United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-15/002F
Final
9-29-2015
Provisional Peer-Reviewed Toxicity Values for
Carbonyl Sulfide (Carbon Oxide Sulfide)
(CASRN 463-58-1)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
John C. Lipscomb, PhD, DABT, Fellow ATS
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Jeff Swartout
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
li
Carbonyl Sulfide
-------
TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 4
HUMAN STUDIES 10
Oral Exposures 10
Inhalation Exposures 10
ANIMAL STUDIES 10
Oral Exposures 10
Inhalation Exposures 10
Short-Term Tests in Animals 12
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 19
Tests Evaluating Genotoxicity and/or Mutagenicity 19
Supporting Human Studies 19
Supporting Animal Toxicity Studies 19
Metabolism/Toxicokinetic Studies 20
Mode-of-Action/Mechanistic Studies 21
DERIVATION OI PROVISIONAL VALUES 22
DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES 22
DERIVATION OF PROVISIONAL INHALATION REFERENCE CONCENTRATIONS . 22
Derivation of Subchronic Provisional Reference Concentration (p-RfC) 22
Derivation of Chronic Provisional RfC (Chronic p-RfC) 27
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 29
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 29
Derivation of Provisional Oral Slope Factor (p-OSF) 29
Derivation of Provisional Inhalation Unit Risk (p-IUR) 29
APPENDIX A. SCREENING PROVISIONAL VALUES 30
APPENDIX B. DATA TABLES 31
APPENDIX C. SUMMARIES OF SUPPORTING DATA 38
APPENDIX D. BENCHMARK MODELING RESULTS 54
APPENDIX E. REFERENCES 68
in
Carbonyl Sulfide
-------
COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic
Industrial Hygienists
erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere
Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand white (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD
Number
QSAR
quantitative structure-activity
CBI
covalent binding index
relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day
known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase
known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level
iv
Carbonyl Sulfide
-------
FINAL
09-29-2015
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
CARBONYL SULFIDE (CARBON OXIDE SULFIDE; CASRN 463 58 1)
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 Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
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.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse 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. Environmental Protection Agency (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 contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
1
Carbonyl Sulfide
-------
FINAL
09-29-2015
INTRODUCTION
Carbonyl sulfide is ubiquitous in the atmosphere (HSI)B, 2007). This compound occurs
naturally in food and is a byproduct of aerobic metabolism of sulfur-containing compounds.
Natural emissions of carbonyl sulfide occur from microbes, volcanoes, and the burning of
vegetation. Carbonyl sulfide can also be an impurity in natural gas and is a major contributor of
sulfur in the atmosphere. Anthropogenic sources of carbonyl sulfide include releases from the
manufacture of fuels, refinery gases, and carbon disulfide. Carbonyl sulfide is also a combustion
product from sulfur-containing fuels (Weil et aL 2006). Carbonyl sulfide is used as a chemical
intermediate for thiocarbamate herbicides and aliphatic polyureas (HSI)B, 2007). and as an
effective grain fumigant (Bartholomaeus and Haritos, 2005). Anthropogenic sources of carbonyl
sulfide are estimated to be less than one-third of that from natural sources (HSI)B, 2007).
Carbonyl sulfide is listed as a hazardous air pollutant (HAP) under the Clean Air Act as amended
in 1990. Carbonyl sulfide has a high vapor pressure and is expected to be present in the
atmosphere entirely as a gas. The water solubility indicates that the compound may be found as
a water contaminant. The empirical formula for carbonyl sulfide is COS (see Figure 1). A table
of physicochemical properties for carbonyl sulfide is provided below (see Table 1).
Figure 1. Carbonyl Sulfide Structure (CASRN 463-58-1)
Table 1. Physicochemical Properties of Carbonyl Sulfide (CASRN 463-58-l)a
Property (unit)
Value
Boiling point (°C)
-50
Melting point (°C)
-138.8
Density (g/cm3)
1.028
Vapor pressure (mm Hg at 25 °C)
9,034b
pH (unitless)
ND
Solubility in water (g/100 mL at 25°C)
1.22
Relative vapor density (air =1)
2.1
Molecular weight (g/mol)
60.08
•'HSDB (2007).
bSigma-Aldrich (2014).
ND = no data.
A summary of available toxicity values for carbonyl sulfide from U.S. EPA and other
agencies/organizations is provided in Table 2.
2
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 2. Summary of Available Toxicity Values for Carbonyl Sulfide (CASRN 463-58-1)
Source/Parametera'b
Value (applicability)
Notes
Reference
Noncancer
ACGIH (TLV-TWA)
5 ppm (12 mg/m3)
Based on central nervous system
impairment.
ACGIH (2015)
ATSDR
NV
NA
ATSDR (2014)
Cal/EPA
NV
NA
Cal/EPA (2014):
Cal/EPA (2015a):
Cal/EPA (2015b)
NIOSH
NV
NA
NIOSH (2015)
OSHA
NV
NA
OSHA (2006);
OSHA (2011)
IRIS
NV
ND
U.S. EPA (2015)
DWSHA
NV
NA
U.S. EPA (2012a)
HEAST
NV
NA
U.S. EPA (2011)
CARA HEEP
NV
NA
U.S. EPA (1994a)
WHO
NV
NA
WHO (2015)
Cancer
IRIS
NV
ND
U.S. EPA (2015)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
IARC
NV
ND
IARC (2015)
NTP
NV
NA
NTP (2014)
Cal/EPA
NV
NA
Cal/EPA (2015a):
Cal/EPA (2011);
Cal/EPA (2015b)
ACGIH (WOE)
NV
Sufficient data were not available to
recommend a carcinogenicity notation.
ACGIH (2015)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Research; Cal/EPA = California Environmental Protection Agency; CARA = Chemical
Assessments and Related Activities; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; HEEP = Health and Environmental Effects Profiles;
IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; WHO = World Health Organization.
Parameters: TLV-TWA = threshold limit value-time weighted average; WOE = cancer weight of evidence .
NA = not applicable; NV = not available; ND = no data.
3
Carbonyl Sulfide
-------
FINAL
09-29-2015
Literature searches were conducted through June 2015 for studies relevant to the
derivation of provisional toxicity values for carbonyl sulfide (CASRN 463-58-1). Searches were
conducted using U.S. EPA's Health and Environmental Research Online (HERO) database of
scientific literature. HERO searches the following databases: PubMed, ToxLine (including
TSCATS1), and Web of Science. The following databases were searched outside of HERO for
health-related values: ACGM, AT SDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA
OW, U.S. EPA TSCATS2/TSCATS8e, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide an overview of the relevant database for carbonyl sulfide and
include all potentially relevant repeated-dose short-term-, subchronic-, and chronic-duration
studies. Principal studies are identified in bold. The phrase "statistical significance," used
throughout the document, indicates ap-walue of < 0.05, unless otherwise noted.
4
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 3A. Summary of Potentially Relevant Noncancer Data for Carbonyl Sulfide (CASRN 463-58-1)
Number of Male/Female,
Strain, Species, Study Type,
BMDL/
Reference
Category
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMCLa
LOAELa
(comments)
Notesb
Human
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
Short-term
10 M/10 F, S-D rat, 6 hr/d,
0,51, 151,253,
Methemoglobinemia increased in
22
NDr
66
Monsanto
NPR
5 d/wk, 2 wk (whole-body
or 453 ppm
males and females at
(1985)
inhalation chamber)
concentrations of 66 and above
HEC: 0, 22, 66,
111, 199
Short-term
10 M/10 F, F344 rat, 6 hr/d,
0, 300, 400, or
Necrotic brain lesions and
132
NDr
176
Morgan et al.
PR
5 d/wk, 2 wk (whole-body
500 ppm
decreased grip strength
(2004)
chamber)
HEC: 0, 132,
176,219
Short-term
15 M/0 F, F344 rat, 6 hr/d,
0, 300, 400 ppm
Decreased amplitudes of BAER
132
NDr
176
Herr et al.
PR
5 d/wk, 2 wk (whole-body
peak amplitudes, decreased
(2007)
chamber)
HEC: 0, 132,
motor activity and grip strength,
176
slightly abnormal gait, loss of
forelimb proprioceptive placing
response, and gross brain lesions
5
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 3A. Summary of Potentially Relevant Noncancer Data for Carbonyl Sulfide (CASRN 463-58-1)
Category
Number of Male/Female,
Strain, Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAEL1
Reference
(comments)
Notesb
Subchronic
Uncertain sex, white Danish
rabbit, continuous, 7 wk
(whole-body chamber)
0, 54 ppm
HEC: 0, 130
On D 5 of exposure, three
exposed rabbits died and two
rabbits were moribund with signs
of severe neurotoxicity
NDr
NDr
NDr
Hueod (1981):
PR
Hueod and
Astruo (1980);
Kamstrun and
Hueod (1979)
Widely
fluctuating
concentrations;
all rabbits that
died did so on
the same day.
Subchronic
10 M/10 F, F344 rat, 6 hr/d,
5 d/wk, 12 wk (whole-body
chamber)
0,300, or
400 ppm
HEC: 0,132,
176
Necrosis of parietal cortex; and
neuronal loss and microgliosis
in parietal cortex (assessed by
light microscopy)
132 (male)
132 (female)
125 (male)
121 (female)
(neuronal
loss and
microgliosis)
176 (male)
176 (female)
Morgan et al.
PR, PS
(2004)
Subchronic
6 MAS F, F344 rat, 6 hr/d,
5 d/wk, 4, 8, or 12 wk
(whole-body chamber)
0, 200, 300 or
400 ppm
HEC: 0, 87.8,
132, 176
Brain lesions in the posterior
colliculus, anterior olivary
nucleus, and parietal cortex
(assessed by magnetic resonance
microscopy)
132
NDr
176 (brain lesions)
Sills et al.
(2004)
Incidence data
not reported
PR
Subchronic
16 M/16 F, F344 rat, 6 hr/d,
5 d/wk, 12 wk (whole-body
chamber)
0, 200, 300, or
400 ppm
HEC: 0, 87.8,
132, 176
Changes in B AER peak
amplitudes and SEP peak
amplitudes and latencies
132
175
176 (alterations in
BAERs and SEPs)
Herr et al.
(2007)
Responses
combined for
males and
females; only
SEP1
responses
successfully
modeled
PR
Chronic
ND
6
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 3A. Summary of Potentially Relevant Noncancer Data for Carbonyl Sulfide (CASRN 463-58-1)
Category
Number of Male/Female,
Strain, Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAEL1
Reference
(comments)
Notesb
Reproductive
Study 1
0 M/24 F, S-D rat,
one-generation study, 6 hr/d,
5 d/wk, ~11 wk, followed by
7 consecutive d before
mating, 7 d/wk during mating
to unexposed males, and
5 d/wk on GDs 0-19 (total
exposure 15-16 wk); litters
were delivered naturally and
were culled to 8 on PND 4
(4/sex where possible); dams
and 10 F1 pups/sex/group
sacrificed on PND 21
0, 10, 60 or
182 ppm
HEC: 0, 4.6, 27,
84
F0 females: no changes in body
weight, ovary weight,
reproductive tissue histology, or
mating or reproductive indices
F1 pups (PND 21): no changes in
weight, survival, or histology of
33 organs
Reproductive
F0 females: 84
F1 males and
females: 84
NDr
Reproductive
F0 females:
NDr
F1 males and
females: NDr
Monsanto
(1979)
NPR
7
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 3A. Summary of Potentially Relevant Noncancer Data for Carbonyl Sulfide (CASRN 463-58-1)
Category
Number of Male/Female,
Strain, Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAEL1
Reference
(comments)
Notesb
Reproductive
Study 2
24 M/0 F, S-D rat,
one-generation study, 6 hr/d,
5 d/wk for ~11 wk, followed
by 7 consecutive d before
mating and 7 d/wk during
mating to unexposed females
to produce Fla litter (total
exposure ~13 wk).
Males were mated with
48 additional females 10 wk
later to produce Fib litter; F0
males were sacrificed after
Fib mating; half of Fib dams
were sacrificed on GD 14 for
fertility assessment; the other
half of Fib dams and Fla
dams were allowed to deliver
naturally.
Litters were culled to 8 on
PND 4 (4/sex where
possible); Fla and Fib pups
(10/sex/group) were
sacrificed on PND 21.
0, 10, 60 or
182 ppm
HEC: 0, 4.6, 27,
84
F0 males: no statistically
significant changes in body
weight, testicular weight,
reproductive tissue histology, or
reproductive performance
Fla generation: no changes in
body or organ weights, survival,
or histology of 33 organs
Fib generation: no changes in
body or organ weights, survival,
or histology of 33 organs
Reproductive
F0 males: 84
Fla pups: 84
Fib pups: 84
NA
Reproductive
NDr
Fla pups: NDr
Fib pups: NDr
Monsanto
(1979)
NPR
aDosimetry: The units for inhalation exposure units are expressed as HECs (mg/m3). Exposure values (2 weeks and longer) are converted from a discontinuous to a continuous
(weekly) exposure. Values from animal reproductive studies are not adjusted to a continuous exposure basis.
HECexresp = (ppm x molecular weight [60.08 g/mol] ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x ratio of animal:humanblood:gas partition coefficients
[default value of 1].
bNotes: PR = peer reviewed; NPR = not peer reviewed; PS = principal study.
BAER = brainstem auditory evoked response; F = female; FEL = frank effect level; GD = Gestation Day; M = male; NA = not applicable; ND = no data; NDr = not determined;
PND = Postnatal Day; S-D = Sprague-Dawley; SD = standard deviation; SEP = sensory evoked potential.
8
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 3B. Summary of Potentially Relevant Cancer Data for Carbonyl Sulfide (CASRN 463-58-1)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry
Critical Effects
BMDL/
BMCL
Reference (comments)
Notes
Human
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
ND = no data.
9
Carbonyl Sulfide
-------
FINAL
09-29-2015
HUMAN STUDIES
Oral Exposures
No studies have been identified.
Inhalation Exposures
No studies have been identified.
Three case studies have reported reversible effects potentially attributable to acute
inhalation exposure to carbonyl sulfide. Two occupational studies reported illness following
acute exposure to gaseous mixtures including carbonyl sulfide [Benson et al. (1996) as cited in
ACGIH (2012); Praxair (2003)1. Subjects recovered fully from observed effects, which included
respiratory distress, nausea, and intravascular hemolysis with severe anemia and the beginning of
acute renal failure. Similarly, a man reported rapid, but transient, dizziness, inability to stand,
chest pressure, and ringing in the ears following intentional inhalation of "pure carbonyl sulfide
gas" [Klason (1887) as cited in Bartholomaeus and Haritos (2005)1. These studies are included
in Appendix C, Table C-2 (Other Studies).
ANIMAL STUDIES
Oral Exposures
No adequate studies have been identified on the oral exposure of carbonyl sulfide to
animals. A series of studies by Wang et al. (1999) examined toxicity endpoints in
Sprague-Dawley (S-D) rats fed food fumigated with 20,000-500,000 mg/m3 carbonyl sulfide for
3-24 months. However, the study design and reporting were inadequate for hazard identification
or to determine a no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect
level (LOAEL) because the concentration of the agent in the feed was not measured
(see Appendix C, Table C-2 [Other Studies]).
Inhalation Exposures
Potentially relevant data for noncancer effects include: a series of subchronic-duration
studies of general toxicity (lethality, morbidity, body weight) and cardiovascular effects in white
Danish rabbits exposed to carbonyl sulfide gas for 7 weeks (Hugod. 1981; Hugod and Astrup.
1980; Kamsttup and Hugod. 1979); a series of subchronic- and short-term-duration studies of
neurological effects in rats exposed to carbonyl sulfide gas for 2 or 12 weeks (Herr et al. 2007;
Morgan et al. 2004; Sills et al. 2004); a short-term-duration toxicity study of rats exposed to
carbonyl sulfide gas for 2 weeks (Monsanto. 1985); and a series of one-generation reproduction
toxicity studies in rats exposed to carbonyl sulfide gas for ~11 weeks before mating and during
mating (Monsanto. 1979).
Results from these inhalation-exposure animal studies show:
1) A human equivalent concentration LOAEL (LOAELhec) of 176 mg/m3 (400 ppm)
and a human equivalent concentration NOAEL (NOAELhec) of 132 mg/m3
(300 ppm) for neurological effects in rats, including necrotic brain lesions, altered
electrophysiology (brainstem auditory evoked responses [BAER], somatosensory
evoked potentials [SEP]), and neurobehavioral alterations following exposure for
6 hours/day, 5 days/week for 2 or 12 weeks (Herr et al. 2007; Morgan et al. 2004;
Sills et al. 2004).
10
Carbonyl Sulfide
-------
FINAL
09-29-2015
2) A human equivalent concentration frank effect level (FELhec) of 200 mg/m3
(453 ppm) and a NOAELhec of 110 mg/m3 (253 ppm) for morbidity and clinical
signs of neurotoxicity in male and female rats during Week 2 of exposure
6 hours/day, 5 days/week (Monsanto. 1985).
3) A LOAELhec of 66 mg/m3 (151 ppm) and a NOAELhec of 22 mg/m3 (51 ppm) for
methemoglobinemia in male and female rats during a 2-week exposure for
6 hours/day, 5 days/week (Monsanto. 1985).
4) A FELhec of 130 mg/m3 (widely fluctuating concentrations averaging 54 ppm; the
only concentration tested) for increased mortality and morbidity (severe neurological
disorder) in rabbits after the 5th day of exposure during a continuous exposure of
carbonyl sulfide for a 7-week exposure period. The 13 rabbits that survived the
7 weeks of exposure showed no exposure-related effects on neurological function,
cholesterol levels, or histology of coronary or pulmonary arteries, aortic arch,
thoracic aorta, or lungs (Hugod. 1981; Hugod and Astrup. 1980; Kamstrup and
Hugod. 1979).
5) A NOAELhec of 84 mg/m3 (the highest concentration tested, 182 ppm 6 hours/day
before and during mating to unexposed partners and during Gestation Days [GDs]
0-19) for the absence of statistically significant exposure-related changes in
reproductive performance in F0 female rats, weight and survival of F1 pups, and
histology of reproductive tissues from F0 rats and histology of 33 tissues in F1
offspring at Postnatal Day (PND) 21 (Monsanto. 1979). At PND 21, F1 male
offspring of F0 females (but not female offspring) exposed to 182 or 60 ppm showed
decreased absolute and relative liver weight, but no exposure-related histological
changes in liver. The liver weight changes are of uncertain toxicological
significance in consideration of the inconsistent dose-response relationship, the
absence of histological changes, the large functional reserve of the liver, and the
absence of liver-weight effects in female offspring or in exposed animals in other
studies. Additional support for dismissal of this effect as adverse is provided by a
lack of clinical chemistry findings in an unpublished 14-week study (DuPont 1992).
6) A NOAELhec of 84 mg/m3 (the highest concentration tested, 182 ppm 6 hours/day
before and during mating to unexposed partners) for the absence of clear adverse
effects on the ability of F0 male rats to impregnate females and produce two litters
(Fla and Fib), and no exposure-related histological changes in F0 male reproductive
tissue or 33 organ tissues in PND-21 F1 offspring (Monsanto. 1979).
An additional 14-week sub chronic-duration inhalation toxicity study of rats was located;
however, the report was only available in summary form (DuPont 1992); therefore, available
data are inadequate for independent review of the results or a reliable NOAEL/LOAEL
determination (see Table C-2 in Appendix C). Summaries of two developmental toxicity studies
were also located (DuPont 1992). but it is unclear whether these studies are resubmissions of
findings previously reported by Monsanto (1985) and Monsanto (1979). Again, available data
are inadequate for independent review of the results or a reliable NOAEL/LOAEL determination
(see Table C-2 in Appendix C). No chronic-duration/carcinogenicity inhalation studies were
located.
11
Carbonyl Sulfide
-------
FINAL
09-29-2015
Short-Term Tests in Animals
Monsanto (1985)
In a non-peer-reviewed report, groups of S-D rats (10/sex/group) were exposed to
nominal concentrations of 0, 50, 150, 250, or 450 ppm (analytical concentrations: 0, 51, 151,
253, or 453 ppm) carbonyl sulfide for 6 hours/day, 5 days/week for 2 weeks in whole-body
inhalation chambers. Rats were housed individually and randomly assigned to exposure groups
via a computer program on the basis of initial body weight. Male and female rats were 37 and
36 days of age, respectively, at the start of the study. On exposure days, animals were observed
before, during, and after exposure periods for mortality and clinical signs of toxicity. Animals
were also checked for mortality on nonexposure days. Animal body weights were recorded
weekly. Blood was collected just prior to sacrifice at 2 weeks for hematological evaluations
including red blood cell (RBC) count, white blood cell (WBC) count, platelets, hematocrit,
hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration.
Percentages of oxy-, carboxy-, and methemoglobin were determined via spectrophotometry. At
sacrifice, animals were examined for gross pathological changes. Organs were not weighed, and
tissues were not preserved for histological evaluation.
Clinical signs of neurotoxicity were evident in rats in the 453-ppm group during the
second week of exposure, including ataxia, head tilt, circling, pivoting, prostrate and arched back
postures, tremors, loss of muscular control, convulsions, and bulging, dilated eyes
(see Table B-l). Toxicity led to moribund sacrifice of 2/10 males and 3/10 females after the
eighth exposure. Additional signs of toxicity resulting from a viral infection
(sialodacryoadenitis) were evenly distributed across exposure groups (e.g., lacrimation, swollen
eyes, nasal discharge, salivation, and swollen submaxillary salivary glands). Body weight was
significantly reduced in females, but not males, in the 453-ppm group, compared with controls;
however, all terminal body weights were within 5% of control values (see Table B-l). When
compared to concurrent control values, statistically significantly increased methemoglobin
concentrations were observed in blood of rats at >151 ppm (see Table B-l), representing a
potentially decreased oxygen delivering capacity of the blood. Methemoglobinemia (not in
combination with other effects) serves as the critical effect for oral reference dose (RfD) values
on IRIS (U.S. EPA. 2015) for nitrate and nitrite (effect observed in humans) and nitrobenzene,
where the effect was observed in rats. However, the extent of methemoglobin in humans was
10% (Walton, 1951) and the duration of the rat study was 90 days ( N I P. 1983).
The analytical concentrations 0, 51, 151, 253, and 453 ppm in this study were converted
to HECs of 0, 22, 66, 111, and 199 mg/m3 for extrarespiratory effects from a category 3 gas,
based on the following equation: CONChec = CONCppm x (molecular weight ^ 24.45) x (hours
exposed ^ 24 hours) x (days exposed ^ 7 days) x blood:air partition coefficient ratio (U.S. EPA.
1994c). The values for the human and rat blood:air partition coefficients are unknown, so the
default ratio of 1 was applied. A LOAELhec of 66 mg/m3 (151 ppm) and a NOAELhec of
22 mg/m3 (51 ppm) were identified in male and female rats for increased methemoglobin
concentration, compared with controls.
Morgan et al. (2004)
Preliminary to the 12-week study summarized below, Morgan et al. (2004) exposed
Fischer 344 rats (10/sex/group) to 0, 300, 400, or 500 ppm 6 hours/day, 5 days/week for 2 weeks.
The corresponding HECs are 0, 132, 176, and 219 mg/m3, respectively. Neurobehavior was
assessed with a functional observational battery (FOB) and brain lesions were assessed as
12
Carbonyl Sulfide
-------
FINAL
09-29-2015
described for the 12-week study. All male rats and 4/10 female rats died or were sacrificed
moribund (hypothermia, lethargy, ataxia) in the 500-ppm group; no deaths or clinical signs of
toxicity were observed in other dose groups. In the FOB, decreased grip strength was observed
in rats exposed to >400 ppm, and hypotonia and slight gait abnormalities were observed in
surviving females from the 500-ppm group (data not reported by study authors). Significant
increases in brain lesion incidence were observed in the parietal cortex and putamen in the
400-ppm group. At 500 ppm, necrotic brain lesions were observed in multiple brain regions of
all rats (see Table B-2). No exposure-related findings were observed in the 300-ppm rats. A
LOAELhec of 176 mg/m3 (400 ppm) and aNOAELHEC of 132 mg/m3 (300 ppm) were identified
in male and female rats for exposure-related lesions in multiple brain regions and decreased grip
strength, compared with controls.
Herr et al. (2007)
Herr et al. (2007) exposed groups of rats (15 males/group) to 0, 300, or 400 ppm for
6 hours/day, 5 days/week for 2 weeks. The corresponding HECs are 0, 132, and 176 mg/m3,
respectively. The animals were examined using a FOB and response modification audiometry
(RMA). No exposure-related effects were found on body weight. Exposure-related changes in
the FOB were only observed in the 400-ppm group, including decreased motor activity,
decreased grip strength, slightly abnormal gait, and loss of forelimb proprioceptive placing
response (data not reported). No changes were observed in the startle response (RMA).
Significantly decreased amplitude of BAER peaks were measured in 400-ppm rats, compared
with responses in 0- and 300-ppm rats (data reported graphically). Peak-to-peak amplitudes and
latencies for cortical and cerebellar SEPs from forelimb stimulation were not significantly
changed among the groups, but some qualitative changes in shape and morphology of waveforms
were noted in the 400-ppm group. No exposure-related changes were observed for peripheral
nerve compound nerve action potentials (CNAPs) or nerve conduction velocity (NCV), or flash-
evoked potentials (FEPs). Grossly visible cortical lesions (cavitation) were observed in
1 1/15 rats in the 400-ppm group, similar to that observed in the earlier study (Morgan et al..
2004). No grossly visible cortical lesions were seen in 0- or 300-ppm rats. A LOAELhec of
176 mg/m3 (400 ppm) and aNOAELHEC of 132 mg/m3 (300 ppm) were identified in male rats
for gross brain lesions, altered neurobehavior and reflexes (decreased motor activity, decreased
grip strength, slightly abnormal gait, loss of forelimb proprioceptive placing response), and
decreased BAER peak amplitudes (Herr et al.. 2007).
Subchronic-Duration Studies
Hugod (1981); Hugodand Astrup (1980); Kamstrup andHugod (1979)
In three peer-reviewed studies from the same laboratory, groups of white Danish country
breed rabbits were continuously exposed to nominal carbonyl sulfide concentrations (purity and
source not reported) of 0 or 50 ppm. Hugod and Astrup (1980) reported that exposure
concentrations varied, with a minimum detected value of 40 and a maximum detected value of
75 ppm. The average of detected concentrations was 54 ppm, a HEC of 130 mg/m3.
While it seems clear from the study design and level of reporting that these studies report
results from the same group of exposed rabbits, details of sex and exposure concentration are
inconsistently reported. Carbonyl sulfide exposures were described as being to "pure COS"
(source and purity not presented) delivered from a gas cylinder and mixed with atmospheric air
(Hugod and Astrup. 1980; Kamstrup and Hugod. 1979). While the number of dead (three) and
moribund (two) animals is reported on the same study day in reports by both Kamstrup and
13
Carbonyl Sulfide
-------
FINAL
09-29-2015
Hugod (1979) and Hugod and Astrup (1980). the former study reports groups of n= 17 (control)
and n = 18 (treated) female rabbits and analytical concentrations of 0 and mean concentrations of
54 ppm (range 40-75 ppm), while the latter reports group sizes of 6-24 male animals and no
analytic values for measured chamber concentrations. Body weight was monitored at regular
intervals throughout exposure (data not reported). Blood samples were collected from a
marginal ear vein before exposure and at weekly intervals during exposure to determine serum
total (free + esterified) cholesterol and triglyceride levels. After the 7-week exposure period,
cholesterol dynamics using injection of labelled cholesterol was measured using two methods.
In four rabbits/group, blood samples were collected at intervals over 20 hours following injection
of la,2a[N]-3H-cholesterol dissolved in ethanol (direct injection method). In three rabbits/group,
blood samples were collected at regular intervals for 5 hours following injection with in vivo
labelled plasma obtained from two donor rabbits injected with la,2a [N]-3H-cholesterol 20 hours
prior to bleeding (donor plasma method). Free cholesterol levels were measured in the inner
(intima + internal media) and outer (media) layers of the aorta from seven to nine rabbits/group.
Eight rabbits/group were sacrificed for histopathological examination of the coronary arteries,
aortic arch, thoracic aorta, pulmonary arteries and lungs, and ultrastructural examination of the
myocardium of the left ventricle.
As reported in Kamstrup and Hugod (1979) and in Hugod and Astrup (1980). on the fifth
day after the initiation of exposure, three exposed animals died and two were sacrificed
moribund due to serious (unspecified) neurological disorders (see Table B-3). The three dead
animals were excluded from the study; however, the two sacrificed animals were included in the
histopathological evaluation. None of the 13 surviving animals demonstrated signs of altered
neurological function (Kamstrup and Hugod. 1979). No exposure-related body-weight effects
were observed. Overall, no consistent, exposure-related changes in cholesterol levels were
found. Significant increases were observed in serum cholesterol levels at Weeks 1, 6, and 7 and
serum triglyceride levels at Weeks 4 and 6 (data presented graphically). No exposure-related
changes were observed in cholesterol dynamics using either method. Free cholesterol measured
in the outer media layer of the aorta was statistically significantly increased by 22% compared
with controls; however, no statistically significant effect on free cholesterol levels in the inner
intima and internal media aortic layers was observed (see Table B-3). No exposure-related
histological changes were observed in the coronary arteries, aortic arch, thoracic aorta,
pulmonary arteries, or lungs, and no exposure-related ultrastructural myocardial changes were
observed (see Table B-3).
The results of the three rabbit studies are dubious for several reasons. First, the treatment
dose that caused mortality and severe neurotoxicity in the rabbits is only moderately above that
which produced no or minimal effects in rats (Monsanto. 1985). Second, the studies reported
inconsistent sexes. Third, all of the rabbits that died did so on the same day of the exposure
regimen. Fourth, the exposure concentrations ranged widely and actual maximum exposure
values may have exceeded those reported. And lastly, none of the surviving rabbits
demonstrated signs of toxicity. Therefore, no point-of departure (POD) values are estimated due
to the lack of confidence in the data from the rabbit studies. Results from these studies will not
be further considered for POD derivation.
Jlcrr t't al. (2007); Morgan et al. (2004); Sills et al. (2004)
In a series of peer-reviewed National Institute of Environmental Health Sciences
(NIEHS) studies, neurobehavior, neurophysiology, and neuroanatomy were evaluated following
14
Carbonyl Sulfide
-------
FINAL
09-29-2015
inhalation exposure to carbonyl sulfide for 2 or 12 weeks. In all studies, F344 rats were exposed
to carbonyl sulfide (<98.1% pure; Tex-La Gases, Houston, TX) at two or three of the following
concentrations for 6 hours/day, 5 days/week in whole-body inhalation chambers to target
concentrations of 0, 200, 300, 400, or 500 ppm (concentrations were measured but not reported).
Rats (6-7-weeks-old) were obtained from Charles River Laboratories (Raleigh, NC) and housed
individually at the NIEHS inhalation facility in Hazelton-2000 inhalation exposure chambers.
Feed was removed during the 6-hour exposures and for 6 hours/day on nonexposure days. Water
was provided ad libitum. Rats were 8-9-weeks-old at the start of exposures.
Morgan et al. (2004) is selected as the principal study for the derivation of the
subchronic and chronic provisional reference concentrations (p-RfCs). Morgan et al. (2004)
exposed rats (10/sex/group) to 0, 300, or 400 ppm for up to 12 weeks. The corresponding HECs
are 0, 132, and 176 mg/m3, respectively. Rats were observed twice daily for clinical signs of
toxicity and morbidity. Individual body weights were recorded the day before the first exposure
and weekly thereafter. Immediately after the 12-week exposure, behavioral changes were
assessed with a complete functional observation battery (FOB): general appearance (lacrimation,
salivation, ptosis, pupil size, piloerection), reaction to handling, 2-minute observation of
open-field behavior (activity level, arousal, posture, gait, occurrence of involuntary motor
movements), reflex tests (click and tail-pinch response, pupil response, righting reflex), grip
strength, and foot-splay. A 30-minute photocell-based assessment of motor activity was also
conducted. After behavioral assessment, blood was collected for clinical chemistry from five
rats/sex/group (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline
phosphatase [ALP], sorbitol dehydrogenase [SDH], blood urea nitrogen [BUN], cholesterol, total
protein, creatine kinase [CK], creatinine, and glucose). All animals were sacrificed, and brains
were harvested and prepared for histological examination of 36 areas from six brain regions
(frontal cortex through chiasmi, frontoparietal cortex through the infundibulum, mid-anterior
colliculi, posterior colliculi at the level just anterior to the pons, cerebellum and medulla at its
midpoint through the cochlear nuclei, and obex at the posterior medulla at the origin of the spinal
central canal).
Following 12 weeks of exposure to carbonyl sulfide, there were no exposure-related
deaths, morbidity, clinical signs of toxicity, or body-weight effects. Slight, but statistically
significant, decreases in serum ALP, SDH, cholesterol, protein, and creatinine were observed in
all groups of exposed males (data not reported by the study authors). The toxicological
significance of these findings is unclear, as magnitude and pattern of change were not reported.
Increased incidence of lesions was observed in several brain regions in male and female rats
exposed to 400 ppm, compared with controls (see Table B-4). Findings included necrosis in the
parietal cortex and neuronal loss and microgliosis in the posterior colliculus. In male rats,
necrosis in the parietal cortex was accompanied by cavitation, a grossly observable absence of
cortical tissue. No exposure-related lesions were observed in the brains of rats exposed to
300 ppm. No consistent, concentration-related changes were observed in the FOB or motor
activity. The preliminary assessment of BAERs showed decreased amplitudes and increased
latencies of peak amplitudes in males exposed to 400 ppm, compared with controls. A more
complete analysis of BAERs after 12-week exposures was conducted by Herr et al. (2007) (see
below). A LOAELhec of 176 mg/m3 (400 ppm) and a NOAELhec of 132 mg/m3 (300 ppm)
were identified in male and female rats for exposure-related necrosis in the parietal cortex and
neuronal loss and microgliosis in the posterior colliculus, compared with controls.
15
Carbonyl Sulfide
-------
FINAL
09-29-2015
Sills et al. (2004) exposed rats to 0, 200, 300, or 400 ppm for up to 12 weeks and
examined tissues at end of 12 weeks treatment, as well as tissues from interim sacrifices at 4 and
8 weeks (6/sex/group per time-point) with magnetic resonance microscopy (MRM) to provide a
histologic characterization of lesions (neither statistical evaluation nor incidence data reported).
The corresponding HECs are 0, 87.8, 132, and 176 mg/m3, respectively. At sacrifice, rats were
injected with the contrast agent Prohance (gadoteridol) prior to MRM. Following MRM, fixed
brains were removed and placed in 10% neutral buffered formalin for light microscopy for
verification of MRM findings. No exposure-related brain lesions were identified with MRM or
light microscopy in 200- or 300-ppm rats. In rats exposed to 400 ppm, altered MRM intensities
were identified in the posterior colliculus, anterior olivary nucleus, and parietal cortex after 4, 8,
and 12 weeks of exposure. Light microscopy confirmed damage to these areas, including focal
areas of gliosis in the posterior colliculus and anterior olivary nucleus and massive loss of
neurons within the parietal cortex. Lesion incidence data were not reported; however, the study
authors reported that the "most consistent" lesion on MRM was within the posterior colliculus.
As with Morgan et al. (2004). a LOAELhec of 176 mg/m3 (400 ppm) and a NOAELhec of
132 mg/m3 (300 ppm) were identified in male and female rats for exposure-related lesions in
multiple brain regions. Because of the nature of data presentation, benchmark dose modeling
was not possible.
Herr et al. (2007) reported data from electrophysiological measurements and
neurobehavioral observations in groups of rats (16/sex/group) exposed to 0, 200, 300, or
400 ppm for 12 weeks. The corresponding HECs are 0, 87.8, 132, and 176 mg/m3, respectively.
At 34-40 days following the last exposure, the rats were surgically implanted with epidural
screw electrodes to record electrical potentials from the cortical SI hindlimb/tail region (sensory
evoked potential [SEPlcortex]), cortical SI facial region (SEP2COrtex), over the cerebellum
(SEP cerebellum), brainstem (BAER), and posterior to the hairline of the tail (compound nerve action
potentials [CNAP]). Following surgery, 4, 0, 1, and 0 males and 3, 2, 4, and 4 females were
excluded from the 0, 200-, 300-, and 400-ppm groups, respectively, due to surgical
complications. The animals were allowed approximately 1 week to recover prior to
neurophysiological testing. All evoked potentials were measured in a single test session in the
following order: CNAP, SEPlcortex, SEP2COrtex, SEPcerebeiium, nerve conduction velocity (NCV),
and BAER. Colonic temperature was measured immediately following electrophysiological
testing. Electrophysiological data were analyzed using step-down analyses of variance
(ANOVAs) with a Greenhouse-Geisser correction factor for degrees of freedom for
within-subject effects. The critical a level for peak amplitudes and latencies was calculated to be
0.025 using a Bonferroni correction, and further adjusted based on the number of peak
amplitudes, latencies, and step-down ANOVAs (e.g., the level of statistical significance varied
among tests and was at mostp < 0.025). While these adjustments decrease Type I statistical
errors, they may also decrease statistical power. Therefore, for the purposes of this review, data
are considered statistically significant at< 0.05. Herr et al. (2007) also assessed neurobehavior
5 days after the last exposure by FOB and a motor activity assessment [as described by Morgan
et al. (2004)1. Startle response was assessed by reflex modification audiometry (RMA) 11 days
after the end of exposure. About 27 days after exposure, electrophysiological tests were
conducted: CNAP, NCV, SEPlcortex, SEP2COrtex, SEPcerebeiium, BAER, and flash-evoked potentials
(FEP). Six hours after neurophysiological testing, brains were removed and prepared for
histological examination.
16
Carbonyl Sulfide
-------
FINAL
09-29-2015
Following 12 weeks of exposure, no clinical signs of toxicity or body-weight effects were
observed (Herr et aL 2007). Because "no gender related differences were apparent," the study
authors combined data from males and females. Statistically significant increases in peak
SEP2COrtex and SEP 1 cortex amplitudes were observed in 400-ppm rats, compared with controls
(see Table B-5). A significant trend toward increased peak SEPlcortex latency was also reported
(see Table B-5). In BAER measurements, significant changes in peak amplitudes were observed
in 400-ppm rats following both click and tone pip (4 kHz, 16 kHz) stimuli, but not following
stimulus with 64 kHz tone pip (see Table B-5). Graphic presentations of BAER results indicated
significant BAER peak amplitude changes in rats exposed to 400 ppm, but not at 300 ppm or
lower concentrations. No significant exposure-related effects were noted for peak latencies in
BAER waveforms. No exposure-related findings were observed in SEP or BAER tests in
200- or 300-ppm rats, and no exposure-related differences were observed in peripheral nerve
electro-physiological measures (CNAP, NCV) in any group. There were also no
exposure-related differences in colonic temperature at 12 weeks. A LOAELhec of 176 mg/m3
(400 ppm) and a NOAELhec of 132 mg/m3 (300 ppm) were identified in male and female rats
for exposure-related lesions in multiple brain regions, and changes in BAER and SEP peak
amplitudes and SEP peak latencies, compared with controls (Herr et aL 2007).
One-Generation Reproduction Studies
Monsanto (1979)
A series of non-peer reviewed one-generation studies were conducted by the Monsanto
Agricultural Company. In all studies, S-D rats were obtained from Charles River Breeding
Laboratory (Kingston, NY) and quarantined for 2 weeks prior to exposure to carbonyl sulfide
(99.1% pure, Matheson, Inc, Gloucester, MA). Rats were approximately 7 weeks at the start of
the experiment. Rats were housed separately during whole-body exposure except during mating.
Food and water were available ad libitum.
In Study 1, groups of female S-D rats (24/group) were exposed to nominal carbonyl
sulfide concentrations of 0, 10, 60, or 180 ppm (analytical concentrations: 0, 10, 60, or
182 ppm), 6 hours/day, 5 days/week for ~11 weeks followed by 7 consecutive exposure days
premating, 7 days/week during mating to unexposed males, and 5 days/week during gestation
until GD 19 (total exposure 15-16 weeks). Rats were assessed for mortality and morbidity twice
daily, with detailed observations once weekly in dams and on days of litter weight measurements
in F1 offspring. Body weights were measured weekly in F0 females, litter weights were
measured on PNDs 0, 4, 7, and 14, and individual pup weights were measured on PND 21.
Dams were allowed to deliver naturally, and all litters were culled to eight pups on PND 4 (four
per sex where possible). Reproductive indices evaluated included mating and pregnancy rates,
precoital length, pregnancy rate, gestation length, number of live and dead pups, and postnatal
survival. F0 females and 10 F1 weanlings/sex in the control and high-dose groups were
sacrificed on PND 21. All animals were examined grossly for pathological lesions. Organs
weighed included F0 female ovaries and F1 weanling adrenals, brain, heart, kidneys, liver, testes
with epididymides, and ovaries. In dams, organs retained for microscopic histology included
ovaries, uterus, vagina, and gross lesions. In weanlings, organs retained for microscopic
histology included adrenals, bone with marrow, brain, colon, duodenum, esophagus, eyes, heart,
ileum, jejunum, kidneys, liver, lung with mainstem bronchi, lymph node (mesenteric and
submandibular), muscle (quadriceps femoris), ovaries, pancreas, pituitary, prostate, sciatic nerve,
submaxillary salivary gland, skin with mammary tissue, spleen, stomach, testes with
epididymides, thymus, thyroid/parathyroid, trachea, uterus (corpus and cervix), vagina, urinary
17
Carbonyl Sulfide
-------
FINAL
09-29-2015
bladder, seminal vesicles, and all gross lesions. Organs were only microscopically examined in
the control and high-dose animals unless grossly evident lesions were observed in the low- and
mid-exposure groups. Reproductive organs were examined in all females that failed to produce a
litter, regardless of exposure group.
No exposure-related mortalities, clinical signs of toxicity, or body-weight effects were
observed in F0 females. No statistically significant, exposure-related changes were observed in
mating or pregnancy rates, precoital length, gestational length, or number of live pups
(see Table B-6). Differences in pup weight and survival were not statistically significant among
groups, and no clinical signs of toxicity were observed. There were no exposure-related effects
on ovary weight or reproductive tissue histology in F0 females.
The analytical concentrations 0, 10, 60, and 182 ppm were converted to HECs of 0, 4.6,
27, and 84 mg/m3 for extrarespiratory effects from a Category 3 gas, based on the following
equation: CONChec = [(number of weeks exposed 5 days/week x (CONCppm x (molecular
weight ^ 24.45) x (hours exposed ^ 24 hours) x (5 days ^ 7 days) x blood:air partition
coefficient ratio) + [(number of weeks exposed 7 days/week x (CONCppm x (molecular
weight ^ 24.45) x (hours exposed ^ 24 hours) x blood:air partition coefficient ratio)] ^ total
number of weeks (U.S. EPA. 1994c). The values for the human and rat blood: air partition
coefficients are unknown, so the default ratio of 1 was applied. A reproductive NOAELhec of
84 mg/m3 (182 ppm) was identified for F0 females based on a lack of adverse reproductive
effects.
In F1 weanlings, no exposure-related histopathological lesions were observed in any of
the 33 examined organs, with the exception of extramedullary hematopoiesis observed in the
liver of two male and two female rats in the high-dose group and in one control female. In F1
males, but not females, absolute and relative liver weights were significantly decreased by
18-23% in the 60- and 182-ppm groups (HEC values of 27 and 84 mg/m3, respectively), but not
in the 10-ppm (4.6 mg/m3 HEC) group (see Table B-7). Several issues complicate a clear
understanding of the toxicological significance of this effect. The concentration dependency of
the effect is poor, there are no exposure-related histological changes that would account for this
effect (see Table B-7), and no clinical chemistry abnormalities are available (DuPont 1992)
(90-day study) to provide additional explanation for weight changes. In addition, no benchmark
response level has been established for the decrease in liver weight in adults or in animals
exposed in utero. No exposure-related weight changes were observed in any other organs in F1
PND 21 offspring. The highest exposure level (a HEC of 84 mg/m3 or 182 ppm) is considered to
be a NOAEL for all endpoints considered.
In Study 2, groups of male S-D rats (24/group) were exposed to nominal carbonyl sulfide
concentrations of 0, 10, 60, or 180 ppm (analytical concentrations: 0, 10, 60, 182 ppm),
6 hours/day, 5 days/week for ~11 weeks followed by 7 consecutive exposure days premating and
7 days/week during mating to unexposed females (total exposure -13 weeks) which produced
the Fla litter. The previously exposed males were allowed 10 weeks without exposure to
carbonyl sulfide, and then were mated again with 48 unexposed females which produced the Fib
litter. Half of the females were allowed to deliver; the other half were sacrificed "mid-gestation"
to obtain fertility data. Reproductive indices measured were as described for Study 1. F0 males
were sacrificed after the second mating and 10 Fla and 10 Fib weanlings/sex/group were
sacrificed on PND 21. Clinical observations, measures of body weights and weanling organ
18
Carbonyl Sulfide
-------
FINAL
09-29-2015
weight, and histopathological examinations of 33 organ tissues in PND-21 F1 animals were
conducted as described for Study 1. Testes were weighed in F0 males, and organs were retained
for histopathology (examined in control and high-dose only) included testes, epididymis,
prostate, seminal vesicle, and gross lesions. Reproductive organs were assessed in all males that
failed to produce offspring, regardless of exposure group.
No exposure-related mortalities, clinical signs of toxicity, or body-weight effects were
observed in F0 males. For the Fla generation, no statistically significant change was observed in
the mating rate; however, the pregnancy rate in unexposed females that mated males exposed to
182 ppm was 57%, compared with a pregnancy rate of 87% in controls (see Table B-6). This
finding suggests decreased fertility in males; however, the difference did not reach statistical
significance after the Bonferroni correction of the Fisher's exact test (as reported by the study
authors). A statistically nonsignificant trend toward increased precoital time was also observed,
but no statistically significant changes were observed in gestational length or number of live
pups (see Table B-6). For the Fib generation, no statistically significant, exposure-related
changes were observed in mating or pregnancy rates, precoital length, gestational length, or
number of live pups (see Table B-6). Additionally, no exposure-related histopathological
findings were observed in F0 male reproductive tissues. The highest exposure level (a HEC of
84 mg/m3 or 182 ppm) is considered to be a NOAEL for the absence of clear effects on male
reproductive performance or reproductive tissues.
No exposure-related changes in pup weight, survival, organ weight, or histology of the
33 organs were observed in PND 21 rats from the Fla or Fib generations of F0 exposed males.
Clinical signs of toxicity were not observed in Fla or Fib pups. A developmental NOAELhec of
84 mg/m3 (182 ppm) was identified for Fla and Fib weanling males and females for lack of
exposure-related effects.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tests Evaluating Genotoxicity and/or Mutagenicity
Genotoxicity testing of carbonyl sulfide is limited to a series of in vivo and in vitro
studies by (Wane et al.. 1999) and an in vitro bacterial mutagenicity study by the NTP (1995)
(see Table C-l in Appendix C for more details). Micronuclei were not induced in mouse bone
marrow, and chromosomal aberrations (CA) were not induced in mouse spermatocytes following
acute inhalation or oral exposure, and reverse mutations were not induced in Salmonella
typhimurium or Escherichia coli strains Wane et al. (1999). NTP (1995) reported "weakly
positive" results for reverse mutation in S. typhimurium strain TA97, but not in strains TA98,
TA100, or TA1535.
Supporting Human Studies
Three case studies report reversible respiratory and central nervous system effects that
could potentially be attributed to acute carbonyl sulfide exposure (see Table C-2).
Supporting Animal Toxicity Studies
A number of inadequately reported animal toxicity studies and short-term studies were
identified. Reported findings (see Table C-2 in Appendix C for more details) include:
1) No carcinogenic or exposure-related noncancer effects following subchronic- or
chronic-duration oral exposure of S-D rats to feed fumigated with
19
Carbonyl Sulfide
-------
FINAL
09-29-2015
20,000-500,000 mg/m3 carbonyl sulfide (actual concentrations of carbonyl sulfide in
the feed used for this study were not determined) (Wang et al.. 1999).
2) Reduced postnatal growth and survival, but no exposure-related reproductive effects,
in rats in one- or two-generation oral exposure studies (feed fumigated with
20,000-500,000 mg/m3 carbonyl sulfide; actual compound consumption levels were
not determined) Wang et al. (1999).
3) Lack of developmental toxicity following gestational exposure of rats to carbonyl
sulfide concentrations up to 1,108 mg/m3 (451 ppm), even at doses that caused
maternal toxicity (855-1,108 mg/m3; 348-451 ppm); results were reported in a study
summary only (DuPont 1992).
4) No exposure-related changes in urinalysis, clinical chemistry, gross or histological
pathology, pupillary reflexes, or clinical signs of toxicity in rats exposed to
concentrations of carbonyl sulfide up to 447 mg/m3 (182 ppm) for -14 weeks; a
specific hematological effect (lymphocytopenia) was identified, but potential
adversity of effects cannot be determined based on available data, which were
reported in a study summary only (DuPont 1992).
5) Statistically significant increases in methemoglobinemia were reported in a
non-peer-reviewed study by Monsanto (1985). The concentrations reached the level
of statistical significance at concentrations of 66 mg/m3 (HEC) and above. There
were no effects noted at 22 mg/m3 (HEC).
6) Short-term LOAELs and NOAELs for neurological effects of 1,474 mg/m3
(600 ppm) and 737 mg/m3 (300 ppm), respectively, in rats exposed to carbonyl
sulfide for 1-4 days (Morgan et al.. 2004; Sills et al.. 2004).
7) In a neurotoxicity examination, Herr et al. (2007) demonstrated increased incidences
of neuropathology, and altered behavioral endpoints demonstrating a LOAELhec of
176 mg/m3 and a NOAELhec of 132 mg/m3.
Reported acute lethality values for carbonyl sulfide include: rat 4-hour inhalation median
lethal concentration (LCso) values ranging from 2,659-2,730 mg/m3 (1,082-1,111 ppm)
(DuPont 1992; Monsanto. 1982); mouse 35-minute inhalation LCso of 2,940 mg/m3 (1,196 ppm)
[Sax and Lewis (1986) as cited in Bartholomaeus and Haritos (2005)1; mouse inhalation LCso of
2,770 mg/m3 (1,127 ppm), duration unspecified [RTECS (1997) as cited in Bartholomaeus and
Haritos (2005)1; rabbit inhalation LCso of 2,550 mg/m3 (1,038 ppm), duration unspecified
[RTECS (1997) as cited in Bartholomaeus and Haritos (2005)1; and a rat intraperitoneal (i.p.)
LD511 of 22.5 mg/kg (Chengelis and Neal. 1980). Ninety-minute exposures to 488 ppm
(1,200 mg/m3) caused no deaths in two rats, two rabbits, and two guinea pigs, but exposure to
997 ppm (2,450 mg/m3) caused deaths in 3/6 rats, 8/14 rabbits, and 0/6 guinea pigs [Thiess et al.
(1968) as cited in Bartholomaeus and Haritos (2005)1. The results indicate that guinea pigs may
be more resistant to the acute lethality of carbonyl sulfide than rats and rabbits (see Table C-2 in
Appendix C for more details).
Metabolism/Toxicokinetic Studies
Toxicokinetic studies have demonstrated that carbonyl sulfide formation in vivo arises
through the carbonic anhydrase-catalyzed metabolism of carbon disulfide. The metabolic
pathway for carbonyl sulfide is as follows: carbonic anhydrase catalyzes the equilibrium
relationship between carbonyl sulfide and monothiocarbonic acid concentrations.
Monothiocarbonic acid is hydrolyzed to carbon dioxide (CO2) and hydrogen sulfide (HS ) (Dalvi
and Neal. 1978); hydrogen sulfide is further oxidized into thiosulfate and sulfate (Chengelis and
20
Carbonyl Sulfide
-------
FINAL
09-29-2015
Neal. 1987. 1980. 1979). The formation of hydrogen sulfide via this pathway has been shown to
be responsible for the toxic action of carbonyl sulfide, as inhibitors of carbonic anhydrase
(acetazolamine) and inhibitors of sulfide toxicity (sodium nitrite) have been shown to decrease
and/or prevent carbonyl-sulfide mortality in rats (Cfaengelis and Neal. 1980) and flour beetles
(Haritos and Doichinov. 2005). A study in lactating goats reports that35S can be transferred to
milk following oral exposure to carbonyl sulfide, and that 35S is eliminated from milk in
two stages, with a short first half-life (~1 day) and a longer second half-life (>40 days) (Howard
et aL 2007). No other absorption, distribution, metabolism, elimination (ADME) studies were
identified.
Mode-of-Action/Mechanistic Studies
Mechanistic studies are limited to two studies investigating mechanisms underlying
observed neurotoxicity of carbonyl sulfide following short-term inhalation exposure. Morgan et
al. (2004) reported decreased levels of brain cytochrome oxidase (a heme-containing enzyme) in
the posterior colli cuius, a region susceptible to carbonyl sul fide-induced lesions (Morrison et al..
2009; Morgan et al.. 2004; Sills et al.. 2004). This effect may be due to the parent compound or
to the hydrogen sulfide metabolite (Pietri et al.. 2011). Inhibition of brain cytochrome oxidase
could potentially limit oxidative phosphorylation, contributing to observed neuronal necrosis and
death in this and other brain regions following carbonyl sulfide exposure (Morgan et al.. 2004).
Additionally, significant gene expression changes were observed in the posterior colliculus at
time points preceding morphological changes (Morrison et al.. 2009). These gene expression
changes, including up-regulation of genes involved in deoxyribonucleic acid (DNA) damage and
Gl/S checkpoint regulation, apoptosis, and vascular mediators, may be predictive of central
nervous system (CNS) lesions, and further study may lead to better mechanistic understanding of
carbonyl sul fide-induced neurotoxicity (Morrison et al.. 2009).
There have been no mechanistic studies specifically directed toward understanding the
development of methemoglobinemia by carbonyl sulfide. However, several pieces of
information are pertinent and may describe a mode of action for this effect. Binding of
carbon- and sulfur-containing functional groups to hemoglobin causes the production of
methemoglobin and sulfhemoglobin, respectively. Each of these causes a decrease in the oxygen
carrying capacity of hemoglobin, though they are distinguished by the reversibility of
methemoglobin by methylene blue administration, whereas the formation of sulfhemoglobin
results in a permanent (irreversible change) in hemoglobin. However, when blood is analyzed
spectrophotometrically, the shifts in absorbance from that characteristic of oxygenated
hemoglobin induced by sulfhemoglobin formation or methemoglobin formation may be
indistinguishable (Williams. 2001). Both hydroxylamine and carbonyl sulfide are metabolized to
hydrogen sulfide (U.S. EPA. 1994b; Dalvi and Neal. 1978); hydrogen sulfide converts
hemoglobin to sulfhemoglobin (Michel. 1938). perhaps via a direct interaction with the ferrous
iron component of heme (Pietri et al.. 2011). Because of the reporting of sulfhemoglobin (and
methemoglobin) in humans exposed to hydroxylamine (Gharahbaghian et al.. 2009). it is
possible that exposure to carbonyl sulfide results in sulfhemoglobin production in humans.
Carbonyl sulfide is a primary metabolite of carbon disulfide, which is catalyzed by
carbonic anhydrase. Inhibition of carbonic anhydrase has been shown to decrease the lethality of
carbon disulfide toxicity (Chengelis and Neal. 1987. 1980). presumably by decreasing the
formation of carbonyl sulfide. The involvement of sulfhemoglobin formation in toxicity of
carbonyl sulfide is supported by the protective effect (against sulfhemoglobin formation) of
21
Carbonyl Sulfide
-------
FINAL
09-29-2015
methemoglobin-forming compounds prior to administration of carbonyl sulfide (Cfaengelis and
Neal. 1980). While it seems likely that carbonyl sulfide exposure results in the formation of
sulfhemoglobin, regardless whether the conversion of hemoglobin is to methemoglobin or
sulfhemoglobin, the oxygen carrying capacity of blood may be slightly diminished by carbonyl
sulfide exposure.
DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present a summary of noncancer reference values and cancer values,
respectively, for carbonyl sulfide. IRIS data are indicated in the table, if available.
Table 4. Summary of Noncancer Reference Values for
Carbonyl Sulfide (CASRN 463-58-1)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Subchronic p-RfD
Not derived due to inadequate data
Chronic p-RfD
Not derived due to inadequate data
Subchronic p-RfC
Rat/females
Neurotoxicity
1 mg/m3
BMCL
126 mg/m3
100
Morgan et al.
(2004)
Chronic p-RfC
Rat/females
Neurotoxicity
0.1 mg/m3
BMCL
126 mg/m3
1,000
Morgan et al.
(2004)
BMCL = benchmark concentration lower confidence limit
Table 5. Summary of Cancer Values for Carbonyl Sulfide (CASRN 463-58-1)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
Provisional oral slope factor (p-OSF)
Not derived due to inadequate data
Provisional inhalation unit risk (p-IUR)
Not derived due to inadequate data
DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES
Human and animal data are inadequate to derive subchronic or chronic p-RfDs for
carbonyl sulfide.
The only available information on the oral toxicity of carbonyl sulfide comes from a
report of a series of studies of rats in which the concentration of carbonyl sulfide in fumigated
feed was not determined (Wang et aL 1999).
DERIVATION OF PROVISIONAL INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic Provisional Reference Concentration (p-RfC)
The study of neurological endpoints in rats exposed by inhalation to carbonyl sulfide for
12 weeks is selected as the principal study for the derivation of the subchronic p-RfC.
22
Carbonyl Sulfide
-------
FINAL
09-29-2015
Neurological effects (brain lesions and altered sensory evoked potentials [SEPs] in hindlimb/tail
and facial regions) were considered as potential critical effects based on NOAEL/LOAEL
values. Neuronal loss and microgliosis was selected as the critical effect on the basis of the
lower BMCL value.
Justification for the Critical Effect
Methemoglobinemia was considered, but dismissed as the critical effect.
1) Some evidence supports the formation of sulfhemoglobin, rather than
methemoglobin from the ingestion of carbonyl sulfide. This evidence is from
hydroxylamine, which (like carbonyl sulfide) is metabolized to carbon sulfide, and
from the finding that carbon sulfide converts hemoglobin to sulfhemoglobin.
However, none of the available evidence directly supports the formation of
sulfhemoglobin from carbonyl sulfide, primarily due to the lack of specificity of the
analytical procedure employed by Monsanto (1985).
2) Statistically significantly increased blood methemoglobin was reported in rats
exposed to concentrations >151 ppm for 2 weeks 6 hours/day, 5 days/week
(Monsanto, 1985) (see Table B-l), but the percentage of methemoglobin was <2.3%
in all dose groups (e.g., 2.1 and 2.3% in the highest exposure group [453 ppm, or
HEC 219 mg/m3]). In humans, the normal range of methemoglobin has been
reported to be 1.9-3.8%) in healthy adults and 3.61-6.44%) in healthy children
(Rechetzki et aL 2012). and the range of methemoglobin levels in control laboratory
rats has been reported to be 0.1-0.4 mg methemoglobin/dL (compared to 16 mg
oxyhemoglobin/dL) (approximately 0.6-2.4% as methemoglobin) (Car et ai, 2005).
No other exposure-related effects on comprehensive hematological endpoints were
found in this 2-week study.
3) Humans might be anticipated to tolerate methemoglobin concentrations as high as
10%o, but may not tolerate concentrations between 10 and 15% (Coleman and
Coleman. 1996).
4) It seems reasonable that humans may tolerate concentrations of methemoglobin that
are statistically significantly elevated over controls, and that early symptoms may be
mild (Coleman and Coleman. 1996).
5) Methemoglobinemia is biologically reversible through erythrocyte-contained
NADPH oxidase systems, as well as by clinical methods.
6) Among the assessments involving methemoglobin on the IRIS database, there
appears to be no consensus on the extent of MeHb in humans deemed adverse, and
no studies of methemoglobinemia of this duration have been used heretofore to
support derivation of reference doses or concentrations.
Neurological effects were chosen as the critical effects for the subchronic p-RfC for
carbonyl sulfide because they are the most clearly identified hazard in the short-term- and
subchronic-duration studies of animals exposed by inhalation. Several studies observed
neurological effects, and data are adequate to describe dose-response relationships (i.e.,
NOAEL/LOAEL) for brain lesions, changes in evoked potentials, and neurobehavioral
endpoints. Several of these data sets were amenable to benchmark dose modeling. Effects
observed in studies examining neurological endpoints include:
23
Carbonyl Sulfide
-------
FINAL
09-29-2015
1) Histological brain lesions (e.g., cortical necrosis or cavitation in parietal cortex area
1 and neuronal loss or microgliosis in posterior colliculus), and changes in evoked
potentials (BAER or SEP) in rats exposed to 400 ppm (176 mg/m3 HEC), but not to
concentrations <300 ppm (132 mg/m3 HEC), for 12 weeks, 6 hours/day, 5 days/week
(Herr et al.. 2007; Morgan et aL 2004; Sills et al.. 2004).
2) Altered neurobehavior (e.g., decreased motor activity and grip strength), gross brain
lesions, and decreased peak amplitude of BAER in rats exposed to 400 ppm
(176 mg/m3 HEC), but not to concentrations <300 ppm (132 mg/m3 HEC), for
2 weeks, 6 hours/day, 5 days/week (Herr et al. 2007).
3) Clinical signs of neurotoxicity (e.g., ataxia, prostrate and hunched back postures,
tremors, loss of muscular control) in rats exposed to 453 ppm (199 mg/m3 HEC), but
not to concentrations <253 ppm (111 mg/m3 HEC), for 2 weeks 6 hours/day,
5 days/week (Monsanto. 1985).
4) Severe neurological symptoms (not otherwise described) in 2/10 rabbits and deaths
in 3/10 rabbits exposed continuously to widely varying concentrations which
averaged 54 ppm (130 mg/m3 HEC) for 5 days in a planned 7-week-exposure study
(Hugod. 1981; Hugod and Astrup. 1980; Kamstrup and Hugod. 1979); the remaining
rabbits survived the full exposure period, but the available reports did not specify
whether or not survivors showed clinical signs of neurotoxicity.
The evidence for decreased ability of male rats to impregnate unexposed females
observed in a reproductive study (Monsanto. 1979) is not as strong as the evidence for
neurological effects. This effect (i.e., decreased pregnancy index) in producing an Fla
generation (but not an Fib generation) was reported for male rats exposed to 182 ppm (HEC
84 mg/m3) 6 hours/day before and during mating (57 versus 87% in controls; see Table B-l in
Appendix B) (Monsanto. 1979). This change was statistically significantly (p < 0.05) different
from the control value by Fisher's exact test, but not significant (p > 0.05, actual />level not
reported) when Bonferroni correction was applied. No exposure-related histological changes in
reproductive tissues were found in the exposed male rats. Therefore, it was not selected as
critical effects for the subchronic p-RfC.
Justification for the Principal Study
The design, performance and reporting of the 12-week studies reported by Morgan et al.
(2004) and Herr et al. (2007) are adequate to describe dose-response relationships for brain
lesions and changes in sensory evoked potentials, respectively. Sills et al. (2004) did not present
dose-response data but provided a histologic characterization of lesions whose incidence data
were reported by Morgan et al. (2004). The results indicate a NOAELhec of 132 mg/m3 and a
LOAELhec of 176 mg/m3 for increased incidence of brain lesions (Morgan et al.. 2004) and
changes in evoked potentials (Herr et al.. 2007). Although this series of neurotoxicity studies did
not include histological examination of a comprehensive set of tissues, the available database
includes two one-generation reproductive toxicity studies reported by Monsanto (1979). which
found no exposure-related histological effects in reproductive tissues from F0 male and F0
female rats exposed (before and during mating) to concentrations as high as 182 ppm (HEC
84 mg/m3) or in 33 tissues in F1 male and female offspring.
Approach for Deriving the Subchronic p-RfC
The most sensitive neurological endpoints showing changes considered to be adverse in
the principal study of rats exposed for 12 weeks were increased incidence of necrosis in the
24
Carbonyl Sulfide
-------
FINAL
09-29-2015
parietal cortex, and neuronal loss or microgliosis in the posterior colliculus (see Table B-4) and
altered peak amplitude of SEP in the hindlimb tail region (peak amplitude SEP 1 cortex), the facial
region (peak amplitude SEP2COrtex), and brainstem auditory evoked response (peak amplitude
BAER), shown in Table B-5. Data sets for these endpoints were selected to determine potential
POD values for the p-RfC values and are summarized in Table 6.
Table 6. Data for the Most Sensitive Neurological Endpoints in the Principal Study of
Rats Exposed to Carbonyl Sulfide for 12 Weeks (6 Hours/Day, 5 Days/Week)a
Parameter
Exposure Group, ppm Carbonyl Sulfide
(HEC in mg/m3)
0
200 (87.8)
300 (132)
400 (176)
Neuronal loss or microgliosis in posterior colliculus
Male
Female
0/9b
0/9
NA
NA
0/9
0/9
7/9*
5/9*
Cortical necrosis or cavitation in parietal cortex area 1
Male
Female
0/10
0/10
NA
NA
0/10
0/10
5/10*
4/10*
SEP 1 cortex (hindlimb/tail region); P14N27 peak
amplitude (|iV)c
41.83 ±4.69
43.33 ±4.51
41.08 ±3.38
60.42 ±6.57*
SEP2cortex (facial region); P16N21 peak amplitude (|iV)
10.62 ±0.79
11.83 ±0.65
10.48 ±0.98
15.94 ± 1.36*
BAER - click stimulus (80 dB)
P4 peak amplitude (|iV)
20.44
20.81 (+2%)
20.32 (-1%)
12.1* (-41%)
P5 peak amplitude (|iV)
14.06
14.62 (+4%)
14.34 (+2%)
10.79* (-23%)
P6 peak amplitude (|iV)
7.54
7.09 (-6%)
7.54 (0%)
9.41* (+25%
BAER - 4 kHz tone pip stimulus (80 dB)
P4 peak amplitude (|iV)
7.81
8.42 (+8%)
7.32 (-6%)
4.87* (-38%)
BAER - 16 kHz tone pip stimulus (80 dB)
P4 peak amplitude (|iV)
13.9
13.53 (-3%)
13.29 (-4%)
6.73* (-52%)
aHerr et al. (2007): Morgan et al. (2004)
incidence data are presented as incidence/number of animals examined; Other data are presented as
Mean + standard error of the mean (SEM).
°n values for combined males and females were control (0 mg/m3) = 25; 200 mg/m3 = 30; 300 mg/m3 = 27;
400 mg/m3 = 28.
* Statistically significantly different from controls at p< 0.05, based on statistics presented by study authors
(step-down ANOVA)
NA = not available.
POD values were converted to HEC values by adjusting for duration of exposure and blood:air partition coefficient,
for a category 3 gas. Because blood:air partition coefficients for carbonyl sulfide in rats and humans were not
available, the default DAF value of 1 was used.
These potential critical effect data sets for neurological effects following
subchronic-duration exposure were modeled with BMD models (see details in Appendix D) and
results are summarized in Table 7. Of the two neurological lesions observed, neuronal
25
Carbonyl Sulfide
-------
FINAL
09-29-2015
loss/microgliosis and cortical necrosis, the most sensitive lesions (i.e., neuronal loss or
microgliosis) was modeled. Because the standard deviations for BAER responses were not
available (Herr et aL 2007). these data could not be modeled.
Table 7. Potential Points of Departure for Neurological Endpoints
Effect
NOAELhec
(mg/m3)
LOAELhec
(mg/m3)
BMCLhec
(mg/m3)
POD
(mg/m3)
Neuronal loss or microgliosis in males
(Morgan et al.. 2004)
132
176
128
128
Neuronal loss or microgliosis in females
(Morgan et al., 2004)
132
176
126
126
SEP1 peak amplitude*
(Herr et al.. 2007)
132
176
171
171
SEP2 peak amplitude*
(Herr et al.. 2007)
132
176
NR
132
BAER peak amplitude*
(Herr et al.. 2007)
132
176
NA
132
*Data for males and females combined by study authors.
NA = not available (standard deviation values not available, modeling not possible); NR = not reported (models
failed to give an acceptable fit to data SEP2).
The BMCLhec value for brain lesions described as neuronal loss or microgliosis in the
posterior colliculus of female rats (126 mg/m3) is selected as the POD for the p-RfC, because it is
the lowest POD, and increased incidence of these effects is considered clearly adverse.
The subchronic p-RfC for carbonyl sulfide is derived as follows:
Subchronic p-RfC = BMCLhec ^ UFc
= 126 mg/m3 100
= 1 mg/m3
Table 8 summarizes the uncertainty factors (UFs) for the subchronic p-RfC for carbonyl
sulfide.
26
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 8. Uncertainty Factors for the Subchronic p-RfC for Carbonyl Sulfide
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for residual uncertainty associated with extrapolating
from animals to humans, using toxicokinetic cross-species dosimetric adjustment for
extraresmratorv effects from a category 3 gas. as specified in U.S. EPA (1994c) guidelines for
deriving RfCs.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of carbonyl sulfide in
humans.
UFd
3
A UFd of 3 (10°5) is applied to account for deficiencies and uncertainties in the database. The
critical effect is defined in subchronic-duration studies in rats. The database also includes two
adequate one-generation reproductive toxicity studies in rats and a limited report of
developmental toxicity study. The database lacks a multigenerational reproductive toxicity
study and a comprehensive report of a developmental toxicity study.
UFl
1
A UFl of 1 is applied because POD is a BMCL value.
UFS
1
A UFS of 1 is applied because the POD is derived from a subchronic-duration study of rats.
UFC
100
Composite UF = UFA x UFH x UFD x UFL x UFS
The confidence in the subchronic p-RfC for carbonyl sulfide is low as explained in
Table 9.
Table 9. Confidence Descriptors for the Subchronic p-RfC for Carbonyl Sulfide
Confidence Categories
Designation3
Discussion
Confidence in study
M
Confidence in the principal study is medium. While the principal
studv (Morgan et al.. 2004) contains reasonable numbers of rats of
each sex and appears to be a well-conducted study reported in the
peer-reviewed literature, the study is restricted to neurological
endpoints.
Confidence in database
M
Confidence in the database is medium because it contains several
subchronic-duration inhalation studies, and one generation
reproductive toxicity studies. However, the database lacks a
multigenerational reproductive toxicity study, and an adequate report
of developmental toxicity study.
Confidence in subchronic
p-RfC
M
The overall confidence in the subchronic p-RfC is medium.
aM = medium
Derivation of Chronic Provisional RfC (Chronic p-RfC)
In the absence of studies of toxicity endpoints in humans or animals chronically exposed
to carbonyl sulfide by inhalation, a chronic p-RfC for carbonyl sulfide is derived from the
subchronic p-RfC.
27
Carbonyl Sulfide
-------
FINAL
09-29-2015
Justification for selecting the critical effect and principal study are described in the
previous section of this document. The selected POD is a BMCLhec of 126 mg/m3 for increased
incidence of brain lesions in female rats exposed to carbonyl sulfide for 12 weeks.
The chronic p-RfC for carbonyl sulfide, based on a BMCLhec of 126 mg/m3 for brain
lesions in female rats is derived as follows:
Chronic p-RfC = BMCL hec - UFC
= 126 mg/m3 1,000
= 1 x 10 1 mg/m3
Table 10 summarizes the UFs for the chronic p-RfC for carbonyl sulfide.
Table 10. Uncertainty Factors for the Chronic p-RfC for Carbonyl Sulfide
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for residual uncertainty associated with extrapolating
from animals to humans, using toxicokinetic cross-species dosimetric adjustment for
extraresmratorv effects from a cateeorv 3 sas. as specified in U.S. EPA f 1994c) guidelines for
deriving RfCs.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of carbonyl sulfide in
humans.
UFd
3
A UFd of 3 (10°5) is applied to account for deficiencies and uncertainties in the database. The
critical effect is defined in subchronic-duration studies in rats. The database also includes two
adequate one-generation reproductive toxicity studies in rats and a limited report on
developmental toxicity study. The database lacks a multigenerational reproductive toxicity
study and a comprehensive report of a developmental toxicity study.
UFl
1
A UFl of 1 is applied because the POD is a BMCL value.
CO
IJ-H
£
10
A UFS of 10 is applied to account for uncertainty in deriving the screening chronic p-RfC based
on subchronic duration studies.
UFC
1,000
Composite UF = UFA x UFH x UFD x UFL x UFS
The confidence descriptors for the chronic p-RfC are described in Table 11.
28
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table 11. Confidence Descriptors for the Chronic p-RfC for Carbonyl Sulfide
Confidence Categories
Designation3
Discussion
Confidence in study
M
Confidence in the principal study is medium. While the principal study
(Morgan et al.. 2004) contains reasonable numbers of rats of each sex and
appears to be a well-conducted study reported in the peer-reviewed
literature, the study is restricted to neurological endpoints.
Confidence in database
L
Confidence in the database is low because it contains several
subchronic-duration inhalation studies, and one generation reproductive
toxicity studies. However, the database lacks an inhalation study of
chronic duration, a multigenerational reproductive toxicity study, and an
adequate report of developmental toxicity study.
Confidence in chronic
p-RfCb
L
The overall confidence in the chronic p-RfC is low.
aL = low; M = medium.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 12 identifies the cancer weight-of-evidence (WOE) descriptor for carbonyl sulfide.
Table 12. Cancer WOE Descriptor for Carbonyl Sulfide (CASRN 463-58-1)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
No human data are available.
"Likely to Be Carcinogenic
to Humans "
NS
NA
No adequate chronic-duration animal cancer
bioassays are available.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No adequate chronic-duration animal cancer
bioassays are available.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
NA
No adequate chronic-duration animal cancer
bioassays are available. No studies are
available assessing the carcinogenic potential
of carbonyl sulfide in humans or animals.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
No evidence of noncarcinogenicity is available.
No adequate chronic-duration animal cancer
bioassays are available.
NA = not applicable; NS = not selected
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
Not derived due to inadequate data.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
Not derived due to inadequate data.
29
Carbonyl Sulfide
-------
FINAL
09-29-2015
APPENDIX A. SCREENING PROVISIONAL VALUES
No screening values are derived.
30
Carbonyl Sulfide
-------
FINAL
09-29-2015
APPENDIX B. DATA TABLES
Table B-l. Survival, Clinical Signs, Body Weight, and Methemoglobinemia Findings in
Male and Female Rats after Inhalation Exposure to Carbonyl Sulfide for 2 Weeks
(6 Hours/Day, 5 Days/Week)a
Parameter
Exposure Group, ppm Carbonyl Sulfide (HEC in mg/m3)b
Male
0
51 (22)
151 (66)
253 (111)
453 (199)
Sacrificed in moribund
condition
0/10
0/10
0/10
0/10
2/10
Clinical signs of
neurotoxicity0
0/10
1/10
0/10
0/10
3/10
Terminal body weight (g)d
237.6 ±7.78
236.7 ± 12.42
(0%)
235.1 ±9.60
(-1%)
241.8±10.83
(+2%)
228.5 + 9.61
(-4%)
Methemoglobinemia (%)d
0.8 ±0.2
1.0 ±0.1
(+25%)
1.3 ±0.1*
(+63%)
1.6 + 0.3*
(+100%)
2.1+0.2*
(+163%)
Female
0
51 (22)
151 (66)
253 (111)
453 (199)
Sacrificed in moribund
condition
0/10
0/10
0/10
0/10
3/10
Clinical signs of
neurotoxicity
0/10
0/10
0/10
0/10
7/10®
Terminal body weight (g)d
162.4 ±5.13
162.3 ±4.37
(0%)
164.9 ±4.72
(+2%)
161+6.27
(-1%)
154 + 5.97*
(-5%)
Methemoglobinemia (%)d
1.0 ±0.2
1.0 ±0.1
(0%)
1.4 ± 0.1*
(+40%)
1.8 + 0.2*
(+80%)
2.3+0.2*
(+130%)
aMonsanto (1985).
bConcentrations have been converted to HECs of 0, 22, 66, 111, and 199 mg/m3 based on the following equation:
CONChec = CONCppm x (molecular weight + 24.45) x (hours exposed + 24 hours) x (days
exposed + 7 days) x blood:air partition coefficient ratio (U.S. EPA. 1994c): molecular weight = 60.08 g/mol. The
values for the human and rat blood:air partition coefficients are unknown, so the default ratio of 1 was applied.
°Clinical signs were observed during Week 2, and included ataxia, head tilt, circling, pivoting, prostrate and arched
back postures, tremors, loss of muscular control, convulsions, and bulging, dilated eyes.
dValues are expressed as mean ± SD (percent change compared with control); percent change control = [(treatment
mean - control mean) + control mean] x 100.
"Statistically significantly different from controls at p< 0.05, as calculated for this review (Fisher's exact test).
* Statistically significantly different from controls at p< 0.05, as reported by study authors (Dunnett's test).
31
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table B-2. Necrotic Brain Lesions observed in Male and Female Rats after Inhalation
Exposure to Carbonyl Sulfide for 2 Weeks (6 Hours/Day, 5 Days/Week)a
Parameter
Exposure Group, ppm Carbonyl Sulfide (HEC in mg/m3)b
0
300 (132)
400 (176)
500 (219)
Male
Parietal cortex area 1
0/10
0/10
5/10*
6/6*
Retrosplenial cortex
0/10
0/10
0/10
4/6*
Putamen
0/10
0/10
5/10*
6/6*
Thalamus (necrosis or
vacuolization)
0/10
0/10
0/10
2/6
Posterior colliculus
0/10
0/10
2/7
3/3*
Anterior olivary nucleus
0/10
0/10
0/10
5/6*
Female
Parietal cortex area 1
0/10
1/10
8/10*
10/10*
Retrosplenial cortex
0/10
0/10
0/10
7/10*
Putamen
0/10
0/10
6/10*
8/9*
Thalamus (necrosis or
vacuolization)
0/10
0/10
0/10
6/10*
Posterior colliculus
0/10
0/10
3/9
8/10*
Anterior olivary nucleus
0/8
0/10
0/10
6/10*
"Morgan et al. (2004).
bConcentrations have been converted to HECs of 0, 132, 176, and 219 mg/m3 based on the following equation:
CONChec = CONCppm x (molecular weight ^ 24.45) x (hours exposed ^ 24 hours) x (days
exposed ^ 7 days) x blood:air partition coefficient ratio (U.S. EPA. 1994c): molecular weight = 60.08 g/mol. The
values for the human and rat blood:air partition coefficients are unknown, so the default ratio of 1 was applied.
* Statistically significantly different from controls at p< 0.05, as reported by study authors (Fisher's exact test).
32
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table B-3. Survival, Cholesterol Parameters, and Histological Findings in Female
Rabbits After Continuous Inhalation Exposure to Carbonyl Sulfide for 7 Weeks"
Parameter
Exposure Group, ppm Carbonyl Sulfide
(HEC in mg/m3)b
0
54 (130)
Survival
Animals dead or sacrificed moribund
0/17
5/18°
Aortic free cholesterold
Number of animals examined
7
9
Inner intima and internal media layers (nmole/mg tissue)
2.9 ±0.2
3.2 ±0.3 (+10%)
Outer media layer (nmole/mg tissue)
1.8 ±0.1
2.2 ± 0.2* (+22%)
Cholesterol dynamics'1
Number of animals analyzed using direct injection"
4
4
Uptake of labelled plasma total cholesterol by the aortic wall
(nmole/g tissue/hr)
2.7 ±0.2
3.8 ±0.8 (+41%)
Number of animals analyzed using donor plasma injectionf
3
3
Uptake of labelled plasma total cholesterol by the aortic wall
(nmole/g tissue/hr)
1.4 ±0.3
1.5 ±0.1 (+7%)
Histology
Number of animals with abnormal morphology
Coronary arteries
0/8
0/7
Aortic arch
4/8
2/8
Thoracic aorta
4/8
2/8
Pulmonary arteries
2/8
1/8
Lungs
1/8
0/8
Number of animals with abnormal myocardial ultrastructure
4/8
0/8
aHugod (1981): Hugod and Astrup (1980): Kanistrup and Hugod (1979).
bAnalytical concentrations have been converted to HECs of 0 and 130 mg/m3 based on the following equation:
CONChec = CONCppm x (molecular weight + 24.45) x (hours exposed + 24 hours) x (days
exposed + 7 days) x blood:air partition coefficient ratio (U.S. EPA. 1994c): molecular weight = 60.08 g/mol. The
values for the human and rat blood:air partition coefficients are unknown, so the default ratio of 1 was applied.
Statistically significantly different from controls atp< 0.05, as calculated for this review (Fisher's exact test);
deaths (three rabbits) or moribund state (two rabbits) occurred within the first 5 days of exposure.
dValues are expressed as mean ± SEM (percent change compared with control); percent change
control = [(treatment mean - control mean) + control mean] x 100.
eBlood samples were collected at intervals over 20 hours following injection of la,2a (N)-3H-cholesterol dissolved
in ethanol.
fBlood samples were collected at regular intervals for 5 hours following injection with in vivo labelled plasma,
obtained from two donor rabbits injected with la,2a (N)-3H-cholesterol 20 hours prior to bleeding.
* Statistically significantly different from controls at p< 0.05, as calculated by study authors (statistical test not
reported).
33
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table B-4. Histological Brain Lesions Observed in Male and Female Rats After
Inhalation Exposure to Carbonyl Sulfide for 12 Weeks (6 Hours/Day, 5 Days/Week)a
Parameter
Exposure Group, ppm Carbonyl Sulfide (HEC in mg/m3)b
0
300 (132)
400 (176)
Male
Posterior colliculus
Neuronal loss or microgliosis
0/9
0/9
7/9*
Hemorrhage
0/9
0/9
2/9
Parietal cortex area 1
Cortical necrosis or cavitation
0/10
0/10
5/10*
Putamen
Necrosis or cavitation
0/10
0/10
2/10
Thalamus
Necrosis
0/10
0/10
1/10
Lateral anterior olivary nucleus
Neuronal loss or microgliosis
0/10
0/9
1/10
Female
Posterior colliculus
Neuronal loss or microgliosis
0/9
0/9
5/9*
Hemorrhage
0/9
0/9
1/9
Parietal cortex area 1
Cortical necrosis
0/10
0/10
4/10*
Putamen
Necrosis or cavitation
0/10
0/10
0/10
Thalamus
Necrosis
0/10
0/10
0/10
Lateral anterior olivary nucleus
Neuronal loss or microgliosis
0/9
0/10
0/9
"Morgan et al. (2004).
Concentrations have been converted to HECs of 0, 132, and 176 mg/m3 based on the following equation:
CONChec = CONCppm x (molecular weight ^ 24.45) x (hours exposed ^ 24 hours) x (days
exposed 7 days) x blood:air partition coefficient ratio (U.S. EPA. 1994c): molecular weight = 60.08 g/mol.
The values for the human and rat blood:air partition coefficients are unknown, so the default ratio of 1 was
applied.
* Statistically significantly different from controls at p< 0.05, as reported by study authors (Fisher's exact test).
34
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table B-5. SEP and BAERs in Male and Female Rats (Combined) After Inhalation
Exposure to Carbonyl Sulfide for 12 Weeks (6 Hours/Day, 5 Days/Week)a
Parameter
Exposure Group, ppm Carbonyl Sulfide (HEC in
mg/m3)b
0
200 (87.8)
300 (132)
400 (176)
Animal number
25
30
27
28
SEP 1 cortex (hindlimb/tail region)
C
P14N27 peak amplitude (|iV)
41.83 ±4.69
43.33 ±4.51
(+4%)
41.08 ±3.38
(-2%)
60.42 ±6.57*
(+44%)
N27 peak latency (|iV)
23.08 ±0.39
25.11 ±0.66
(+9%)
24.71 ±0.39
(+7%)
25.88 ±0.72f
(+12%)
P36 peak latency (|iV)
27.57 ±0.59
29.6 ±0.66
(+7%)
29.92 ±0.59
(+9%)
30.84 ±0.85f
(+12%)
SEP2COrtex (facial region)0
P16N21 peak amplitude (|iV)
10.62 ±0.79
11.83 ±0.65
(+11%)
10.48 ±0.98
(-1%)
15.94 ± 1.36*
(+50%)
BAER—click stimulus (80 dB)d
P3 peak amplitude (|iV)
12.62
12.45 (-1%)
13.04 (+3%)
9.92 (-21%)
P4 peak amplitude (|iV)
20.44
20.81 (+2%)
20.32 (-1%)
12.1* (-41%)
P5 peak amplitude (|iV)
14.06
14.62 (+4%)
14.34 (+2%)
10.79* (-23%)
P6 peak amplitude (|iV)
7.54
7.09 (-6%)
7.54 (0%)
9.41* (+25%)
BAER—4 kHz tone pip stimulus (80 dB)d
P4 peak amplitude (|iV)
7.81
8.42 (+8%)
7.32 (-6%)
4.87* (-38%)
BAER—16 kHz tone pip stimulus (80 dB)d
P4 peak amplitude (|iV)
13.9
13.53 (-3%)
13.29 (-4%)
6.73* (-52%)
BAER—64 kHz tone pip stimulus (80 dB)d
P4 peak amplitude (jiV)
6.75
6.5 (-4%)
5.29 (-22%)
3.59 (-47%)
aHerr et al. (2007).
bConcentrations have been converted to HECs of 0, 87.8, 132, and 176 mg/m3 based on the following equation:
CONChec = CONCppm x (molecular weight + 24.45) x (hours exposed + 24 hours) x (days
exposed + 7 days) x blood:air partition coefficient ratio (U.S. EPA. 1994c): molecular weight = 60.08 g/mol. The
values for the human and rat blood:air partition coefficients are unknown, so the default ratio of 1 was applied.
°SEP values were extracted from Figure 2 in the primary report using Grablt! software. Values are presented as
means ± SEM (percent change compared with control); percent change control = [(treatment mean - control
mean) + control mean] x ioo.
dB AER mean values for 80-dB peak sound pressure level intensity were extracted from Figures 4-6 in the primary
report using Grablt! software. Values are presented as means (percent change compared with control); percent
change control = [(treatment mean - control mean) + control mean] x 100. SEM values could not be extracted.
* Statistically significantly different from controls at p< 0.05, based on statistics reported by study authors
(step-down ANOVA).
f Statistically significant concentration-related trend at p< 0.05, as reported by study authors (ANOVA).
SEP = sensory evoked potential; BAER = brainstem auditory evoked response.
35
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table B-6. Reproductive Performance of Male and Female Rats Exposed to
Carbonyl Sulfide for 5 Days/Week for ~11 Weeks Followed by 7 Exposure Days
(Premating) and Exposure 7 Days/Week during Mating to an Unexposed Partner
(6 Hours/Day)a
Parameter
Exposure Group, ppm Carbonyl Sulfide (HEC in mg/m3)b
Study 1: exposed females and
unexposed males
0
10 (4.6)
60 (27)
182 (84)
Mating index (% copulation)
20/24 (83%)
21/24 (88%)
23/24 (96%)
23/24 (96%)
Pregnancy index of mated females
(% pregnant)
16/20
(80%)
17/21
(81%)
17/23
(74%)
19/23
(83%)
Precoital length (d)°
3.5 ±2.8
3.2 ± 2.3 (-9%)
3.3 ± 1.9 (-6%)
3.1 ±2.0 (-11%)
Gestation length (d)°
22.3 ±0.6
22.2 ± 0.4 (0%)
22.4 ± 0.5 (0%)
22.7 ± 0.7 (+2%)
Live pups/litter11
12.5
12.9 (+3%)
13.2 (+6%)
10.6 (-15%)
Study 2: exposed males and
unexposed females
0
10 (4.7)
60 (28)
182 (84)
Fla generation
Mating index (% copulation)
23/24 (96%)
23/24 (96%)
23/24 (96%)
21/24 (88%)
Pregnancy index of mated females
(% pregnant)
20/23
(87%)
20/23
(87%)
20/23
(87%)
12/21
(57%)e
Precoital length (d)°
3.6 ±2.4
3.4 ± 2.4 (-6%)
3.3 ±2.4 (-8%)
2.9 ± 1.9 (-19%)
Gestation length (d)°
22.1 ±0.4
22.3 ± 0.6 (+1%)
22.1 ± 0.4 (0%)
22.3 ± 0.5 (+1%)
Live pups/litter11
12.4
12.6 (+2%)
13.3 (+7%)
11.8 (-5%)
Fib generation
Mating index (% copulation)
44/48 (92%)
48/48 (100%)
48/48 (100%)
46/48 (96%)
Pregnancy index of mated females
(% pregnant)
43/44
(98%)
46/48
(96%)
45/48
(94%)
44/46
(96%)
Precoital length (d)°
2.7 ± 1.3
3.0 ± 1.9 (+11%)
2.6 ± 1.3 (-4%)
3.0 ± 1.9 (+11%)
Gestation length (d)°
22.0 ±0.2
22.2 ± 0.4 (+1%)
22.1 ± 0.3 (0%)
22.1 ± 0.3 (0%)
Live pups/litter"1
13.0
11.7 (-10%)
12.9 (-1%)
13.0 (0%)
"Monsanto (1979).
bTWA analytical concentrations have been converted to HECs of 0, 4.6, 27, and 84 mg/m3 based on the following
equation: CONChec = [(number of weeks exposed 5 days/week x (CONCppm x (molecular
weight + 24.45) x (hours exposed + 24 hours) x (5 days + 7 days) x blood:air partition coefficient
ratio) + [(number of weeks exposed 7 days/week x (CONCppm x (molecular weight + 24.45) x (hours
exposed + 24 hours) x blood:air partition coefficient ratio )| + total number of weeks (U.S. EPA. 1994c):
molecular weight = 60.08 g/mol. The values for the human and rat blood:air partition coefficients are unknown,
so the default ratio of 1 was applied.
°Values are presented as means ± SD (percent change compared with control); percent change
control = [(treatment mean - control mean)/control mean] x 100.
dValues are presented as means (percent change compared with control); percent change control = [(treatment
mean - control mean)/control mean] x 100.
eFinding is borderline significant (as reported by study authors): it is statistically significantly different from
controls at p< 0.05 in the uncorrected x2 and Fisher's test, but no longer statistically significant following the
Bonferroni correction (p > 0.05).
SD = standard deviation.
36
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table B-7. Liver Weights and Histology in F1 Male and Female Weanlings Exposed to
Carbonyl Sulfide via Dams on GDs 0-19 (6 Hours/Day, 5 Days/Week)a
Parameterb
Exposure Group, ppm Carbonyl Sulfide (HEC in mg/m3)c
0
10 (4.6)
60 (27)
182 (84)
Males
10
10
10
10
Liver weight
Absolute (g)
3.792 ±0.196
3.411 ±0.191
(-10%)
2.937 ±0.174*
(-23%)
2.980 ±0.247*f
(-21%)
Relative (% body weight)
6.783 ±0.189
6.502 ±0.189
(-4%)
5.256 ±0.242*
(-23%)
5.590 ±0.381*
(-18%)
Liver histology
Number of animals with lesiond
0/10
ND
ND
2/10
Females
10
10
10
10
Liver weight
Absolute (g)
3.604 ±0.211
3.666 ±0.198
(+2%)
3.669 ±0.163
(+2%)
3.510 ± 0.331
(-3%)
Relative (% body weight)
7.419 ±0.351
7.347 ±0.374
(-1%)
6.797 ±0.216
(-8%)
6.842 ±0.551
(-8%)
Liver histology
Number of animals with lesiond
1/10
ND
ND
2/10
"Monsanto (1979).
bValues are presented as means ± SEM (% change compared with control); % change control = [(treatment
mean - control mean) control mean] x 100.
TWA analytical concentrations have been converted to HECs of 0, 4.6, 27, and 84 mg/m3 based on the following
equation: CONChec = [(number of weeks exposed 5 days/week x (CONCPpm x (molecular
weight ^ 24.45) x (hours exposed ^ 24 hours) x (5 days ^ 7 days) x blood:air partition coefficient
ratio) + [(number of weeks exposed 7 days/week x (CONCPpm x (molecular weight ^ 24.45) x (hours
exposed ^ 24 hours) x blood:air partition coefficient ratio )| ^ total number of weeks (U.S. EPA. 1994c):
molecular weight = 60.08 g/mol. The values for the human and rat blood:air partition coefficients are unknown,
so the default ratio of 1 was applied.
dAll animals with liver lesions presented with extramedullary hematopoiesis. No other liver lesions were observed.
* Statistically significantly different from controls at p< 0.05, as reported by study authors (Absolute: Dunnett's
multiple comparison test; Relative: Mann-Whitney test with Bonferroni inequality procedure).
f Statistically significant concentration-related trend at p< 0.05, as reported by study authors (ANOVA).
ND = not determined by study author.
37
Carbonyl Sulfide
-------
FINAL
09-29-2015
APPENDIX C. SUMMARIES OF SUPPORTING DATA
Table C-l. Summary of Carbonyl Sulfide Genotoxicity
Endpoint
Test System
Dose/
Concentration3
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Mutation
S. typhimurium strain TA97,
TA98, TA100, TA1535
0,0.58, 1.15,
1.73,2.31,
2.89 (ig/plate
(+)
TA97
(")
TA98,
TA100,
TA1535
(+)
TA97
(")
TA98,
TA100,
TA1535
The number of reversions in TA97
was increased 1.5-2-fold at
1.73-2.31 |ig/platc. Cytotoxicity
occurred at 2.89 |ig/platc. Positive
controls produced >2-fold more
reversion colonies than negative
control.
NTP (1995)
Mutation
S. typhimurium strain TA97,
TA98, TA100, TA102
50,000 mg/m3
Positive controls (4QNO, 2-AF)
produced >2-fold more reversion
colonies than negative control.
Wane et al. (1999)
Mutation
E. coli of tryptophan auxotroph
(WP2, WP2uvra,
CMR891), E. coli of lactose
and VB2 auxotroph (NDi6o
MR2-102)
1,000 mg/m3
Positive controls (4QNO, 2-AF)
produced >2-fold more reversion
colonies than negative control.
Wane et al. (1999)
Genotoxicity studies in nonmammalian eukaryotic organisms
ND
Genotoxicity studies in mammalian cells—in vitro
ND
Genotoxicity studies in mammals—in vivo
Mouse bone marrow
MN test (inhalation)
Mouse (10/group, unspecified
strain and sex); 2 inhalation
exposures, 2 hr/exposure at 1
and 24 hr; sacrifice 30 hr after
second exposure
2,000 mg/m3
Wane et al. (1999)
38
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-l. Summary of Carbonyl Sulfide Genotoxicity
Endpoint
Test System
Dose/
Concentration3
Resultsb
Comments
References
Without With
Activation Activation
Mouse bone marrow
MN test (oral)
Mouse (10/group, unspecified
strain and sex); 2 doses via
gavage in plant oil at 1 and
24 hr; sacrifice 30 hr after
second exposure.
100 mg/kg per
dose
Wane et al. (1999)
CAs in mouse
spermatocytes
(inhalation)
Mouse (unspecified number,
strain, and sex); inhalation
exposure for 2 hr/d for 5 d;
sacrifice 13 d postexposure.
1,000 mg/m3
Wangetal. (1999)
CAs in mouse
spermatocytes (oral)
Mouse (unspecified number,
strain, and sex); once daily
exposure via gavage in plant
oil for an unspecified number
of days; sacrifice 13 d later.
100 mg/kg-d
Wane et al. (1999)
Genotoxicity studies in subcellular systems
No data.
aHighest dose tested for negative results.
b(+) = weak positive; - = negative.
ND = no data.
39
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—cancer effects in humans
ND
Supporting evidence—noncancer effects in humans
Case report
NA
Upon hospitalization, upper respiratory
distress, nausea, severe anemia, and the
beginning of acute renal failure were noted
in a man who was exposed for "seconds to
minutes" to a combination of carbonyl
sulfide, hydrogen sulfide, and nitrogen gas.
Following hospitalization, rest, and
rehydration, the subject recovered fully.
Given the apparently short latency between
exposure and hospitalization, and the
exposure to a mixture of gases, the likelihood
that exposure to carbonyl sulfide was
involved in the etiology of the effects noted
cannot be determined.
Praxair (2003)
Case report
NA
A construction worker became ill following
brief exposure to a gaseous mixture of
carbonyl sulfide, carbon disulfide, and
sulfur dioxide. Specific symptoms were
not available. Exposure was estimated to
be 1,000 ppm of each gas (2,457 mg/m3
carbonyl sulfide).
Patient responded to inhaled arynyl nitrite
and intravenous sodium; recovery period was
not specified. Study authors concluded that
the poisoning was due to metabolism of
carbonyl sulfide into hydrogen sulfide.
Benson etal (1996)
as cited in ACGIH
(2012)
Case report
NA
Following acute, intentional exposure to
"pure carbonyl sulfide gas," a man reported
dizziness, inability to stand, chest pressure,
and ringing in the ears after ~10 sec.
Symptoms ceased ~2 min after cessation of
exposure.
Effects following acute high exposures of a
human subject were rapid and transient.
Klason (1887) as
cited in
Bartholomaeus and
Haritos (2005)
40
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—cancer in animals
Carcinogenicity
(oral)
In a poorly reported study,
weanling S-D rats were fed basal
diet fumigated with 0, 20,000,
50,000, 100,000, 200,000, or
500,000 mg/m3 for 2 yr (25/group;
sex unspecified).
Details for pathological
examination methods were not
provided. The amount of
compound absorbed by the feed
during fumigation was not
determined; therefore, compound
consumption levels are unknown.
The average life span was significantly
decreased in males from the 100,000-,
200,000-, and 500,000-mg/m3 groups. No
compound-related "pathological" or
"tumorous" changes were observed.
Carbonyl sulfide was not a carcinogenic
compound under the test conditions;
however, confidence in this study is low due
to inadequate reporting and unknown
compound consumption levels.
Wang et al. (1999)
41
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—noncancer effects in animals
Subchronic,
chronic, (oral)
In a series of poorly reported
studies, weanling S-D rats were fed
basal diet fumigated with 0, 20,000,
50,000, 100,000, 200,000, or
500,000 mg/m3 for various
durations
Subchronic: 90 d (males and
females; number unspecified)
Chronic: 12, 18, or 24 mo
(4-11/sex/group per time point)
Study descriptions were brief and
details on reported effects were
limited. Endpoints available are in
the results column; it is unclear
whether other endpoints were
assessed. Details for pathological
examination methods were not
provided. The amount of
compound absorbed by the feed
during fumigation was not
determined; therefore, compound
consumption levels are unknown.
Subchronic: No treatment-related changes
were observed in body weight or relative
organ weights. No pathological
abnormality was observed in the "main
organs." Food consumption was
significantly increased in high-dose
females. The percentage of lymphocytes
was significantly elevated and the
percentage of neutrophils was significantly
depressed in male rats in the 200,000- and
500,000-mg/m3 groups. No other
exposure-related hematological changes
were observed. Serum albumin levels were
significantly elevated in all exposed male
rats except the 20,000-mg/m3 group.
Chronic: The only significant,
exposure-related findings were decreased
hemoglobin in the 100,000-, 200,000-, or
500,000-mg/m3 females after 6 mo and
males after 12 mo. ALP was significantly
increased in 500,000-mg/m3 males. No
"special pathological injurions [sic]" were
observed in exposed groups.
Subchronic- and chronic-duration studies: No
consistent exposure-related effects were
found across studies. Reliable
NOAEL/LOAEL determinations could not be
made due to inadequate reporting and
unknown compound consumption levels.
Wang et al. (1999)
Subchronic
(inhalation)
Male and female S-D rats (number
unspecified) were exposed to 0, 10,
60, or 182 ppm (0, 25, 147, or
447 mg/m3), 6 hr/d, 5 d/wk for
-14 wk.
Body weight was decreased in all exposed
males, but findings were not concentration
related. No treatment-related changes in
clinical chemistry were observed.
Lymphopenia was observed in all exposed
males; however, findings in males were not
concentration related.
The full report is unavailable. Due to lack of
details in the study summary, reliable
NOAEL/LOAEL determinations could not be
made. The toxicological significance of
lymphopenia cannot be determined without
review of the magnitude and pattern of
response.
DuPont (1992)
42
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Reproductive/
developmental
studies (oral)
Developmental and reproductive
toxicity were assessed in S-D rats
fed diets fumigated with 0, 20,000,
50,000, 100,000, 200,000, or
500,000 mg/m3 carbonyl sulfide.
The amount of compound absorbed
by the feed during fumigation was
not determined; therefore,
compound consumption levels in
these studies are unknown.
Developmental study: Gestation
(days not specified);
9-12 dams/group; (20,000- and
50,000-mg/m3 groups were not
included).
One generation study: Male and
female weanlings
(10-11/sex/group) were exposed
for 90 d prior to within-group
mating. It is unclear if
carbonyl sulfide exposure
continued through mating and
gestation.
Two generation study: F0 and
F1 male and female weanlings
(20-24/sex/group per generation)
were exposed for 100 d prior to
within-group mating. Exposure
continued during gestation and
lactation.
Developmental study: There were no
exposure-related changes in fetal body
weight, number of live or dead fetuses, or
number of resorptions. No external or
skeletal abnormalities were observed.
One-generation study: Fetal body weight
was statistically significantly lower in the
100,000-, 200,000-, and 500,000-mg/m3
groups. No significant, exposure-related
changes in the number of live or dead
fetuses or the number of resorptions were
observed. It is not clear if fetuses were
examined for external, internal, or skeletal
abnormalities. No reproductive indices
were reported.
Two-generation study: There were no
exposure-related changes in mating or
pregnancy rate or the number of live pups.
The percent survival at weaning was
significantly decreased in the F1
500,000-mg/m3 group and the F2
200,000- and 500,000-mg/m3 groups. The
study authors suggest that this indicates
decreased lactation in dams exposed to
higher concentrations; however, no data
were provided to support this hypothesis.
It is not clear whether fetuses were
examined for external, internal, or skeletal
abnormalities.
Developmental study: Carbonyl sulfide was
not a developmental toxicant under the test
conditions; however, reliable
NOAEL/LOAEL determinations could not be
made due to unknown compound
consumption levels.
One-generation study: Exposure to carbonyl
sulfide prior to mating (and potentially during
mating and gestation) led to decreased fetal
body weight at high concentrations; however,
reliable NOAEL/LOAEL determinations
could not be made due to unknown
compound consumption levels.
Two-generation study: Carbonyl sulfide was
not a reproductive toxicant under the
exposure conditions. Exposure to carbonyl
sulfide led to decreased postnatal survival in
both the F1 and F2 generations; however,
reliable NOAEL/LOAEL determinations
could not be made due to unknown
compound consumption levels.
Wang et al. (1999)
43
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Developmental
studies (inhalation)
Study 1: Pregnant rats (strain and
number not specified) were
exposed daily for 6 hr to 50, 149,
250, 348, or 451 ppm (123, 366,
614, 855, or 1,108 mg/m3) carbonyl
sulfide on GDs 6-15. Day of
sacrifice was not reported, and it is
unclear whether a concurrent
control group was used.
Study 2: Pregnant S-D rats (number
not specified) were exposed to 0,
50, 200, or 400 ppm (0, 123, 491,
or 983 mg/m3) carbonyl sulfide on
GDs 6-15 (daily duration not
reported). Dams were sacrificed on
GD 21.
Study 1: Maternal toxicity was evident in
dams exposed to 855 and 1,108 mg/m3
(decreased weight gain during treatment
period). One high-exposure dam died.
No exposure-related effects were noted for
litter size, live fetuses/litter, or total
resorptions. No abnormalities were noted
during gross fetal examination.
Study 2: Maternal toxicity was evident in
dams exposed to 983 mg/m3 (decreased
weight gain and food consumption,
maternal death).
No exposure-related effects were noted for
pregnancy rate, reproductive parameters,
fetal body weights, or fetal sex distribution.
No exposure-related gross, visceral, or
skeletal malformations or variations were
attributed to treatment.
The study summary suggests that carbonyl
sulfide did not cause developmental toxicity,
even at maternally toxic doses. However,
because the full report is unavailable, data
cannot be independently reviewed and
reliable NOAEL/LOAEL determinations
cannot be made.
DuPont (1992)
(unpublished report
summary; full
report unavailable)
One-generation
reproduction
(inhalation)
Male S-D rats (number
unspecified) were exposed to 0, 10,
60, or 182 ppm (0, 25, 147, or
447 mg/m3), 6 hr/d, 5 d/wk for
-14 wk.
Body weight was decreased in all exposed
males, but findings were not
concentration-related. A 40% reduction in
pregnancy rates resulting from male high
dose exposure were noted. Lymphopenia
was observed in all exposed males;
however, findings in males were not
concentration-related.
The full report is unavailable. Due to lack of
details in the study summary, reliable
NOAEL/LOAEL determinations could not be
made. The toxicological significance of
lymphopenia cannot be determined without
review of the magnitude and pattern of
response.
DuPont (1992)
(unpublished report
summary; full
report unavailable)
44
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
One-generation
reproduction
(inhalation)
Female S-D rats (number
unspecified) were exposed to 0, 10,
60, or 182 ppm (0, 25, 147, or
447 mg/m3), 6 hr/d, 5 d/wk for
-14 wk.
No exposure-related effects were observed
in urinalysis, clinical chemistry, gross or
histological pathology, pupillary reflexes,
or clinical signs of toxicity. "Equivocal
decreases in male weanling liver weight"
were observed at 60 and 182 ppm
accompanying premating exposure of
female rats. Lymphopenia was observed in
high-exposure females.
The Ml report is unavailable. Due to lack of
details in the study summary, reliable
NOAEL/LOAEL determinations could not be
made. The toxicological significance of
lymphopenia cannot be determined without
review of the magnitude and pattern of
response. Given the lack of details regarding
reduction in liver weight, and the lack of an
Agency-established benchmark response
level for this effect, it was not given further
consideration.
DuPont (1992)
(unpublished report
summary; full
report unavailable)
Short-term-duration
studies (inhalation)
S-D rats (10 males/10 females)
were exposed to 2,000 mg/m3,
2 hr/d for 14 d in a whole-body
inhalation chamber. A 4 x 5 cm2
area was clipped free of fur on the
back of exposed rats.
No mortality or clinical signs of toxicity
were observed. No skin or eye irritation
was observed. No other endpoints were
examined/reported.
Reliable conclusions cannot be drawn, as it is
unclear if a control group was used. Skin and
eye irritation were not assessed according to
OECD guidelines.
Wane et al. (1999)
Short-term-duration
studies (inhalation)
S-D rats (10 males, 10 females per
group) were exposed 6 hr/day,
5 d/wk for 2 wkto 0, 51, 151, 253,
or 453 ppm carbonyl sulfide.
Central nervous system dysfunction and
sacrifice in extremis were reported for
2 males and 3 females in the high-dose
group. Concentration-related increases in
methemoglobinemia were reported at
151 ppm and higher concentrations.
The full report is unavailable. Due to lack of
details in the study summary, reliable
NOAEL/LOAEL determinations could not be
made.
DuPont (1992)
[This study seems to
be a resubmission of
Monsanto (1985)1
Neurotoxicity
(inhalation)
F344 rats (5 males/group) were
exposed to 0, 75, 150, 300, or
600 ppm (0, 184,369, 737, or
1,474 mg/m3), 6 hr/d for 4 d. At
sacrifice, brains were removed and
prepared for microscopy.
No mortality, morbidity, clinical signs of
toxicity, or brain lesions were observed at
<737 mg/m3. At 1,474 mg/m3, rats were
moribund after 2 d showing hypothermia,
lethargy, head tilt, and ataxia. Necrosis
was observed by light microscopy in
parietal cortex area 1, thalamus,
retrosplenial granular cortex, red nucleus,
cerebellar roof nucleus, posterior collicular
nucleus, anterior olivary nucleus, and
posterior colliculus.
The NOAEL for mortality, morbidity, clinical
signs of CNS toxicity, and brain lesions was
737 mg/m3 for 4 d. At 1,475 mg/m3, 2 d of
exposure produced clinical signs of CNS
toxicity and brain lesions.
Morgan et al.
(2004)
45
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Neurotoxicity
(inhalation)
F344 rats (5 males/group) were
exposed to 0, 75, 150, 300, or
600 ppm (0, 184,369, 737, or
1,474 mg/m3) for 6 hr and held for
2 wk without exposure. At
sacrifice, brains were removed and
prepared for microscopy.
No mortality, morbidity, clinical signs of
toxicity or brain lesions were observed at
< 737 mg/m3. At 1,474 mg/m3, clinical
signs during exposure were less severe than
those observed with 2 6-hr exposures and
diminished during 14 d of recovery, but
several rats still showed ataxia and head tilt
after 14 d. Brain lesions observed after
14 d in the 1,474 mg/m3-group included
microgliosis in the cerebellar roof nucleus,
internal capsule, and thalamus and
vacuolation of the cerebellar medullary
white matter and 5th cranial nerve tract.
Clinical signs of CNS toxicity from
1,474 mg/m3 diminished through a 14 d
recovery period, but several rats still showed
ataxia and head tilt at the end of the recovery
period.
The persistent signs of toxicity were linked
with necrosis in several brain regions.
Morgan et al.
(2004)
Neurotoxicity
(inhalation)
F344 rats (6 males/group) were
exposed to 0 or 600 ppm (0 or
1,475 mg/m3), 6 hr/d for 2 d and
held for 2 wk without exposure.
After the 2-wk period, rats were
sacrificed and injected with MRI
contrast (Prohance). Specimens
were evaluated with MRM. After
MRM, brains were removed and
prepared for light microscopy.
MRM detected lesions in multiple brain
regions in the 1,475-mg/m3 group,
including the posterior thalamic nuclear
group and zona inserta of the hypothalamus
and the posterior colliculus. Light
microscopy confirmed neuronal loss and
microgliosis in the hypothalamus and
neuronal loss, microgliosis, hemorrhage,
and accumulation of hemosiderin laden
macrophages in the posterior colliculus.
This study is primarily a methods paper,
demonstrating that MRM is an effective tool
for identifying brain lesions following
chemical exposure. This study confirms
previous reports that acute exposure to
1,475 mg/m3 caused brain lesions detected by
light microscopy (Morgan et al. 20041
Sills et al. (2004)
Neurotoxicity
(inhalation)
Groups of 15 male rats were
exposed to concentrations of 0,
300, or 400 ppm (738 or
983 mg/m3) carbonyl sulfide
6 hr/day, 5 d/wk for 2 wk. Rats
were evaluated via FOB, CNS
histopathology, and CNS
electrophysiology was measured.
Brainstem and cortical evoked potentials,
an increase in grossly observable cortical
lesions, and increases in FOB alterations
including decreased grip strength, slightly
abnormal gait, and decreased motor activity
were observed at 983, but not at
738 mg/m3.
This preliminary investigation identified CNS
alterations to be investigated more fully in
12-wk investigations bv Morgan et al. (2004).
Herr et al. (2007). Sills et al. (2004)
Herr et al. (2007)
46
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute lethality
studies
(inhalation)
Groups of 10 male Crl:CD rats
were exposed to concentrations of
477, 943, 981, 1,050, 1,090, 1,160,
1,210, 1,270, or 2,180 ppm (1,098,
2,317, 2,411, 2,580, 2,678, 2,850,
2,973, 3,121, or 5,357 mg/m3)
carbonyl sulfide for up to 4 hr.
Surviving rats were weighed and
observed daily for a 14-d recovery
period.
Deaths occurred in groups exposed to all
concentrations >2,678 mg/m3. The number
of deaths occurring during exposure
increased from 2/10 at 2,678 mg/m3 to
10/10 at 5,357 mg/m3. All deaths occurred
between D 1 and 9 of the observation
period.
Clinical signs of toxicity increased with
increasing exposure concentration. During
exposure, these included labored breathing,
impaired response to sound, lack of
coordination, convulsion, head bobbing,
and uncontrolled body movements.
Postexposure signs included slight to
severe body weight loss, lethargy, stained
nose and mouth, partially closed eyes, and
lack of righting reflex.
LCso (4-hr) =1,111 ppm (2,730 mg/m3); 95%
CI 1,058-1,158 ppm (2,600-2,846 mg/m3).
DuPont (1992)
47
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute lethality
studies (inhalation)
S-D rats (6 males/6 females) were
exposed to concentrations of 804,
993, 1,062, 1,096, 1,147, or
1,189 ppm (1,976, 2,440, 2,610,
2,693, 2,818, or 2,922 mg/m3)
carbonyl sulfide for up to 4 hr.
Surviving rats were observed for a
14-d period. Necropsy was
performed on all animals found
dead and rats sacrificed at the end
of the observation period.
Deaths occurred in groups exposed to all
concentrations >2,610 mg/m3. The number
of deaths occurring increased from
1/6 males and 3/6 females in the
2,610-mg/m3 group to 6/6 males and
5/6 females in the 2,922-mg/m3 group. All
deaths except one occurred during or
within 24 hr of exposure.
Clinical signs of toxicity were observed
during and immediately postexposure in
rats exposed to 2,610-2,922 mg/m3,
including breathing difficulties,
convulsions, tremors, and behavioral
abnormalities. Postexposure signs included
slight to severe body weight loss, stained
nose and mouth, hypoactivity, and
abnormal circling behavior. At necropsy, a
concentration-related increase in lung
congestion was observed in rats exposed to
2,610-2,922 mg/m3.
LC50 (4-hr) =
Combined: 1,082 ppm (2,659 mg/m3);
95% CI 1,059-1,102 ppm
(2,602-2,708 mg/m3)
Males: 1,094 ppm (2,688 mg/m3); 95% CI
1,055-1,136 (2,592-2,791 mg/m3)
Females: 1,070 ppm (2,629 mg/m3); 95%
CI 1,022-1,100 (2,511-2,703 mg/m3)
Slope of lethality curve =
Combined: 60.8
Males: 59.2
Females: 71.0
Monsanto (1982)
Acute lethality
studies (inhalation)
Lethality was determined in rats,
guinea pigs, and rabbits exposed
whole-body to 1,200, 2,450, or
3,185 mg/m3 carbonyl sulfide for
75-120 min.
1,200 mg/m3 (488 ppm): No deaths in any
species (2 animals/species) exposed for
90 min.
2,450 mg/m3 (997 ppm):
Rats: 0/6 dead after 75 min, 3/6 dead after
90 min.
Guinea pig: 0/6 dead after 90 min.
Rabbit: 8/14 dead after 90 min, 2/4 dead
after 120 min.
3,185 mg/m3 (1,296 ppm):
Guinea pig: no deaths after 90 min.
Guinea pigs appeared to be more resistant to
the acute lethality of carbonyl sulfide than
rats and rabbits.
Theiss et al. (1968)
as cited in
Bartliolomaeus and
Haritos (2005)
48
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute lethality
studies (inhalation)
Individual white mice were
exposed to carbonyl sulfide for
various periods of time and
observed for clinical signs of
neurotoxicity and death.
Concentrations >3,000 mg/m3 led to
convulsions and prostration within a few
minutes and death within ~45 min. At
2,200 mg/m3, no clinical signs of toxicity
were observed with exposure up to 16 min.
Data provided bv Bartholomaeus and Haritos
(2005) are inadeauate to make
NOAEL/LOAEL determinations; original
manuscript is in German.
Klemenc (1943) as
cited in
Bartholomaeus and
Haritos (2005)
Acute lethality
studies (inhalation)
Other short-term-duration acute
lethality studies with limited
reporting of experimental details, as
collected, reviewed, and reported
bv Bartholomaeus and Haritos
(2005).
Mouse LC50 (35 min) = 2,940 mg/m3.
Sax and Lewis
(1986) as cited in
Bartholomaeus and
Haritos (2005)
Mouse LC50 (unspecified duration) = 2,770 mg/m3.
RTECS (1997) as
cited in
Bartholomaeus and
Haritos (2005)
Rabbit LC50 (unspecified duration) = 2,550 mg/m3.
RTECS (1997) as
cited in
Bartholomaeus and
Haritos (2005)
Rats: 10-hr exposure to 1,200 mg/m3 is lethal.
Hayashi et al.
(1971) as cited in
Bartholomaeus and
Haritos (2005)
Acute lethality
studies other than
oral/inhalation
Male S-D rats (11-18/group) were
given single i.p. injections of
carbonyl sulfide gas at doses of 20,
25, and 30 mg/kg. It is not clear
how long animals were observed
following injections.
Death occurred within 10 min of dosing in
1/11, 11/18, and 13/18 rats from the 20-,
25-, and 30-mg/kg groups, respectively.
Observed clinical signs of toxicity included
ataxia, loss of righting reflex, cyanosis,
difficulty breathing, and convulsions.
Animals that did not die within 10 min
recovered fully.
Rat LD50 (i.p.) = 22.5 mg/kg
Chengelis and Neal
(1980)
49
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Studies of absorption, distribution, metabolism, or elimination (ADME)
ADME
Metabolite formation was
determined in rat hepatocyte
cultures incubated with
carbonyl sulfide gas. Metabolite
formation was also measured
following coincubation of
CYP450 inhibitors (SKF 525-a,
4-methylpyrazole, or metyrapone),
the CYP450 substrate
carbon disulfide, and the carbonic
anhydrase inhibitor acetazolamine.
Additional studies measured
carbonyl sulfide metabolism by
bovine erythrocyte carbonic
anhydrase.
Metabolites identified included CO2,
hydrogen sulfide, and thiosulfate.
Formation of metabolites was inhibited by
acetazolamine, but not carbon disulfide or
inhibitors of CYP450.
Bovine erythrocyte carbonic anhydrase also
metabolized carbonyl sulfide into CO2,
hydrogen sulfide, and thiosulfate.
Findings indicate that carbonyl sulfide is a
substrate for carbonic anhydrase. The
proposed pathway is as follows:
carbonic anhydrase catalyzes the formation of
monothiocarbonic acid, which is hydrolyzed
to CChand hydrogen sulfide. Hydrogen
sulfide is further hydrolyzed into thiosulfate
and sulfate.
Dalvi and Neal
(1978)
ADME
Mortality and blood levels of
carbonyl sulfide and hydrogen
sulfide were measured in male S-
D rats following i.p. injections of
carbonyl sulfide gas
(20-30 mg/kg). A separate group
of rats were pretreated with the
carbonic anhydrase inhibitor
acetazolamine or sodium nitrate (to
decrease sulfide toxicity).
Animals exposed to 30 mg/kg that died
within 10 min had blood hydrogen sulfide
levels of 0.3-0.5 |imol/mL. However,
animals sacrificed 10 min after exposure to
30 mg/kg that were pretreated with
acetazolamine had "barely detectable"
blood levels of hydrogen sulfide.
Pretreatment with acetazolamine also
decreased the carbonyl sulfide-induced
mortality by -40-50%. Pretreatment of
rats with sodium nitrate completely
protected rats from carbonyl sulfide
toxicity (no mortalities).
Findings indicate that carbonyl sulfide is a
substrate for carbonic anhydrase and that the
metabolite hydrogen sulfide is responsible for
observed acute toxicity.
Chengelis and Neal
(1980)
50
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
ADME
The affinity of the bovine carbonic
anhydrase II for carbonyl sulfide
(0.05-3 mM) was measured using
in vitro kinetic metabolism studies.
Mortality in the Tribolium
castaneum (flour beetle) larvae
following exposure to carbonyl
sulfide gas with and without
pretreatment with the carbonic
anhydrase inhibitor acetazolamine
was also determined.
Carbonic anhydrase II has a high affinity
for carbonyl sulfide. The metabolism of
carbonyl sulfide to hydrogen sulfide
yielded velocity curves used to calculate
Michaelis-Menten parameters. Mean
parameters for six replicate curves were
Km= 1.86 mM and the maximum turnover
number (/\C(ll) = 41 s 1 at 25°C. Formation
of hydrogen sulfide was inhibited by
specific inhibitors of carbonic anhydrase
(acetazolamide, ethoxyzolamide, and
methazolamide), with IC50 values in the
20-50 nM range.
Mortality in beetles was reduced 12-fold (at
35 mg/L carbonyl sulfide) following
pretreatment with acetazolamine.
Findings indicate that carbonyl sulfide is a
high-affinity substrate for carbonic anhydrase
and that the metabolite, hydrogen sulfide, is
responsible for observed acute toxicity in
flour beetles.
Haritos and
Doichinov (2005)
ADME
The transfer of35 S into goat milk
was determined in lactating goats
following a single feeding of grass
contaminated aerially by
carbonyl sulfide. 35S transfer was
also determined in goats given
single oral doses of sulphate or
L-methionine or a single feeding of
grass contaminated by root uptake
from soil contaminated with
sulphate.
35S was present in goat milk after all
exposures. Concentrations were similar for
all sources, except L-methionine, which led
to significantly higher transfer levels.
Double exponential curves demonstrated 2
phases of elimination, resulting in 2
half-life values (Ti/2(i) and Ti/2(2)). For all
sources, T1 /2(i) was approximately 1 d. For
all sources except grass contaminated with
carbonyl sulfide, T1/2® was 9-14 d. In
contrast, T1/2® was 44 d for grass
contaminated with carbonyl sulfide.
35S can be transferred to milk in lactating
goats following oral exposure to
carbonyl sulfide (and other 35S sources). 35S
is eliminated from milk in 2 stages, with a
short (~1 d) first half-life and a longer (>40 d)
second half-life. Elimination of35S
transferred from carbonyl sulfide is slower
than 35S transferred from other 35S sources.
Howard et al.
(2007)
51
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Studies of mode of action/mechanism
Mode of
action/mechanistic
F344 rats (5/sex/group) were
exposed to 0, 200, 300, or 400 ppm
(0, 737, 983, or 1,229 mg/m3)
6 hr/d, 5 d/wk for 3, 6, or 12 wk in
whole-body inhalation chambers.
On D 24, 52, and 86, respectively,
rats were sacrificed to determine
brain cytochrome oxidase activity.
A concentration-dependent decrease in
cytochrome oxidase was observed in the
posterior colliculus and parietal cortex of
exposed rats, brain regions that exhibit
lesions and neuronal loss following
short-term- and subchronic-duration
carbonvl sulfide exposure (Morgan et al..
2004: Sills et al.. 20041
Inhibition of brain cytochrome oxidase could
potentially limit oxidative phosphorylation,
contributing to observed neuronal death in
these brain regions following carbonyl sulfide
exposure.
Morgan et al.
(2004)
52
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table C-2. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Mode of action/
mechanistic
Time-course study: F344 rats
(15 males/group/time-point) were
exposed to 0 or 500 ppm (0 or
1,229 mg/m3) 6 hr/d for 1, 2, 3, 4,
5, 8, or 10 d. At sacrifice, brains
were removed and prepared for
microscopy (10/group) or assessed
for neuronal degeneration (cupric
silver method) and astrocytic
response (GFAP
immuno histochemistry).
Gene expression study: F344 rats
(males and females, 3/group per
time point) were exposed to 0 or
500 ppm (0 or 1,229 mg/m3) 6 hr/d
for 1 or 2 d. After sacrifice,
posterior colliculi were removed
and processed for RNA isolation
for microarray analysis (Aglient
Rat Oligo Microarrays,
-22,000 probes). Significant
microarray results (transcripts with
a >1.3-fold change and a
p-valuc <0.01) were verified with
real-time polymerase chain reaction
(RT-PCR).
Time-course study: Carbonyl sulfide
induced lesions after >3 d of exposure.
The posterior colliculus was most
susceptible to damage. Following
appearance of lesions, astrocytic response
and neuronal degeneration occurred.
Gene expression study: Gene expression in
the posterior colliculus was assessed after
1- and 2-d exposures, prior to the onset of
morphological change. Analysis indicated
upregulation of genes involved in DNA
damage and Gl/S checkpoint regulation
(KLF4, BTG2, GADD45g), apoptosis
(TGM2, GADD45g, RIPK3), and vascular
mediators (ADAMTS, CTGF, CYR61,
VEGFC). Proinflammatory mediators
(CCL2, CEBPD) were upregulated prior to
increases in GFAP (astrocytic marker) and
CSF2rbl (macrophage marker).
Significant gene expression changes were
observed at time points preceding
morphological changes. These gene
expression changes may be predictive of CNS
lesions, and further study may lead to better
mechanistic understanding of
carbonyl sulfide-induced neurotoxicity.
Morrison et al.
(2009)
CI = confidence interval; NA = not applicable; ND = no data; S-D = Sprague-Dawley.
53
Carbonyl Sulfide
-------
FINAL
09-29-2015
APPENDIX D. BENCHMARK MODELING RESULTS
MODELING PROCEDURE FOR DICHOTOMOUS DATA
The benchmark dose (BMD) modeling of dichotomous data (neuronal loss or
microgliosis, the most sensitive histopathological lesions of brain tissue, Table 6) was conducted
with the U.S. EPA's Benchmark Dose Software (BMDS) (Version 2.5). For these data, all of the
dichotomous models (i.e., Gamma, Multistage, Logistic, Log-logistic, Probit, Log-probit, and
Weibull models) available within the software were fit using a default benchmark response
(BMR) of 10% extra risk based on the U.S. EPA's Benchmark Dose Technical Guidance
Document (U.S. EPA. 2012b). Adequacy of model fit was judged based on the
X2 goodness-of-fit p-value (p > 0.1), magnitude of scaled residuals in the vicinity of the BMR,
and visual inspection of the model fit. Among all models providing adequate fit, the lowest
benchmark dose lower confidence limit (BMDL) was selected if the BMDLs estimated from
different models varied greater than threefold; otherwise, the BMDL from the model with the
lowest Akaike's information criterion (AIC) was selected as a potential point of departure (POD)
from which to derive a provisional oral reference dose (p-RfD).
In addition, data from exposures much higher than the study lowest-observed-
adverse-effect level (LOAEL) do not provide reliable information regarding the shape of the
response curve at low doses. However, such exposures can have a strong effect on the shape of
the fitted model in the low-dose region of the dose-response curve in some cases. Thus, if lack
of fit is due to characteristics associated with dose-response data for high doses, then the
U.S. EPA's Benchmark Dose Technical Guidance Document allows for data to be adjusted by
eliminating high-dose groups (U.S. LP A. 2012b).
MODELING PROCEDURE FOR CONTINUOUS DATA
The BMD modeling of continuous data (SEP1 and SEP2 evoked potentials, Table 6) was
conducted with the U.S. EPA's BMDS (Version 2.5). For these data, all continuous models
available within the software were fit using a default BMR of 1 standard deviation (SD) relative
risk. For changes in body weight, a BMR of 10% change relative to the control mean was also
used. An adequate fit was judged based on the goodness-of-fit p-v alue (p> 0.1), magnitude of
the scaled residuals in the vicinity of the BMR, and visual inspection of the model fit. In
addition to these three criteria forjudging adequacy of model fit, a determination was made as to
whether the variance across dose groups was constant. If a constant variance model was deemed
appropriate based on the statistical test provided in BMDS (i.e., Test 2), the final BMD results
were estimated from a constant variance model. If the test for homogeneity of variance was
rejected (p< 0.1), the model was run again while modeling the variance as a power function of
the mean to account for this nonconstant variance. If this nonconstant variance model did not
adequately fit the variance data (i.e., Test 3;p<0. 1), the data set was considered unsuitable for
BMD modeling. Among all models providing adequate fit, the lowest BMDL was selected if the
BMDLs estimated from different models varied greater than 3-fold; otherwise, the BMDL from
the model with the lowest AIC was selected as a potential POD from which to derive a p-RfD.
54
Carbonyl Sulfide
-------
FINAL
09-29-2015
The following data sets were selected for BMD modeling:
• incidence data for neuronal loss or microgliosis in male rats (Morgan et aL 2004)
• incidence data for neuronal loss or microgliosis in female male rats (Morgan et al..
2004)
• continuous data for changes in SEP1 evoked potential in combined male and female
rats (Herr et al.. 2007)
• continuous data for changes in SEP2 evoked potential in combined male and female
rats (Herr et al.. 2007)
Data describing carbonyl sulfide dependent cortical necrosis (Morgan et al.. 2004) were
not modeled because this endpoint was less sensitive than neuronal loss of microgliosis. Data
describing changes in other measures of central nervous system electrophysiology (Herr et al..
2007) were not modeled because of lack of availability of data describing group variability (e.g.,
SD or SEM values).
For the male rat neuronal loss or microgliosis data (see Table B-2), the Multistage
Models failed due to unacceptable %2 goodness-of-fit criteria (see Table D-l). Among the
remaining models, BMCL values were within three-fold, and the BMCL for the model with the
lowest AIC value (LogProbit) was selected as the POD for this effect (see Table D-l).
Table D-l. Modeling Results for Incidence of Posterior Colliculus Neuronal Loss or
Microgliosis—Male Rats Exposed to Carbonyl Sulfide for 12 Weeks3
Model
DF
X2
X2 Goodness-of-Fit
/>-Valueb
Scaled
Residuals0
AIC
BMCio
(HEC mg/m3)
BMCLio
(HEC mg/m3)
Gammad
2
3.13
0.2092
-1.391
16.3322
120.382
98.4963
Logistic
1
0
0.9998
0.00
13.5347
168.597
126.509
LogLogistic6
2
0.18
0.9157
-0.401
11.8691
146.103
125.516
LogProbit®
2
0
1.00
0.00
11.5348
157.088
127.913
Multistage (1-degree/
2
7.08
0.029
-2.064
21.4945
68.8387
23.9681
Multistage (2-degree/
2
5.5
0.0638
-1.889
19.627
89.8501
39.0493
Probit
1
0
0.9998
0.00
13.5347
162.013
127.19
Weibulld
2
0.08
0.9624
0.275
11.6864
151.944
125.201
"Morgan et al. (2004)
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
cScaled residuals for dose group near BMC.
dPower restricted to >1.
"Slope restricted to >1.
fBetas restricted to >0.
BMC = maximum likelihood estimate of the concentration associated with the selected BMR; BMCL = 95% lower
confidence limit on the BMC (subscripts denote BMR: i.e., io = dose associated with 10% extra risk); DF = degrees
of freedom.
BMDS outputs for the selected best-fitting model (LogProbit) follow.
55
Carbonyl Sulfide
-------
FINAL
09-29-2015
LogProbit Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
LogProbit
0.6
~o
(D
= 1
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 5 00
56
Carbonyl Sulfide
-------
FINAL
09-29-2015
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -42.5422
slope = 8.37579
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept
intercept 1
Parameter Estimates
Interval
Variable
Limit
background
intercept
91.3921
slope
Estimate
0
-92.3041
18
Std. Err.
NA
0.465292
NA
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-93.216
NA - Indicates that this parameter has hit a bound
implied by some ineguality constraint and thus
has no standard error.
Analysis of Deviance Table
Model Log(likelihood)
Full model -4.7 6736
Fitted model -4.7674
Reduced model -15.4516
# Param's Deviance Test d.f. P-value
3
1 9.15 034e-005 2 ]
1 21.3684 2 <.0001
AIC:
11.5348
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
132.0000
176.0000
0.0000
0.0000
0.7778
0.000
0.000
7.000
0.000
0.000
7.000
9.000
9.000
9.000
0. 000
-0.007
0. 000
Chi^2 = 0.00
d.f. = 2
P-value = 1.0000
57
Carbonyl Sulfide
-------
FINAL
09-29-2015
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 157.088
BMDL = 127.913
For the female rat neuronal loss or microgliosis data (see Table B-2), the Multistage
Models failed due to high scaled residuals at the dose response level close to the BMR and poor
curve fitting judged by visual inspection (see Table D-2). Among the remaining models, BMCL
values were within three-fold, and the BMCL for the model with the lowest AIC value
(LogProbit) was selected as the POD for this effect (see Table D-2).
Table D-2. Modeling Results for Incidence of Posterior Colliculus Neuronal Loss or
Microgliosis—Female Rats Exposed to Carbonyl Sulfide for 12 Weeks"
Model
DF
x2
X2 Goodness-of-Fit
/j-Valueb
Scaled
Residuals0
AIC
BMCio
(HEC mg/m3)
BMCLio
(HEC mg/m3)
Gammad
2
1.45
0.4853
-0.999
16.7022
132.041
100.858
Logistic
1
0
0.9998
0
16.3653
170.419
123.85
LogLogistice
2
0.06
0.9688
0.041
14.49
154.092
123.907
LogProbit6
1
0
1
-1.588
14.3653
162.638
125.808
Multistage (1-degree/
2
4.09
0.1291
-1.446
20.3043
86.1863
30.1114
Multistage (2-degree/
2
3.12
0.2102
0
19.124
105.05
40.2893
Probit
1
0
0.9998
0.019
16.3653
165.194
124.652
Weibulld
2
0.04
0.9796
0
14.4472
157.211
123.311
"Morgan et at (2004)
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
°Scaled residuals for dose group near BMC.
dPower restricted to >1.
"Slope restricted to >1.
fBetas restricted to >0.
BMC = maximum likelihood estimate of the concentration associated with the selected BMR; BMCL = 95% lower
confidence limit on the BMC (subscripts denote BMR: i.e., io = dose associated with 10% extra risk); DF = degrees
of freedom.
BMDS outputs for the selected best-fitting model (LogProbit) follow.
58
Carbonyl Sulfide
-------
FINAL
09-29-2015
LogProbit Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
LogProbit
0.6
~o
CD
O
CD
<
£=
O
0.4
u
01
Ll_
0.2
BMDL
3MD
0
20
40
60
80
100
120
140
160
180
dose
14:35 09/15 2015
Figure D-l. LogProbit Fit for Incidence of Posterior Colliculus Neuronal Loss or
Microgliosis in Female Rats (Morgan et al., 2004).
Probit Model. (Version: 3.3; Date: 2/28/2013)
Input Data File: C:/Users/JLIPSCOM/Desktop/BMDS260/Data/lnp_morgan new
microgliosis female_Lnp-BMR10-Restrict.(d)
Gnuplot Plotting File: C:/Users/JLIPSCOM/Desktop/BMDS260/Data/lnp_morgan new
microgliosis female_Lnp-BMR10-Restrict.pit
Tue Sep 15 14:35:00 2015
BMDS Model Run
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),
where CumNormf .) is the cumulative normal distribution function
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
59
Carbonyl Sulfide
-------
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -31.9341
slope = 6.20325
FINAL
09-29-2015
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
intercept
intercept 1
the user,
Parameter Estimates
Interval
Variable
Limit
background
intercept
92.1073
slope
Estimate
0
-92.929
18
Std. Err.
NA
0.419254
NA
NA - Indicates that this parameter has hit a bound
implied by some ineguality constraint and thus
has no standard error.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-93.7507
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-6.18265
-6.18266
-12.9375
14.3653
# Param's Deviance Test d.f. P-value
3
1 4.22125e-006 2 1
1 13.5096 2 0.001165
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
132.0000
176.0000
Chi^2 = 0.00
0.0000
0.0000
0.5556
d.f. = 2
0.000 0.000 9.000
0.000 0.000 9.000
5.000 5.000 9.000
P-value = 1.0000
0. 000
-0.001
0. 000
Benchmark Dose Computation
60
Carbonyl Sulfide
-------
FINAL
09-29-2015
Specified effect
Risk Type
Confidence level
BMD
BMDL
0.1
Extra risk
0. 95
162.638
125.808
61
Carbonyl Sulfide
-------
FINAL
09-29-2015
SEP1 amplitude data are presented in Table B-3; to complete BMD modeling, SEM
values were converted to SD values by multiplying by the square root of the respective n values.
For the combined male and female SEP1 amplitude data, all constant variance models failed.
Among all the nonconstant models, only Exponential Model 3, Hill Model, and Power Model
provide adequate fit to the data. BMCL values from these adequate fitted models varied less
than three-fold. The BMCL from the model with the lowest AIC value (Power) was selected as
the POD for this effect (see Table D-3).
Table D-3. Modeling Results for SEP1 Hindlimb/Tail Region Peak Amplitude
Measurements in Male and Female Rats Exposed to Carbonyl Sulfide for 12 Weeks"
Model
Test for
Significant
Difference
7?-Valueb
Variance
/j-Value'
Means
p-Value0
Scaled
Residuals'1
AIC
BMCisd
(HEC mg/m3)
BMCLisd
(HEC mg/m3)
Constant variance
Exponential (Model 2)e
0.004761
0.004761
0.07
1.27
83.05
255.00
164.34
Exponential (Model 3)e
0.004761
0.004761
0.73
0.0008
830.89
178.68
NA
Exponential (Model 4)e
0.004761
0.004761
0.02
1.47
836.52
308.12
174.18
Exponential (Model 5)e
0.004761
0.004761
NA
0.001
832.89
179.28
173.78
Hill6
0.004761
0.004761
0.72
0.001
830.90
179.34
173.73
Lineal
0.004761
0.004761
0.06
1.47
834.52
308.12
174.18
Polynomial (2-degree/
0.004761
0.004761
0.18
0.81
831.17
212.06
166.34
Polynomial (3-degree/
0.004761
0.004761
0.34
0.48
830.92
196.37
168.76
Power6
0.004761
0.004761
0.94
0.001
828.90
179.28
173.78
Nonconstant variance
Exponential (Model 2)e
0.004761
0.5381
0.001
1.359
832.71
255.36
154.09
Exponential (Model 3)e
0.004761
0.5381
0.121
0.001
823.48
177.43
NA
Exponential (Model 4)e
0.004761
0.5381
0.0002
1.534
835.28
309.46
NA
Exponential (Model 5)e
0.004761
0.5381
NA
0.004
825.49
177.74
171.30
Hill®
0.004761
0.5381
0.120
0.004
823.49
177.75
NA
Lineal
0.004761
0.5381
0.001
1.53
833.28
309.45
163.38
Polynomial (2-degree/
0.004761
0.5381
0.005
0.962
829.65
209.40
157.38
Polynomial (3-degree/
0.004761
0.5381
0.015
0.639
827.48
193.20
161.14
Power®
0.004761
0.5381
0.298
0.004
821.49
177.74
171.30
aHerr et al. (2007)
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals for dose group near the BMC.
"Power restricted to >1.
Coefficients restricted to be positive.
NA = model failed to indicate value
BMC = maximum likelihood estimate of the concentration associated with the selected BMR; BMCL = 95% lower
confidence limit on the BMC (subscripts denote BMR: i.e., io = dose associated with 10% extra risk); NA = not
applicable (BMCL computation failed or the BMC was higher than the highest dose tested).
62
Carbonyl Sulfide
-------
FINAL
09-29-2015
BMDS outputs for the best-fitting model (Power nonconstant variance) follow.
Power Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
c
o
Q_
0
C
c
70
80
50
40
30
15:47 09/15.2015
Power
BMDU BMD
80 100
dose
Figure D-3. Power Nonconstant Variance for
SEP1 Tail Region Peak Amplitude (Kerr et al., 2007)
Power Model. (Version: 2.18; Date: 05/19/2014)
Input Data File: C:/Users/jzhao/Desktop/pow_COS Herr combined SEP1 _Pow-
ModelVariance-BMRlStd-Restrict.(d)
Gnuplot Plotting File: C:/Users/jzhao/Desktop/pow_COS Herr combined SEP1
_Pow-ModelVariance-BMRlStd-Restrict.pit
Tue Sep 15 15:47:12 2015
BMDS Model Run
The form of the response function is:
Y[dose] = control + slope * dose^power
Dependent variable = Mean
Independent variable = Dose
The power is restricted to be greater than or egual to 1
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
63
Carbonyl Sulfide
-------
FINAL
09-29-2015
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
lalpha = 6.51679
rho = 0
control = 41.08
slope = 2.18829e-006
power = 3.0934 4
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -power
have been estimated at a boundary point, or have been specified by
the user,
lalpha
rho
control
slope
and do not appear in the correlation matrix )
lalpha
1
-1
-0.36
0. 69
rho
-1
1
0.33
-0.69
control
-0.36
0.33
1
-0.35
slope
0.69
-0.69
-0.35
1
Interval
Variable
Limit
lalpha
5.89235
rho
4.82757
control
46.8418
slope
039
power
Estimate
-3.10431
2.47867
42.1044
6.96588e-040
18
Parameter Estimates
Std. Err.
4 .59022
1.19844
2.41708
2.62763e-040
NA
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-12.101
0.12976
37.367
1. 81582e-040 1.21159e-
NA - Indicates that this parameter has hit a bound
implied by some ineguality constraint and thus
has no standard error.
Table of Data and Estimated Values of Interest
Dose
Obs Mean
Est Mean Obs Std Dev Est Std Dev Scaled Res.
0
87.8
25
30
41.8
43.3
42.1
42.1
23.5
24.7
21.
21.
-0.0629
0.308
64
Carbonyl Sulfide
-------
FINAL
09-29-2015
132 27 41.1 42.2 17.6 21.9 -0.268
176 28 60.4 60.4 34.8 34.1 0.00403
Model Descriptions for likelihoods calculated
Model A1: Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)^2
Model A3: Yij = Mu(i) + e(ij)
Var{e(ij)} = exp(lalpha + rho*ln(Mu(i)))
Model A3 uses any fixed variance parameters that
were specified by the user
Model R: Yi = Mu + e(i)
Var{e(i)} = Sigma^2
Likelihoods of Interest
Model
A1
A2
A3
fitted
R
Log(likelihood)
-411.385922
-404.914225
-405.533876
-406.744954
-416.548709
# Param's
5
8
6
4
2
AIC
832.771845
825.828451
823.067752
821. 489908
837.097417
Explanation of Tests
Test 1:
Test
Test
Test
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adeguately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test
-2*log(Likelihood Ratio) Test df
p-value
Test
Test
Test
Test
23.269
12.9434
1.2393
2.42216
0.0007112
0.004761
0.5381
0.2979
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is less than .1. A non-homogeneous variance
model appears to be appropriate
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adeguately describe the data
65
Carbonyl Sulfide
-------
FINAL
09-29-2015
Benchmark Dose Computation
Specified effect
1
Risk Type
Estimated standard deviations from the control mean
Confidence level
0.95
BMD = 177.737
BMDL = 171.295
SEP2 amplitude data are presented in Table B-3; to complete BMD modeling, SEM
values were converted to SD values by multiplying by the square root of the respective n values.
For the combined male and female SEP2 amplitude data, all constant and nonconstant variance
models failed. The dataset (SEP2 facial region) was not amenable to BMD analysis; none of the
models provided adequate fit with or without the nonconstant variance model applied to the data
(see Table D-4).
66
Carbonyl Sulfide
-------
FINAL
09-29-2015
Table D-4. Modeling Results for SEP2 Facial Region Peak Amplitude Measurements in
Male and Female Rats Exposed to Carbonyl Sulfide for 12 Weeks"
Model
Test for
Significant
Difference
7?-Valueb
Variance
/j-Value'
Means
p-Value0
Scaled
Residuals'1
AIC
BMCisd
(HEC mg/m3)
BMCLisd
(HEC mg/m3)
Constant variance
Exponential (Model 2)e
<0.0001
0.0006
0.01
1.50
481.88
195.88
140.98
Exponential (Model 3)e
<0.0001
0.0006
0.27
0.001
475.90
180.27
172.39
Exponential (Model 4)e
<0.0001
0.0006
0.001
1.78
484.75
219.20
141.92
Exponential (Model 5)e
<0.0001
0.0006
NA
0.0016
477.90
180.32
172.10
Hill®
<0.0001
0.0006
0.27
0.0016
475.90
180.33
172.06
Linearf
<0.0001
0.0006
0.006
1.78
482.75
219.20
141.92
Polynomial (2-degree/
<0.0001
0.0006
0.04
0.947
479.05
184.48
152.64
Polynomial (3-degree/
<0.0001
0.0006
0.10
0.55
477.19
181.39
161.02
Power6
<0.0001
0.0006
0.54
0.0016
473.90
180.32
172.10
Nonconstant variance
Exponential (Model 2)e
<0.0001
0.08
0.01
1.70
470.87
175.14
116.16
Exponential (Model 3)e
<0.0001
0.08
0.56
0.21
464.50
175.02
149.82
Exponential (Model 4)e
<0.0001
0.08
0.002
1.92
473.93
194.21
116.69
Exponential (Model 5)e
<0.0001
0.08
NA
0.21
466.51
174.86
149.66
Hill6
<0.0001
0.08
NA
0.21
466.51
174.85
151.98
Linearf
<0.0001
0.08
0.008
1.91
471.93
194.21
116.69
Polynomial (2-degree/
<0.0001
0.08
0.18
1.20
465.58
170.82
133.67
Polynomial (3-degree/
<0.0001
0.08
0.51
0.78
463.49
171.29
143.97
Power6
<0.0001
0.08
0.55
0.21
464.51
174.86
149.66
aHerr et al. (2007)
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals for dose group near the BMC.
Tower restricted to >1.
Coefficients restricted to be positive.
BMC = maximum likelihood estimate of the concentration associated with the selected BMR; BMCL = 95% lower
confidence limit on the BMC (subscripts denote BMR: i.e., io = dose associated with 10% extra risk); NA = not
applicable (BMCL computation failed or the BMC was higher than the highest dose tested).
No model results follow.
67
Carbonyl Sulfide
-------
FINAL
09-29-2015
APPENDIX E. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2015). 2015 TLVs and
BEIs. Based on the documentation of the threshold limit values for chemical substances
and physical agents and biological exposure indices [TLV/BEI], Cincinnati, OH.
http://www.acgih.ore/forms/store/ProductFormPublic/20154lvs-and-beis
ACGIH. ACoGIH. (2012). Carbonyl sulfide. In Documentation of the threshold limit values and
biological exposure indices (7th ed.). Cincinnati, OH: American Conference of
Governmental Industrial Hygienists.
AT SDR (Agency for Toxic Substances and Disease Registry). (2014). Minimal risk levels
(MRLs). Atlanta, GA: Agency for Toxic Substances and Disease Registry, Centers for
Disease Control and Prevention.
http://www.atsdr.cdc.gov/mrls/pdfs/atsdr mrls december 2014.pdf
Bartholomaeus. AR; Haritos. VS. (2005). Review of the toxicology of carbonyl sulfide, a new
grain fumigant [Review], Food Chem Toxicol 43: 1687-1701.
http://dx.doi.Org/10.1016/i.fct.2005.06.016
Cal/EPA (California Environmental Protection Agency). (201 1). Hot spots unit risk and cancer
potency values. Appendix A. Sacramento, CA: Office of Environmental Health Hazard
Assessment, http://www.oehha.ca.gov/air/hot spots/2009/AppendixA.pdf
Cal/EPA (California Environmental Protection Agency). (2014). All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as of June 2014. Sacramento, CA: Office of
Health Hazard Assessment, http://www.oehha.ca.gov/air/allrels.html
Cal/EPA (California Environmental Protection Agency). (2015a). Chemicals known to the state
to cause cancer or reproductive toxicity August 14, 2015. (Proposition 65 list).
Sacramento, CA: California Environmental Protection Agency, Office of Environmental
Health Hazard Assessment.
http://oehha.ca.gov/prop65/prop65 list/files/P65single060614.pdf
Cal/EPA (California Environmental Protection Agency). (2015b). OEHHA toxicity criteria
database [Database], Sacramento, CA: Office of Environmental Health Hazard
Assessment. Retrieved from http://www.oehha.ca.gov/tcdb/index.asp
Car. BP; Eng. VM; Everds. NE; Bounous. PL (2005). Clinical pathology of the rat. In MA
Suckow; SH Veisboth; CL Franklin (Eds.), The laboratory rat (pp. 127-146). Amsterdam,
The Netherlands: Academic Press.
http://www.sciencedirect.com/science/book/9780120749Q34
Chengelis, CP; Neal, RA. (1979). Hepatic carbonyl sulfide metabolism. Biochem Biophys Res
Commun 90: 993-999.
Chengelis. CP; Neal. RA. (1980). Studies of carbonyl sulfide toxicity: Metabolism by carbonic
anhydrase. Toxicol Appl Pharmacol 55: 198-202. http://dx.doi.org/10.1016/0Q41-
008Xf80)90236-7
Chengelis. CP; Neal RA. (1987). Oxidative metabolism of carbon disulfide by isolated rat
hepatocytes and microsomes. Biochem Pharmacol 36: 363-368.
http://dx.doi.org/10.1016/0006-2952(87)90295-4
Coleman. MP; Coleman. NA. (1996). Prug-induced methaemoglobinaemia. Treatment issues
[Review], Prug Saf 14: 394-405.
Palvi. RR; Neal. RA. (1978). Metabolism in vivo of carbon disulfide to carbonyl sulfide and
carbon dioxide in the rat. Biochem Pharmacol 27: 1608-1609.
http://dx.doi.org/10.1016/0006-2952(78)90494-X
68
Carbonyl Sulfide
-------
FINAL
09-29-2015
DuPont (E. I. du Pont de Nemours and Company). (1992). Intital submission: letter from EI
Dupont de Nemours & Co to USEPA regarding toxicity studies with carbonyl sulfide
with cover letter dated 09/01/92. (TSCATS/440041. OTS0555041. Section 8ECP. 88-
920008223; 8EHQ-0892-9921).
https://ntrl.ntis.gov/NTRL/dashboard/searchResults.xhtml?searchQuery=OTS0555041
Gharahbaghian, L; Massoudian, B; DiMassa, G. (2009). Methemoglobinemia and
sulfhemoglobinemia in two pediatric patients after ingestion of hydroxylamine sulfate.
West J Emerg Med 10: 197-201.
Haritos. ¥S; Doichinov. G. (2005). Carbonic anhydrase metabolism is a key factor in the toxicity
of C02 and COS but not CS2 toward the flour beetle Tribolium castaneum [Coleoptera:
Tenebrionidae], Comp Biochem Physiol C Toxicol Pharmacol 140: 139-147.
http://dx.doi.Org/10.1016/i.cca.2005.01.012
Herr. DW; Graff. IE; Moser. VC: Crofton. KM; Little. PB; Morgan. PL; Sills. RC. (2007).
Inhalational exposure to carbonyl sulfide produces altered brainstem auditory and
somatosensory-evoked potentials in Fischer 344N rats. Toxicol Sci 95: 118-135.
http://dx.doi. org/10.1093/toxsci/kfl 146
Howard. BJ; Beresford. NA; Mayes. RW; Lamb. CS; Barnett. CL. (2007). The transfer of
different forms of 35S to goat milk. J Environ Radioact 98: 177-190.
http://dx.doi.Org/10.1016/i.ienvrad.2006.08.012
HSDB (Hazardous Substances Data Bank). (2007). Carbonyl sulfide. Available online at
http://toxnet.nlm.nih.gOv/cgi-bin/sis/search2/f7./temp/~8i9hC5:l:FULL
Hugod. C. (1981). Myocardial morphology in rabbits exposed to various gas-phase constituents
of tobacco smoke: An ultrastructural study. Atherosclerosis 40: 181-190.
http://dx.doi .org/10.1016/0021-9150(81)9003 7-X
Hugod. C; Astrup. P. (1980). Exposure of rabbits to carbon monoxide and other gas phase
constituents of tobacco smoke. MMW Munch Med Wochenschr 122 Suppl 1: 18-24.
I ARC (International Agency for Research on Cancer). (2015). I ARC Monographs on the
evaluation of carcinogenic risk to humans. Geneva, Switzerland: International Agency for
Research on Cancer, WHO. http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php
Kamstrup, O; Hugod, C. (1979). Exposure of rabbits to 50 parts per million carbonyl sulfide: A
biochemical and histomorphological study. Int Arch Occup Environ Health 44: 109-116.
http://dx.doi.org/10.1007/BF0Q386744
Michel. HO. (1938). A study of sulfhemoglobin. J Biol Chem 126: 323-348.
Monsanto (Monsanto Company). (1979). A one-generation reproduction fertility study on 2,3-
dichloropropene in rats with attached studies, cover sheets and letter dated 022190.
(TSCATS/406698. OTS0522997. Section 8E. 88-900000064; 8EHQ-0290-0892).
Washington, DC: Bio/Dynamics Inc.
Monsanto (Monsanto Company). (1982). Initial submission: acute toxicity of carbon oxysulfide
administered by inhalation to male and female Sprague-Dawley rats (final report) with
attachments and letter dated 112791. (TSCATS/420707. OTS0534820. Section 8ECP.
88-920000368). Monsanto Agricultural Company.
Monsanto (Monsanto Company). (1985). Initial submission: Two week study with carbonyl
sulfide administered by inhalation to rats with cover letter dated 052892.
(TSCATS/427204. OTS0540051. Section 8ECP. 88-920003400; 8EHQ-0692-4757).
Washington, DC.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults.xhtml?searchQuery=OTS0540051
69
Carbonyl Sulfide
-------
FINAL
09-29-2015
Morgan. PL; Little. PB; Herr. DW; Moser. VC: Collins. B; Herbert, R; Johnson. GA; Maronpot
RR: Harry. GJ; Sills. RC. (2004). Neurotoxicity of carbonyl sulfide in F344 rats
following inhalation exposure for up to 12 weeks. Toxicol Appl Pharmacol 200: 131-145.
http://dx.doi.Org/10.1016/i.taap.2004.04.013
Morrison. IP; Ton. T; Collins. IB; Switzer. RC; Little. PB; Morgan. PL; Sills. RC. (2009). Gene
expression studies reveal that DNA damage, vascular perturbation, and inflammation
contribute to the pathogenesis of carbonyl sulfide neurotoxicity. Toxicol Pathol 37: 502-
511. http://dx.doi.org/10.1177/0192623309335631
NIOSH (National Institute for Occupational Safety and Health). (2015). NIOSH pocket guide to
chemical hazards. Index of chemical abstracts service registry numbers (CAS No.).
Atlanta, GA: Center for Disease Control and Prevention, U.S. Department of Health,
Education and Welfare, http://www.cdc.gov/niosh/npg/npgdcas.html
NTP (National Toxicology Program). (1983). Report on the subchronic toxicity via gavage of
nitrobenzene (C60082) in Fischer 344 rats and B6C3F1 mice [unpublished], (MRI-
NTP08-83-19). Research Triangle Park, NC: Prepared by the EG&G Mason Research
Institute, Worcester, MA, for the National Toxicology Program, National Institute of
Environmental Health Services, Public Health Service, U.S. Department of Health and
Human Services.
NTP (National Toxicology Program). (1995). Chemical Effects in Biological Systems (CEBS);
Study information: Carbonyl sulfide; CASRN: 463-58-1. (CEBS Accession Number:
002-01834-0001-0000-9). Research Triangle Park, NC: National Institutes of
Environmental Health.
http://tools.niehs.nih.gov/cebs3/ntp¥iews/?activeTab=detail&studvNumber=A35125
NTP (National Toxicology Program). (2014). Report on carcinogens. Thirteenth edition.
Research Triangle Park, NC: U.S. Department of Health and Human Services, Public
Health Service, http://ntp.niehs.nih.gov/pubhealth/roc/rocl3/index.html
OSHA (Occupational Safety & Health Administration). (2006). Table Z-l limits for air
contaminants. Washington, DC: Occupational Safety and Health Administration
(OSHA).
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table ST A N D A R D S£ p
id=9992
OSHA (Occupational Safety & Health Administration). (201 1). Air contaminants: occupational
safety and health standards for shipyard employment, subpart Z, toxic and hazardous
substances. (OSHA Standard 1915.1000). Washington, DC: U.S. Department of Labor.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table ST A N D A R D S£ p
id=l0286
Pietri. R: Roman-Morales. E; Lopez-Garriga. J. (201 1). Hydrogen sulfide and hemeproteins:
Knowledge and mysteries. Antioxid Redox Signal 15: 393-404.
Praxair (Praxair, Inc.). (2003). Follow-up letter to earlier report of a worker's accidental chemical
exposure [TSCA Submission], (8EHQ-0903-15274 B. DCN: 89030000267).
http://vosemite.epa.gov/oppts/epatscat8.nsf/ReportSearchView/5DC548CP29A5858A85
256EFC0068PE75
Rechet/.ki. KF; Henneberg. R: da Silva. PH; Do Nascimento. AJ. (2012). Reference values for
methemoglobin concentrations in children. Revista Brasileira de Hematologia e
Hemoterapia 34: 14-16. http://dx.doi.org/10.5581/1516-8484.201200Q7
Sigma-Aldrich. (2014). Carbonyl sulfide 97.5% 463-58-1 [Fact Sheet],
http://www.sigmaaldrich.com/catalog/product/aldrich/295124?lang=en®ion=US
70
Carbonyl Sulfide
-------
FINAL
09-29-2015
Sills. RC; Morgan. PL; Herr. DW; Little. PB; George. NM; Ton. TV; Love. NE; Maronpot RR:
Johnson. GA. (2004). Contribution of magnetic resonance microscopy in the 12-week
neurotoxicity evaluation of carbonyl sulfide in Fischer 344 rats. Toxicol Pathol 32: 501-
510. http://dx.doi.org/10.1080/01926230490493918
U.S. EPA (U.S. Environmental Protection Agency). (1994a). Chemical assessments and related
activities (CARA) [EPA Report], (600/R-94/904; OHEA-I-127). Washington, DC: U.S.
Environmental Protection Agency, Office of Health and Environmental Assessment.
http://nepis.epa. gov/Exe/ZyPURL.cgi?Dockev=6000 lG8L.txt
U.S. EPA (U.S. Environmental Protection Agency). (1994b). Chemical summary for carbonyl
sulfide. (EPA 749/F-94/009a). Washington, DC: Office of Pollution Prevention and
Toxics, U.S. Environmental Protection Agency.
http://www.epa.gov/chemfact/s carbns.txt
U.S. EPA (U.S. Environmental Protection Agency). (1994c). Methods for derivation of
inhalation reference concentrations and application of inhalation dosimetry. (EPA/600/8-
90/066F). Research Triangle Park, NC: U.S. Environmental Protection Agency,
Environmental Criteria and Assessment Office.
http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=71993
U.S. EPA (U.S. Environmental Protection Agency). (201 1). Health effects assessment summary
tables (HEAST). Washington, DC: U.S. Environmental Protection Agency, Office of
Emergency and Remedial Response, http://epa-hea.st.ornl.gov/
U.S. EPA (U.S. Environmental Protection Agency). (2012a). 2012 Edition of the drinking water
standards and health advisories [EPA Report], (EPA/822/S-12/001). Washington, DC:
Office of Water.
http://water.epa.gov/action/advisories/drinking/upload/dwstandards2012.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2012b). Benchmark dose technical
guidance. (EPA/100/R-12/001). Washington, DC: Risk Assessment Forum.
http://www.epa.gov/raf/publications/pdfs/benchmark dose guidance.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2015). EPA's Integrated Risk Information
System Program (IRIS). Progress report and report to Congress. Washington, DC: U.S.
Environmental Protection Agency, IRIS, http://www.epa.gov/iris/index.html
Walton. G. (195 1). Survey of literature relating to infant methemoglobinemia due to nitrate-
contaminated water. Am J Public Health 41: 986-996. http://dx.doi.org/doi:
10.2105/AJPH.41.8_Pt_l.986
Wang. R: Li. X; Cen. X; /eng. L; Tan. X. (1999). Report on toxicity test of carbonyl sulfide. In
Z Jin; Q Liang; Y Liang; X Tan; L Guan (Eds.), Proceedings of the 7th International
Working Conference on Stored-Product Protection (pp. 572-583). Chengdu, China:
Sichuan Publishing House of Science and Technology.
http://spiru.cgahr.ksu.edu/proi/iwcspp/iwcspp7.html
Weil. ED; Sandler. SR; Gernon. M. (2006). Sulfur compounds. In Kirk-Othmer Encyclopedia of
Chemical Technology. New York, NY: John Wiley & Sons.
http://dx.doi.Org/10.1002/0471238961.1921120623050912.a01.pub2
WHO (World Health Organization). (2015). Online catalog for the Environmental Health
Criteria (EHC) monographs. Geneva, Switzerland: World Health Organization (WHO).
http://www.who.int/ipcs/publications/ehc/en/
Williams. SR. (2001). Methemoglobin. In LJ Ling; RF Clark; TB Erickson; JH Trestrial (Eds.),
Toxicology secrets. Philadelphia, PA: Hanley and Belfus Publishing.
71
Carbonyl Sulfide
------- |