheduled sacrifice. No exposure-related changes in maternal
body weights or food consumption occurred. No toxicologically relevant findings were noted at
necropsy. No exposure-related changes were observed for reproductive or developmental
endpoints.
Statistical significance of reported data (mean, standard error, and animal number) was analyzed using the
Student's t-test calculator available from the open-source software, GraphPad.
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Based on available data, the highest administered dose of 1,000 mg/kg-day is identified
as a reproductive and developmental NOAEL for lack of toxicologically relevant effects. A
LOAEL was not identified. However, quantitative data were not available for independent
review.
ECHA (2005)
The ECHA database summarized findings from a Good Laboratory Practice
(GLP)-compliant, OECD Guideline 414 developmental study conducted in 2004-2005. The full
study report was not available. In this study, mated female Sprague Dawley rats (25/group) were
administered dimethyl sulfide (reported as pure active substance) at doses of 0, 100, 500, or
1,000 mg/kg-day via gavage in corn oil on GDs 6-19. Dams were observed daily for mortality
and clinical signs of toxicity. Body weights were recorded on GD 0 and daily on GDs 6-20.
Food consumption was monitored at unspecified intervals. Dams were sacrificed on GD 20 and
examined for gross pathologic changes. The uterus and ovaries were removed, and gravid uterus
weight was measured. The numbers of corpora lutea, implantations, viable fetuses, and early and
late resorptions were determined. Placentae were also examined. All fetuses were weighed and
examined for external alterations, and all viable fetuses were examined for skeletal and visceral
alterations. Statistical analyses were performed by the study authors. Analysis of variance
(ANOVA), Snedecor and Cochran, or Kruskal-Wallis tests were used to test for intergroup
differences. Where appropriate, Dunnett's or Mann-Whitney U tests were used for pairwise
comparisons. No quantitative data were reported in the available study summary.
One dam at 1,000 mg/kg-day was found dead due to gavage error on Day 8. All other
females survived to scheduled sacrifice. No significant clinical findings were observed. No
changes to maternal body weight, uterine weight, or food consumption were observed. There
were no changes in reproductive endpoints or intrauterine growth or survival. There were no
exposure-related external, visceral, or skeletal malformations or variations.
Based on available data, the highest administered dose of 1,000 mg/kg-day is identified
as a reproductive and developmental NOAEL for lack of toxicologically relevant effects. A
LOAEL was not identified. However, it is noted that quantitative data were not available for
independent review.
Chronic/Carcinogenicity Studies
No chronic/carcinogenicity studies of dimethyl sulfide adequate for quantitative
dose-response analysis were identified.
However, a Russian language study was briefly summarized in a secondary source
[Koptyaev (1967) as cited in EFSA CEF Panel (2010)1. In this study, rats (5 per group) and
rabbits (18 total) were exposed to gavage doses of 0, 0.0015, 0.015, 0.6, or 15 mg/kg-day for
225 days; however, no information on the endpoints evaluated or the effects observed was
provided. The EFSA CEF Panel (2010) report identified the 0.6-mg/kg-day exposure level as a
NOAEL; however, effects observed at 15 mg/kg-day were not identified. The EFSA CEF Panel
(2010) report indicated that the primary study lacked histopathology data and was insufficiently
reported; therefore, the European Food Safety Authority (EFSA) determined that the validity of
the study could not be evaluated. Due to the lack of available details regarding experimental
methods and results, this study cannot be properly evaluated, and reliable NOAEL and LOAEL
values cannot be determined.
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2.2.2. Inhalation Exposures
No inhalation studies that were adequate for quantitative dose-response were identified
evaluating the subchronic, chronic, developmental, or reproductive toxicity or the
carcinogenicity of dimethyl sulfide in animals.
However, in a Russian language study available only from a secondary source
[Selyuzhitskii (1972) as cited in Opdyke (1979)1. rats (15/group; species and sex not specified)
were exposed by inhalation to dimethyl sulfide concentrations ranging from 5 to 25 mg/m3 for
6 months (6 hours/day). Details regarding experimental protocol and conditions were not
provided in the available summary. Reported effects at unspecified exposure levels included
decreased body weight gain, increased heart weight, decreased oxygen consumption, increased
serum cholesterol, and a variety of biochemical changes in whole blood and tissue homogenates.
Transient changes were reported to occur at the low concentration of 5 mg/m3, but a description
of these effects was not provided. This study also reported acute inhalation median lethal
concentration (LCso) values for dimethyl sulfide of 31.62 mg/m3 for 2 hours in mice and
50.12 mg/m3 for 4 hours in rats. These values are orders of magnitude lower than those reported
in other acute studies, described below (see Table 4 A), which suggests that the results of the
study may not be reliable. Due to the lack of details regarding experimental methods and results,
this study cannot be properly evaluated, and reliable NOAEL and LOAEL values cannot be
determined.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 4 A provides an overview of other supporting studies on dimethyl sulfide and
Table 4B provides an overview of genotoxicity studies of dimethyl sulfide and.
2.3.1. Supporting Animal Studies
Several acute studies were identified. These studies are summarized in Table 4A.
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Table 4A. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute Studies in Animals
Acute (oral)
Two rats (sex and strain not
specified) were exposed once
to dimethyl sulfide at
2,000 mg/kg via gavage in corn
oil.
All rats survived. Slight liver damage (not
further described) was observed at necropsy.
Timing of necropsy was not reported.
Rat LDlo >2,000 mg/kg
Dow Chemical (1957)
Acute (oral)
Six female Sprague Dawley
rats were exposed once to
dimethyl sulfide at
2,000 mg/kg via gavage in corn
oil and observed for 14 d.
All rats survived. Clinical signs included
piloerection (three of six) and hunched posture
(two of six) on Day 1. Body-weight gain
during the 14-d observation period was lower
than historical controls in four of six females.
No gross lesions were observed at necropsy.
Rat LDlo >2,000 mg/kg
ECHA (2015)
Acute (oral)
ICR mice (five/sex/group per
time point) were exposed once
to 0, 1,250, 2,500, or
5,000 mg/kg via gavage in corn
oil and sacrificed 24, 48, or
72 h later for determination of
MN in bone marrow.
Lethargy was observed in both sexes at all
dose levels. Dimethyl sulfide did not induce
MN in bone marrow at any time point.
A LOAEL of 1,250 mg/kg was
identified based on clinical signs of
CNS depression. No NOAEL was
identified.
ECHA (1995b)
Acute (oral)
Acute oral lethality study in
rats and mice (no additional
details provided).
The LD50 values for rats and mice were
reported as 3,300 and 3,700 mg/kg,
respectively.
Rat LD50 = 3,300 mg/kg
Mouse LD50 = 3,700 mg/kg
EFSA CEF Panel
(2010)
Acute (inhalation)
Three rats were exposed to a
"saturated" atmosphere of
dimethyl sulfide for up to
9 min.
Labored breathing, nasal irritation, and
unconsciousness were observed within 3 min;
two of the three animals died within 9 min.
Brief exposures to air saturated with
dimethyl sulfide can produce nasal and
respiratory irritation, CNS depression,
and death.
Dow Chemical (1957)
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Table 4A. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (inhalation)
White female rats (one/group)
were exposed to
3,000-140,000 mg/m3 for up to
30 min.
No overt effects were noted in the rat at
3,000 mg/m3. The following effects were
observed at higher concentrations: closed eyes
(2 min) and laying down (10 min) at
14,500 mg/m3; closed eyes (immediately) and
slow, irregular respiration (5 min) at
34,600 mg/m3; prostration with dyspnea
(20 min) at 76,000 and 80,000 mg/m3; and
dyspnea (2 min), nasal discharge of fluid
(5 min), and death (15 min) at 140,000 mg/m3.
Rats exposed to <80,000 mg/m3 recovered
once removed from the exposure chamber.
Irritation to mucous membranes, evidenced by
secretion from the eyes and nose, was
observed, but the exposure levels for this
effect were not reported. No macroscopic
changes were seen at necropsy.
A NOAEL of 3,000 mg/m3 and a
LOAEL of 14,500 mg/m3 were
identified based on transient clinical
signs of toxicity. It is noted that no
controls were included, and only one
animal per exposure level was used.
Liuneeren and
Norbers (1943)
Acute (inhalation)
Groups of Sprague Dawley rats
(five/sex) were exposed to 0,
800, 3,000, 6,000, 12,000,
24,000, 36,000, 39,000, 42,000,
45,000, or 48,000 ppm (0,
2,030, 7,620, 15,200, 30,490,
60,990, 91,480, 99, 100,
106,700, 114,300, or
122,000 mg/m3) for 4 h and
observed for 14 d.
No deaths were observed at <24,000 ppm.
Mortalities were observed at 36,000 ppm
(2/10), 39,000 ppm (5/10), 42,000 ppm (5/10),
45,000 ppm (8/10), and 48,000 ppm (9/10).
The study authors calculated an LCso (95%
CI) of 40,250 (38.018—42,613) ppm. The
following clinical signs were observed at
unspecified concentrations: huddling, eye
closure, and labored breathing. At
>36,000 ppm, rats seized wire mesh floor of
cage (teeth and claws) and maintained a rigid
posture with hunched back and extended tail.
No macroscopic changes were seen at
necropsy.
Rat 4-h LCso = 40,250 ppm
(102,300 mg/m3)
Rat 4-h LClo = 36,000 ppm
(91,480 mg/m3)
Tansv et al. (1981)
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Table 4A. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (inhalation)
Mice (strain and sex NS;
five/group) were exposed to
68,000, 116,000, 236,000,
340,000, or 506,000 ppm
(172,800, 294,800, 599,700,
864,000, or 1,286,000 mg/m3)
for up to 8 min.
Inability to stand was observed within 1 min
at all tested concentrations, with respiratory
arrest and death in <8 min. Average times to
respiratory arrest at 68,000, 116,000, 236,000,
340,000, and 506,000 ppm were 5.92, 3.15,
1.39, 1.54, and 0.81 min, respectively.
100% mortality at >68,000 ppm
(172,800 mg/m3) within 8 min.
Terazawa et al.
(1991b)
Acute (inhalation)
Male Holtzman or
Sprague Dawley rats (three to
five/group) were exposed to
dimethyl sulfide at
concentrations up to
-105,000 ppm
(-266,800 mg/m3) (estimated
from graphically presented
data) for 15 min to determine
the ECso for production of
coma (defined as complete loss
of righting reflex).
The 15-min ECso for production of coma was
calculated to be 96,000 ppm. Coma was
preceded by a brief period of excitement. All
animals regained consciousness within
30 min.
Coma ECso = 96,000 ppm
(243,900 mg/m3)
Zieve et al. (1974)
Acute (dermal)
Rabbits (number NS) were
dennally exposed to dimethyl
sulfide (10% solution or
undiluted) on intact skin
(10 applications) or abraded
skin (3 applications).
Observations included slight-to-moderate
hypermedia, edema, and exfoliation following
exposure to 10% solution on intact skin.
Similar findings, as well as necrosis and scab
formation, were observed following exposure
to 10% solution on abraded skin or undiluted
dimethyl sulfide on intact or abraded skin.
Skin appeared normal within 16-21 d
postexposure.
Dimethyl sulfide is a skin irritant.
Dow Chemical (1957)
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Table 4A. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (ocular)
Dimethyl sulfide (10% solution
or undiluted) was applied to
rabbit eyes (number not
specified). No further
information was provided.
Observations at both concentrations included
slight immediate pain, slight-to-moderate
conjunctival irritation lasting >48 h, and slight
corneal damage and iritis lasting up to 24 h.
Dimethyl sulfide is an eye irritant.
Dow Chemical (1957)
aValues in the study report were given in ppm. Values in mg/m3 = exposure in ppm x dimethyl sulfide MW ^ 24.45. The MW of dimethyl sulfide is 62.13 g/mol (U.S.
EPA. 2024a).
CI = confidence interval; CNS = central nervous system; ECso = concentration associated with a 50% effect incidence; LCso = median lethal concentration;
LClo = lowest concentration associated with mortality; LD50 = median lethal dose; LDlo = lowest dose associated with mortality;
LOAEL = lowest-observed-adverse-effect-level; MN = micronuclei; MW = molecular weight; NOAEL = no-observed-adverse-effect-level; NS = not specified.
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Table 4B. Summary of Dimethyl Sulfide Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
Without
Activation3
Results
With
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Salmonella tvphimurium
TA98, TA100, TA1535, and
TA1537; Escherichia coli
WP2 uvrA
0, 100, 333,
1,000,3,333,
5,000 (ig/plate
Preincubation assay. There was no evidence
of mutagenicity with or without exogenous
metabolic activation. Cytotoxicity and
precipitation were not observed at any dose.
ECHA (1995a)
DNA damage
S. tvphimurium
TA1535/pSK1002
Up to
14,700 (ig/mL
SOS response {umu test system). There was
no significant increase in umu gene
expression with or without exogenous
metabolic activation. No data on
cytotoxicity or solubility were provided.
Nakamura et al. (1987)
Genotoxicity studies in mammalian cells—in vitro
Mutation
Mouse lymphoma L5178Y
cells
0,0.313,0.625,
1.25,2.5,5,
10 mM
Forward mutation assay (thymidine kinase
locus). There was no evidence of
mutagenicity with or without exogenous
metabolic activation. Cytotoxicity and
precipitation were not observed at any dose.
ECHA (2010)
Genotoxicity studies—in vivo
MN
ICR mice exposed once via
gavage in corn oil; animals
sacrificed 24, 48, or 72 h
after treatment
(five/sex/group per time
point)
0, 1,250, 2,500,
5,000 mg/kg
NA
Mammalian erytlirocyte micronucleus test.
There was no significant increase in
MNPCEs in bone marrow from treated mice
at any time point, compared to vehicle
controls.
ECHA (1995b)
a- = negative; NA = not applicable.
DNA = deoxyribonucleic acid; MN = micronuclei; MNPCE = micronucleated polycliromatic erytlirocyte.
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Supporting Oral Route Studies
Reported oral medial lethal dose (LD50) values in rats and mice are 3,300 and
3,700 mg/kg, respectively; no additional details were available (EFSA CEF Panel 2010). In
another study in rats, all animals survived treatment with a single dose of 2,000 mg/kg (ECHA.
2015). Clinical signs of toxicity observed at 2,000 mg/kg in a subset of animals included
piloerection (three of six rats) and hunched posture (two of six rats). Body-weight gain during
the 14-day observation period was also lower than historical controls in four of six females. No
macroscopic findings were noted. Another acute lethality study reported 100% survival at
2,000 mg/kg in rats; slight liver damage (not further described) was observed at necropsy (Dow
Chemical 1957). In an acute study designed as a micronucleus assay, lethargy was noted in mice
following a single gavage exposure to doses >1,250 mg/kg (ECHA. 1995b).
Supporting Inhalation Route Studies
The acute inhalation 4-hour median lethal concentration (LC50) value for rats was
determined to be 40,250 ppm (102,300 mg/m3); the minimal lethal level (LClo) was 36,000 ppm
(91,480 mg/m3) (Tansy et al. 1981). Clinical signs associated with exposure (at unspecified
concentrations) included huddling, eye closure, labored breathing, and rigid posture. Higher
concentrations were associated with death in rodents after <10 minutes of exposure, including
death of two of three rats exposed to a "saturated" atmosphere and 100% of mice at >68,000 ppm
(172,800 mg/m3) (Terazawa et al. 1991b; Dow Chemical 1957). Brief, nonlethal exposures
<30 minutes are associated with transient clinical signs, including nasal irritation, eye closure,
labored breathing, huddling, rigid posture, staggering, prostration, and coma at >14,500 mg/m3
(Zieve et al. 1974; Dow Chemical. 1957; Liunggren and Norberg. 1943). No macroscopic
changes were noted at necropsy in any of these acute inhalation studies.
Supporting Studies from Other Routes of Exposure
Dimethyl sulfide is a skin and eye irritant (Dow Chemical. 1957). Dermal testing in
rabbits resulted in slight-to-moderate hypermedia, edema, and exfoliation following repeated
exposure to intact skin of a 10% solution over 10 applications. Similar findings, as well as
necrosis and scab formation, were observed following 10 applications of undiluted dimethyl
sulfide to intact skin or 3 applications of 10% solution or undiluted dimethyl sulfide to abraded
skin. Skin appeared normal within 16-21 days postexposure. Application of a 10% solution or
undiluted dimethyl sulfide to the eyes of rabbits resulted in slight immediate pain,
slight-to-moderate conjunctival irritation lasting >48 hours, and slight corneal damage and iritis
lasting up to 24 hours.
2.3.2. Genotoxicity
Available genotoxicity data for dimethyl sulfide are limited and primarily from secondary
sources, but indicate that dimethyl sulfide is not mutagenic, clastogenic, or damaging to
deoxyribonucleic acid (DNA) (see Table 4B). Dimethyl sulfide was not mutagenic to Salmonella
typhimurium, Escherichia coli (ECHA. 1995a). or mouse lymphoma cells (ECHA. 2010). It also
did not induce DNA damage or repair in S. typhimurium (Nakamura et al. 1987). In vivo,
dimethyl sulfide did not induce micronuclei (MN) in mouse bone marrow following acute oral
exposure (ECHA. 1995b).
2.3.3. Absorption, Distribution, Metabolism, and Excretion (ADME) Studies
No quantitative absorption data are available for dimethyl sulfide in humans or animals.
However, absorption through the lungs is expected based on vapor pressure, water solubility, and
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octanol/water partition coefficient (log Kow) values. Distribution and toxicity data from acute
human and animal inhalation exposure studies indicate that dimethyl sulfide is absorbed through
the lungs (Terazawa et al. 1991a; Terazawa et al.. 1991b; Tansy et al.. 1981; Dow Chemical
1957; Liunggren and Norberg. 1943). Based on blood metabolite detection in rats following oral
exposure (ECHA. 20161 oral absorption in rats is rapid; there are no data available to determine
the extent of oral absorption. Quantitative dermal absorption data are not available; however,
limited qualitative reporting from skin irritation tests in rabbits indicate that "there is no
indication that [dimethyl sulfide] is absorbed through the skin in toxic amounts" (Dow Chemical
1957).
Distribution of dimethyl sulfide is widespread following inhalation exposure in humans
and mice (Terazawa et al. 1991a; Terazawa et al. 1991b). Distribution data are not available in
humans or animals following oral exposure; however, based on the rate of metabolism and
excretion in animal studies (ECHA. 2016; Susman et al. 1978; Williams et al. 1966; Maw.
1953). distribution is expected to be rapid. Accumulation of dimethyl sulfide in the body is not
expected due its low log Kow value.
Data from a gavage study in rats and a subcutaneous (s.c.) injection study in rabbits
indicate that the primary metabolites of dimethyl sulfide are DMSO and dimethyl sulfone
(DMSO2) (ECHA. 2016; Williams et al. 1966). Following a single gavage exposure, the
maximum concentrations of DMSO and DMSO2 in blood plasma were attained within 6 and
24 hours, respectively, after administration (ECHA. 2016). Both metabolites are formed by
oxidization reactions, with dimethyl sulfide oxidizing to DMSO, which is in turn oxidized to
DMSO2. Following initial metabolism, DMSO can be reduced back to dimethyl sulfide;
however, DMSO2 does not appear to undergo reduction back to DMSO or dimethyl sulfide in
vivo (Williams et al. 1966). In vitro data from human embryonic kidney (HEK293) cells
indicate that reduction of DMSO to dimethyl sulfide can occur via the endogenous enzyme,
methionine sulfoxide reductase A (MsrA) (Chippendale et al. 2014). There is evidence that
dimethyl sulfide may be metabolized by removal of the methyl groups by transmethylation
reactions in aerobic or anaerobic conditions in Thiobaceillus bacteria (Visscher and Taylor.
1993). However, demethylation does not appear to be an important metabolic pathway in vivo,
as sulfate was not detected in the urine of rats following exposure to dimethyl sulfide via the diet
or injection (Maw. 1953).
There is no evidence that oral exposure to dimethyl sulfide leads to induction of
metabolic enzymes in the liver; however, there is limited experimental evidence available. A
single study found that oral exposure to dimethyl sulfide for 4 days did not result in significant
effects on protein levels or enzymic activity of the following monooxygenase enzymes in rat
liver: 7-ethoxyresorufin O-deethylase (EROD), methoxyresorufin (9-demethylase (MROD),
pentoxyresorufin O-depentylase (PROD), nitrosodimethylamine A-demethylase (NDMAD), or
erythromycin A-demethylase (ERDM) (Siess et al. 1997). It is unclear if longer exposures to
dimethyl sulfide would have different effects on metabolic enzyme induction in the liver.
An undetermined proportion of the administered dose of dimethyl sulfide in injection
studies was excreted in expired breath (Susman et al. 1978; Williams et al. 1966; Maw. 1953).
Susman et al. (1978) evaluated a suite of sulfide chemicals, including dimethyl sulfide, via
intraperitoneal (i.p.) injection, and found that dimethyl sulfide was the only sulfide compound
that was exhaled unchanged. However, the study authors did not provide a timeframe for
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exhalation. Maw (1953) indicated that dimethyl sulfide was "clearly detectable" in the breath
within 1 hour of injection, and Williams et al. (1966) presumed that the "malodorous breath"
observed during the experiment was due to exhaled dimethyl sulfide (no timeframe was
provided). In a s.c. study in rabbits, urinary excretion of DMSO and DMSO2 over a 4-day period
accounted for approximately 8.6 and 9.8%, respectively, of the administered dimethyl sulfide
dose (Williams et al.. 1966). After 3 days, DMSO2 was no longer detected, but DMSO levels in
urine were increased 4 days postexposure. Based on additional experiments in which rabbits
were exposed to DMSO, the study authors estimated that only about half of the total DMSO
excretion amount was recovered during the first 4 days. Other studies did not evaluate urinary
excretion. Additionally, none of the studies evaluated feces, so it is unknown if dimethyl sulfide
or its metabolites are excreted via that route.
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF ORAL REFERENCE DOSES
Animal data for dimethyl sulfide relevant to provisional reference dose (p-RfD)
derivation include a subchronic rat study that observed no toxicologically relevant effects for
endpoints evaluated at doses up to 250 mg/kg-day (Butterworth et al.. 1975). developmental
studies in rats that observed no toxicologically relevant effects at maternal doses up to
1,000 mg/kg-day (ECHA. 2005. 2004). and a subchronic study in rabbits with several limitations
(single dose level, small groups of mixed sexes, limited endpoint evaluation, no quantitative
histology) that identified a LOAEL of 2,000 mg/kg-day based on decreased liver weight and
elevated lung weight associated with pulmonary congestion (Wood et al.. 1971). These studies
are inadequate to support derivation of p-RfD values due to lack of toxicologically relevant
effects (ECHA. 2005. 2004; Butterworth et al.. 1975) or study limitations (Wood et al.. 1971).
However, the free-standing NOAEL (i.e., the highest dose tested) from the comprehensive
subchronic rat study by Butterworth et al. (1975). supported by the free-standing LOAEL
(i.e., lowest dose tested) reported by Wood et al. (1971). provide a sufficient basis to develop
screening-level p-RfD values that may be useful in certain instances (see Appendix A).
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No adequate studies were located regarding toxicity of dimethyl sulfide to humans or
animals following repeat-dose inhalation exposure. Due to the lack of adequate repeat-dose
inhalation toxicity data for dimethyl sulfide, subchronic and chronic provisional reference
concentrations (p-RfCs) could not be derived using chemical-specific information. Instead,
screening subchronic and chronic p-RfCs are derived in Appendix A using an alternative
analogue approach.
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
Table 5 presents a summary of noncancer screening provisional reference values for
dimethyl sulfide.
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Table 5. Summary of Noncancer Reference Values for Dimethyl
Sulfide (CASRN 75-18-3)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
(HED/HEC)
UFc
Principal Study
Screening
subchronic
p-RfD (mg/kg-d)
Rat/
M.F
No
toxicologically
relevant
effects
2 x KT1
NOAEL
58
300
Butterworth et al.
(1975)
Screening
chronic p-RfD
(mg/kg-d)
Rat/
M.F
No
toxicologically
relevant
effects
2 x 1(T2
NOAEL
58
3,000
Butterworth et al.
(1975)
Screening
subchronic
p-RfC
(mg/m3)
Rat/M
Nasal lesions
2 x 1(T3
NOAEL
0.64 (based on
analogue PODa)
300
Brenneman et al.
(2000) as cited in
ATSDR (2016)
Screening
chronic p-RfC
(mg/m3)
Rat/M
Nasal lesions
2 x 1(T4
NOAEL
0.64 (based on
analogue PODa)
3,000
Brenneman et al.
(2000) as cited in
U.S. EPA (2003a)
and U.S. EPA
(2003b)
aHydrogen sulfide was selected as a suitable source analogue for dimethyl sulfide as described in Appendix A.
F = female; HEC = human equivalent concentration; HED = human equivalent dose; M = male;
NOAEL = no-observed-adverse-effect level; POD = point of departure p-RfC = provisional inhalation reference
concentration; p-RfD = provisional oral reference dose; UFC = composite uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No studies examining the carcinogenic potential of dimethyl sulfide in humans or animals
were located. Genotoxicity data are limited and primarily from secondary sources, but indicate
that dimethyl sulfide is not mutagenic, clastogenic, or DNA damaging. Under the U.S. EPA
Cancer Guidelines (U.S. EPA. 2005). there is "Inadequate Information to Assess the
Carcinogenic Potential' of dimethyl sulfide by oral or inhalation exposure (see Table 6).
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Table 6. Cancer WOE Descriptor for Dimethyl Sulfide (CASRN 75-18-3)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to humans "
NS
NA
The available data do not support this
descriptor.
"Likely to be carcinogenic
to humans "
NS
NA
The available data do not support this
descriptor.
"Suggestive evidence of
carcinogenic potential"
NS
NA
The available data do not support this
descriptor.
"Inadequate information to
assess carcinogenic
potential"
Selected
Both
No adequate chronic animal cancer
bioassays are available to assess the
carcinogenic potential of dimethyl sulfide
by the oral or inhalation routes of
exposure.
"Not likely to be
carcinogenic to humans "
NS
NA
The available data do not support this
descriptor.
NA = not applicable; NS = not selected; WOE = weight of evidence.
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
The absence of data indicating a tumorigenic effect precludes development of cancer risk
estimates for dimethyl sulfide (see Table 7).
Table 7. Summary of Cancer Risk Estimates for Dimethyl
Sulfide (CASRN 75-18-3)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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APPENDIX A. NONCANCER SCREENING PROVISIONAL VALUES
Due to the lack of evidence described in the main Provisional Peer-Reviewed Toxicity
Value (PPRTV) assessment, it is inappropriate to derive provisional toxicity values for dimethyl
sulfide. However, some information is available for this chemical, which although insufficient to
support derivation of a provisional toxicity value under current guidelines, may be of limited use
to risk assessors. In such cases, the Center for Public Health and Environmental Assessment
(CPHEA) summarizes available information in an appendix and develops a "screening value."
Appendices receive the same level of internal and external scientific peer review as the
provisional reference values to ensure their appropriateness within the limitations detailed in the
document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there could be more uncertainty associated with deriving an appendix screening
toxicity value than for a value presented in the body of the assessment. Questions or concerns
about the appropriate use of screening values should be directed to the CPHEA.
Screening subchronic and chronic provisional reference doses (p-RfDs) were derived for
dimethyl sulfide using the limited available data for the chemical, as described in the sections
below. For inhalation, no suitable chemical-specific data were located, and an alternative
analogue approach was utilized to derive screening subchronic and chronic provisional reference
concentration (p-RfC) values.
ORAL NONCANCER TOXICITY VALUES
As discussed in the main body of the report, available oral studies are not adequate to
support derivation of p-RfDs. Screening-level values can, however, be derived from the 14-week
oral study in rats that reported no toxicologically relevant effects at doses up to 250 mg/kg-day
(Butterworth et al.. 1975). This study provides an evaluation of a diverse range of health
endpoints, including body weights, food/water intake, hematology, clinical chemistry and
urinalysis evaluations, organ weights, and histopathological evaluations. The developmental
no-observed-adverse-effect level (NOAEL) of 1,000 mg/kg-day from the study summarized in
ECHA (2005) was not selected because it is unknown if it would be protective of systemic
effects (only limited endpoints were evaluated in dams); additionally, quantitative data were not
included in the available study summary, precluding independent review of the data. The free-
standing lowest-observed-adverse-effect level (LOAEL) of 2,000 mg/kg-day in rabbits by Wood
et al. (1971) based on decreased relative liver weights and increased relative lung weights
associated with pulmonary congestion was not selected due to numerous study limitations,
including use of a single dose level, small groups of mixed sexes, limited endpoint evaluation,
and no quantitative histology; however, the systemic NOAEL of 250 mg/kg-day from
Butterworth et al. (1975) is expected to be protective of liver and lung effects following oral
exposure to dimethyl sulfide. To account for the uncertainty associated with deriving a reference
dose from a free-standing NOAEL, the assessment is considered a screening-level assessment.
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Derivation of a Screening Subchronic Provisional Reference Dose
The NOAEL of 250 mg/kg-day based on no toxicologically relevant effects in rats
following exposure for 14 weeks (Butterworth et al.. 1975) was selected as the point of departure
(POD) for derivation of the screening subchronic p-RfD. The POD was converted into a human
equivalent dose (HED) of 58 mg/kg-day4.
The screening subchronic p-RfD is derived by applying a composite uncertainty factor
(UFc) of 300 (reflecting an interspecies uncertainty factor [UFa] of 3, a database uncertainty
factor [UFd] of 10, and an intraspecies uncertainty factor [UFh] of 10) to the selected POD of
58 mg/kg-day.
Screening Subchronic p-RfD = POD (HED) UFc
= 58 mg/kg-day -^300
= 2 x 10"1 mg/kg-day
Table A-l summarizes the uncertainty factors for the screening subchronic p-RfD for
dimethyl sulfide.
4HEDs were calculated using dosimetric adjustment factors (DAFs), as recommended by the U.S. EPA (2011c). The
DAF of 0.23 was calculated as follows: DAF = (BWaI/4 ^ BWh1'4), where BWa = animal body weight and
BWh = human body weight. Time-weighted average (TWA) body weights of 0.186 kg were calculated for female
rats, based on reported body weight data on Days 0, 34, 62, and 90 for high-dose rats (Butterworth et al.. 1975). The
more health-protective TWA weight for females (0.186 kg) and the human reference body weight of 70 kg
recommended by the U.S. EPA (1988) were used to calculate the DAF.
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Table A-l. Uncertainty Factors for the Screening Subchronic p-RfD for
Dimethyl Sulfide (CASRN 75-18-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10"5) is applied to account for remaining uncertainty associated with extrapolating
from animals to humans when cross-species dosimetric adjustment (HED calculation) is performed.
UFd
10
A UFd of 10 is applied to reflect database limitations and uncertainties. The oral database for
dimethyl sulfide is limited to a well-reported subchronic study identifying a free-standing NOAEL,
preliminary and final developmental studies in a single species available only as incomplete reports
in a secondary source, and a subchronic study with methodological limitations. There is no
2-generation reproductive toxicity data or neurotoxicity data for dimethyl sulfide.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human variability in
susceptibility, in the absence of information to assess toxicokinetics and toxicodynamics of
dimethyl sulfide in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the POD was derived from a study of suitable duration (14 weeks)
for a subchronic value.
UFC
300
Composite UF = UFA x UFH x UFD x UFL x UFS.
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect-level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty
factor; UFS = subchronic-to-chronic uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Dose
The NOAEL of 250 mg/kg-day based on no toxicologically relevant effects in rats
following exposure for 14 weeks (Butterworth et al.. 1975) was selected as the POD for
derivation of the screening chronic p-RfD. The POD was converted to an HED of 58 mg/kg-day
as described above using female rat body weight. The screening chronic p-RfD is derived by
applying a UFc of 3,000 (reflecting a UFa of 3, a UFd of 10, a UFh of 10, and a
subchronic-to-chronic uncertainty factor [UFs] of 10) to the selected POD of 58 mg/kg-day.
Screening Chronic p-RfD = POD (HED) UFc
= 58 mg/kg-day ^ 3,000
= 2 x 10"2 mg/kg-day
Table A-2 summarizes the uncertainty factors for the screening chronic p-RfD for
dimethyl sulfide.
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Table A-2. Uncertainty Factors for the Screening Chronic p-RfD for
Dimethyl Sulfide (CASRN 75-18-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10115) is applied to account for remaining uncertainty associated with extrapolating
from animals to humans when cross-species dosimetric adjustment (HED calculation) is performed.
UFd
10
A UFd of 10 is applied to reflect database limitations and uncertainties. The oral database for
dimethyl sulfide is limited to a well-reported subchronic study identifying a free-standing NOAEL,
preliminary and final developmental studies in a single species available only as incomplete reports
in a secondary source, and a subchronic study with methodological limitations. There is no
2-generation reproductive toxicity data or neurotoxicity data for dimethyl sulfide.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human variability in
susceptibility, in the absence of information to assess toxicokinetic and toxicodynamic variability of
dimethyl sulfide in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because the POD was derived from a less-than-chronic study.
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-
effect-level; POD = point of departure; p-RfD = provisional reference dose; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
INHALATION NONCANCER TOXICITY VALUES
As discussed in the main body of the document, there are no adequate repeat-dose
inhalation toxicity data for dimethyl sulfide. Therefore, an alternative analogue approach method
was employed to derive screening level values.
APPLICATION OF AN ALTERNATIVE ANALOGUE APPROACH (METHODS)
The analogue approach allows for the use of data from related compounds to calculate
screening values when data for the target chemical are limited or unavailable. Details regarding
searches and methods for analogue analysis are adapted from Wang et al. (2012) and Lizarraga et
al. (2023) (described further in Appendix C) and chemical-specific parameters of read-across
tools can be found in Appendix D. Candidate analogues are identified on the basis of three
similarity categories (structure, toxicokinetics [metabolism] and toxicodynamics [toxicity and
mode of action; MO A]) to facilitate the final source analogue selection. The analogue approach
may or may not be route-specific or applicable to multiple routes of exposure. All information is
considered together as part of the final weight-of-evidence (WOE) approach to select the most
suitable source analogue.
In this assessment, an expanded analogue identification approach was utilized to collect
an augmented set of candidate analogues for the target chemical. As described below, this
approach applies a variety of tools and methods for identifying candidate analogues that are
similar to the target chemical based on structural features; metabolic relationships; or related
toxic effects and mechanisms of action. The application of a variety of different tools and
methods to identify candidate analogues minimizes the impact of limitations of any individual
tool or method on the pool of chemicals included, chemical fragments considered, and methods
for assessing similarity. Further, the inclusion of techniques to identify analogues based on
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metabolism and toxicity or bioactivity expands the pool of candidates beyond those based
exclusively on structural similarity. The specific tools described below used for the expanded
analogue searches were selected because they are publicly available, supported by U.S. and
Organisation for Economic Co-operation and Development (OECD) agencies, updated regularly,
and widely used.
To identify structurally related compounds, an initial pool of analogues is identified using
automated tools, including ChemlDplus5 (NLM. 2022). the CompTox Chemicals Dashboard6
(U.S. EPA. 2022bI and the OECD Quantitative Structure-Activity Relationship (QSAR)
Toolbox7 (OECDa^022). Additional analogues identified as ChemlDplus-related substances,
mixtures, and CompTox "related substances"8 are also considered. CompTox General
Read-Across (GenRA)9 analogues are collected using the methods deployed on the publicly
available GenRA Beta version, which may include Morgan fingerprints, Torsion fingerprints,
ToxPrints and the use of ToxCast, Tox21, and ToxRef data (Patlewicz and Shah. 2023). For
compounds that have very few analogues identified by structural similarity using a similarity
threshold of 0.8 or 80%, substructure searches may be performed in the QSAR Toolbox, or
similarity searches may be rerun using a reduced similarity threshold (e.g., <80%). Structural
analogues are clustered using the Chemical Assessment Clustering Engine (ChemACE)10 (U.S.
EPA. 2011a) based on chemical fragments to support expert-driven refinement of the candidate
pool. The ChemACE output is reviewed by an experienced chemist, who narrows the list of
structural analogues based on expert judgment of multiple lines of evidence including known or
expected structure-activity relationships, reactivity, and known or expected metabolic pathways.
5ChemIDPlus is a free, web search system that provides access to the structure and nomenclature authority files used
for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the
TOXNET system. The database contains over 350,000 chemical records, of which over 80,000 include chemical
structures and allows users to draw a chemical structure to search for similar substances using PubChem
Substructure fingerprints (NLM. 2009: Liwanag et al„ 2000). NLM retired ChemlDplus in December 2022.
6The U.S. EPA's CompTox Chemicals Dashboard provides publicly-accessible chemistry, toxicity, and exposure
information for over one million chemicals (Williams et al„ 2017). Using EPAM's Bingo fingerprints, the "Similar
Compounds" tab provides a list of chemicals that are similar in structure to the selected chemical, based on the
Tanimoto similarity search metric with a minimum similarity factor threshold of 0.8 (EPAM. 2024).
7The OECD QSAR Toolbox is a software application intended to be used by government, industry, and other
stakeholders to fill gaps in data needed for assessing the hazards of chemicals. The application allows users to search
for analogues based on structure similarity criteria and input similarity thresholds (OECD. 2017). It also contains
metabolism simulators, which are simplified versions of the simulators in CATALOGIC and TIMES and consist of
hierarchically ordered molecular transformations (Yordanova et al.. 2019).
8The CompTox Chemicals Dashboard "Related Substances" tab provides a chemical list of all chemicals related to
the queried chemical through mapped relationships underlying the database. Relationships include searched
chemical (self-relationship), salt form, monomer, polymer, predecessor component, component, Markush parent,
Markush child, transformation parent, and transformation product (Williams et al.. 2021).
9Operationalized within the CompTox Chemicals Dashboard, GenRA is an algorithmic approach that makes read-
across predictions on the basis of a similarity weighted activity of source analogues (nearest neighbors). GenRA
gives users the ability to identify candidate analogues based on structural and bioactivity information (U.S. EPA.
2024b).
1 "ChemACE clusters chemicals into groups based on structural features and a reasonable presumption that toxicity
may be influenced by such structural characteristics (e.g., structural alerts, toxicophores). ChemACE identifies
structural diversity in a large chemical inventory and highlights analogous clusters for potential read across. In the
expanded analogue approach, clustering with ChemACE supports expert refinement of the candidate analogue pool.
The ChemACE methodology is based on logic implemented in the Analog Identification Methodology (AIM) tool
(http://aim.epa. gov) that identifies analogues based on the presence of common fragments using a tiered approach
(U.S. EPA 2011a).
34
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Initially, candidate analogues are screened for structural and chemical similarity to confirm that
the analogues have the same reactive functional groups and similar overall size and structural
features as the target chemical. Chemicals lacking key functionality or bearing additional
functionality relative to the target are less desirable as analogues and are not selected as
structural analogues. The selection may be expanded to include chemicals expected to be part of
a metabolic series (either as metabolic precursors or as metabolites) of the target chemical.
Chemicals that produce metabolites in common with the target may also be selected if the
metabolite is known or suspected to be part of the mechanism of action. All candidate analogues
are then screened for structural features that can influence their activity relative to the target.
Examples of such features include steric influences of bulky substituent groups, branching,
rigidity, presence of blocking groups on a functional group, and differing substitution patterns on
aromatic rings. Finally, key physical and chemical properties of the candidate analogues are
compared with the target to confirm that they can be expected to have similar bioavailability,
similar transport, and similar abiotic transformation properties.
Toxicokinetic studies tagged as potentially relevant supplemental material during
screening are used to identify metabolic analogues (metabolites and metabolic precursors).
Metabolites are also identified from two OECD QSAR Toolbox metabolism simulators (in vivo
rat metabolism simulator and rat liver S9 metabolism simulator). Targeted PubMed searches are
conducted to identify metabolic precursors and other compounds that share any of the observed
or predicted metabolites identified for the target chemical.
In vivo toxicity data for the target chemical (if available) are evaluated to determine
whether characteristic effects associated with a particular mechanism of toxicity are observed
(e.g., cholinesterase inhibition, inhibition of oxidative phosphorylation). In addition, in vitro
mechanistic data tagged as potentially relevant supplemental material during screening or
obtained from tools including GenRA, ToxCast/Tox21u, and Comparative Toxicogenomics
Database (CTD)12 (CTD. 2022) are also evaluated for this purpose. ToxCast/Tox21 data
available from the CompTox Chemicals Dashboard are collected for the target chemical to
determine bioactivity in in vitro assays that may indicate potential mechanism(s) of action. The
GenRA tool is used to search for analogues using Morgan, Torsion and ToxPrints fingerprint
similarities and activity in ToxCast/Tox21 in vitro assays or ToxRef data (10 analogues collected
from each neighbor's data set). Using the ToxCast/Tox21 bioactivity data, nearest neighbors
identified may be considered potential candidate analogues. The CTD is searched to identify
compounds with gene interactions similar to those induced by the target chemical; compounds
with gene interactions similar to the target chemical (similarity index >0.5) may be considered
potential candidate analogues.
Candidate analogues identified on the basis of the structural, metabolic, and
toxicodynamic similarity contexts are interrogated through the CompTox Chemicals Dashboard,
where QSAR-ready simplified molecular-input line-entry system (SMILES) are collected and
toxicity value availability is determined (e.g., from the Agency for Toxic Substances and Disease
Registry [ATSDR], California Environmental Protection Agency [CalEPA] Office of
nToxCast and Tox21 are publicly available databases containing high-throughput assay endpoints covering a range
of high-level cell responses (Thomas et al.. 2018: U.S. EPA. 2018b).
12The CTD is a publicly available database that provides manually curated information about chemical-gene/protein
interactions, chemical-disease and gene-disease relationships. The CTD allows users to identify chemicals that
induce gene interactions similar to those induced by the target chemical (Davis et al.. 2021).
35
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Environmental Health Hazard Assessment [OEHHA), U.S. EPA Integrated Risk Information
System [IRIS], PPRTVs). Analogues that have subchronic or chronic toxicity data or toxicity
values available from other public health agencies are flagged for potential consideration as
supportive evidence.
Analogue Search Results for Dimethyl Sulfide
Candidate analogues for dimethyl sulfide were identified based on structural, metabolic,
and toxicity/mechanisms/MOA relationships. For candidates identified through these
approaches, U.S. EPA (IRIS and PPRTV), ATSDR, and CalEPA sources were searched for
subchronic, intermediate, and chronic inhalation toxicity values. Details are provided below.
Identification of Structural Analogues with Established Toxicity Values
Dimethyl sulfide is not a member of an existing OECD or U.S. EPA New Chemical
category. Candidate structural analogues for dimethyl sulfide were searched using structural
similarity searches in the OECD QSAR Toolbox (OECD. 2021). the U.S. EPA CompTox
Chemicals Dashboard (U.S. EPA. 2022a). and ChemlDplus tools (NLM. 2022). A total of
44 unique structural analogues were identified for dimethyl sulfide based on chemical similarity
scores from ChemlDplus, CompTox Chemicals Dashboard, and OECD QSAR Toolbox using an
80% similarity threshold, and including the nearest 10 analogues from each GenRA neighbor's
data set.
The list of potential analogues was reviewed by a chemist with expertise in read-across.
Criteria for excluding candidates were as follows:
1. Exclude radical-containing compounds since they may behave differently in vivo.
Radicals are highly chemically reactive.
2. Exclude radionuclides and isotopically enriched ([13C] or [2H]) compounds, which tend to
be used for experimental studies. There are little to no toxicity data generated solely for
the labeled substances.
3. Exclude mixtures since they include components that may impart additional toxicity or
have little to no toxicity data available.
4. Exclude compounds that do not contain sulfur or contain elements other than sulfur,
carbon, hydrogen, and oxygen since dimethyl sulfide is a small molecule and the
presence of other elements is expected to impart significant differences in biological
activity.
5. Exclude compounds with molecular weight greater than twice the molecular weight of
dimethyl sulfide (the molecular weight of dimethyl sulfide is 62.13 g/mol; excluded
compounds had a molecular weight >125 g/mol). Molecular weight correlates to
molecular size and other key properties that influence how a chemical behaves in a
physical or biological system (including bioavailability). When evaluating the potential
analogues for dimethyl sulfide, a distinction in molecular size and octanol/water partition
coefficient (log Kow) was observed in the chemicals with approximately twice the
molecular weight of dimethyl sulfide. Many of the chemicals with molecular weights
exceeding 15 g/mol are large cyclic compounds and all have estimated log Kow values
that are >2 log units higher than dimethyl sulfide (the log Kow for dimethyl sulfide is
1.05, compared to log Kow values >3).
36
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Using these criteria and approaches, two compounds were identified: 1,3-dithietane
(CASRN 287-53-6) and l,l-bis(methylthio)ethane (CASRN 7379-30-8). Neither of these
identified structural analogues had an inhalation toxicity value. Appendix C (see Table C-l)
contains further documentation for candidate structural analogues.
Because compounds with very simple molecular structures (like dimethyl sulfide) have
fewer components (molecular features, atoms, connectivity, etc.) for analogue search tools to use
to identify similar chemicals, and because the pool of appropriate chemicals did not yield
candidates with inhalation toxicity data, additional search strategies were employed to identify
more structural analogues for consideration. Additional potential analogues were identified by
searching the U.S. EPA, ATSDR, and CalEPA toxicity value databases for the terms "sulfide"
and "mercaptan." The following three potential analogues were identified by this method:
hydrogen sulfide, carbon disulfide, and carbonyl sulfide. From the list, only hydrogen sulfide
was considered a potentially viable analogue. Carbon disulfide and carbonyl sulfide were not
considered suitable because they exhibit differences in both structure and reactivity relative to
the target compound. Both compounds are sulfur analogues of carbon dioxide and differ from
dimethyl sulfide in that they have sulfur double-bonded to carbon (C = S). The double bond
limits steric rotation and makes the molecule more reactive than dimethyl sulfide, which contains
only single bonds and alkyl substituents. The mechanism of toxicity for carbon disulfide is
reported to be related to the formation of dithiocarbamates from the reaction of CS2 with amines.
The dithiocarbamates are implicated in enzyme inhibition, potentially as a result of chelating key
transition elements, and in producing nervous system lesions as a result of crosslinking on
neurological tissues (NRC. 2009: JECFA 2000). This reaction pathway is not relevant to
dimethyl sulfide. Hydrogen sulfide, the remaining candidate structural analogue of dimethyl
sulfide identified by this method, has an existing inhalation toxicity value that is based on a
10-week study in rats [Brenneman et al. (2000) as cited in (ATSDR. 2016)1. However, hydrogen
sulfide lacks the methyl groups of the dimethyl sulfide molecule. To provide additional
comparative toxicokinetic and toxicodynamic information pertaining to the influence of the
methyl groups, two additional structural analogues were considered as C, although they do not
have inhalation toxicity values: methyl mercaptan (which has one methyl group on the sulfur)
and dimethyl disulfide (two methyl groups and two sulfur atoms). These data-gap filling
analogues provide supporting information to further evaluate the impact of unique structural
moieties on metabolism and toxicity.
As shown in Table A-3, five candidate structural analogues for dimethyl sulfide were
considered and only one had a relevant inhalation toxicity value: hydrogen sulfide.
37
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Table A-3. Candidate Structural Analogues Identified for Dimethyl Sulfide
Based on Tools and Expert Judgment
S CHd
/
H3C
Tool (method)
Analogue (CASRNs) Selected for Toxicity
Value Searches
Structure
GenRA (neighbors by
ToxPrints, filtered by all
data)
1,3-Dithietane (CASRN 287-53-6)
s^s
\/
1,1 -Bis(methylthio)ethane (CASRN 7379-30-8)
hsc^Sxy"S^ch=
ch3
Manual search using
chemistry expertise in
read-across
Hydrogen sulfide (CASRN 7783-06-4)a
h-/h
Methyl mercaptan (CASRN 74-93 -l)b
HS CHj
Dimethyl disulfide (CASRN 624-92-0)b
H3C\
s xh3
"Bold shows compound with inhalation toxicity values.
bCompound carried forward as data-gap filling analogue to provide supporting information and comparisons.
Identification of Toxicokinetic Precursors or Metabolites with Established Toxicity
Values
PubMed searches (searching terms related to "dimethyl sulfide" or "75-18-3" and
"metabolite") were conducted to identify metabolic precursors to dimethyl sulfide. Methyl
mercaptan (also known as methanethiol) and 3-methylthiopropionate were identified as potential
metabolic precursors. The two metabolites of dimethyl sulfide reported in the literature are
dimethyl sulfoxide (DMSO) and dimethyl sulfone (ECHA. 2016; Williams et al.. 1966). DMSO
was also predicted as a metabolite of dimethyl sulfide by both the in vivo rat metabolism
simulator and the rat liver S9 metabolism simulator in the OECD QSAR Toolbox (OECD. 2021).
Reductive metabolism of DMSO can regenerate dimethyl sulfide (Brayton. 1986; Layman and
Jacob. 1985). Dimethyl sulfone, however, does not undergo reduction to DMSO in vivo
(Williams et al.. 1966). Pulmonary excretion of dimethyl sulfide was seen following
intraperitoneal (i.p.) administration of methyl mercaptan to mice (Susman et al.. 1978). Dimethyl
sulfide, methyl mercaptan, and methyl mercaptan-mixed disulfides were formed when human
and rat hepatocytes were cultured in vitro with 3-methylthiopropionate (Blom and Tangerman.
1988). PubMed was also searched to identify other compounds that are metabolized to any of the
observed or predicted metabolites of dimethyl sulfide (searching the metabolite name or
38
Dimethyl Sulfide
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EPA 690 R-24 006F
[CASRN if available] and "metabolite"). No compounds that share at least one metabolite with
dimethyl sulfide were identified in these searches.
Table A-4 summarizes the four identified candidate metabolic analogues for dimethyl
sulfide (dimethyl sulfoxide was identified as both a metabolic precursor and a metabolite).
Searches for relevant toxicity values for the candidate metabolic analogues of dimethyl sulfide
did not identify inhalation toxicity values for any of these compounds.
Table A-4. Candidate Metabolic Analogues of Dimethyl Sulfide
Relationship to Dimethyl Sulfide
Analogue (CASRN)3
Structure
Metabolic precursor
Methyl mercaptan
(CASRN 74-93-1)
HS CH3
3 -Methy lthiopropionate
(CASRN 646-01-5)
h3C/S^^0H
o
Dimethyl sulfoxide
(CASRN 67-68-5)
CH,
/
h3c S
0
Observed Metabolite
Dimethyl sulfoxide13
(CASRN 67-68-5)
/CH3
H'C \\
0
Dimethyl sulfone
(CASRN 67-71-0)
VCHj
»A
Shares common metabolite(s)
None identified
Not applicable
aMetabolic precursors and metabolites were identified from the PubMed Searches unless otherwise specified.
bAlso predicted by OECD QSAR Toolbox metabolism simulators (in vivo rat metabolism simulator [version 3.5]
and rat liver S9 simulator [version 3.7]).
OECD = Organisation for Economic Co-operation and Development; QSAR = quantitative structure-activity
relationship.
Identification of Analogues on the Basis of ToxicityZMechanistic/MOA Information
and Established Toxicity Values
Toxicity and mechanistic data for dimethyl sulfide were evaluated to determine whether
there were in vivo toxicity data suggesting characteristic effects associated with a particular
MO A (e.g., cholinesterase inhibition, inhibition of oxidative phosphorylation) that could
potentially be used to identify candidate analogues. However, available inhalation data for
dimethyl sulfide are inadequate for these purposes. Human data are limited to studies in which
39
Dimethyl Sulfide
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EPA 690 R-24 006F
subjects were exposed to unknown quantities of dimethyl sulfide in combination with other
chemicals, and animal studies are limited to acute exposure studies and one chronic study
available only from a secondary source [Selyuzhitskii (1972) as cited in Opdyke (1979)1. which
made the study considered unreliable for quantitative provisional value derivation. Oral toxicity
data for dimethyl sulfide also provide only limited information. No toxicologically relevant
effects were identified in a 14-week gavage study in rats that evaluated body weights, food/water
intake, hematology, clinical chemistry, and urinalysis parameters, organ weights, and
histopathology (Butterworth et al.. 1975). A 13-week drinking-water study in rabbits showed
increased relative lung weight, decreased relative liver weight, and some findings on gross
examination (pulmonary congestion and renal pyelonephritis), but did not include
histopathological examination (Wood et al.. 1971). Oral studies indicating a lack of
toxicologically relevant effects and the limited database of inhalation studies did not identify any
shared toxicological endpoints or targeted effects. There is limited evidence from in vitro studies
suggesting that dimethyl sulfide may disrupt oxidative metabolism and energy production
(Mhatre et al.. 1983; Yahlkamp et al.. 1979). Oxidative metabolism and energy production
endpoints have not been evaluated in available in vivo studies.
Dimethyl sulfide was queried for bioactivity in assays reported in the U.S. EPA
CompTox Chemicals Dashboard (U.S. EPA. 2020). No ToxCast assays for dimethyl sulfide were
reported in the U.S. EPA CompTox Dashboard at the time of the search (accessed on September
21, 2020). There were no PubChem assays (n = 3) in which dimethyl sulfide was active
(accessed on September 21, 2020). The GenRA tool was not available to search for additional
analogues because there were no ToxCast in vitro bioactivity data identified. The CTD did not
identify compounds with chemical-gene interactions similar to interactions induced by dimethyl
sulfide (Davis et al.. 2021).
The methods outlined above did not identify any candidate mechanistic analogues for
dimethyl sulfide.
Candidate Analogues Moving Forward for Evaluation
Searches for structural, metabolic, and toxicity/mechanistic analogues for dimethyl
sulfide resulted in eight unique candidate analogues for consideration: five structural analogues,
four metabolic analogues, and no toxicity/mechanistic analogues (methyl mercaptan was
identified as both a structural and metabolic analogue). Of the candidate analogues, only
hydrogen sulfide has inhalation toxicity values from the U.S. EPA, ATSDR, or CalEPA.
Additional data-gap filling analogues (methyl mercaptan, dimethyl disulfide, DMSO) were
carried through the analogue evaluation process to provide comparative toxicokinetic and
toxicodynamic information pertaining to the influence of the methyl groups.
Structural Analogues
Hydrogen sulfide was the only candidate structural analogue identified for dimethyl
sulfide that has an inhalation toxicity value. Since hydrogen sulfide lacks the methyl groups of
the dimethyl sulfide molecule, methyl mercaptan, dimethyl disulfide, and DMSO were evaluated
as data-gap filling analogues to provide comparative toxicokinetic and toxicodynamic
information pertaining to the influence of the methyl groups, although they do not have
inhalation toxicity values.
40
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Dimethyl sulfide and all candidate analogues are small molecules, consisting only of
sulfur, hydrogen, and (for all but hydrogen sulfide) carbon; DMSO also contains an oxygen.
Dimethyl sulfide, dimethyl disulfide, and DMSO are organic sulfides (R-S-R1), while methyl
mercaptan and hydrogen sulfide are both sulfhydryls (R-SH). Table A-5 illustrates the chemical
structures and summarizes the physicochemical properties for dimethyl sulfide and the four
candidate analogues.
41
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-5. Physicochemical Properties of Dimethyl Sulfide (CASRN 75-18-3), Candidate Analogue3, and Data-Gap
Filling Analogues
Chemical
Target Chemical
Candidate Analogue
Data-Gap Filling Analoguesb
Dimethyl sulfide
Hydrogen sulfide
Methyl mercaptan
Dimethyl disulfide
Dimethyl sulfoxide
Structure
s—ch3
/
h3c
„-s/H
HS CH3
H3C\
s xh3
0
/s\
h3c ch3
CASRN
75-18-3
7783-06-4
74-93-1
624-92-0
67-68-5
Molecular weight
(g/mol)
62.13
34.08
48.1
94.19
78.13
Melting point (°C)
-92.5
-85.0°
-122
-85
18.4
Boiling point (°C)
37.8
-60.0°
5.97
109
189
Vapor pressure
(mm Hg at 25°C)
502
1.26 x 104
(predicted value)
1.51 x 103
28.7
6.01 x 10-1
Henry's law constant
(atm-m3/mole at 25°C)
1.61 x 10"3
9.11 x 103
(calculated VP/WS)d
4.68 x 10 3
(predicted average)
1.21 x 10-3
1.51 x 10~9
Water solubility (mg/L)
2.2 x 104
(reported as 0.355 mol/L)
3.74 x 103 at 21°Ce
1.54 x 104
(reported as 0.321 mol/L)
3.0 x 103
(reported as 3.18 x 10 2 mol/L)
1.0 x 106
(reported as 12.8 mol/L)
Octanol/water partition
coefficient (log Kow)
1.05
NAf
0.864
(predicted average)
1.77
-1.35
aData are from the U.S. EPA CompTox Chemicals Dashboard, and reflect experimental averages, unless otherwise noted, accessed August 27, 2024 (dimethyl sulfide
[CASRN 75-18-3] https://comptox.epa.gov/dashboard/chemical/details/DTXSID9026398: hydrogen sulfide [CASRN 7783-06-4]
https://comptox.epa.gov/dashboard/chemical/details/DTXSID4024149: methanethiol [CASRN 74-93-1]
https://comptox.epa.gov/dashboard/chemical/details/DTXSID5026382: methyl disulfide [CASRN 624-92-0]
https://comptox.epa.gov/dashboard/chemical/details/DTXSID4025117: dimethyl sulfoxide [CASRN 67-68-5]
https://comptox.epa. gov/dashboard/chemical/details/DTXSID202173 5).
bData-gap filling analogues without adequate toxicity values.
Experimental median was selected due to wide experimental range in reported experimental values.
dEPI Suite (U.S. EPA 2012b).
ePhysProp database in EPI Suite™ (U.S. EPA. 2012b).
fNA since hydrogen sulfide is a gas under standard temperature and pressure conditions.
EPI = Estimation Programs Interface; NA = not applicable; U.S. EPA = U.S. Enviromnental Protection Agency; VP = vapor pressure; WS = water solubility.
42
Dimethyl Sulfide
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Data-gap filling analogues, the candidate analogue, and the target compound have similar
molecular weights (ranging from 34.08 to 94.19 g/mol, compared to 62.13 g/mol for dimethyl
sulfide). The target compound and two of the data-gap filling analogues, dimethyl disulfide and
DMSO, are liquids (melting point <25°C, boiling point >25°C) under standard temperature and
pressure. The candidate analogue, hydrogen sulfide, and the data-gap filling analogue, methyl
mercaptan, are gases (boiling point <25°C). Despite a wide range of measured vapor pressures,
values indicate that these chemicals will exist mostly in the vapor (gas) phase in the atmosphere
and are expected to volatize from soil to air. Other than DMSO, dimethyl sulfide and its
analogues are expected to volatilize from water to air and moist soil to air, based on their
Henry's law constants. In contrast, the low Henry's law constant of DMSO suggests that it is
essentially nonvolatile from water to air and moist soil to air. DMSO is highly soluble in water
with a very low log Kow, while dimethyl sulfide and methyl mercaptan and dimethyl disulfide
analogues are moderately soluble in water and have similar measured log Kow values. Hydrogen
sulfide, however, is a gas under standard temperature and pressure and so does not have a log
Kow for comparison. Based on their log Kow values (ranging from -1.35 to 1.77), dimethyl
sulfide and most candidate analogues are likely to partition to water, with dimethyl disulfide
being the least hydrophilic of all the analogues and DMSO being the most hydrophilic. The
target compound and all analogues are expected to be bioavailable by the inhalation route (based
on vapor pressure, water solubility, and log Kow values). All compounds appear to be potentially
suitable analogues for dimethyl sulfide based on available physicochemical data.
Relevant structural alerts and toxicity predictions for noncancer health effects were
identified using computational tools from the OECD (2021) QSAR Toolbox profilers, OCHEM
(2022) ToxAlerts, and IDEAconsult (2018) Toxtree. The model results for dimethyl sulfide and
analogue compounds are shown in Figure A-l. Concerns for hepatotoxicity and metabolism/
reactivity were indicated for dimethyl sulfide and analogues containing one or more methyl
groups (methyl mercaptan, dimethyl disulfide, DMSO). Concerns for protein binding were
indicated for methyl mercaptan and dimethyl disulfide but not for dimethyl sulfide or DMSO.
There were no structural alerts identified for hydrogen sulfide. The absence of a structural alert
returned by the computational tools does not strictly correspond to an absence of toxicity, but
rather indicates that the chemical does not meet the criteria specified by the existing profiling
schemes.
43
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Structural Category
Compounds (CASRN)
Target
Chemical
Candidate
Analogue
Data-Gap Filling Analogues
Source
Dimethyl
Sulfide
(75-18-3)
Hydrogen
Sulfide
(7783-06-4)
Methyl
Mercaptan
(74-93-1)
Dimethyl
Disulfide
(624-92-0)
Dimethyl
Sulfoxide
(67-68-5)
Protein Binding
Protein binding (based on
interchange reaction with SN2
for thiols)—OASIS
OECD
QSAR
Toolbox
Protein binding (based on SN2
reaction with sulfur atom for
thiols)—OECD
OECD
QSAR
Toolbox
Protein binding potency Cys
(DPRA above 21%) based on
thiols alert—DPRA 13%
OECD
QSAR
Toolbox
Protein binding potency
(moderately active based on
thiols and disulfides alert
[SN2])—GSH
OECD
QSAR
Toolbox
SN2 class alert for nucleophilic
aliphatic substitution
NA
NA
Toxtree
Hepatotoxicity
Hepatotoxicity based on
thiocarbamates/sulfides—HE S S
OECD
QSAR
Toolbox
Hepatotoxicity based on
thioalcohols alert—HESS
OECD
QSAR
Toolbox
Metabolism/Reactivity
CYP450-mediated drug
metabolism predicted (based on
the presence of sp3 hybridized
carbon atoms)
NA
ToxAlerts
CYP450-mediated drug
metabolism predicted (based on
the presence of sulfur atom)
NA
ToxAlerts
C Model results or structural alert indicating concern for noncancer toxicity/endpoint of interest.
D Model results or structural alert indicating no concern for noncancer toxicity/endpoint of interest.
aModels with results are presented in the heat map (models without results indicate that the queried chemical fell
outside of the applicability domain and are omitted).
CYP450 = cytochrome P450; DPRA = direct peptide reactivity assay; GSH = glutathione; HESS = Hazard
Evaluation Support System; NA = no results available for this compound in the models; OECD = Organisation for
Economic Co-operation and Development; QSAR = Quantitative Structure-Activity Relationship.
Figure A-l. Structural Alerts for Dimethyl Sulfide and its Candidate Analogues3
44
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Toxtree indicated potential for protein binding for the methyl mercaptan and dimethyl
disulfide analogues based on nucleophile aliphatic substitution via SN2 mechanism. For these
same analogues, the OECD QSAR Toolbox also identified protein binding alerts based on
interchange reaction with SN2 and on SN2 reaction with sulfur atoms for thiols, protein binding
potency Cys (direct peptide reactivity assay [DPRA] above 21%) based on thiols, and protein
binding potency (moderately active) based on thiols and disulfides alert (SN2). Protein binding
was not indicated for dimethyl sulfide, hydrogen sulfide, or DMSO.
The OECD QSAR Toolbox repeated-dose Hazard Evaluation Support System (HESS)
model showed a concern for hepatotoxicity for dimethyl sulfide (target chemical) and the
dimethyl disulfide analogue based on the thiocarbamates/sulfides alert (toxicologically relevant
effects in the liver); the alert was characterized by the profiler as a mechanism that is 'not well-
known.' A concern for hepatotoxicity (central lobular necrosis, hepatic fibrosis) was predicted
for methyl mercaptan based on the thioalcohols alert. No alert for hepatotoxicity was identified
for hydrogen sulfide or DMSO.
ToxAlerts indicated a potential for cytochrome P450 (CYP450)-mediated drug
metabolism for dimethyl sulfide, methyl mercaptan, dimethyl disulfide, and DMSO based on the
sp3 hybridized carbon atoms and for dimethyl disulfide and DMSO based on the presence of a
sulfur atom. No results were available for hydrogen sulfide in the predictive models for
CYP450-mediated metabolism.
The OECD QSAR Toolbox did not indicate a potential for estrogen receptor binding for
dimethyl sulfide or any of the analogues.
The OECD (2021) QSAR Toolbox did not identify dimethyl sulfide or the hydrogen
sulfide, dimethyl disulfide, or DMSO analogues as members of an OECD High Production
Volume (HPV) or U.S. EPA New Chemical Category. Methyl mercaptan is a member of the
Methyl Mercaptans OECD HPV Chemical Category and the Thiols (acute toxicity) U.S. EPA
New Chemicals Category.
In summary, dimethyl sulfide and its analogues are all small molecules consisting only of
sulfur, hydrogen, and (for all but hydrogen sulfide) carbon. DMSO also contains an oxygen.
Dimethyl sulfide, dimethyl disulfide, and DMSO are organic sulfides (R-S-R), while methyl
mercaptan and hydrogen sulfide are both sulfhydryls (R-SH). Like dimethyl sulfide, dimethyl
disulfide and DMSO are liquids at standard temperature and pressure; in contrast, hydrogen
sulfide and methyl mercaptan are gases. In general, dimethyl sulfide and candidate analogues
exhibit similar environmental fate properties (molecular weight, water solubility, Henry's law
constant, and log Kow). However, DMSO is nonvolatile and more water-soluble than dimethyl
sulfide and other candidate analogues. Structural alerts for dimethyl sulfide were identified for
hepatotoxicity and CYP450-mediated drug metabolism. These alerts were also identified for
dimethyl disulfide (both), methyl mercaptan (both), and DMSO (CYP450-mediated drug
metabolism). Based on the available data, all analogues evaluated appear to be suitable structural
analogues for dimethyl sulfide.
45
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Metabolic Analogues
Absorption, distribution, metabolism, and excretion (ADME) data for dimethyl sulfide
and the analogues are presented in Table A-6. Key observations and comparisons are discussed
below.
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Table A-6. Comparison of ADME Data for Dimethyl Sulfide (CASRN 75-18-3) and Its Candidate Analogues
Target Chemical
Candidate Analogue
Data-Gap Filling Analogues
Type of Data
Dimethyl Sulfide
Hydrogen Sulfide
Methyl Mercaptan
Dimethyl Disulfide
Dimethyl Sulfoxide
Structure
S CH,
/
h3c
h-.'"
HS CH3
xh3
O
h3c ch3
CASRN
75-18-3
7783-06-4
74-93-1
624-92-0
67-68-5
Absorption
Rate and extent of
absorption
Humans and laboratory animals
(all routes):
• No quantitative absorption data;
however, limited qualitative
reporting from skin irritation
tests in rabbits indicate that
"there is no indication [dimethyl
sulfide] is absorbed through the
skin in toxic amounts."
• Absorption through the lungs is
expected based on vapor
pressure, water solubility, and
log Kow values. In support,
distribution and toxicity data
from acute human and animal
inhalation exposure studies
indicate that it is absorbed
through the lungs.
• Based on blood metabolite
detection, oral absorption in rats
is rapid. There are no data
available to determine extent of
oral absorption.
Humans and laboratory
animals (all routes):
• Rapidly absorbed
through lungs; no
data available to
determine extent of
absorption.
• Absorption through
the skin has been
shown in rabbits and
guinea pigs, but only
when large surface
areas were exposed.
There are no data on
the rate or extent of
dermal absorption.
• Oral absorption data
are not available; oral
exposure is not
expected (hydrogen
sulfide is a gas at
room temperature).
Humans and laboratory
animals (inhalation):
• No quantitative
absorption data.
• Absorption through
the lungs is expected
based on vapor
pressure, water
solubility, and log Kow
values. In support,
toxicity data from
human and animal
acute inhalation
studies indicate that it
is absorbed through
the lungs.
• Absorption through
the skin is expected to
be -80% based on
molecular weight and
log Kow.
• Oral absorption data
are not available; oral
exposure is not
expected (methyl
Laboratory animals (oral,
inhalation):
• No quantitative
absorption data.
• Absorption through the
lungs is expected based
on vapor pressure, water
solubility, and log Kow
values.
• Absorption through the
gastrointestinal tract is
expected based on low
molecular weight and
sufficient lipophilicity.
• Toxicity data from
animal inhalation and
oral studies confirm that
dimethyl disulfide is (at
least to some extent)
absorbed through the
lungs and
gastrointestinal tract.
Humans and laboratory
animals (all routes):
• Rapidly absorbed through
the skin and
gastrointestinal tract in
humans, monkeys, and
rats.
• Absorption estimates for
oral exposure are 70% in
rats and humans; for
dermal exposures,
estimates are 66% in rats
and 31% in humans.
• There are no experimental
data on inhalation
absorption; however,
absorption through the
lungs is expected based on
low molecular size, high
polarity, and water
solubility.
• Data from animal
inhalation studies confirm
that DMSO is (at least to
some extent) absorbed
through the lungs.
47
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-6. Comparison of ADME Data for Dimethyl Sulfide (CASRN 75-18-3) and Its Candidate Analogues
Type of Data
Target Chemical
Candidate Analogue
Data-Gap Filling Analogues
Dimethyl Sulfide
Hydrogen Sulfide
Methyl Mercaptan
Dimethyl Disulfide
Dimethyl Sulfoxide
mercaptan is a gas at
room temperature).
Distribution
Rate and extent of
distribution
Humans and laboratory animals
(oral, inhalation):
• Distribution is widespread
following inhalation exposure in
humans and mice.
• Based on rate of metabolism and
excretion in animal studies,
distribution following oral
exposure is expected to be rapid.
• Accumulation is not expected
due to low log Kow value.
Humans and laboratory
animals (inhalation):
• Distribution
following inhalation
exposure is rapid and
widespread in
humans, rats, and
rabbits.
• No data are available
regarding distribution
following exposure
by other routes.
• Storage is limited by
rapid metabolism and
excretion.
Laboratory animals
(i-P):
• Distribution in rats 6 h
after i.p. injection
was: 22.7% in plasma
proteins, 17.8% in the
liver, 16.7% in the
intestinal mucosa,
11.5% in the lungs,
11.4% in the kidneys,
9.8% in the spleen,
and 8.5% in the testes.
• Storage is limited by
rapid metabolism and
excretion.
Laboratory animals (i.p.):
• Distribution is rapid in
mice after i.p. injection.
• Based on physico
chemical properties,
accumulation is not
expected.
Humans and laboratory
animals (oral, dermal):
• Distribution is rapid
following oral or dermal
exposure in humans and
rats. Distribution was
widespread in rats via both
routes, with high
distribution to ocular
tissues.
• DMSO can penetrate
mucous membranes,
blood-brain barrier, and
cell and organelle
membranes.
• Storage is limited by rapid
metabolism and excretion.
Metabolism
Rate; primary
reactive metabolites
Laboratory animals (oral, s.c.), in
vitro:
• Major metabolic pathway is
oxidation to DMSO, which is
further oxidized into DMSO2.
• Peak blood plasma times for
DMSO and DMSO2 were 6 and
24 h, respectively, after oral
exposure.
• DMSO can be reduced back into
dimethyl sulfide via MsrA.
Humans and laboratory
animals (inhalation), in
vitro:
• Metabolism is rapid
(<1 d).
• At physiological pH,
hydrogen sulfide is
-69% ionized
(hydrosulfide anion).
• Major metabolic
pathway: oxidation of
Laboratory animals (i.p.,
i.v.), in vitro:
• Major metabolic
pathway: oxidation by
erythrocytes to form
formic acid, sulfite,
and sulfate.
• Minor metabolic
pathway: methylation
to dimethyl sulfide via
Laboratory animals, in
vitro:
• Reductive metabolism
is rapid and extensive.
• The primary metabolite
in hepatic culture was
methyl mercaptan, with
dimethyl sulfide as a
minor metabolite
(methylation of methyl
mercaptan via
Humans and laboratory
animals (all routes), in vitro:
• Metabolism is rapid.
• Major metabolic pathway:
oxidation to DMSO2.
• Minor metabolic pathway:
reduction to dimethyl
sulfide, which can be
reconverted back to DMSO
via oxidation.
48
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-6. Comparison of ADME Data for Dimethyl Sulfide (CASRN 75-18-3) and Its Candidate Analogues
Type of Data
Target Chemical
Candidate Analogue
Data-Gap Filling Analogues
Dimethyl Sulfide
Hydrogen Sulfide
Methyl Mercaptan
Dimethyl Disulfide
Dimethyl Sulfoxide
• No evidence of demethylation
and subsequent formation of
sulfate in vivo.
sulfide into
thiosulfate (by sulfide
oxidase), which is
further converted into
sulfate (by sulfite
oxidate).
• Minor metabolic
pathway: methylation
via thiol-.S'-mcthvl-
transferase to methyl
mercaptan, which can
be further methylated
to dimethyl sulfide.
• Minor metabolic
pathway: interactions
with metalloproteins
(iron, copper) and
plasma proteins via
disulfide linkage.
• Minor metabolic
pathway: glutathione
conjugation.
thiol-.S'-mctlvvl-
transferase.
• Minor metabolic
pathway: interactions
with plasma proteins
via disulfide linkage.
• Following i.v.
administration, the
metabolic half-life
was reported to be
1.21 h.
thiol-.S'-mctlvvl-
transferase).
• Further oxidation of the
minor metabolite
dimethyl sulfide to
DMSO and DMS02
was not observed in
hepatocytes during a
4-h incubation.
• No evidence of
demethylation and
subsequent formation of
sulfate in vivo.
Induction of
metabolic enzymes
Laboratory animals (oral):
• Oral exposure did not induce
monooxygenase enzymes in rat
liver.
• No data.
• No data.
Laboratory animals (oral):
• Oral exposure did not
induce monooxygenase
enzymes in rat liver.
• No data.
49
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-6. Comparison of ADME Data for Dimethyl Sulfide (CASRN 75-18-3) and Its Candidate Analogues
Type of Data
Target Chemical
Candidate Analogue
Data-Gap Filling Analogues
Dimethyl Sulfide
Hydrogen Sulfide
Methyl Mercaptan
Dimethyl Disulfide
Dimethyl Sulfoxide
Excretion
Elimination half-
time; route of
excretion
Laboratory animals (i.p., s.c.):
• Eliminated as DMSO and
DMSO2 in the urine following
s.c. injection; after 3 d, DMSO2
was no longer detected, but
DMSO levels in urine were still
increasing 4 d postexposure.
• Eliminated (unchanged) via
expired breath as soon as 1 h
after i.p. injection exposure.
• Elimination half-time not
reported.
Humans and laboratory
animals (inhalation):
• Elimination is rapid,
and peaks within
1-2 h after inhalation
exposure.
• Eliminated primarily
as thiosulfate in
urine.
• Limited evidence of
elimination as
sulfides (unspecified)
via expired breath.
Laboratory animal (i.p.,
i.v.):
• Elimination is rapid
(<1 d).
• Following i.v.
administration, the
elimination half-life
was reported to be
8.47 h.
• Eliminated primarily
as sulfur compounds
(primarily sulfates) in
urine following
injection exposure.
• Small amounts
eliminated as parent
compound, dimethyl
sulfide, or CO2 via
expired breath after
injection exposure.
Laboratory animals (i.p.)
• Eliminated primarily in
urine as cysteine
disulfide.
• Small amounts
eliminated as parent
compound, methyl
mercaptan, and
dimethyl sulfide via
expired breath (peak
excretion within
3-5 min) after injection
exposure; compounds
accounted for 6, 0.5,
and 0.5% of the
injected dose,
respectively.
Humans and laboratory
animals (all routes):
• Eliminated primarily in
urine as parent compound
and DMSO2.
• Small amounts eliminated
as dimethyl sulfide via
expired breath.
• Limited-to-no excretion via
feces following oral
exposure.
• Elimination half-lives
following oral exposure are
4 d in humans, 16 h in
monkeys, and 6-8 h in
rats.
• Elimination half-lives
increased by approximately
1/3 with dermal exposure.
References
Am et al. (2020); ECHA (2016);
ChiDDcndalc et al. (2014); DeVito
(2000): Siess etal. (1997):
Terazawa et al. (1991a): Terazawa
ATSDR (2016): U.S.
EPA (2003a): Tansv et
al. (1981)
Am etal. (2021b):
DeVito (2000): ATSDR
(1992): Blom and
Taneerman (1988):
Anastassiadou et al.
(2019): ECHA (2012):
DeVito (2000): Siess et al.
(1997): Tansv et al.
ECHA (2022): Hartwie and
MAK Commission (2017):
Bravton (1986): Lavman and
Jacob (1985): Kocsis et al.
et al. (1991b): Tansv et al. (1981):
Susman et al. (1978): Williams et
al. (1966): Dow Chemical (1957):
Tansv et al. (1981):
Susman et al. (1978):
Liuneeren and Norbere
(1981): Susman et al.
(1978): Liuneeren and
Norbere (1943)
(1975): Gerhards and Gibian
(1967): Kolb etal. (1967):
Hucker et al. (1966a): Hucker
Maw (1953): Liuneeren and
Norbere (1943)
(1943)
et al. (1966b): Williams et al.
(1966)
ADME = absorption, distribution, metabolism, excretion; CO2 = carbon dioxide; DMSO = dimethyl sulfoxide; DMSO2 = dimethyl sulfone; i.p. = intraperitoneal;
i.v. = intravenous; log Kow = octanol/water partition coefficient; MsrA = methionine sulfoxide reductase A; s.c. = subcutaneous.
50
Dimethyl Sulfide
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EPA 690 R-24 006F
No quantitative inhalation absorption data or blood-gas partition coefficients were located
for dimethyl sulfide, methyl mercaptan, dimethyl disulfide, or DMSO. However, all are expected
to be absorbed via the lung to some extent, based on vapor pressure, water solubility, and log
Kow values (see Table A-6). Distribution and/or toxicity data from inhalation exposure studies
indicate that these compounds are absorbed (at least to some extent) through the lungs (Terazawa
et al.. 1991a; Terazawa et al.. 1991b; Tansy et al.. 1981; Dow Chemical 1957; Liunggren and
N orb erg. 1943). Experimental data indicate that hydrogen sulfide is rapidly absorbed through the
lungs (ATSDR.. 2016; U.S. EPA. 2003a). Oral absorption is rapid for dimethyl sulfide and
DMSO (ECHA. 2016; Gerhards and Gibian. 1967; Hucker et al.. 1966a). and is expected for
dimethyl disulfide, based on low molecular weight and sufficient lipophilicity. Oral exposure is
not expected for hydrogen sulfide or methyl mercaptan (gasses at room temperature). No
quantitative data regarding dermal absorption are available for dimethyl sulfide; however,
limited qualitative reporting from skin irritation tests in rabbits indicate that "there is no
indication that [dimethyl sulfide] is absorbed through the skin in toxic amounts" (Dow Chemical.
1957). No data regarding dermal absorption are available for dimethyl disulfide. Dermal
absorption is rapid for DMSO and has been demonstrated for hydrogen sulfide (Hartwig and
MAK Commission. 2017; AT SDR. 2016; U.S. EPA 2003 a; Kolb et al.. 1967; Hucker et al..
1966a). Dermal absorption is expected to occur for methyl mercaptan, based on its molecular
weight and log K OW value.
Distribution of dimethyl sulfide in mice is widespread following acute inhalation
exposure (Terazawa et al.. 1991b). Widespread distribution was also observed in a human case
report following lethal exposure to dimethyl sulfide in a confined space (Terazawa et al.. 1991b).
In rats, distribution is expected to be rapid following oral exposure based on metabolism and
excretion rates (ECHA. 2016). Distribution data are not available in humans or animals
following oral exposure; however, based on the rate of metabolism and excretion in animal
studies (ECHA. 2016; Susman et al.. 1978; Williams et al.. 1966; Maw. 1953). distribution is
expected to be rapid. For the analogues, distribution is rapid (see Table A-6 for citations).
Distribution is widespread for hydrogen sulfide, methyl mercaptan, and DMSO; data on extent of
distribution are not available for dimethyl disulfide. Based on low log Kow value, dimethyl
sulfide is not expected to accumulate in the body. Animal studies with DMSO indicate a lack of
accumulation (Kolb et al.. 1967; Hucker et al.. 1966a); for other candidate analogues,
accumulation is not expected based on rapid metabolism and excretion.
Metabolism is rapid for dimethyl sulfide and all candidate analogues. Dimethyl sulfide is
oxidized to DMSO and DMSO2 (ECHA. 2016; Williams et al.. 1966). DMSO can be reduced
back into dimethyl sulfide (Bravton. 1986; Layman and Jacob. 1985). There is no evidence of
demethylation or subsequent formation of sulfate in vivo (Maw. 1953). Oxidation is the major
metabolic pathway for hydrogen sulfide, methyl mercaptan, and DMSO. The primary oxidative
metabolites are thiosulfate and sulfate for hydrogen sulfide (ATSDR. 2016; U.S. EPA. 2003a);
formic acid, sulfite, and sulfate for methyl mercaptan (Api et al.. 2021b; ATSDR. 1992); and
DMSO2 for DMSO (Hucker et al.. 1966a; Hucker et al.. 1966b). For dimethyl disulfide, methyl
mercaptan is the primary metabolite, with dimethyl sulfide as a minor metabolite (Anastassiadou
et al.. 2019). There is no evidence of subsequent metabolism of the minor metabolite (dimethyl
sulfide) to DMSO or DMSO2 in cultured hepatocytes following exposure to dimethyl disulfide.
Dimethyl sulfide and dimethyl disulfide did not induce metabolic enzymes in the liver following
oral exposure (Siess et al.. 1997); no data on metabolic enzyme induction were available for
hydrogen sulfide, methyl mercaptan, or DMSO.
51
Dimethyl Sulfide
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EPA/690/R-24/006F
Elimination is rapid for dimethyl sulfide and all analogues (see Table A-6 for citations).
Urinary excretion of metabolites is the primary excretion route for dimethyl sulfide and all
analogues, with small amounts of parent compound and/or metabolites eliminated via exhaled
breath.
In summary, absorption and distribution of dimethyl sulfide and all candidate analogues
are expected to be similar. The primary metabolite for dimethyl sulfide and DMSO is the same
(DMSO2), and interconversion between dimethyl sulfide and DMSO has been demonstrated
in vivo. Experimental metabolism data indicate that while there is some overlap of metabolic
pathways between dimethyl sulfide and the analogues (other than DMSO), metabolic products
differ. While both methyl mercaptan and dimethyl disulfide can be metabolized into dimethyl
sulfide, it is not their primary metabolic pathway and there is no evidence of subsequent DMSO
or DMSO2 formation. Elimination rate and routes are similar between dimethyl sulfide and the
evaluated analogues. However, primary excretion products for the analogues are sulfates and
sulfides, while the primary excretion products for dimethyl sulfide are DMSO and DMSO2.
Overall, DMSO is the most appropriate metabolic analogue for dimethyl sulfide. Based on
differences in metabolic pathways and metabolic end products, the remaining analogues are less
suitable metabolic analogues for dimethyl sulfide.
Toxicity-Like Analogues
The only analogue with inhalation toxicity values is hydrogen sulfide; these are shown in
Table A-7. Comparative inhalation toxicity information for the dimethyl sulfide, hydrogen
sulfide, and the other data-gap filling analogues are presented in Table A-8. Key observations are
discussed below.
52
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-7. Comparison of Available Inhalation Toxicity Values for
(CASRN 75-18-3) and Its Candidate Analogue
Target Chemical
Candidate Analogue
Type of Data
Dimethyl Sulfide
Hydrogen Sulfide
Structure
s—ch3
/
h3c
„_s/H
CASRN
75-18-3
7783-06-4
Subchronic inhalation toxicity values
POD (mg/m3 [ppm])
ND
0.64 [0.46]
POD type
ND
NOAEL (HEC)
Subchronic UFC
ND
30 (UFa, UFh,)
Intermediate MRL (mg/m3 [ppm])
ND
3 x 10-2 [2 x 10-2]
Critical effects
ND
Nasal lesions of the olfactory mucosa (olfactory
neuron loss and basal cell hyperplasia) at
>42 mg/m3
Species
ND
Rat
Duration
ND
10 wk (6 h/d, 7 d/wk)
Route
ND
Inhalation
Source
NA
ATSDR (2016)13
Chronic inhalation toxicity values
POD (mg/m3)
ND
0.64
POD type
ND
NOAEL (HEC)
Chronic UFC
ND
300 (UFa, UFh, UFs)
Chronic RfC (mg/m3)
ND
2 x 10-3
Critical effects
ND
Nasal lesions of the olfactory mucosa (olfactory
neuron loss and basal cell hyperplasia) at
>42 mg/m3
Species
ND
Rat
Duration
ND
10 wk (6 h/d, 7 d/wk)
Route
ND
Inhalation
Source
NA
U.S. EPA (2003a)13
HEC = human equivalent concentration; MRL = Minimal Risk Level; NA = not applicable; ND = no data;
NOAEL = no-observed-adverse-effect-level; POD = point of departure; RfC = reference concentration;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFH = intraspecies uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
13The intermediate-duration study [Brenneman et al. (2000) as cited in ATSDR (2016)1 selected for the derivation of
the intermediate-duration inhalation MRL was also selected by U.S. EPA (2003b) for derivation of the chronic
reference concentration (RfC) for hydrogen sulfide.
53
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-8. Comparison of Available Inhalation Toxicity Data for Dimethyl Sulfide (CASRN 75-18-3) and Its
Analogues
Type of Data
Target Chemical
Candidate Analogue
Data-Gap Filling Analogues
Dimethyl Sulfide
Hydrogen Sulfide
Methyl Mercaptan
Dimethyl Disulfide
Dimethyl Sulfoxide
Structure
s—ch3
/
h3c
h-.'"
HS CHj
H3C\ /S
s ^ch3
O
h3ct ch3
CASRN
75-18-3
7783-06-4
74-93-1
624-92-0
67-68-5
Repeated-dose inhalation toxicity data
LOAEC (mg/m3 [ppm])a
ND
42 [30]
1 [0.5]
39 [10]
2,783 [870.9]
Critical effects
ND
Nasal lesions of the olfactory
mucosa (olfactory neuron loss
and basal cell hyperplasia)
Pulmonary edema and
lesions (terminal
bronchiole constriction,
alveolar congestion, and
erythrocyte exudation)
Nasal lesions (squamous
metaplasia of respiratory
epithelium; atrophy and
microcavitation of olfactory
epithelium)
Nasal lesions
(pseudogland formation,
epithelial hyperplasia, and
inflammation in the
respiratory epithelium;
eosinophilic inclusions of
the olfactory epithelium)
Species
ND
Rat
Rat
Rat
Rat
Duration
ND
10 wk (6 h/d, 7 d/wk)
30 d (6 h/d, 7 d/wk)
13 wk (6 h/d, 5 d/wk)
13 wk (6 h/d, 7 d/wk)
Route (method)
ND
Inhalation
Inhalation
Inhalation
Inhalation
Source
NA
ATSDR (2016); U.S. EPA
Jians et al. (2021)
Am et al. (2021a): ECHA
Hartwie and MAK
(2003a)
(1992)
Commission (2017)
54
Dimethyl Sulfide
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EPA 690 R-24 006F
Table A-8. Comparison of Available Inhalation Toxicity Data for Dimethyl Sulfide (CASRN 75-18-3) and Its
Analogues
Type of Data
Target Chemical
Candidate Analogue
Data-Gap Filling Analogues
Dimethyl Sulfide
Hydrogen Sulfide
Methyl Mercaptan
Dimethyl Disulfide
Dimethyl Sulfoxide
Single-dose inhalation toxicity data
4-h LCso in rats (mg/m3
[ppm])a
102,300 [40,250]
619 [444]
1,328 [675]
3,101 [805]
>5,300 [>1,659]
Lethal concentration in
10-20 min
(mg/m3 [ppm] )a
140,000 [55,090]
ND
20,000 [10,200]
20,000 [5,190]
ND
Concentration inducing
50% coma incidence in
15 min (mg/m3 [ppm] )a
243,900 [96,000]
ND
1,600 [813.3]
ND
ND
LOAECs
(mg/m3 [ppm] )a for
respiratory effects in rats
following acute
inhalation exposure
<30 min: irregular
respiration
(34,600 [13,620])
and nasal discharge
(140,000 [55,090]);
no macroscopic
changes in lungs
4-h: nasal irritation (14 [10]),
nasal lesions (110 [78.9]), lung
edema (120 [86.1]), and
irregular respiration (140 [100])
<30 min: thickened
alveolar walls
(3,000 [1,520]) and
irregular respiration,
emphysema, and serous
fluid accumulation
(20,000 [10,200])
<25 min: irregular respiration
(7,100 [1,843]), thickened
alveolar walls with spotty
macrophage infiltration
(12,900 [3,349]), and nasal
discharge and fluid-filled lungs
(19,200 [4,984])
4-h: no clinical signs of
respiratory irritation or
macroscopic lung changes
References
Tansv et al. (1981);
Zieve et al. (1974);
ATSDR (2016): Tansv et al.
(1981)
Tansv et al. (1981): Zieve
et al. (1974): Liuneeren
Tansv et al. (1981): Liuneeren
and Norbere (1943)
ECHA (1998)
Liuneeren and
and Norbere (1943)
Norbere (1943)
aValues in ppm = exposure in mg/m3 x 24.45 MW of compound. The MWs of dimethyl sulfide, hydrogen sulfide, methyl mercaptan, dimethyl disulfide, and dimethyl
sulfoxide are 62.13, 34.08, 48.1, 94.19, and 78.13 g/mol, respectively (U.S. EPA. 2024a).
LCso = median lethal concentration; LOAEC = lowest-observed-adverse-effect-concentration; MW = molecular weight; NA = not applicable; ND = no data.
55
Dimethyl Sulfide
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EPA 690 R-24 006F
Reliable repeat-exposure inhalation toxicity data for dimethyl sulfide are not available.
The only repeat-exposure inhalation toxicity study of dimethyl sulfide is a 6-month rat study of
uncertain reliability from the Russian literature available only as reported in a secondary source
[Selyuzhitskii (1972) as cited in Opdyke (1979)1. The available summary of the study lacked
adequate details regarding experimental methods and results. Additionally, associated acute
lethality data from this study [Selyuzhitskii (1972) as cited in Opdyke (1979)1 were orders of
magnitude lower than those reported in other acute studies, suggesting that the results are
uncertain.
The only candidate analogue with inhalation toxicity values is hydrogen sulfide. Both the
intermediate Minimal Risk Level (MRL) and the chronic RfC are based on increased incidence
of nasal lesions of the olfactory mucosa in rats following exposure to 30 ppm (42 mg/m3) for
10 weeks (ATSDR 2016; U.S. EPA. 2003a). The lesions observed at the LOAEL were olfactory
neuron loss and basal cell hyperplasia. While repeat-exposure inhalation data are not available
for dimethyl sulfide, nasal irritation (nasal discharge or not otherwise described) has been
reported in rats acutely exposed to lethal concentrations (140,000 mg/m3) of dimethyl sulfide
(Dow Chemical 1957; Liunggren and Norberg. 1943).
Nasal lesions and/or irritation have also been observed following inhalation exposure to
two additional candidate analogues, DMSO and dimethyl disulfide; the nasal cavity has not been
evaluated following inhalation exposure to methyl mercaptan. Lesions observed in rats following
exposure to 2,783 mg/m3 DMSO for 13 weeks included lesions in the respiratory epithelium
(pseudogland formation, epithelial hyperplasia, inflammation in the squamous epithelium) and
olfactory epithelium (eosinophilic inclusions). For dimethyl disulfide, reversible inflammatory
changes in the nasal mucosa were reported in rats following exposure to 10 ppm (39 mg/m3) for
13 weeks; findings were not reversible at 50 ppm (190 mg/m3). No damage to olfactory neurons
was described in repeat-exposure studies with DMSO or dimethyl disulfide (Api et al.. 2021a;
Anastassiadou et al.. 2019; Hartwig and MAK Commission. 2017; ECHA. 1992). In acute
studies, nasal irritation (nasal discharge) has been reported in rats exposed to lethal
concentrations (19,200 mg/m3) of dimethyl disulfide (Liunggren and Norberg. 1943). but not to
nonlethal DMSO concentrations up to 5,300 mg/m3 for 4 hours (ECHA. 1998). While the nasal
cavity was not evaluated in repeat-exposure inhalation studies in animals of methyl mercaptan,
the respiratory system has been identified as a sensitive toxicity target for this chemical. Mucous
membrane irritation was reported in workers exposed to methyl mercaptan at unspecified levels
(U.S. EPA. 2004). In rats, pulmonary edema and lesions (terminal bronchiole constriction,
alveolar congestion, and erythrocyte exudation) were observed after exposure to 0.5 ppm
(1 mg/m3) methyl mercaptan for 6 hours/day for 30 days (Jiang et al.. 2021); nasal tissues were
not examined for histopathology. Pulmonary effects were also observed following acute
exposures to lethal concentrations (>3,000 mg/m3) of methyl mercaptan (Liunggren and
Norberg. 1943).
Several mechanisms have been proposed to contribute to nasal lesions following
inhalation exposure to hydrogen sulfide, including local irritation and inhibition of cytochrome
oxidase (Govak and Lewis. 2021; ATSDR. 2016; U.S. EPA. 2003a). Hydrogen sulfide is a weak
acid and dissociates in water, resulting in slightly lowered pH, which could irritate the nasal
passages. Inhibition of cytochrome oxidase results in impaired oxidative respiration and energy
production; neuronal tissues (including olfactory neurons) are particularly susceptible to
disruption of oxidative metabolism (ATSDR. 2016). Govak and Lewis (2021) proposed that the
56
Dimethyl Sulfide
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EPA 690 R-24 006F
loss of olfactory neurons after hydrogen sulfide exposure could trigger remodeling of the
olfactory epithelium, leading to basal cell hyperplasia. No information was located on the
mechanisms underlying nasal lesions observed following exposure to DMSO and dimethyl
disulfide. However, there is limited evidence suggesting that dimethyl sulfide, DMSO, and
methyl mercaptan may disrupt oxidative metabolism and energy production in other tissues. For
example, dimethyl sulfide induced uncoupling of oxidative phosphorylation in rat liver
mitochondria in vitro, measured as decreased oxygen consumption, adenosine diphosphate:
oxygen (ADP/O) ratio, and respiratory control index (RCI) (Mhatre et al.. 1983). Dimethyl
sulfide also mildly inhibited mitochondrial respiration in cultured rat hepatocytes (Vahlkamp et
al.. 1979). DMSO did not induce uncoupling of oxidative phosphorylation in vitro; however,
uncoupling (decreased oxygen consumption, ADP/O ratio, and RCI) was observed in rat liver
mitochondria up to 5 days after a single i.p. injection (Mhatre et al.. 1983). Additionally, methyl
mercaptan inhibited cytochrome oxidase in isolated rat liver mitochondria and disrupted the
electron-transport chain in rat brain mitochondria (Vahlkamp et al.. 1979).
Review of limited inhalation data for methyl mercaptan, dimethyl disulfide, and DMSO
did not identify any additional sensitive target organs for the analogues beyond the respiratory
system.
Acute lethality and toxicity data were also reviewed to evaluate relative toxicity of
dimethyl sulfide and the analogues. Exposure to dimethyl sulfide in a confined space was
reported to cause two human fatalities (Terazawa et al.. 1991b). Air samples taken after the event
showed concentrations of methyl mercaptan at <10 ppm, dimethyl sulfide at "several" ppm, and
dimethyl disulfide at <1 ppm in air. Death was attributed to asphyxia, and autopsy revealed
congestion of the internal organs and pulmonary edema. Dimethyl sulfide was detected in blood
and tissues from one of the victims. Hydrogen sulfide is well-known to be fatal at concentrations
>500 ppm in confined spaces (ATSDR. 2016)14. Reports of fatalities after human exposure to
methyl mercaptan, dimethyl disulfide, and DMSO were not located. In animals, a few acute
inhalation studies compared the acute toxicity of dimethyl sulfide with that of one or more of the
analogues. The available quantitative data are presented in Table A-8. In a single study that
tested the target and three of the analogues, the acute inhalation median lethal concentration
(LC50) values were in the order of hydrogen sulfide < methyl mercaptan < dimethyl
disulfide < dimethyl sulfide (Tansy et al.. 1981). The inhalation LC50 for dimethyl sulfide was
markedly higher (i.e., less toxic) than those of its analogues (>2 orders of magnitude higher than
the most acutely toxic analogue, hydrogen sulfide). DMSO was not tested in this study; reported
4-hour acute LC50 values for DMSO are >5,300 mg/m3 in rats (ECHA. 1998). When rats were
acutely exposed to dimethyl sulfide or methyl mercaptan by inhalation, the concentrations
resulting in 50% coma incidence were 243,900 and 1,600 mg/m3, respectively (Zieve et al..
1974). The blood concentrations associated with coma were 7,000 nmol/mL for dimethyl sulfide
and 0.5 nmol/mL for methyl mercaptan. These data suggest that dimethyl sulfide was less potent
than methyl mercaptan under the study conditions.
In summary, the critical effect for the only analogue with inhalation toxicity values
(hydrogen sulfide) is nasal lesions (basal cell hyperplasia and olfactory neuronal loss). For the
"Analytical concentrations of 1, 10, and 500 ppm were converted to mg/m3 using the following formula: mg/m3 =
(ppm x MW)/24.45, where MW = 62.13 g/mol (the molecular weight of dimethyl sulfide) and 24.45 is the volume
occupied by 1 g/mol of any compound in a gaseous state at 0°C and 760 mm Hg.
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analogues that lacked toxicity values but were included to provide toxicity comparison
information, two (DMSO and dimethyl disulfide) also showed nasal lesions following repeated
inhalation exposure. The third data-gap filling analogue (methyl mercaptan) did not have any
nasal cavity toxicity data; however, pulmonary effects were observed. There is limited in vitro
evidence that dimethyl sulfide may inhibit oxidative phosphorylation, one of two mechanisms
proposed for the nasal lesions resulting from hydrogen sulfide. Based on acute inhalation
lethality data and inhalation toxicity data for dimethyl disulfide, methyl mercaptan, and DMSO,
hydrogen sulfide may be lethal at lower exposure concentrations and more toxic to the
respiratory system, compared to dimethyl sulfide.
Weight-of-Evidence Approach
A WOE approach is used to evaluate information available for candidate analogues as
described by Wang et al. (2012) and Lizarraga et al. (2023). Similarities between candidate
analogues and the target chemical are identified across the three major categories of evidence:
structural/physicochemical properties; toxicokinetics (ADME) and toxicodynamics (toxicity or
MO A). Evidence of toxicological and/or toxicokinetic similarity is prioritized over evidence of
similarity in structural/physicochemical properties. Candidate analogues are excluded if they
demonstrate substantial differences from the pool of candidate analogues as a whole and/or the
target chemical in any of the three categories of evidence. From the remaining pool of candidate
analogues, the most suitable analogue (i.e., the analogue that displays the closest biology or
toxicological similarity to the target chemical) with the greatest structural similarity and/or most
health-protective point-of-departure is selected. Additional considerations include preference for
evidence from existing U.S. EPA assessments and suitability of study duration (i.e., chronic
studies are preferred over subchronic studies when selecting an analogue for the derivation of a
chronic value.)
Hydrogen sulfide is a suitable analogue based on structural characteristics and
physicochemical properties, and the only analogue with an inhalation toxicity value. Observed
(or predicted) absorption, distribution, and excretion are expected to be similar for dimethyl
sulfide and all analogues. DMSO is likely the most appropriate metabolic analogue, as DMSO
and dimethyl sulfide are interconverted via redox reactions and DMSO2 is the primary
metabolite for DMSO and a secondary metabolite for dimethyl sulfide; however, DMSO lacks an
inhalation toxicity value. Like dimethyl sulfide and DMSO, hydrogen sulfide is also oxidatively
metabolized, with conversion of its sulfide to thiosulfate, and eventually sulfate. Other analogues
are less suitable metabolic analogues due to key differences in metabolism (e.g., formation of
dimethyl sulfide as a metabolite via minor metabolic pathways as described in Table A-6).
Hydrogen sulfide is the only analogue with an available inhalation toxicity value, which is based
on nasal lesions. Respiratory lesions are observed following exposure to all data-gap filling
analogues. Nasal lesions were also observed in repeat-exposure inhalation studies of dimethyl
disulfide and DMSO. Nasal tissues were not examined following repeated inhalation exposure to
methyl mercaptan; however, lesions were observed in the lower respiratory tract. The proposed
mechanisms of action underlying nasal lesions following exposure to hydrogen sulfide include
irritation due to reduced pH and inhibition of cytochrome oxidase. There is limited evidence that
dimethyl sulfide and its metabolite, DMSO, may inhibit oxidative phosphorylation. Additionally,
nasal and respiratory lesions associated with inhalation exposure to DMSO are consistent with
irritation, and clinical signs of nasal irritation have been observed following acute inhalation
exposure to dimethyl sulfide. Taken together, available data suggest potential toxicodynamic
similarities between dimethyl sulfide and hydrogen sulfide.
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In summary, the only candidate analogue with an inhalation toxicity value is hydrogen
sulfide. As with hydrogen sulfide, studies of two data-gap filling analogues that lack toxicity
values (i.e., dimethyl disulfide and DMSO) also show nasal lesions, suggesting that nasal tissues
are a sensitive target for this group of compounds. However, available repeat-dose inhalation
toxicity data show that nasal toxicity associated with dimethyl sulfide's metabolite, DMSO,
occurs at concentrations >50-fold higher than nasal lesions associated with hydrogen sulfide.
Additionally, acute inhalation lethality data indicate that lethal concentrations for dimethyl
sulfide are >150-fold higher than those associated with hydrogen sulfide. Therefore, the
inhalation toxicity value for hydrogen sulfide is expected to be protective of potential toxic
effects following inhalation exposure to dimethyl sulfide. It is unclear whether the observed
differences in acute potency between dimethyl sulfide and hydrogen sulfide would be observed
with longer duration, repeat-dose toxicity studies examining more sensitive (i.e., not frank)
health effects.
Derivation of a Screening Subchronic Provisional Reference Concentration
Based on the overall analogue approach presented in this PPRTV assessment, hydrogen
sulfide is selected as the source analogue for dimethyl sulfide for deriving the screening
subchronic and chronic p-RfCs. The principal study used for the ATSDR intermediate inhalation
MRL value for hydrogen sulfide is a 10-week inhalation study in rats [Brenneman et al. (2000)
as cited in ATSDR (2016)1. The Toxicological profile for hydrogen sulfide and carbonyl sulfide
provided the following summary for Brenneman et al. (2000) as cited in ATSDR (2016)15:
Groups of male Sprague Daw ley rats (12 group) were exposed to 0, 10,
30, or 80 ppm hydrogen sulfide 6 hours day, 7 days week for 10 weeks.
Parameters used to assess toxicity were limited to extensive histopathological
examination of the nasal cavity (six transverse sections examined via light
microscopy; transverse sections form a series of circumferential slices [labeled
levels 1—6], which allow for a thorough evaluation of all major structures and
mucosae of the nasal cavity).
Nasal lesions occurred only in the olfactory mucosa in rats exposed to
30 or 80 ppm and consisted of multifocal, bilaterally symmetrical olfactory
neuron loss and basal cell hyperplasia affecting the lining of the dorsal medial
meatus and the dorsal and medial regions of the ethmoid recess. The severity of
the olfactory lesions was scored as 1 mild, 2 moderate, or 3 severe. For the
olfactory neuron loss, the mild, moderate, or severe severity scores corresponded
to 26- 50, 51-75, and 76-100%, respectively, reduction in the normal thickness
of the olfactory neuron layer. For the basal cell hyperplasia, mild, moderate, or
severe severity scores corresponded to 1-33, 34-67, or 68-100% of the normal
thickness of the olfactory neuron cell layer replaced by basal cells. No olfactory
lesions were observed in the controls or rats exposed to 10 ppm. At 30 ppm,
olfactory neuron loss was observed at nasal levels 4 (11/12, severity 1.4) and
5 (9/12, severity 1.1) and basal cell hyperplasia was observed at nasal levels
4 (10/12, severity 1.8) and 5 (11/12, severity 1.3). At 80ppm, olfactory neuron
loss was observed at levels 3 (8/8, severity 2.4), 4 (12/12, severity 2.4), 5 (11/12,
15Brenneman KA, James RA, Gross EA, et al. 2000. Olfactory neuron loss in adult male CD rats following
subchronic inhalation exposure to hydrogen sulfide. Toxicol Pathol 28(2):326-333. [as cited in ATSDR (2016)1
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severity 1.5), and 6 (5/12, severity 1.2-incidence not statistically significant) and
basal cell hyperplasia was observed at nasal levels 4 (12/12, severity 1.2),
5 (11/12, severity 1.3), and6 (6/12, severity 1.0).
The NOAEL of 10 ppm for nasal lesions was selected as the POD for hydrogen sulfide
(ATSDR. 2016). The POD was converted into a human equivalent concentration (HEC) using
the regional gas dose ratio for the extrathoracic region (RGDRet) (U.S. EPA. 1994). Since the
release of the U.S. EPA's 1994 "Methods for derivation of inhalation reference concentrations
and applications of inhalation dosimetry" (U.S. EPA. 1994). considerations and approaches for
inhalation gas dosimetry in the extrathoracic or upper respiratory tract, tracheobronchial,
pulmonary, and extrarespiratory systems have been developed as extensions and advancements
of the 1994 RfC guidelines (U.S. EPA. 2012a. 201 Id. 2009b). A key finding of U.S. EPA
(2012a) is that "internal dose equivalency in the extrathoracic region for rats and humans is
achieved through similar external exposure concentrations. For gas deposition in the
extrathoracic region, the internal target-tissue dose equivalency between humans and rats is
achieved through equivalency at the level of the externally applied concentration, i.e., for both
rats and humans, the same external air concentration, rather than one adjusted by Ve/SA, leads to
the similar internal target-tissue dose to the upper respiratory tract." However, in the absence of
chemical-specific data on dimethyl sulfide, the POD was adopted from ATSDR (2016).
Therefore, the values developed using these standard approaches (U.S. EPA. 1994) are
considered reasonable and expected to be health protective.
The NOAEL of 10 ppm was converted to a NOAELhec of 0.46 ppm by ATSDR (2016):
NOAELadj = 10 ppm x 6 hours 24 hoars x 7 days/7 days = 2.5 ppm
The HEC was calculated using the following equation (EPA 1994b) for
category 1 gases:
NOAELhec = NOAEL.wd x RGDRet
The regional gas dose ratio for the extrathoracic region (RGDRet) of
0.184 was calculated using the following equation:
(
VE
RGDRrr —
i SAft j
\ hi J rat
ET ~ r v \
' E
v ^' ^£1 J human
where Ve is the minute volume and SAet is the surface area of the
extrathoracic (ET) region of the respiratory tract.
Minute volume (Jre)
Human: 13.8 L minute (EPA 1994b)
Rat: 0.190 L minute; calculated using the following EPA equation:
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InfVeJ = bo + biln(BW)
For rats, bo equals -0.578 and bi = 0.821.
Because limited body weight data were reported in the study, a reference
body weight of 0.267 kg (U.S. EPA 1988) was used.
EPA (1994b) rat and human respiratory surface area reference values:
Extrathoracic 15.0 cm2 (rat) 200 cnf (human)
NOAEL[hecj = NOAEL(ADJ) x RGDRet = 2.5 ppm x 0.184 = 0.46ppm
AT SDR (2016) considered available computational fluid dynamic models for hydrogen
sulfide inadequate for predicting HECs:
The dosimetric model typically used to estimate a concentration for
humans that would be equivalent to the exposure concentration in rats takes into
account species differences in the surface area of the upper respiratory tract and
inhalation rates. However, the model does not take into consideration that a
larger portion of the rat nasal cavity is lined with olfactory epithelium compared
to humans (50% in rats compared to 10% in humans) and differences in airflow
patterns. A computational fluid dynamics model of the rat nasal epithelium
developedfor hydrogen sulfide (Moulin et al. 2002; Schroeter et al. 2006a,
2006b) found strong correlations between the amount of hydrogen sulfide
reaching the olfactory tissue and the severity of the lesions (Moulin et al. 2002)
and between hydrogen sulfide flux (uptake by the olfactory tissue) and the lesion
incidence (Schroeter et al. 2006a). Using data generatedfrom hydrogen sulfide
uptake simulations in the human nasal passage at exposure levels of 1—50 ppm,
Schroeter et al. (2006a) derived regression equations for predicting the maximum
and 99th percentile flux values in the human olfactory region. However, data for
the uptake simulations in the human nasal passage were based on a model
reconstructedfrom magnetic resonance imaging (MRI) images from one male
individual and did not take into account the potential individual variability in
parameters. Schroeter et al. (2010) noted that there is considerable variation in
nasal anatomy that could affect airflow patterns and dosimetry of inhaled gases.
No actual measurements of gas delivery or absorption across nasal membranes
were made; the simulations of a single computer model were used by Schroeter et
al. (2006a) to predict HECs. When Schroeter et al. (2010) used the same male
subject and a different computer model to simulate gas uptake, the average
airflux was 14% lower than estimated by Schroeter et al. (2006a). Using MRI
data for five adults and two children aged 7 and 8 years, Schroeter et al. (2010)
concluded that normal variations in nasal anatomy, breathing rate, and airflow
distribution were not likely to result in large variations in olfactory wall mass flux
of hydrogen sulfide. However, the study did not address potential variations in a
wide range of childhood ages (including newborns and infants) or the sensitivity
of hydrogen sulfide dosimetry to variations in pharmacokinetic parameters. The
investigators recommended additional research on the influence of interindividual
variability in absorption and pharmacodynamics effects of hydrogen sulfide in the
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nasal tissues to olfactory dose. Based on these uncertainties in the computational
fluid dynamics model to predict a HEC, ATSDR estimated the NOAELhec using
the dosimetric model, which adjusts for surface area and breathing rate
differences between rats and humans. Additionally, the Schroeter et al. (2010)
study does not support a reduction in the uncertainty factor for human variability.
The intermediate ATSDR MRL for hydrogen sulfide is derived from the NOAELhec of
0.46 ppm (0.64 mg/m3), using a UFc of 30, reflecting a 10-fold UFh and a 3-fold UFa (ATSDR.
2016). Wang et al. (2012) indicated that the uncertainty factors typically applied in deriving a
toxicity value for the chemical of concern are the same as those applied to the analogue unless
additional information is available. For this assessment, the uncertainty factors for hydrogen
sulfide were adopted for dimethyl sulfide, with an additional UFd of 10 to account for database
limitations.
Screening Subchronic p-RfC = Analogue POD ^ UFc
= 0.64 mg/m3 300
= 2 x 10"3 mg/m3
Table A-9 summarizes the uncertainty factors for the screening subchronic p-RfC for
dimethyl sulfide.
Table A-9. Uncertainty Factors for the Screening Subchronic p-RfC for
Dimethyl Sulfide (CASRN 75-18-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10"5) is applied to account for remaining uncertainty associated with extrapolating from
animals to humans when a cross-species dosimetric adjustment (HEC calculation) is performed as
specified in the U.S. EPA (1994) guidelines.
UFd
10
A UFd of 10 is applied to reflect the database limitations for the target compound, dimethyl sulfide,
and an application of a read across-based analogue assessment. For dimethyl sulfide, there were no
adequate subchronic inhalation toxicity studies or any repeated-dose studies evaluating
developmental/reproductive toxicity. The only repeat-exposure inhalation toxicity study of dimethyl
sulfide is a 6-mo rat study of uncertain reliability from the Russian literature available only as
reported in a secondary source and lacking key experimental details.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of dimethyl sulfide in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the POD was derived from a study of suitable duration (10 weeks) for
a subchronic value.
UFC
300
Composite UF = UFA x UFH x UFD x UFL x UFS.
HEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure;
p-RfC = provisional reference concentration; UF = uncertainty factor; UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor;
UFl = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
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Derivation of a Screening Chronic Provisional Reference Concentration
Hydrogen sulfide is also selected as the source analogue for dimethyl sulfide for
derivation of a screening chronic p-RfC. The intermediate study [Brenneman et al. (2000) as
cited in ATSDR (2016)1 selected for the derivation of the intermediate inhalation MRL was also
selected by the U.S. EPA (2003b) for derivation of the chronic RfC for hydrogen sulfide. A
summary of this study is provided in the previous section "Derivation of a Screening Subchronic
Provisional Reference Concentration" for the interested reader. The IRIS summary for hydrogen
sulfide; 7783-06-4 (U.S. EPA. 2003a) contains a similar study summary and converts the
exposure concentrations to HEC values using the same methodology.
The inhalation RfC for hydrogen sulfide is derived from the NOAELhec of 0.64 mg/m3,
based on nasal lesions of the olfactory epithelium, using a UFc of 300, reflecting a 10-fold UFh,
a 3-fold UFa, and a 10-fold UFs; a UFd was not applied (U.S. EPA. 2003a. b). Wang et al.
(2012) indicated that the uncertainty factors typically applied in deriving a toxicity value for the
chemical of concern are the same as those applied to the analogue unless additional information
is available. For this assessment, the uncertainty factors for hydrogen sulfide were adopted for
dimethyl sulfide, with an additional UFd of 10 to account for database limitations.
Screening Chronic p-RfC = Analogue POD ^ UFc
= 0.64 mg/m3 3,000
= 2 x 10"4 mg/m3
Table A-10 summarizes the uncertainty factors for the screening chronic p-RfC for
dimethyl sulfide.
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Table A-10. Uncertainty Factors for the Screening Chronic p-RfC for
Dimethyl Sulfide (CASRN 75-18-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10"5) is applied to account for remaining uncertainty associated with extrapolating from
animals to humans when a cross-species dosimetric adjustment (HEC calculation) is performed as
specified in the U.S. EPA (1994) guidelines.
UFd
10
A UFd of 10 is applied to reflect the database limitations for the target compound, dimethyl sulfide,
and an application of a read across-based analogue assessment. For dimethyl sulfide, there were no
adequate subchronic inhalation toxicity studies or any repeated-dose studies evaluating
developmental/reproductive toxicity. The only repeat-exposure inhalation toxicity study of dimethyl
sulfide is a 6-mo rat study of uncertain reliability from the Russian literature available only as
reported in a secondary source and lacking key experimental details.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of dimethyl sulfide in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because the principal study is less-than-chronic duration.
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
HEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure;
p-RfC = provisional reference concentration; UF = uncertainty factor; UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor;
UFl = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
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APPENDIX B. DATA TABLES
Table B-l. Select Urinalysis Values in Wistar Rats Administered Dimethyl
Sulfide via Gavage 7 Days/Week for 6 or 14 Weeks3
Dose Group, [HED] (mg/kg-d)
Parametersbc
0
2.5 [0.58]
25 [5.8]
250 [57.5]
6 Weeks
Males
Volume (mL) at 0-6 h
3.4
NA
2.2 (-35%)
2.0* (-41%)
Volume (mL) at 16-20 h
0.3
NA
0.2 (-33%)
0.5 (+67%)
Females
Volume (mL) at 0-6 h
2.0
NA
2.3 (+15%)
3.0 (+50%)
Volume (mL) at 16-20 h
0.1
NA
0.4* (+300%)
0.1 (+0%)
14 Weeks
Males
Specific gravity at 0-6 h
1.068
1.067 (-0%)
1.068 (+0%)
1.060 (-1%)
Specific gravity at 16-20 h
1.079
1.081 (+0%)
1.091** (+1%)
1.084 (+0%)
Females
Specific gravity at 16-20 h
1.059
1.052 (-1%)
1.061 (+0%)
1.041** (-2%)
Specific gravity at 16-20 h
1.093
1.089 (-0%)
1.091 (-0%)
1.086 (-1%)
aButterworth et al. (1975).
bData are mean values for 5 rats/group at 6 weeks and 15 rats/group at 14 weeks (measure of variance not reported
by the study authors).
°Value in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05), as reported by the study authors.
**Significantly different from control (p < 0.01), as reported by the study authors.
HED = human equivalent dose; NA = not applicable.
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Table B-2. Select Organ Weights in Wistar Rats Administered Dimethyl
Sulfide via Gavage 7 Days/Week for 14 Weeks3
Dose Group,
HED] (mg/kg-d)
Parametersbc
0
2.5 [0.58]
25 [5.8]
250 [57.5]
Males
Terminal body weight (g)
388
413 (+6%)
393 (+1%)
396 (+2%)
Liver weight
Absolute (g)
10.70
11.43 (+7%)
10.85 (+1%)
11.21 (+5%)
Relative (g/100 gbody weight)
2.74
2.76 (+1%)
2.76 (+1%)
2.82 (+3%)
Kidney weight
Absolute (g)
2.17
2.21 (+2%)
2.18 (+1%)
2.17 (+0%)
Relative (g/100 gbody weight)
0.56
0.54 (-4%)
0.56 (+0%)
0.55 (-2%)
Small intestine weight
Absolute (g)
8.53
9.34* (+9%)
9.42* (+10%)
9.54* (+12%)
Relative (g/100 gbody weight)
2.21
2.27 (+3%)
2.40* (+9%)
2.41* (+9%)
Thyroid weight
Absolute (g)
16.7
18.2 (+9%)
18.7 (+12%)
19.7 (+18%)
Relative (g/100 gbody weight)
4.31
4.42 (+3%)
4.78 (+11%)
5.12* (+19%)
Females
Terminal body weight (g)
229
229 (0%)
235 (+3%)
228 (-0%)
Liver weight
Absolute (g)
6.38
6.43 (+1%)
6.69 (+5%)
6.04 (-5%)
Relative (g/100 gbody weight)
2.79
2.80 (+0%)
2.85 (+2%)
2.66 (-5%)
Kidney weight
Absolute (g)
1.38
1.39 (+1%)
1.47 (+7%)
1.43 (+4%)
Relative (g/100 gbody weight)
0.61
0.61 (+0%)
0.63 (+3%)
0.63 (+3%)
Small intestine weight
Absolute (g)
7.03
7.00 (+0%)
7.54 (+7%)
6.72 (-4%)
Relative (g/100 gbody weight)
3.00
3.07 (+2%)
3.23 (+8%)
2.95 (-2%)
Thyroid weight
Absolute (g)
15.6
14.1 (-10%)
13.7 (-12%)
12.0** (-23%)
Relative (g/100 gbody weight)
6.82
6.22 (-9%)
5.91 (-13%)
5.25** (-23%)
aButterworth et al. (1975).
bData are mean values for 15 rats/group (measure of variance not reported by the study authors).
°Value in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05), as reported by the study authors.
**Significantly different from control (p < 0.01), as reported by the study authors.
HED = human equivalent dose.
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Table B-3. Select Organ Weights in New Zealand White Rabbits
Administered Dimethyl Sulfide in Drinking Water for 13 Weeks3
Parametersbc
Dose Group,
[HED] (mg/kg-d)
0
2,000 [460]
Terminal body weight (g)
3,290 ± 54
3,110 ± 125 (-5%)
Relative liver weight (g/100 g body weight)
3.32 ± 0.11
2.71 ±0.10* (-18%)
Relative kidney weight (g/100 g body weight)
0.23 ±0.01
0.23 ± 0.01 (±0%)
Relative lung weight (g/100 g body weight)
0.36 ±0.02
0.54 ±0.03* (±50%)
aWood etal. (1971).
bData are mean ± standard error for 10 rabbits/group (sexes combined).
°Value in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control by Student's Me st (p < 0.05), as conducted for this review.
HED = human equivalent dose.
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APPENDIX C. ANALOGUE STRUCTURES, SOURCE, AND SELECTION CRITERIA
Table C-l presents the considered (included and excluded) analogues that were identified
using the criteria and approaches described in Appendix A "Analogue Search Results for
Dimethyl Sulfide (Inhalation Exposure)" A total of six suitable candidate analogues were
identified, as presented in Table C-l. One of the candidate analogues (hydrogen sulfide) had a
relevant toxicity value.
Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
S CH,
/
h3c
Dimethyl sulfide
(75-18-3)
Target chemical
Included analogues
h3c ch3
ch3
1,1 -Bis(methyltliio)ethane
(7379-30-8)
GenRA
s
s
1,3-Ditliietane
(287-53-6)
GenRA
h-.'"
Hydrogen sulfide
" (7783-06-4)
Manual search using
chemistry expertise
in read-across
HS -CH3
Methyl mcrcaptair1
(74-93-1)
Manual search using
chemistry expertise in
read-across
s xh3
Dimethyl disulfide3
(624-92-0)
Manual search using
chemistry expertise in
read-across
Radicals and isotopically enriched compounds excluded
2h s
J><[ ^
2h
Methane-d3, (methyltliio)-
(4752-12-9)
Dashboard
ChemlDplus
QSAR Toolbox
h313c^ 13ch3
Dimethyl-13 C2 sulfide
(136321-14-7)
Dashboard
GenRA
2h 2h
Di((2H3)methyl) sulpliide
(926-09-0)
Dashboard
ChemlDplus
QSAR Toolbox
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Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
H2C^ ^CH3
Methylthiomethyl radical
"(31533-72-9)
ChemlDplus
Mixtures and complexes excluded
h3c ch3
s
Bromo(tliiobis(methane)) copper
(54678-23-8)
ChemlDplus
GenRA
Br Cu
H
H | H
B
t
(Dimethyl sulfide)trihydroboron
' (13292-87-0)
ChemlDplus
QSAR Toolbox
GenRA
I
/5\
h3c ch3
ch3
s
: Au CI
ch3
Cliloro(dimethyl sulfide) gold (I)
(29892-37-3)
GenRA
h2o
(Methylsulfanyl)methane-water (1/1)
(58328-83-9)
GenRA
h3c ch3
H2C = 0
h2c=o
H2C = 0
HgC Q
H2C = 0
Cr
H3C CH3
Chromium, pentacarbonyl-
(dimethylsulfide)-
(31172-83-5)
ChemlDplus
H
H—B—H
L H-B^-——B——^B-H S CH,
NH, \\l/7 /
H—B—H 11 J
H HjC
DL-Methionine, compd. with
decaborane (8) and thiobis(methane)
(1:1:1)
(59690-63-0)
ChemlDplus
69
Dimethyl Sulfide
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Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
H-.C XMj
N./
CI Cl
Ft
Diclilorobis (dimethyl
sulfide)platinum(II)
(55449-91-7)
GenRA
P?*
JH, C
Platinum(2+) cliloride
[(6-methylheptyl)sulfanyl] acetate-
(methylsulfanyl) methane (1/1/1/1)
(68630-78-4)
ChemlDplus
h3c ch3
s
Br B
mono-Bromoborane methyl sulfide
complex
(55652-52-3)
GenRA
h3c ch3
Boron dibromide methyl sulfide
complex
(55671-55-1)
GenRA
Br Br
B
Li'
Lithium; methylsulfanylmethane
(127540-40-3)
GenRA
h3c .ch3
70
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Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
Cl HlC\
Copper iodide dimethyl sulfide complex
(914915-20-1)
GenRA
Discrete chemicals lacking sulfur or composed of elements besides carbon, hydrogen, oxygen, and sulfur
excluded
OH
h3c'/^ch3
Isopropanol
(67-63-0)
GenRA
h3c xh3
Dimethyl ether
(115-10-6)
GenRA
H3C—Br
Methyl bromide
(74-83-9)
GenRA
H3C 1
Methyl iodide
(74-88-4)
GenRA
CH,
CI
1,1 -Dichloroethane
(75-34-3)
GenRA
/CH3
H?N N
\
CH3
1,1-Dimethylhydrazine
(57-14-7)
GenRA
h -°^//S IYV1 Sxv°-
H3C 0 0 CH,
Temephos
(3383-96-8)
GenRA
71
Dimethyl Sulfide
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Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
/
1
Terbufos
(13071-79-9)
GenRA
h3c / !
CH,
/^ch3
h3c
H^C
S
Prometryn
(7287-19-6)
GenRA
CHj N CH3
H H 3
H3C\ /°^//
/ 0
L
Phorate
(298-02-2)
GenRA
/^S ^CH3
h3c
,N
N- S f/
\—s
Methylene bis(thiocyanate)
(6317-18-6)'
GenRA
ch3
0\//s
0 S
Disulfoton
(298-04-4)
GenRA
^—CH3
H3C\ /CH3
ch3 n
/N\ /S\ /nN.
H3c 5
S
Bis(dimethylaminothiocarbonyl)
disulfide
(137-26-8)
GenRA
0
II
S P NH?
/ 1
h3c 0.
CH3
Methamidophos
(10265-92-6)
GenRA
/N
/
2-(Thiocyanomethylthio) benzotliiazole
(21564-17-0)
GenRA
co^~
72
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Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
H3C c>
N N 0
Aldicarb
(116-06-3)
GenRA
r
Xj-
0—'
Carbophenotliion
(786-19-6)
GenRA
,S_ /H,
H!C 0
v-°\
H,C V O V.
s
Fenthion
(55-38-9)
GenRA
HoC
\ 0
h^°>C
// N CH3
0 H
Acephate
(30560-19-1)
GenRA
Molecular weight >125 g/mol excluded
ch3
s
.Sv Jv .ch3
H3C
.S
h3c^
1,1,2,2-Tetrakis (methylsulfanyl) ethane
(5418-87-1)
GenRA
ch3
1,3,5,7-T etramethy 1-
4,8,9,10-tetratliiatricyclo
(5.1.1.1(3,5))decane
(6638-47-7)
GenRA
1,2,3,6-Tetrathionane
(106874-24-2)
GenRA
s
\^/
/ 1/1
\ )
0
' (/>
1,3,5,7,9 -Pentatliiecane
(2372-99-8)
GenRA
0
1,3,5,7-Tetratliiocane
(2373-00-4)
GenRA
73
Dimethyl Sulfide
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Table C-l. Structure, Source, and Selection Criteria for Dimethyl Sulfide
(CASRN 75-18-3) and its Structural Analogues
Structure
Name (CASRN)
Source
cps
1,4,7,10,13,16-Hexatliiacy clo-
octadecane
(296-41-3)
GenRA
r
ch3
1,1,1 -Tris(methylsulfany 1) ethane
(6156-22-5)'
GenRA
Chemicals that exhibit differences in both structure and reactivity relative to the target excluded
s^C
Carbon disulfide
(75-15-0)
Manual search using
chemistry expertise
in read-across
c^s
0^
Carbonyl sulfide
(463-58-1)
Manual search using
chemistry expertise
in read-across
Bold shows compounds with available inhalation toxicity values.
aAlthough lacking inhalation toxicity values, evaluated as a data-gap filling analogue to provide additional
comparative toxicokinetic and toxicodynamic information pertaining to the influence of the methyl groups.
GenRA = General Read-Across; QSAR = Quantitative Structure-Activity Relationship.
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APPENDIX D. PARAMETERS OF TOOLS USED FOR READ-ACROSS
Table D-l. Parameters of Tools Used for Read-Across Evaluation of Dimethyl Sulfide
Similarity Context
[number of analogues
identified]3
Tool Name
[number identified]
Settings/Parameters
Searched by
(date)
Structural [44]
U.S. EPA CompTox Chemicals
Dashboard [3]
Tanimoto similarity threshold of 0.8 and related substances
CASRN
(February-
ChemlDplus [8]
ChemlDplus similarity search (default method) with >80% threshold and
related substances, parent (or exact structure match), salts, and mixtures'3
May 2022)
GenRA Beta version (in the U.S. EPA
CompTox Chemicals Dashboard) [38]
Collect 10 nearest neighbors by each similarity setting and combination
available:
• Morgan Fingerprints
• T orsion F ingerprints
• ToxPrints
• Morg2TorlBiol
• CTl:Bio3
Using each of the following data sources: ToxCast, Tox 21, and ToxRef
OECD QSAR Toolbox [3]
Similarity search with >80% similarity threshold using default settings:
• Dice similarity
• Atom centered fragments
• Hologram calculation.
• All features combined
• Atom characteristics: atom type, count H attached and hybridization
QSAR Toolbox Profilers0
No settings or parameters; results obtained from:
• HESS model
• Protein binding by OECD
• DART model
SMILESd
(December 2021)
Tox Alerts0
No settings or parameters; structural alerts obtained from:
Cytochrome P450-mediated drug metabolism alert
SMILES
(November 2021)
Toxtree0
No settings or parameters; results obtained from:
• Protein binding (based on nucleophilic aliphatic substitution SN2 alert)
• Protein binding (based on Michael acceptor alert)
SMILES
(February 2022)
75
Dimethyl Sulfide
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Table D-l. Parameters of Tools Used for Read-Across Evaluation of Dimethyl Sulfide
Similarity Context
[number of analogues
identified]3
Tool Name
[number identified]
Settings/Parameters
Searched by
(date)
Metabolic [4]
OECD QSAR Toolbox Metabolism
Simulators [1]
No settings or parameters; results obtained from:
• Rat liver S9 metabolism simulator version 3.7
• in vivo rat metabolism simulator version 3.5
SMILES6
(December 2021)
Toxicity/Mechanistic [0]
GenRA beta version (in the U.S. EPA
CompTox Chemicals Dashboard) [0]
Collected 10 nearest neighbors using the ToxCast similarity settings:
• Nearest neighbors with a similarity index >0.5 considered for use as
analogue
CASRN
(December 2021-
January 2022)
Comparative Toxicogenomics
Database (CTD) [0]
Compounds identified with gene interactions similar to those induced by
dimethyl sulfide:
• Used the interacting genes comparison search
• A similarity index of >0.5 is considered for use as a mechanistic
analogue
aNumber of unique analogues identified using analogue identification search tools.
bFor more information, see https://www.nlm.nih.gov/pubs/techbull/ma06/ma06 technote.html.
Tool used for candidate analogue evaluation.
dSMILES collected from the U.S. EPA CompTox Chemicals Dashboard batch search of the structural analogues CASRN.
"Dimethyl sulfide SMILES: CSC (CASRN 75-18-3).
DART = developmental and reproductive toxicity; GenRA = General Read-Across; HESS = Hazard Evaluation Support System; OECD = Organisation for Economic
Co-operation and Development; QSAR = quantitative structure-activity relationship; SMILES = Simplified Molecular Input Line Entry System;
U.S. EPA = U.S. Enviromnental Protection Agency.
76
Dimethyl Sulfide
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