SEPA
EPA/690/R-20/009F | September 2020 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
Vinyl Bromide
(CASRN 593-60-2)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United Stiles
MKHu Environmental Protection
IbbI # % Agency
EPA/690/R-20/009F
September 2020
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Vinyl Bromide
(CASRN 593-60-2)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
ii
Vinyl bromide
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Allen Davis, MSPH
Center for Public Health and Environmental Assessment, Washington, DC
Deborah Segal, MS
Center for Public Health and Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development's (ORD's) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
in
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
INTRODUCTION 3
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7
HUMAN STUDIES 12
ANIMAL STUDIES 12
Oral Exposures 12
Inhalation Exposures 12
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 18
Genotoxicity Studies 18
Supporting Animal Toxicity Studies 23
Absorption, Distribution, Metabolism, and Excretion (ADME) Studies 31
Mode-of-Action/Mechanistic Studies 32
DERIVATION 01 PROVISIONAL VALUES 34
DERIVATION 01 ORAL REFERENCE DOSES 34
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 34
Derivation of Subchronic Provisional Reference Concentration 34
Derivation of Chronic Provisional Reference Concentration 37
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 38
MODE-OF -ACTION DISCISSION 39
Hypothesis 39
Mode-of-Action Conclusions 41
DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 41
Derivation of Provisional Oral Slope Factor 41
Derivation of Provisional Inhalation Unit Risk 41
APPENDIX A. SCREENING PROVISIONAL VALUES 44
APPENDIX B. DATA TABLES 45
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 58
APPENDIX D. REFERENCES 98
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
LC50
median lethal concentration
ACGIH
American Conference of Governmental
LD50
median lethal dose
Industrial Hygienists
LOAEL
lowest-observed-adverse-effect level
AIC
Akaike's information criterion
MN
micronuclei
ALD
approximate lethal dosage
MNPCE
micronucleated polychromatic
ALT
alanine aminotransferase
erythrocyte
AR
androgen receptor
MOA
mode of action
AST
aspartate aminotransferase
MTD
maximum tolerated dose
atm
atmosphere
NAG
7V-acetyl-P-D-glucosaminidase
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMC
benchmark concentration
NTP
National Toxicology Program
BMCL
benchmark concentration lower
NZW
New Zealand White (rabbit breed)
confidence limit
OCT
ornithine carbamoyl transferase
BMD
benchmark dose
ORD
Office of Research and Development
BMDL
benchmark dose lower confidence limit
PBPK
physiologically based pharmacokinetic
BMDS
Benchmark Dose Software
PCNA
proliferating cell nuclear antigen
BMR
benchmark response
PND
postnatal day
BUN
blood urea nitrogen
POD
point of departure
BW
body weight
PODadj
duration-adjusted POD
CA
chromosomal aberration
QSAR
quantitative structure-activity
CAS
Chemical Abstracts Service
relationship
CASRN
Chemical Abstracts Service registry
RBC
red blood cell
number
RDS
replicative DNA synthesis
CBI
covalent binding index
RfC
inhalation reference concentration
CHO
Chinese hamster ovary (cell line cells)
RfD
oral reference dose
CL
confidence limit
RGDR
regional gas dose ratio
CNS
central nervous system
RNA
ribonucleic acid
CPHEA
Center for Public Health and
SAR
structure activity relationship
Environmental Assessment
SCE
sister chromatid exchange
CPN
chronic progressive nephropathy
SD
standard deviation
CYP450
cytochrome P450
SDH
sorbitol dehydrogenase
DAF
dosimetric adjustment factor
SE
standard error
DEN
diethylnitrosamine
SGOT
serum glutamic oxaloacetic
DMSO
dimethylsulfoxide
transaminase, also known as AST
DNA
deoxyribonucleic acid
SGPT
serum glutamic pyruvic transaminase,
EPA
Environmental Protection Agency
also known as ALT
ER
estrogen receptor
SSD
systemic scleroderma
FDA
Food and Drug Administration
TCA
trichloroacetic acid
FEVi
forced expiratory volume of 1 second
TCE
trichloroethylene
GD
gestation day
TWA
time-weighted average
GDH
glutamate dehydrogenase
UF
uncertainty factor
GGT
y-glutamyl transferase
UFa
interspecies uncertainty factor
GSH
glutathione
UFC
composite uncertainty factor
GST
glutathione-S-transferase
UFd
database uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFh
intraspecies uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFl
LOAEL-to-NOAEL uncertainty factor
HEC
human equivalent concentration
UFS
subchronic-to-chronic uncertainty factor
HED
human equivalent dose
U.S.
United States of America
i.p.
intraperitoneal
WBC
white blood cell
IRIS
Integrated Risk Information System
IVF
in vitro fertilization
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
VINYL BROMIDE (CASRN 593-60-2)
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.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. Environmental
Protection Agency's (EPA's) PPRTV website at https://www.epa.gov/pprtv. PPRTV
assessments are eligible to be updated on a 5-year cycle and revised as appropriate to incorporate
new data or methodologies that might impact the toxicity values or affect the characterization of
the chemical's potential for causing adverse human-health effects. Questions regarding
nomination of chemicals for update can be sent to the appropriate U.S. EPA Superfund and
Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-science).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV assessments receive internal peer review by at least two Center for Public
Health and Environmental Assessment (CPHEA) scientists and an independent external peer
review by at least three scientific experts. The reviews focus on whether all studies have been
correctly selected, interpreted, and adequately described for the purposes of deriving a
provisional reference value. The reviews also cover quantitative and qualitative aspects of the
provisional value development and address whether uncertainties associated with the assessment
have been adequately characterized.
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DISCLAIMERS
The PPRTV 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. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA Office of Research and Development (ORD) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
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INTRODUCTION
Vinyl bromide (CASRN 593-60-2) belongs to the halogenated olefin class of compounds
(N I P. 2016). It is primarily used in polymer and copolymer production. Vinyl bromide is also
used in pharmaceutical and fumigant production (N I P. 2016; Belpoggi et al.. 2012; HSDB.
2009). It is listed on the U.S. EPA's Toxic Substances Control Act (TSCA) public inventory
(U.S. HP A. 2018b) and is registered with Europe's Registration, Evaluation, Authorisation and
Restriction of Chemicals (REACH) program (ECHA. 2018).
Vinyl bromide is produced by hydrogen bromide addition to acetylene in the presence of
mercury and/or copper halide catalysts. It may also be produced by partial debromination of
1,2-dibromoethane with alcoholic potassium hydroxide (Belpoggi et al.. 2012). Vinyl bromide
may be formed in air as a degradation product of 1,2-dibromoethane (HSDB, 2009).
The empirical formula for vinyl bromide is C2H3Br; its structure is shown in Figure 1.
Table 1 summarizes the physicochemical properties of vinyl bromide. It is a flammable,
colorless gas and a liquid below 15.8°C. Although secondary sources [e.g., N I P (2017);
Belpoggi et al. (2012); IARC (2008)1 have reported that vinyl bromide is insoluble in water, no
study details are available to substantiate this reported insolubility. In contrast to those reports,
the water solubility of vinyl bromide is estimated to be high at 1.82 mol/L (U.S. HP A. 2012c)
based on a measured log Kow of 1.57 and water solubility data for analogous chemicals,
including bromoethane, vinyl chloride, and chloroethane, with experimental water solubility
values of 9, 8.8, and 6.7 g/L, respectively (ChemlDptus, 2018a. b, c). In the air, vinyl bromide
will exist in the gas phase, based on its vapor pressure of 1,033 mm Hg. It will be degraded in
the atmosphere by reaction with photochemically produced hydroxyl radicals and have a half-life
of 2.4 days, calculated from a measured reaction rate constant of
6.8 10 12 cm 7molecule-second at 25°C (HSDB. 2009). Reaction of vinyl bromide with ozone
in the atmosphere is expected to occur more slowly, based on an estimated rate constant of
2.5 x 10~19 cmVmolecule-second at 25°C, corresponding to a half-life of 47 days. Volatilization
of vinyl bromide from dry soil surfaces is expected based on its vapor pressure. Volatilization
from water or moist soil surfaces is expected based on an estimated Henry's law constant of
7.26 x 10~3 atm-m3/mole. The estimated Koc of 31.2 L/kg for vinyl bromide indicates the
potential for mobility in soil and a negligible potential to adsorb to suspended solids and
sediment in aquatic environments. Hydrolysis of vinyl bromide is not expected because it lacks
hydrolysable functional groups (HSDB. 2009). The compound will polymerize rapidly in
sunlight and react vigorously in the presence of oxidizing materials (Belpoggi et al .. 2012).
Furthermore, the blood-air partition coefficients determined for vinyl bromide in humans and
rats are 2.27 and 4.05 (Gargas et al.. 1989). respectively, which are important for understanding
regional deposition/absorption of this chemical and for dosimetry conversions (see section on
"Animal Studies" for more details).
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Br^^CH2
Figure 1. Vinyl Bromide (CASRN 593-60-2) Structure
Table 1. Physicochemical Properties of Vinyl Bromide (CASRN 593-60-2)
Property (unit)
Value
Physical state
Colorless gas (>15.8°C) or liquid (<15.8°C)a
Boiling point (°C)
15.8a
Melting point (°C)
-137.83
Density (g/cm3 at 20 °C)
1.49333
Vapor pressure (mm Hg at 25°C)
l,033a
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mol/L at 25°C)
1.82 (predicted average)b
Octanol-water partition constant (log Kow)
1.57a
Henry's law constant (atm-m3/mol at 20°C)
7.26 x 10 3 (predicted average)b
Soil adsorption coefficient Koc (L/kg)
31.2 (predicted average)b
Atmospheric OH rate constant (cm3/molecule-sec at
25°C)
6.8 x 10-12a
Atmospheric half-life (d)
2.4 (calculated based on its measured OH rate constant)3
Relative vapor density (air = 1)
3.7a
Molecular weight (g/mol)
106.943
Flash point (°C)
5°
aHSD6 (2009).
bData were extracted from the U.S. EPA CompTox Chemicals Dashboard (vinyl bromide; CASRN 593-60-2;
https://comDtox.epa.gov/dashboard/dsstoxdb/resiilts7searclFDTXSID8021432. Accessed July 15, 2020).
°6elpoggi et at (2012).
NA = not applicable.
A summary of available toxicity values for vinyl bromide from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for Vinyl Bromide (CASRN 593-60-2)
Source (parameter)3'b
Value (applicability)
Notes
Reference0
Noncancer
IRIS (RfC)
0.003 mg/m3
Based on hypertrophy and basophilic
and eosinophilic foci in the liver in a
chronic inhalation study in rats
U.S. EPA (2003)
HEAST (sRfC)
0.003 mg/m3
The chronic RfC was adopted as the
subchronic RfC; based on hypertrophy
and basophilic and eosinophilic foci in
the liver in a chronic intermittent
inhalation exposure study in rats
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2017)
IPCS
NV
NA
IPCS (2018)
CalEPA
NV
NA
CalEPA (2016);
CalEPA (2017);
CalEPA (2018)
OSHA
NV
NA
OSHA (2017a);
OSHA (2017b)
Cancer
IRIS
NV
NA
U.S. EPA (2018a)
HEAST (IUR)
0.000032 (ng/m3)-1
Based on liver tumors in a chronic
intermittent inhalation exposure study
in rats
U.S. EPA (2011);
U.S. EPA (1984)
HEAST (OSF)
0.11 (mg/kg-d)
Based on liver tumors in a chronic
intermittent inhalation exposure study
in rats
U.S. EPA (2011);
U.S. EPA (1984)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP (WOE)
Reasonably anticipated to be
a human carcinogen
Based on sufficient evidence of
carcinogenicity from studies in
experimental animals
NTP (2016)
I ARC (WOE)
Group 2A: Probably
carcinogenic to humans
Based on inadequate evidence for
carcinogenicity in humans, and
sufficient evidence in experimental
animals, as well as similarity to vinyl
chloride
I ARC (2008);
I ARC (2017)
CalEPA (WOE)
Listed as causing cancer
under Proposition 65
NA
CalEPA (2017);
CalEPA (2018)
ACGIH (TLV-TWA)
2.2 mg/m3
Based on liver cancer
ACGIH (2001);
ACGIH (2016)
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Table 2. Summary of Available Toxicity Values for Vinyl Bromide (CASRN 593-60-2)
Source (parameter)3'b
Value (applicability)
Notes
Reference0
ACGIH (WOE)
A2: Suspected human
carcinogen
Based on evidence in animal studies
and analogy to vinyl chloride
ACGIH (200T):
ACGIH (2016)
NIOSH (WOE)
Potential occupational
carcinogen
NA
NIOSH (2016)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration.
Parameters: IUR = inhalation unit risk; OSF = oral slope factor; RfC = reference concentration; sRfC = subchronic
reference concentration; TLV = threshold limit value; TWA = time-weighted average; WOE = weight of evidence.
°Reference date for the IRIS cancer data is the date the online source was accessed. All other reference dates are
the publication date for the databases.
NA = not applicable; NV = not available.
Non-date-limited literature searches were initially conducted in October 2017 and
updated in December 2019 and June 2020 for studies relevant to the derivation of provisional
toxicity values for vinyl bromide (CASRN 593-60-2). Searches were conducted by U.S. EPA's
Health and Environmental Research Online (HERO) staff and stored in the HERO database.1
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:
American Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic
Substances and Disease Registry (ATSDR), California Environmental Protection Agency
(CalEPA), Defense Technical Information Center (DTIC), European Centre for Ecotoxicology
and Toxicology of Chemicals (ECETOC), European Chemicals Agency (ECHA), U.S. EPA
Chemical Data Access Tool (CDAT), U.S. EPA ChemView, U.S. EPA Health Effects
Assessment Summary Tables (HEAST), U.S. EPA Integrated Risk Information System (IRIS),
U.S. EPA Office of Water (OW), International Agency for Research on Cancer (IARC), Japan
Existing Chemical Data Base (JECDB), National Institute for Occupational Safety and Health
(NIOSH), National Toxicology Program (NTP), Organisation for Economic Co-operation and
Development (OECD) Existing Chemicals Database, OECD Screening Information Data Set
(SIDS) High Production Volume (HPV) Chemicals via International Programme on Chemical
Safety (IPCS) INCHEM, Occupational Safety and Health Administration (OSHA), and World
Health Organization (WHO).
1 U.S. EPA's HERO database provides access to the scientific literature behind U.S. EPA science assessments. The
database includes more than 2,500,000 scientific references and data from the peer-reviewed literature used by
U.S. EPA to develop reports that support critical agency decision-making for developing its regulations.
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer evidence
bases, respectively, for vinyl bromide, and include all potentially relevant repeated short-term,
subchronic, and chronic studies, as well as reproductive and developmental toxicity studies.
Principal studies used in the PPRTV assessment for derivation of provisional toxicity values are
identified in bold. The phrase "statistical significance" and term "significant," used throughout
the document, indicates ap-value of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Vinyl Bromide (CASRN 593-60-2)
Category3
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
Short term
5-10 M, Wistar rat; 7 hr/d, 5 d/wk;
3 d, 1 wk, 2 wk, or 4 wk
Reported analytical concentrations:
0 or 43,763 mg/m3
0, 9,117.3
Clinical signs of toxicity (hypoactivity,
lethargy) and decreased body weight.
NDr
9,117.3
Leone and Torkelson
PR
(1970); Dow
Chemical (1969)
Short term
5 M/5 F, Charles River rat, 7 hr/d,
5 d/wk, 3 wk
Reported analytical concentrations:
0, 256.3, or 486.1 ppm
0, 233.5,442.9
No adverse effects.
442.9
NDr
Leone and Torkelson
PR
(1970); Hazleton
Laboratories (1967)
[interim sacrifice
group]
Subchronic
2-3 M/3-4 F, cynomolgus
monkey, 7 hr/d, 5 d/wk, 6 mo
Reported analytical
concentrations: 0,256.3, or
486.1 ppm
0, 233.5,442.9
Decreased body weight in males and
increased absolute and relative liver
weight in females.
NDr
233.5
Leone and
PR, PS
Torkelson (1970);
Hazleton
Laboratories (1967)
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Table 3A. Summary of Potentially Relevant Noncancer Data for Vinyl Bromide (CASRN 593-60-2)
Category3
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Chronic
25 M/25 F, Charles River rat,
7 hr/d, 5 d/wk, 6 mo
Reported analytical concentrations:
0, 256.3, or 486.1 ppm
0, 233.5,442.9
No effects.
442.9
NDr
Leone and Torkelson
(1970); Hazleton
Laboratories (1967)
PR
Chronic
3 M/3 F, NZW rabbit, 7 hr/d,
5 d/wk, 6 mo
Reported analytical concentrations:
0, 256.3, or 486.1 ppm
0, 233.5,442.9
Increased absolute liver weight in males.
Decreased body weight and increased
relative liver and kidney weight in
females.
NDr
233.5
Leone and Torkelson
(1970); Hazleton
Laboratories (1967)
PR
Chronic
120-144 M/120-144 F, S-D rat,
6 hr/d, 5 d/wk, 24 mo
Reported analytical concentrations:
0, 9.7, 52, 247, or 1,235 ppm
0,7.5,41, 193,
964.6
Increased incidence of non-neoplastic
hepatic lesions (peliosis, eosinophilic
foci, basophilic foci). Additional effects
at higher exposures included increased
hepatocyte hypertrophy, microcytic
anemia, hematuria, decreased body
weight, and increased mortality.
NDr
7.5
Benva et al. (1982);
EPL (1978); Ethvl
Corporation (1979);
Hiintinedon Research
Center (1979); Dorato
(1978)
PR,
IRIS
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Table 3A. Summary of Potentially Relevant Noncancer Data for Vinyl Bromide (CASRN 593-60-2)
Category3
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Reproductive/
Developmental
ND
aDuration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated
exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDosimetry: HECs are calculated for systemic (ER) effects. The HEC values for ER effects were calculated by treating vinyl bromide as a Category 3 gas and using the
following equation from U.S. EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week exposed ^ 7 days) x ratio of
blood-gas partition coefficient (animal:human), using a default coefficient of 1. The default value was used because the blood-air partition coefficients for monkeys and
rabbits are unknown and the rat blood-air partition coefficient of 4.05 is greater than the human blood-air partition coefficient of 2.27 as indicated by Gargas et al.
(1989).
°Notes: IRIS = used by U.S. EPA (2003): PR = peer reviewed; PS = principal study.
ER = extrarespiratory; F = female(s); HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NDr = not
determined; NOAEL = no-observed-adverse-effect level; NZW = New Zealand White; S-D = Sprague-Dawley.
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Table 3B. Summary of Potentially Relevant Cancer Data for Vinyl Bromide (CASRN 593-60-2)
Category
Number of Male/Female, Strain,
Species, Study Type, Reported Doses,
Study Duration
Dosimetry3
Critical Effects
Reference (comments)
Notesb
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
Carcinogenicity
120-144 M/120-144 F, S-D rat, 6 hr/d,
5 d/wk, 24 mo
Reported analytical concentrations: 0,
9.7, 52,247, or 1,235 ppm
0, 7.5, 41,193, 964.6
Significant increase in the incidence of
angiosarcomas (primarily in liver) in males
and females at >7.5 mg/m3;
exposure-related tumors observed at higher
exposures included hepatocellular
neoplasms (combined), and Zymbal gland
squamous cell carcinoma and papilloma.
Kenya et al. (1982):
Ethyl Corporation
(1979): Porato (1978):
EPL (1978):
Huntingdon Research
Center (1979)
PR, PS
"Dosimetry: Inhalation exposure units are expressed as HECs (mg/m3). The HEC for ER effects was calculated by treating vinyl bromide as a Category 3 gas and using
the following equation from U.S. EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week exposed ^ 7 days) x ratio
of blood-gas partition coefficient (animal:human), using a default coefficient of 1 because the rat blood-air partition coefficient of 4.05 is greater than the human
blood-air partition coefficient of 2.27 as indicated by Gargas et al. (1989).
bNotes: PR = peer reviewed; PS = principal study.
ER = extrarespiratory; F = female(s); HEC = human equivalent concentrations; M = male(s); ND = no data; S-D = Sprague-Dawley.
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HUMAN STUDIES
No studies have been identified that evaluated potential health effects in humans
following exposure to vinyl bromide. IARC (1986) reported that exposure to high vapor
concentrations of vinyl bromide can cause unconsciousness; however, no specific source for this
information was cited.
ANIMAL STUDIES
Oral Exposures
No repeated-dose oral studies have been identified.
Inhalation Exposures
Short-Term Studies
Leans and Tor kelson (1970); Dow Chemical (1969)
Groups of Wistar rats (five males/group) were exposed to vinyl bromide (purity 99.7%)
at a mean analytical vapor concentration of 43,763 mg/m3 for 7 hours/day, 5 days/week for
3 days, 1 week, 2 weeks, or 4 weeks via whole-body inhalation. Results are available in both a
published paper by Leong and Torkelson (1970) and an unpublished report by Dow Chemical
(1969). An additional group of 10 male rats served as sham controls, with exposure to filtered
room air under similar conditions for 4 weeks. Food and water were provided ad libitum except
during exposure periods. The rats were observed daily for mortality and clinical signs of
toxicity. Body weights were measured 3 times/week. All animals were sacrificed at the end of
the assigned exposure period and examined for gross and histopathological changes in "major
organs" (not further defined). Control rats were sacrificed with the final exposure group.
Reported statistical analyses were limited to Student's Mest for body-weight data.
One exposed rat was sacrificed moribund on the Exposure Day 9 due to respiratory
distress; all other rats survived until the scheduled sacrifice. Exposed rats showed decreased
activity during the first hour of exposure each day, with drowsiness and inactivity for the
remaining 6 hours of daily exposure. Clinical signs were rapidly reversed upon removal from
the exposure chamber. Body weights in exposed rats were significantly and progressively
decreased by 9 and 11% after 15 and 20 exposures, respectively, compared with control
(see Table B-l). At scheduled necropsy, the study authors reported that no exposure-related
gross or histopathological lesions were observed in major organs (no quantitative data were
reported). Multifocal gray areas were observed in the lung of the rat that was sacrificed
moribund; however, no histopathological lung lesions were observed. The study authors
reported that all other major organs were considered normal at necropsy in this animal.
The only exposure level of 43,763 mg/m3 (HEC = 9,117.3 mg/m3) is identified as a
lowest-observed-adverse-effect level (LOAEL) based on clinical signs of toxicity (hypoactivity,
lethargy) and decreased body weight. The analytical concentration of 43,763 mg/m3 corresponds
to a human equivalent concentration (HEC) value of 9,117.3 mg/m3 for extrarespiratory effects.2
2HEC for extrarespiratory effects calculated by treating vinyl bromide as a Category 3 gas and using the following
equation from U.S. EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day
exposed 24 hours) x (days/week exposed 7 days) x ratio of blood-gas partition coefficient (animal:human),
using a default coefficient of 1 because the rat blood-air partition coefficient of 4.05 is greater than the human
blood-air partition coefficient of 2.27 as indicated by Gargas et al. (1989).
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Subchronic and Chronic Studies with Interim Sacrifice
Le ons and Tor kelson (1970); Hazleton Laboratories (1967)
The results of a 6-month inhalation study of vinyl bromide in rats, monkeys, and rabbits
are described in an unpublished industry report by Hazleton Laboratories (1967) and a
peer-reviewed publication by Leong and Torkelson (1970). The rat study included a 3-week
interim sacrifice group.
Groups of Charles River rats (25/sex/group), cynomolgus monkeys (3/sex/group), and
New Zealand White rabbits (3/sex/group) were exposed to vinyl bromide (purity 99.7%) at
analytical vapor concentrations (mean ± standard deviation [SD]) of 256.3 ± 39.4 ppm
(1,121 ± 172 mg/m3) or 486.1 ± 58.3 ppm (2,126 ± 255 mg/m3),3 for 7 hours/day, 5 days/week
for 6 months via whole-body inhalation. The control animals (2 male and 4 female monkeys,
3 rabbits/sex, 25 rats/sex) were exposed to filtered room air under the same conditions.
Additional groups of rats (5 rats/sex/group) were similarly exposed to vinyl bromide and
sacrificed after 3 weeks (interim sacrifice group). Food and water were provided ad libitum
except during exposure periods. The animals were observed daily for mortality and clinical
signs of toxicity. Body weights were recorded weekly in rats and rabbits, but only before and
after the 6-month exposure period in monkeys. Weekly food consumption was determined
1 week prior to exposure and during the first and sixth month of exposure in five rats/sex/group
and in all rabbits; food consumption was not monitored in monkeys. Hematological parameters
were evaluated prior to exposure and after 2, 10, and 24 weeks of exposure to 0 or 2,126 mg/m3
in all monkeys, five rats/sex/group, and all rabbits. Additionally, hematological parameters were
measured in five rats/sex/group exposed to 0 or 1,121 mg/m3 prior to exposure and after
24 weeks of exposure. Hematological endpoints included red blood cell (RBC) count, white
blood cell (WBC) count, and differential hemoglobin (Hb) and hematocrit (Hct). At sacrifice, all
animals were subjected to gross necropsy, and the lungs, heart, liver, spleen, kidneys, and gonads
were removed and weighed. These organs, along with the thyroid, pancreas, and adrenals, were
examined microscopically. Nasal tissues were not examined for gross or histopathological
changes. Reported statistical analyses were limited to analysis of variance (ANOVA) for body
and -organ-weight data.
Nine rats died during the study, but the deaths were attributed to accidental injuries and
distributed across exposure groups (one male control, two males at 1,121 mg/m3, two males at
2,126 mg/m3, two female controls, and two females at 1,121 mg/m3). No clinical signs of
toxicity, body-weight effects, or changes in food consumption were reported. No
exposure-related hematological changes were observed. At the 3-week interim sacrifice,
significant organ-weight changes included an 18% decrease in absolute kidney weight in females
at 2,126 mg/m3 and a 1.6- to 3-fold increase in relative ovary weight in females at >1,121 mg/m3
(see Table B-2). However, at the 6-month terminal sacrifice, exposure-related changes were not
observed in the kidney or ovary (see Table B-3). Significant organ-weight changes at 6 months
were limited to the low-exposure group, including increases of 13 to 17% in relative heart weight
in males and females, respectively, and increases of 9 and 12% in absolute and relative liver
weight, respectively, in males (see Table B-3). Because of inconsistencies in findings and lack
of associated histopathological lesions, the study authors considered these organ-weight changes
Concentration in mg/m3 = concentration in ppm x molecular weight (106.94 g/mol) 24.45 L/mol.
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incidental. No exposure-related lesions were observed in any organ evaluated at 3 weeks, or
6 months.
All monkeys survived until scheduled sacrifice, and no clinical signs of toxicity were
observed. Terminal body weights in males were decreased by 25% at 2,126 mg/m3, compared
with control (see Table B-4). Terminal body weight in females was biologically significantly
decreased at 1,121 mg/m3 but not at 2,126 mg/m3 (see Table B-4; note that a>10% decrease in
body weight is considered to be biologically significant by the U.S. EPA for the purposes of this
PPRTV assessment). No exposure-related changes in hematological parameters were seen. Some
variation was noted in organ weights at terminal sacrifice, including slight increases in relative
liver weights in males at 2,126 mg/m3, increases in relative spleen weights in both sexes at
>1,121 mg/m3, and decreases in relative thyroid weights in males at 2,126 mg/m3 and females at
>1,121 mg/m3 (see Table B-4); however, these findings were not statistically or biologically
significant. Conversely, both absolute and relative liver weights were biologically significantly
increased in females at >1,121 mg/m3 (note that a >10% increase in absolute and relative liver and
kidney weight is considered biologically significant by the U.S. EPA for the purposes of this PPRTV
assessment). No exposure-related lesions were reported in any of the organs evaluated.
All rabbits survived until scheduled sacrifice. An infestation of ear mites occurred in the
colony during Study Week 16 and was treated by applying castor oil to the ears. Some animals
in all groups had transient diarrhea due to incidental ingestion of the castor oil. No
exposure-related hematological changes were observed. In male rabbits, relative liver and
kidney weights were biologically significantly increased at 1,121 mg/m3 but not at 2,126 mg/m3,
and absolute liver weight was biologically significantly increased at >1,121 mg/m3. In female
rabbits, body weight was biologically significantly decreased (>10%>) at >1,121 mg/m3. Relative
liver weight was biologically significantly increased (>10%>) at 2,126 mg/m3. Relative kidney
weight was biologically significantly increased (>10%>) at >1,121 mg/m3. No exposure-related
changes in organ histology were observed in any organ evaluated.
In rats, the highest exposure level of 2,126 mg/m3 (HEC = 442.9 mg/m3) is a NOAEL
based on a lack of clearly adverse, statistically significant findings. In monkeys, the lowest
concentration of 1,121 mg/m3 (HEC = 233.5 mg/m3) is identified as a LOAEL for increased
absolute and relative liver weights in females. In rabbits, a LOAEL of 1,121 mg/m3
(HEC = 233.5 mg/m3) is identified based on decreased body weight and increased relative
kidney weight in females and increased absolute liver weight in males. The analytical
concentrations of 1,121 and 2,126 mg/m3 correspond to HEC values of 233.5 and 442.9 mg/m3,
respectively, for systemic (extrarespiratory) effects.4
4HEC for extrarespiratory effects calculated by treating vinyl bromide as a Category 3 gas and using the following
equation from U.S. EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day
exposed 24 hours) x (days/week exposed 7 days) x ratio of blood-gas partition coefficient (animal:human),
using a default coefficient of 1 because the monkey and rabbit blood-air partition coefficients for vinyl bromide are
not known, and the rat blood-air partition coefficient of 4.05 is greater than the human blood-air partition coefficient
of 2.27 as indicated by Gargas et at (1989).
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Chronic/Carcinogenicity Study with Interim Sacrifices
Benyaetal (1982); Dorato (1978); EPL (1978); Huntingdon Research Center (1979);
Ethyl Corporation (1979)
Results of a chronic 2-year inhalation bioassay in rats, along with 6-, 12-, and 18-month
interim sacrifices, were reported in a peer-reviewed study by Benva et al. (1982). A series of
unpublished industry reports (Ethyl Corporation. 1979; Huntingdon Research Center. 1979;
Dorato. 1978; EPL. 1978) also provide interim sacrifice data and pathology reports. In this study
(Benva et al .. 1982). groups of Sprague-Dawley (S-D) rats (120/sex/group) were exposed to
vinyl bromide (purity 99.9%) at analytical concentrations (mean ± SD) of 9.7 ±1.5 ppm
(42 ± 6.6 mg/m3), 52 ± 5 ppm (230 ± 20 mg/m3), 247 ± 13 ppm (1,080 ± 57 mg/m3), or
1,235 ± 102 ppm (5,402 ± 446 mg/m3)5 for 6 hours/day, 5 days/week for up to 24 months via
whole-body inhalation. The control group (144 rats/sex) was similarly exposed to filtered and
conditioned outside air. Five rats/sex/group were sacrificed at 6 months, 10 rats/sex/group were
sacrificed at 12 and 18 months, and all remaining rats were scheduled for sacrifice at 24 months.
Food was available ad libitum except during exposure periods, and water was available ad
libitum at all times. The animals were observed daily for mortality and clinical signs of toxicity.
Body weights were recorded weekly. Blood was collected at each interim and terminal sacrifice
for clinical chemistry (glucose, blood urea nitrogen [BUN], alkaline phosphatase [ALP],
aspartate aminotransferase [AST], lactate dehydrogenase [LDH], protein, bilirubin, albumin,
cholesterol, calcium, phosphate) and hematology (WBC count, RBC count, Hb, Hct, mean
corpuscular volume [MCV]). Urine was collected at 6, 12, and 18 months for urinalysis
(bilirubin, occult blood, pH, glucose, ketones, proteins, specific gravity). Prior to exposure,
10 rats/sex/group were evaluated for baseline hematologic, clinical chemistry, and urinalysis
measurements. All animals, including any animal that died or was sacrificed moribund, were
subject to gross necropsy. The adrenal glands, brain, gonads, kidneys, liver, heart, lungs,
trachea, pituitary, spleen, and thyroids were removed and weighed. A complete set of 30 organs
and tissues was examined for histopathological changes at each interim and terminal sacrifice
from all exposure groups. In all rats that died or were sacrificed moribund, the lungs, liver,
Zymbal gland, mammary gland, brain, and gross lesions were examined microscopically.
Statistical analyses included Kruskal-Wallis one-way ANOVA followed by Mann-Whitney U
test for nonparametric continuous data, Bartlett's test followed by Student's /-test for parametric
continuous data, and Yates-corrected x2 test for dichotomous data.
Mortality was increased in a concentration-related manner at exposures >230 mg/m3 after
approximately 12 months of exposure. Based on graphically reported data, mortality at
12 months (not including planned interim sacrifices) was approximately 12% in male and female
rats exposed to 5,402 mg/m3, and <10% in all other groups. At 18 months, the estimated
cumulative unplanned mortality based on graphically reported data was 8-12, 6-13, 15-19,
24-42, and 66-77% in rats exposed to 0, 42, 230, 1,080, and 5,402 mg/m3, respectively.
Because of the high mortality at 5,402 mg/m3, all surviving rats from this group were sacrificed
at 18 months. Mortality in other groups was approximately 40-42, 45-47, 68-82, and 94-95%
at 24-month terminal sacrifice in rats exposed to 0, 42, 230, and 1,080 mg/m3, respectively
(estimated from graphically reported data).
No clinical signs of toxicity aside from mortality were reported. Based on graphically
reported data, body weights were similar to controls throughout the first year of the study in all
Concentration in mg/m3 = concentration in ppm x molecular weight (106.94 g/mol) 24.45 L/mol.
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groups, but decreased over the course of the second year such that terminal body weights
(18 months at 5,402 mg/m3 and 24 months in the other groups) were decreased by approximately
10-20% at exposure levels >230 mg/m3. No significant concentration-related, body-weight
changes were observed at the 6- or 12-month interim sacrifices (see Tables B-5 and B-6); data
for the 18-month interim sacrifice were not available. Significant hematological findings at
18 months included decreases of 12-34% in Hct in females at >1,080 mg/m3 and males at
5,402 mg/m3, decreases of 25-21% in Hb and RBC count in females at 5,402 mg/m3, and
decreases of 6—10% in MCV in males and females at >1,080 mg/m3 (see Tables B-7 and B-8).
The study authors considered the findings to be suggestive of microcytic anemia at 5,402 mg/m3.
Sporadic significant hematological findings were also observed at 6 and 12 months
(see Tables B-7 and B-8). Small, but statistically significant, changes were observed in clinical
chemistry data at 6, 12, and 18 months; however, no clear patterns with respect to concentration,
time, or direction of change were observed (see Tables B-9 and B-10). Urinalysis showed
hematuria at 18 months in male and female rats exposed at 5,402 mg/m3; no other altered
urinalysis parameters were observed (data not shown by the study authors). No hematological,
clinical chemistry, or urinalysis data were presented following terminal sacrifice at 24 months for
groups exposed to concentrations up to 1,080 mg/m3 (all rats exposed to 5,402 mg/m3 were
sacrificed at 18 months).
The study authors qualitatively reported elevated liver weights at >1,080 mg/m3 and
elevated kidney weights at 5,402 mg/m3 after 18-24 months of exposure; however, quantitative
data, the sex of animals affected, the magnitude of change, and statistical significance of these
findings were not reported by Benva et al. (1982). None of the unpublished interim reports
contain these data, but Huntingdon Research Center (1979) reported organ-weight data for the
6- and 12-month interim sacrifices (see Tables B-5 and B-6). The study authors reported
significant increases of 21-39%) in relative liver weight in males at 42-1,080 mg/m3 at 6 months,
and 16%) at 5,402 mg/m3 at 12 months. Elevated absolute liver weights were also observed;
however, the study authors did not report statistics for absolute organ weights. Based on
statistics conducted for this review, absolute liver weights in males were significantly increased
by 18-46% at 230-1,080 mg/m3 at 6 months, and 26% at 5,402 mg/m3 at 12 months. Liver
weights in exposed females did not differ significantly from control. Based on available data,
liver-weights do not display consistent time- and concentration-related changes. Sporadic
significant changes were observed in the kidney and spleen weights of the exposed rats,
compared with control; however, findings were not consistent between sexes or time points and
did not show exposure-related patterns (see Tables B-5 and B-6).
Benva et al. (1982) did not report non-neoplastic microscopic findings. However,
non-neoplastic data are available from unpublished reports describing this study (Ethyl
Corporation. 1979; Huntingdon Research Center. 1979; EPL. 1978). Various non-neoplastic
liver lesions were observed in the exposed animals. The study authors indicated that
exposure-related findings in animals treated for >18 months included hepatocyte hypertrophy,
eosinophilic and basophilic foci, and peliosis; however, the observed lesions differed between
sexes and time points (see Tables B-l 1 and B-12). Statistics were not reported for
non-neoplastic lesions but were conducted for this review. Significant findings at 18 months
included increased incidence of focal hepatocyte hypertrophy in males and females at
>230 mg/m3, basophilic foci in males at >230 mg/m3, eosinophilic foci in males at 230 mg/m3,
and peliosis in males at 230 and 1,080 mg/m3 and in females at 42 mg/m3. At 24 months,
significant findings included increased incidence of eosinophilic and basophilic foci in males at
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42 and 230 mg/m3 and basophilic foci at 42 mg/m3 in females, compared with controls. These
lesions were first observed in unscheduled deaths that occurred between 6 and 12 months, and
low incidences were observed at the 12-month interim sacrifice (see Tables B-l 1 and B-12)
(Huntingdon Research Center. 1979). No exposure-related non-neoplastic lesions were observed
at the 6-month interim sacrifice (Huntingdon Research Center. 1979). The study authors
attributed the lack of consistent significant non-neoplastic hepatic findings at the higher exposure
levels to increased incidence of neoplastic liver lesions (see Table B-13), including hepatic
angiosarcoma, hepatocellular carcinoma, and hepatic neoplastic nodules. All rats exposed to
5,402 mg/m3 showed increased mortality and were sacrificed early. The study authors'
conclusion is supported by the fact that the NTP often considers basophilic and eosinophilic foci
as preneoplastic (Maronpot. 2016). At >230 mg/m3, peliosis was also observed in males, and
focal hepatocyte hypertrophy was observed in males and females after exposure for
18-24 months. Additional effects reported at >1,080 mg/m3 included increased mortality,
decreased body weight, microcytic anemia, and hematuria. The analytical concentrations of 42,
230, 1,080, and 5,402 mg/m3 correspond to HEC values of 7.5, 41, 193, and 964.6 mg/m3,
respectively, for systemic (extrarespiratory) effects.6
A LOAEL of 42 mg/m3 (HEC = 7.5 mg/m3) is identified based on increased incidence of
non-neoplastic hepatic lesions after exposure for 18-24 months, including eosinophilic foci in
males, basophilic foci in males and females, and peliosis in females. No NOAEL is identified.
Exposure-related neoplastic tumors were observed in all treated groups. Table B-13
shows the tumor data for all animals combined, including data at terminal and interim sacrifices
and the number of animals found dead or sacrificed moribund. Neoplasms were first observed in
unscheduled deaths that occurred between the 6- and 12-month interim sacrifice at
>1,080 mg/m3, with low incidences observed at >42 mg/m3 at the 18-month interim sacrifice.
The most common tumors were angiosarcomas, which had a significantly increased incidence in
male and female rats from all exposure groups. These tumors occurred primarily in the liver, but
were observed occasionally in the lung, spleen, nasal cavity, and mesentery. Hepatocellular
carcinoma and neoplastic nodules (combined) were also increased in females at 42 mg/m3 and in
males and females at 1,080 mg/m3. The tumor incidences at 5,402 mg/m3 were not significantly
elevated in either sex, but the study authors attributed this to early mortality and the high
incidence of hepatic angiosarcoma in this group. In the Zymbal gland, the incidence of
squamous cell carcinoma was significantly increased in males at >1,080 mg/m3 and in females at
5,402 mg/m3. Zymbal gland papilloma incidence was significantly increased in males at
5,402 mg/m3 only. Other neoplastic observations were similar between the exposed and control
animals.
Reproductive/Developmental Studies
No reproductive or developmental toxicity studies have been identified.
6HEC for extrarespiratory effects calculated by treating vinyl bromide as a Category 3 gas and using the following
equation from U.S. EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day
exposed 24 hours) x (days/week exposed 7 days) x ratio of blood-gas partition coefficient (animal:human),
using a default coefficient of 1 because the rat blood-air partition coefficient of 4.05 is greater than the human
blood-air partition coefficient of 2.27 as indicated by Gargas et al. (1989).
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Genotoxicity Studies
Available genotoxicity studies are shown in Table 4A and reviewed below. Studies
consistently show that vinyl bromide and/or its metabolites are mutagenic in bacterial and
invertebrate systems and have the potential to cause chromosomal damage. Data in mammalian
species are extremely limited but indicate that vinyl bromide can directly interact with
deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
Vinyl bromide is mutagenic to Salmonella typhimurium both with and without metabolic
activation (N I P. 2017; Wagner et al.. 1992; Roklan-Ariona ct al.. 1991; Lijinskv and Andrews.
1980; Bartsch et al.. 1979a). Vinyl bromide also induces sex-linked recessive lethal mutations,
DNA repair, chromosomal alterations (CAs), and mitotic recombination in Drosophila
melanogaster (Ballerina et al.. 1996; Vogel and Nivard. 1993; Roklan-Ariona ct al.. 1991).
Studies in mammals are limited but showed evidence of DNA damage in multiple organs in mice
following oral exposure (Sasaki et al.. 1998) and DNA and RNA adduct formation by reactive
metabolites following in vitro or in vivo exposure (Guengerich. 1981; Laib et al.. 1980;
Ottenwaider et at.. 1979).
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Table 4A. Summary of Vinyl Bromide Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Salmonella typhimurium
TA100, TA1530
0, 0.2, 2, 20% (v/v in air)
+
+
Plate test (gas exposure); increase
in revertants/plate was >threefold
at all exposure levels with or
without metabolic activation. No
cytotoxicity was observed.
Bartsch et al.
(1979a)
Reverse
mutation
S. typhimurium TA100,
TA1535
0, 1, 5, 10%
+
+
Plate test (gas exposure); increase
in revertants/plate was >twofold at
>5%, both with and without
metabolic activation in TA100
(quantitative results not reported
for TA1535).
Liiinskv and
Andrews (1980)
Reverse
mutation
S. typhimurium TA98,
TA100
0,0.001,0.002,0.007,
0.013, 0.02, 1 ng/plate
+
(TA100)
(TA98)
+
Plate test (gas exposure); increase
in revertants/plate was >twofold at
all exposure levels in TA100, with
or without activation and in TA98
with activation. Slight
cytotoxicity observed at
>0.02 ng/plate.
NTP (2017)
[unpublished]
Reverse
mutation
S. typhimurium TA100
NR
+
+
Desiccator gas-phase exposure
(inverted plate). Mutagenic with
and without metabolic activation.
Wagner et al.
(1992) 1abstract
only]
Forward
mutation
S. typhimurium BA12,
BALI 2
142 x 103 nmol/mL
+
+
Ara assay; alternative assay used
liquid test with fixed dose with
varying durations (0-120 min).
Roldan-Ariona et
al. (1991)
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Table 4A. Summary of Vinyl Bromide Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies—acellular systems in vitro
DNA binding
Calf liver DNA
NR
NA
+
DNA adduct formation was
observed. Coincubation with
epoxide hydrolase decreased
binding by -50%; no change was
observed with coincubation with
dehydrogenases. These results
indicate that 2-bromoethylene
oxide is the predominant
DNA-binding metabolite and
2-bromoacetaldehyde is the
preferred metabolite for protein
binding.
Gueneerich (1981)
RNA binding
Calf liver RNA
NR
NA
+
Gas phase all-glass incubation
system; 14C-labeled vinyl bromide
was used. RNA alkylation
products were detected, including
radioactive ethenoadenosine and
ethenocytidine (adduct formation).
Ottenwalder et al.
(1979)
Genotoxicity studies—mammalian species in vivo
DNA damage
(comet assay)
Male CD-I mice were
exposed to vinyl bromide
via a single gavage dose in
olive oil. Mice were
sacrificed at 0 (zero-time
control), 3, and 24 hr after
treatment. At sacrifice,
stomach, liver, kidney,
urinary bladder, lung, brain,
and bone marrow were
removed and analyzed for
DNA damage.
0, 2,000 mg/kg
+
(stomach, liver,
kidney, urinary
bladder, lung,
brain)
(bone marrow)
NA
Migration of nuclear DNA was
significantly elevated at 3 and/or
24 hr after exposure in all organs
except bone marrow. No deaths,
morbidity, clinical signs, or gross
or microscopic lesions in
evaluated organs were observed.
Sasaki et al. (1998)
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Table 4A. Summary of Vinyl Bromide Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
RNA binding
Rats (strain and sex) were
exposed to 14C-labeled
vinyl bromide via
inhalation for 8 hr; rats
were sacrificed after
exposure; liver RNA was
evaluated for RNA
alkylation.
0, 20, 200 ppm
+
NA
A new protein band was identified
in mRNA analysis, indicating
alkylation of RNA species (adduct
formation).
Laibetal. (1980)
[abstract only]
RNA binding
Male Wister rats (number
not specified) were exposed
to 14C-labeled vinyl
bromide via inhalation for
8 hr; rats were sacrificed
after exposure; liver RNA
was evaluated for RNA
alkylation.
0, 250 ppm
+
NA
RNA alkylation products were
detected in liver samples of
exposed animals, including
radioactive ethenoadenosine and
ethenocytidine (adduct formation).
Ottenwalder et al.
(1979)
Genotoxicity studies—invertebrates in vivo
Sex-linked
recessive lethal
with DNA
repair assay
Drosophila melanogaster
(mus201 ext- [repair
deficient] and mei9 ext
[repair proficient]
genotypes) were evaluated.
Adult males were exposed
via inhalation for 48 hr and
then mated with unexposed
females.
0, 54,000 ppm
+
NA
Induction of recessive lethals in
both genotypes. Enhanced
mutation ratio (exr-exr )
indicates that some DNA
modifications are reparable.
Ballering et al.
(1996)
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Table 4A. Summary of Vinyl Bromide Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
CA (ring
X-chromosome
loss)
D. melanogaster ring-X
CR(l)2yB:BsYy+) males
were exposed via inhalation
for 48 hr and then mated
with unexposed females
(u w spl sn3: bw sp2). The
Fi progeny were scored for
CAs.
0, 14,500 ppm
+
NA
CAs were significantly induced.
The calculated Icl/rl index of 2.4
indicated that vinyl bromide is a
highly clastogenic agent (CL:RL
ratio <1 is nonactive, CL:RL ratio
>2 is highly clastogenic agent).
Ballering et al.
(1996)
Mitotic
recombination
(w/w+ eye
mosaic
bioassay)
D. melanogaster
(four wild-type strains [BK,
OK, LS, 91-C] and
2 DDT-resistant strains
[HK, HG]) were evaluated.
Progeny of mated pairs
(50 pairs/group) were
exposed via inhalation for
17 hr.
0, 2,000, 4,000, 8,000,
16,000, 24,000 ppm
+
(91-C, HG, HK)
±
(LS, BK, OK)
NA
Induction rates were 91-C > HG
~HK > BK ~LS ~OK. A 60-fold
difference in induction was
observed between the highest
induction rate (91-C) and the
lowest (OK). Differences were
attributed to different levels of
bioactivation across strains. The
highest exposure level
(24,000 ppm) was toxic.
Roldan-Ariona et
al. C199D
Mitotic
recombination
(w/w+ eye
mosaic
bioassay)
D. melanogaster larvae
(18-52 hr old; LS
wild-type strain) were
exposed to vinyl bromide
via inhalation for 17 hr.
0, 4,000, 8,000, 32,000,
64,000, 128,000 ppm
+
NA
Results were considered
marginally positive or
inconclusive at 4,000-32,000 ppm
(1.5- to 3.4-fold induction), and
positive at 64,000 ppm (10-fold
induction). The highest exposure
level (128,000 ppm) was lethal.
Voeel and Nivard
(1993)
a+ = positive; ± = weakly positive; - = negative.
Ara = L-Arabinose resistance; CA = chromosomal aberration; CL = chromosome loss; DDT = dichlorodiphenyltrichloroethane; DNA = deoxyribonucleic acid;
ICL/RL = rate of induced chromosome loss over the recessive lethal rate; mRNA = messenger ribonucleic acid; NA = not applicable; NR = not reported; RL = recessive
lethal; RNA = ribonucleic acid.
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Supporting Animal Toxicity Studies
Numerous acute toxicity studies were identified, including studies by oral, inhalation, and
dermal exposure routes. These studies primarily focused on mortality and clinical signs of
toxicity; however, a limited number of studies on hepatoxicity were also identified.
Additionally, supporting studies for carcinogenic effects in animals include a briefly reported
neonatal inhalation study evaluating the development of preneoplastic foci in rat livers, a dermal
skin tumor bioassay, and a subcutaneous tumor bioassay. Supporting studies are shown in
Table 4B and are briefly reviewed below.
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—noncancer effects in animals following oral exposure
Acute (oral)
Rats (2/group; sex and strain unspecified) were
exposed to 500, 1,000, or 2,000 mg/kg via a single
gavage dose in corn oil. Endpoints evaluated
included mortality and clinical signs.
Both animals given 2,000 mg/kg died within minutes and
had severe GI tract distention. Both animals given
1,000 mg/kg died within 3 hr (no additional details
reported). One animal given 500 mg/kg died in 2 d; both
animals had diarrhea and bleeding from the nose.
The lowest
exposure level of
500 mg/kg is an
apparent FEL for
mortality.
Dow Chemical
(1990)
[unpublished]
Acute (oral)
Male CD-I mice (4/group) were exposed to
2,000 mg/kg via a single gavage dose in olive oil.
Mice were sacrificed at 0 (zero-time control), 3,
and 24 hr after treatment. Endpoints evaluated
included mortality, clinical signs, and gross and
microscopic examination of stomach, liver, kidney,
urinary bladder, lung, or brain.
No exposure-related toxicity findings.
The only
administered dose
of 2,000 mg/kg is
an apparent
NOAEL for
evaluated
endpoints.
Sasaki et al.
(1998)
Supporting evidence—noncancer effects in animals following inhalation exposure
Acute
(inhalation)
The ALC, or the concentration at which mortality
was first observed following a 4-hr exposure, was
determined in rats. No further details were
provided.
Vinyl bromide was classified as having low toxicity (ALC
value of >5,000 ppm).
Rat ALC (4-hr) =
30,000 ppm
(131,000 mg/m3).
Kennedy and
(inaenel C199D
Acute
(inhalation)
Rats (3-5/group; sex and strain unspecified) were
exposed to vinyl bromide vapor concentrations of
25,000 ppm for 7 hr, 50,000 ppm for 1.25 or
6.75 hr, or 100,000 ppm for 10 or 15 min.
Endpoints examined included clinical signs and
mortality.
All rats exposed to 100,000 ppm for 15 min, or
50,000 ppm for 6.75 hr become unconscious after 3 and
25 min, respectively; all animals died. Rats exposed to
25,000 ppm for 7 hr, 50,000 ppm for 1.25 hr, or
100,000 ppm for 10 min were also anesthetized, but
regained consciousness after exposure ceased. At
necropsy, lung, liver, and kidney injuries (unspecified)
were observed in dead and surviving animals exposed to
>50,000 ppm.
The lowest
concentration of
25,000 ppm
(109,300 mg/m3) is
identified as a
1 .OAF.I, for
anesthetic effects.
Lethality was
observed at
>50,000 ppm
(218,700 mg/m3).
Dow Chemical
(1990)
[unpublished]
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute
(inhalation)
White mice (10-40/group) were exposed once to
vinyl bromide vapor at three, or more, unspecified
concentrations for 10 min. Endpoints examined
were anesthesia and mortality.
The minimal certain anesthetic concentration was
3.5 mM/L (370,000 mg/m3), and the highest tolerated
(nonlethal) concentration was 7.0 mM/L
(740,000 mg/m3).
The concentration
of 3.5 mM/L
(370,000 mg/m3) is
identified as a
1 .OAF.I, for
anesthetic effects.
Data reporting was
inadequate to
identify a NOAEL.
Abreu et al. (1939)
Acute/short
term
(inhalation)
Male rats (species and number unspecified) were
exposed to 20,000 ppm vinyl bromide vapor via
inhalation for 5 hr/d for 1, 2, 5, or 10 consecutive
d. Additional groups received either phenobarbital
or potassium bromide in drinking water during
exposure to vinyl bromide. Endpoints evaluated
included clinical signs, body weight, food intake,
and hepatic injury (not specified). It is unclear
whether an unexposed control group was included.
CNS depression, decreased body weight, and decreased
food intake were observed in rats exposed to vinyl
bromide alone during the first few d of exposure.
Decreased food intake, and subsequent body-weight
decrease, was attributed to CNS depression. "Toxic
injury to the liver" was observed on D 1 and 2, but not 5
and 10. Serum bromide levels were elevated. Based on
findings from rats exposed to phenobarbital or potassium
bromide, elevated serum bromide was due to vinyl
bromide debromination, not ingestion of bromide from
drinking water.
The only
concentration of
20,000 ppm
(87,500 mg/m3) is
an apparent
LOAEL for CNS
depression and liver
injury; however,
methods and data
reporting are
inadequate for
independent review.
Vanstee et al.
(1977)
[abstract]
Acute
(inhalation)
Twenty white mice were exposed once to vinyl
bromide vapor at 2.5 mM/L for 60 min.
Forty unexposed white mice served as controls.
Endpoints examined were mortality, anesthesia,
and liver bromide levels.
2.5 mM/L (270,000 mg/m3) was established as an
anesthetic concentration. It is unclear whether any mice
died because mortality data were combined for
10 compounds (21/200 anesthetized mice died).
Inorganic bromide levels in the liver were increased by
2.7-fold in exposed mice compared with unexposed
controls.
The only exposure
concentration of
2.5 mM/L
(270,000 mg/m3) is
identified as a
LOAEL for
anesthetic effects.
Abreu and
Emerson (1940)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute
(inhalation)
Male Holtzman rats (3-5/group) were exposed to
vinyl bromide vapor at 11,000, 21,000, 33,000, or
51,000 ppm for 4 hr after pretreatment with PCB
(300 |iIVI via gavage for 3 d prior to vinyl bromide
exposure). Controls were unexposed or treated
with PCB only. Endpoints evaluated included
mortality, clinical signs, SAKT, and liver weight.
Based on reported findings, groups of rats (number
unspecified) were similarly exposed to 0 or
20,000 ppm vinyl bromide after pretreatment with
PCB for examination of liver histology. The study
authors also indicated that additional groups were
exposed to vinyl bromide without PCB
pretreatment and evaluated for all endpoints, but
details regarding exposure level and animal
number were not reported.
One rat exposed to 51,000 ppm + PCB died; no other
mortalities were observed. Clinical signs of toxicity
(e.g., prostration) were observed at 51,000 ppm + PCB.
Significant differences in hepatic endpoints between
PCB-only controls, and PCB + vinyl bromide exposure
groups included a 20-fold increase in SAKT at
33,000 ppm and 20-65% increases in relative liver
weights at all exposure levels. A similar pattern was
observed when PCB + vinyl bromide exposure groups
were compared with unexposed controls (statistics not
reported). No differences in these endpoints were
observed between rats exposed to vinyl bromide alone
and unexposed controls.
Histological changes in the liver of rats exposed to vinyl
bromide + PCB included severe midzonal to centrilobular
necrosis and hemorrhagic areas at 20,000 ppm. In
PCB-only rats, histological changes were limited to
midzonal and centrilobular cytoplasmic vacuolization and
some eosinophilic foci. No histopathological changes
were observed in unexposed controls or rats exposed to
vinyl bromide alone.
Results indicate that
metabolism of vinyl
bromide (induced
by pretreatment
with PCB) produces
a hepatotoxic
compound,
presumably a
reactive epoxide.
Conollv et al.
(1978)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute
(inhalation)
Male Holtzman rats (3-6/group) were exposed to
vinyl bromide vapor at 10,000 ppm for 4 hr after
pretreatment with PCB (300 |iIVI via gavage for 3 d
prior to exposure) with or without exposure to the
epoxide hydrase inhibitor, TCPE (1 mL/kgvia
gavage immediately before vinyl bromide
exposure). Half of the rats were fasted overnight
prior to exposure. Controls were exposed to
PCB + TCPE only. The study did not include an
unexposed control or vinyl bromide-only exposure
group. Endpoints evaluated included mortality and
serum SDH.
Observed mortality was 1/6 of the fed rats and 3/6 of the
fasted rats exposed to vinyl bromide + PCB + TCPE.
SDH levels were significantly elevated by 20-fold in
fasted rats exposed to vinyl bromide + PCB, compared
with fed rats exposed to vinyl bromide + PCB. Increased
toxicity with fasting was attributed to depletion of GSH in
PCB-treated rats. There was no significant difference in
fed or fasted rats exposed to vinyl
bromide + PCB + TCPE, compared with fed or fasted rats
exposed to vinyl bromide + PCB only. However, the
study authors suggested that TCPE findings may have
been confounded by elevated mortality.
Results indicate that
metabolism of vinyl
bromide (induced
by pretreatment
with PCB) produces
a hepatotoxic
compound that is
detoxified via GSH
conjugation.
However, the lack
of proper controls
limits the
conclusions that can
be made from this
study.
Conollv and
Jaeeer (1977)
Acute
(inhalation)
Rats (1-2/group; sex and strain unspecified) were
exposed once to vinyl bromide vapor
concentrations of 10,000, 50,000, 80,000, or
100,000 ppm for 10-60 min. Endpoints examined
included clinical signs and mortality.
One rat died after a 10-min exposure to 100,000 ppm,
another rat survived a 15-min exposure to the same
concentration. Rats exposed to concentrations up to
80,000 ppm for up 15-60 min survived.
The exposure level
of 100,000 ppm
(437,000 mg/m3) is
an apparent FEL for
mortality. Study
design, low animal
number, and limited
reporting preclude
identification of a
NOAEL.
Dow Chemical
(1938)
[unpublished]
Supporting evidence—noncancer effects in animals following exposure via other routes
Acute (dermal)
Undiluted liquid vinyl bromide was applied to the
belly of rabbits (number unspecified) for 10 d
(intact skin) or 3 d (abraded skin) under occluded
conditions. The skin was observed daily and for
21 d after exposure.
Slight to moderate redness was observed after
4-10 applications on intact skin; skin was normal at 21 d.
For abraded skin, slight redness was observed after each
application, then subsided. There was a slight scar at
21 d. No clinical signs of toxicity were observed.
Vinyl bromide is
"essentially"
nonirritating.
Dow Chemical
(1990)
[unpublished]
Acute (ocular)
Undiluted liquid vinyl bromide was applied
directly to rabbit eyes (number unspecified). Both
washed and unwashed protocols were used.
Slight to moderate conjunctivitis with slight swelling was
observed. Symptoms resolved within 48 hr.
Vinyl bromide is a
moderate eye
irritant.
Dow Chemical
(1990)
[unpublished]
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—cancer effects in animals following exposure via any route
Carcinogen-
icity
(inhalation)
Newborn Wistar rats (and their dams) were
exposed to vinyl bromide vapor at 0 or 2,000 ppm
for 8 hr/d, 5 d/wk beginning on the first d of life.
The study authors indicated that young rats were
sacrificed 2 wk after cessation of exposure, but
they reported data for PNW 8, 10, 12, and 15. It is
unclear from the report whether these values refer
to the number of exposure wk or the wk of
sacrifice. Preneoplastic hepatic foci were
quantified by counting ATPase-deficient foci.
A time-related increase in the ATPase-deficient
hepatocytes was observed from 8 to 15 wk (0.04-0.3%).
Data suggest that
vinyl bromide has
oncogenic potential
in neonatal mouse
liver; however, data
reporting is too
limited for
independent review.
Boltetal. (1979)
[letter to the
editor]
Carcinogen-
icity (dermal)
In a complete carcinogenicity assay, 30 female
ICR/Ha Swiss mice were dermally exposed to
15 mg liquid vinyl bromide in 0.1 mL acetone,
3 times/wk for 60 wk under nonoccluded
conditions. An additional group of 30 females was
unexposed (negative control). Skin was evaluated
for tumor formation.
No skin tumors were observed.
Vinyl bromide is
not carcinogenic
under the
conditions of this
study. (Note: vinyl
bromide is volatile,
so a substantial
portion of the dose
may have
evaporated.)
Van Dmiren
(1977)
Carcinogen-
icity (dermal)
In an initiation/promotion assay, 30 female ICR/Ha
Swiss mice were dermally exposed once to 15 mg
liquid vinyl bromide in 0.1 mL acetone under
nonoccluded conditions, followed by dermal
exposure to 2.5 |ig TPA in 0.1 mL acetone
3 times/wk for 60 wk. Additional groups
(30 females/group) were initiated with DMBA
prior to TPA exposure (positive control), exposed
to TPA only, or were unexposed (negative control).
Skin was evaluated for tumor formation.
Only 1/30 mice exposed to vinyl bromide + TPA
developed a skin papilloma at 412 d. One skin carcinoma
was observed in the TPA-only group, and no skin tumors
were observed in the negative control. A high number of
skin tumors was observed in the positive control group.
Vinyl bromide is
not a skin tumor
initiator under the
conditions of this
study. (Note: vinyl
bromide is volatile,
so a substantial
portion of the dose
may have
evaporated.)
Van Dmiren
(1977)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Carcinogen-
icity
(s.c. injection)
Thirty female ICR/Ha Swiss mice were exposed to
liquid vinyl bromide via s.c. injection in trioctanoin
once weekly for 48 wk at a dose of 25 mg/animal.
Additional groups (30/group) were injected with
trioctanoin alone or were left untreated. The
animals were examined for s.c. tumors for up to
420 d.
No local tumors were observed at the injection site. Other
sites were not examined for tumors.
Vinyl bromide is
not carcinogenic
under the
conditions of this
study.
Van Duuren
(1977)
ALC = approximate lethal concentration; ATPase = adenosine triphosphatase; CNS = central nervous system; DMBA = 7,12-dimethylbenz[a]anthracene; FEL = frank
effect level; GI = gastrointestinal; GSH = glutathione; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level;
PCB = polychlorinated biphenyl mixture; PNW = postnatal week; SAKT = serum alanine-a-ketoglutarate transaminase; s.c. = subcutaneous; SDH = sorbitol
dehydrogenase; TCPE = trichloropropane epoxide; TPA = 12-O-tetradecanoylphorbol 13-acetate.
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Supporting Studies for Noncarcinogenic Effects in Animals
Oral toxicity information is limited to data from two single-exposure studies: one in rats
and one in mice. In an unpublished rat study, 1/2, 2/2, and 2/2 rats died following a single
gavage exposure to 500, 1,000, or 2,000 mg/kg, respectively (Dow Chemical 1990). Death
occurred within minutes at the high dose, and the animals had severe gastrointestinal (GI)
distention. Diarrhea and bleeding from the nose were observed at lower doses. In the mouse
study, no exposure-related changes were observed in stomach, liver, kidney, urinary bladder,
lung, or brain histology 3 or 24 hours after a single gavage exposure to 2,000 mg/kg (Sasaki et
al. 1998).
Several studies evaluated mortality and clinical signs following inhalation exposure to
vinyl bromide vapor. The approximate lethal concentration (ALC) in rats following a 4-hour
inhalation exposure was reported as 30,000 ppm (131,000 mg/m3) (Kennedy and Graepel 1991).
Additional studies reported mortalities in rats at 50,000 ppm (218,700 mg/m3) for 6.75 hours or
100,000 ppm (437,000 mg/m3) for >10 minutes; lung, liver, and kidney injuries (unspecified)
were observed in rats exposed to concentrations associated with lethality (Dow Chemical 1990).
No mortalities were reported in mice exposed to concentrations up to 7.0 mM/L
(750,000 mg/m3) for 10 minutes (Abrcu et al.. 1939). Central nervous system (CNS) depression
and anesthetic effects were reported at concentrations as low as 20,000 ppm (87,500 mg/m3) in
rats (Dow Chemical 1990; Vanstee et al. 1977) and 2.5 mM/L (270,000 mg/m3) in mice (Abrcu
and Emerson. 1940; Abrcu et al. 1939).
Two acute inhalation studies focused on hepatic endpoints in rats exposed to vinyl
bromide following pretreatment with polychlorinated biphenyl (PCB) mixtures to induce
metabolism (Conollv et al. 1978; Conollv and Jaeger. 1977). Conollv et al. (1978) reported
elevated liver weight, histopathological liver lesions (centrilobular necrosis, hemorrhagic areas),
and elevated serum alanine-a-ketoglutarate transaminase (SAKT; a marker of hepatic injury) in
PCB-pretreated rats exposed to vinyl bromide at concentrations >11,000 ppm (48,110 mg/m3) for
4 hours, relative to vinyl bromide-only, PCB-only, and untreated controls. Similarly, Conollv
and Jaeger (1977) reported elevated sorbitol dehydrogenase (SDH) levels in PCB-pretreated rats
exposed to vinyl bromide at a concentration of 10,000 ppm (43,7000 mg/m3) for 4 hours, but
only if they were fasted overnight prior to vinyl bromide exposure. This effect was attributed to
glutathione (GSH)-depletion in fasted rats exposed to PCB.
In dermal and ocular irritation studies, liquid vinyl bromide was considered nonirritating
to rabbit skin and moderately irritating to rabbit eyes (Dow Chemical 1990).
Supporting Studies for Carcinogenic Effects in Animals
In a letter to the editor. Bolt et al. (1979) reported induction of preneoplastic foci in
young rats following neonatal exposure to vinyl bromide or vinyl chloride. Starting on the day
of birth, neonates (and their dams) were exposed by inhalation to either vinyl bromide or vinyl
chloride at vapor concentrations of 0 or 2,000 ppm (8,750 mg/m3) for 8 hours/day, 5 days/week
for up to 15 or 17 weeks. The study authors indicated that young rats were sacrificed 2 weeks
after cessation of exposure, but reported data for Postnatal Weeks 8, 10, 12, and 15. It is unclear
from the report whether these values refer to the number of exposure weeks or the week of
sacrifice. Both compounds induced preneoplastic foci at all time points; however, the potency of
vinyl bromide was 1/10 that of vinyl chloride.
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In a series of carcinogenicity studies. Van Duuren (1977) reported that vinyl bromide did
not cause skin tumors alone or as a tumor initiator following dermal exposure, or at the injection
site following subcutaneous exposure. Limitations of these studies include lack of evaluation of
sites away from the site of exposure, as well as lack of control for volatility of vinyl bromide in
the dermal studies.
Absorption, Distribution, Metabolism, and Excretion (ADME) Studies
Absorption
Reported blood-air partition coefficients in humans and rats are 2.27 and 4.05,
respectively (Gargas et al.. 1989; Gargas et al.. 1988). Based on the blood-air partition
coefficients, vinyl bromide vapor is absorbed from the lungs. No data on the absorption of liquid
vinyl bromide following oral exposure were available; however, based on evidence of toxicity in
rats following acute oral exposure (Dow Chemical 1990). it is presumably absorbed to some
degree. Data on the absorption of liquid vinyl bromide following dermal exposure is limited to
an estimated human skin permeability coefficient of 5.5 x 10~3 cm/hour (U.S. EPA. 1992).
Distribution
No in vivo data on distribution following exposure to vinyl bromide are available.
However, distribution is expected to be widespread, and the predicted volume of distribution is
higher for vinyl bromide than related compounds such as vinyl chloride and vinyl fluoride
(IARC. 1986). Based on a general four-compartment pharmacokinetic model developed for
inhaled toxicants with low water solubility, vinyl bromide is expected to rapidly equilibrate
between blood and richly perfused tissues (Andersen et al.. 1980). However, vinyl bromide does
not equilibrate as quickly between blood and poorly perfused tissues (e.g., adipose), and is
therefore expected to accumulate in these tissues (Andersen et al.. 1980). Derived tissue-air
partition coefficients in rats (4.05 in blood, 3.33 in liver, 2.26 in muscle, and 49.2 in fat) support
these model predictions (Gargas et al.. 1988).
Metabolism
Based on in vitro studies, along with analogy to vinyl chloride, the primary oxidative
metabolite of vinyl bromide is bromoethylene oxide (Guengerich, 1981; Bart sell et al.. 1979a;
Barb in et al.. 1975). Bromoethylene oxide can either be rearranged into 2-bromoacetaldehyde or
further metabolized into nonreactive metabolites by epoxide hydrolase and glutathione-S
transferase (GST). 2-Bromoacetaldehyde is oxidized to bromoacetic acid, which can also be
further metabolized into a nonreactive metabolite by GST (NIP. 2015). Evidence of irreversible
nucleic acid and protein binding following in vitro and/or in vivo exposure support metabolic
generation of an alkylating agent (Guengerich, 1981; Guengerich et al.. 1981; Bolt et al.. 1978;
Barb in et al.. 1975). Studies using various metabolic inhibitors have shown that
2-bromoethylene oxide is the primary DNA-binding agent, whereas 2-bromoacetaldehyde
preferably binds protein due to its slower DNA-binding kinetics (Guengerich. 1981; Guengerich
et al.. 1981). Increased levels of serum and hepatic bromide levels following vinyl bromide
exposure also indicate that debromination occurs during metabolism (Gargas and Andersen.
1982; Vanstee et al.. 1977; Leong and Torketson, 1970; Abreu and Emerson, 1940). Release of
bromide is increased following pretreatment with phenobarbital, which induces cytochrome
P450 (CYP450) (Vanstee et al.. 1977).
In vitro experiments using isolated liver tissue have shown that hepatocytes metabolize
vinyl bromide via CYP450 in rats and mice (Ottenwalder and Bolt. 1980; Bartsch et al.. 1979a;
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Bolt et al.. 1978; Barbin et al.. 1975). In rats, the rate of metabolism was approximately
50% slower in liver microsomes from S-D rats than from Wistar rats (Bolt et al.. 1978). In vitro,
vinyl bromide is a substrate for human CYP450 2E1, with a metabolic rate of 0.027 nmol
product/minute nmol CYP, with l,N6-ethanoadenosine as the measured product (Guengerichet
al.. 1991).
A series of gas uptake studies in rats inferred the metabolism kinetics of vinyl bromide
based on the disappearance of vinyl bromide vapor from a recirculated atmosphere (Gargas and
Andersen. 1982; Filser and Bolt. 1981; Andersen et al.. 1980; Filser and Bolt. 1979). These
studies show that vinyl bromide has saturable uptake kinetics. Because vinyl bromide can
readily pass through cell membranes without the aid of carrier proteins, this saturable uptake
most likely reflects saturable metabolism (Andersen et al.. 1980). Filser and Bolt (1979)
identified a vapor concentration of 55 ppm (240 mg/m3) as the saturation point for vinyl bromide
in Wistar rats. In Fischer rats, the saturation point has been identified as "well below 100 ppm"
(437 mg/m3) (Gargas and Andersen. 1982). Below this saturation point, first-order kinetics
applies, and the rate-limiting step is presumably the hepatic perfusion rate. Above this saturation
point, zero-order kinetics applies, and metabolic capacity is the rate-limiting step.
Excretion
Data on excretion are limited; however, unmetabolized vinyl bromide is expected to be
eliminated primarily via exhalation (Andersen. 1980). This is supported by excretion data for
vinyl chloride, which indicate that excretion is primarily via exhalation of the unchanged
compound at exposure concentrations above metabolic saturation; at lower exposure
concentrations, metabolites are primarily excreted via the urine (U.S. EPA. 2000). Leong and
Torkelson (1970) concluded that elimination following inhalation exposure was rapid based on
the observed quick recovery of anesthetized animals following cessation of exposure.
Physiologically Based Pharmacokinetic (PBPK) Modeling
Using a four-compartment pharmacokinetic model for inhaled toxicants with low water
solubility developed from gas uptake studies, an inhalation Km of 18 ppm and Fmax of
2.1 mg/kg-hour were estimated in Fischer rats (Gargas and Andersen, 1982; Andersen, 1980).
However, a three-compartment model based on bromide release into the blood following
inhalation exposure predicted two distinct phases, with an estimated Km of 33 ppm and Fmax of
2.3 mg/kg-hour for low concentrations, and a Km of 11,700 ppm and Fmax of 9.3 mg/kg-hour for
concentrations above saturation (Gargas and Andersen, 1982). The study authors proposed that
the first phase represented a high-affinity metabolic pathway, while the second phase represented
a low-affinity metabolic pathway. They attributed the differences in pharmacokinetic constants
estimated using the different methods to the low sensitivity of the gas uptake methodology in
identifying low affinity pathways.
Mode-of-Action/Mechanistic Studies
Mechanistic studies for non-neoplastic effects are limited. In an abstract, Vanstee et al.
(1977) proposed that the observed CNS depression following inhalation exposure to 20,000 ppm
(87,500 mg/m3) vinyl bromide vapor for 5 hours was in response to observed elevations in serum
bromide concentration. Based on a series of experiments in rats following inhalation exposure to
vinyl halides (vinyl bromide, vinyl chloride, or vinyl fluoride) under various conditions to alter
metabolic function (coexposure to PCB with fasting or the epoxide hydrase inhibitor,
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trichloropropane epoxide), Conollv and Jaeger (1977) proposed that hepatotoxicity of vinyl
halides is mediated via epoxide intermediates.
In contrast to non-neoplastic mechanistic studies, the studies on the mode of action
(MO A) for carcinogenicity of vinyl bromide are extensive. Data presented below are based on
reviews by NTP (2016). NTPC2015). IARC (2008). ACGIH (2001). IARC (1999). and Solomon
(1999). A more detailed presentation of this proposed MO A can be found in the "Cancer
Weight-of-Evidence Descriptor" section.
Carcinogenicity of vinyl bromide is likely mediated via a genotoxic MOA. As discussed
above, vinyl bromide is a direct-acting mutagen and its metabolism produces the DNA, RNA,
and protein alkylating agents, bromoethylene oxide, and 2-bromoacetaldehyde. Based on
analogy to reactive vinyl chloride metabolites, the major DNA adduct is expected to be
7-(2-oxoethyl)guanosine resulting from interaction with the primary DNA binding agent,
bromoethylene oxide. This adduct is considered chemically unstable and can form potentially
mutagenic abasic sites following spontaneous depurination. Cyclic ethenodeoxyadenosine and
ethenodeoxycytidine RNA adducts have also been observed following exposure to vinyl bromide
(and vinyl chloride), and these pro-mutagenic cyclic etheno adducts can result in DNA
miscoding by modifying base-pairing sites. Both 2-bromoethylene oxide and
2-bromo-acetaldehyde, have been proposed to react with adenine and cytosine bases to form
these etheno-RNA adducts. Compared with 7-(2-oxoethyl)guanosine, etheno adducts have a
longer half-life, and thus have a greater capacity to accumulate over time. Therefore, formation
of pro-mutagenic etheno adducts is considered the primary key event for tumor formation
following exposure to vinyl bromide. While direct evidence for the proposed MOA for vinyl
bromide is limited, the proposed MOA is supported by similarities in reactive metabolites,
adduct formation, and primary tumor type (hepatic angiosarcoma) to the established human
carcinogen, vinyl chloride.
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DERIVATION OF PROVISIONAL VALUES
DERIVATION OF ORAL REFERENCE DOSES
The oral database is limited to acute studies, precluding derivation of oral reference
doses.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic Provisional Reference Concentration
The database of potentially relevant studies for deriving a subchronic reference value for
vinyl bromide includes a 4-week study in rats (Leong and Torkelson. 1970; Dow Chemical
1969). a 3-week interim study in rats (Leong and Torkelson. 1970; Hazleton Laboratories. 1967).
and a 6-month study in monkeys (Leong and Torkelson, 1970; Hazleton Laboratories, 1967).
The 6-month studies in rats and rabbits were not considered for deriving the subchronic
provisional reference concentration (p-RfC) because the durations are greater than 90 days,
which is greater than 10% of the life expectancy for rats and rabbits. Therefore, the experiments
in rats and rabbits are considered chronic studies and thus not suitable for deriving a subchronic
reference value (U.S. EPA, 2002). Conversely, the duration of the monkey study is less than
10% of the species life expectancy. In the 4-week rat study, the only exposure level of
43,763 mg/m3 (HEC: 9,117.3 mg/m3) was identified as a LOAEL based on clinical signs of
toxicity during daily exposures (hypoactivity, lethargy), and decreases in body weight >10%
(Leong and Torkelson, 1970; Dow Chemical, 1969). For the 3-week study in rats, the highest
exposure level of 2,126 mg/m3 (HEC: 442.9 mg/m3) was identified as a NOAEL (Leong and
Torkelson, 1970; Hazleton Laboratories, 1967). In the 6-month study in monkeys, the lowest
concentration of 1,121 mg/m3 (HEC: 233.5 mg/m3) is identified as a LOAEL for increased
absolute and relative liver weights in females.
Based on comparison of the PODs, the most sensitive treatment-related changes from the
inhalation toxicity database for vinyl bromide were observed in the 6-month study in monkeys
(Leong and Torkelson, 1970; Hazleton Laboratories, 1967). All available continuous models in
the Benchmark Dose Software (BMDS, Version 2.7) were fit to the data sets for the sensitive
endpoints presented in Table B-4. Appendix C contains details of the modeling results for these
data sets. The HEC, in mg/m3, was used as the dose metric. The benchmark response (BMR)
for changes in liver or body weight used was a 10% relative deviation (RD) change from control
means, which is considered a biologically significant response. For the effects that were
considered for modeling (i.e., decreased body weight in males, increased absolute and relative
liver weight in females), BMD modeling only provided adequate fit for increased relative liver
weight in females. Candidate PODs, including the benchmark concentration lower confidence
limits (BMCLs) from the selected models, are presented in Table 5.
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Table 5. Candidate PODs in Monkeys Administered Vinyl Bromide for the Derivation of
the Subchronic p-RfCa
Endpoint
POD (HEC), mg/m3
Increased absolute liver weight (females)0
233.5 (LOAEL)d
Increased relative liver weight (females)
103.0 (BMCLio)
Decreased body weight (males)
233.5 (NOAEL)d
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bModeling results are described in more detail in Appendix C.
°Chosen as the critical effect for deriving the subchronic p-RfC.
dBMD modeling did not provide adequate fit to the data.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NDr = not determined; NOAEL = no-observed-adverse-effect
level; POD = point of departure; p-RfC = provisional reference concentration.
For decreased body weight in male monkeys, the data did not provide adequate model fit
so the NOAEL (HEC) of 233.5 mg/m3 is considered as a potential POD for this effect. BMD
modeling was also not successful for increased absolute liver weight in female monkeys, so the
LOAEL (HEC) of 233.5 mg/m3 is identified as a potential POD. For increased relative liver
weight in female monkeys, the BMCLio (HEC) of 103.0 mg/m3 is considered as a potential POD.
Of the potential PODs in monkeys exposed to vinyl bromide, the most sensitive is the BMCLio
(HEC) of 103.0 mg/m3 for increased relative liver weight in female monkeys. Although
increased absolute liver weight in female monkeys occurred at the lowest tested concentration
(233.5 mg/m3), the increase was only 10% which is the minimum change for this endpoint to be
considered biologically significant. It is unlikely that a biologically significant change would be
observed for increased absolute liver weight in female monkeys at 103.0 mg/m3, which is the
BMCLio (HEC) for increased relative liver weight in female monkeys. Additionally, relative
liver weight is a relatable index to absolute liver weight. In this case, it is likely that the BMCLio
(HEC) for increased relative liver weight in female monkeys would also be protective for
increased absolute liver weight. Also, the selection of the BMCLio (HEC) of 103.0 mg/m3 for
increased relative liver weight in female monkeys would be protective of decreased body weight
in males (NOAEL [HEC] of 233.5 mg/m3). Therefore, the BMCLio (HEC) of 103.0 mg/m3 for
increased relative liver weight in female monkeys exposed to vinyl bromide vapors for up to
6 months (7 hours/day, 5 days/week), is selected as the point of departure (POD) for deriving the
subchronic p-RfC. Increased liver weights were also observed in male and female rabbits that
were exposed to vinyl bromide via inhalation for 6 months (Leong and Torkelson. 1970;
Hazleton Laboratories, 1967). Furthermore, the study by Benya et al. (1982) identified the liver
as the primary toxicity target of vinyl bromide in rats following inhalation exposure for longer
than 6 months.
The subchronic p-RfC is derived by applying a composite uncertainty factor (UFc) of 300
(reflecting an interspecies uncertainty factor [UFa] of 3, an intraspecies uncertainty factor [UFh]
of 10, and a database uncertainty factor [UFd] of 10) to the selected POD of 103.0 mg/m3.
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Subchronic p-RfC = POD (HEC) - UFc
103.0 mg/m3- 300
= 3 x 101 m «/m3
Table 6 summarizes the uncertainty factors for the subchronic p-RfC for vinyl bromide.
Table 6. Uncertainty Factors for the Subchronic p-RfC for
Vinyl Bromide (CASRN 593-60-2)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans when cross-species dosimetric adjustment (HEC calculation) is performed.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The inhalation
studies considered for derivation of the subchronic p-RfC for vinyl bromide are limited to
two short-term studies in rats (Leone and Torkelson. 1970; Dow Chemical. 1969; Hazleton
Laboratories. 1967) and a 6-mo studv in monkevs (Leone and Torkelson. 1970; Hazleton
Laboratories. 1967). Chronic inhalation data are limited to a 6-mo studv in rats and rabbits and a
sinele cancer bioassav in rats (Bettva et al. 1982). There are no reproductive or developmental
toxicity studies available by inhalation, or oral exposure.
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 vinyl bromide in humans.
UFl
1
A UFl of 1 is applied because the POD is a BMCLio.
UFS
1
A UFS of 1 is applied because the POD was derived from a 6-mo study, which is considered
subchronic in monkeys.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; UF = uncertainty factor; UFA = interspecies uncertainty
factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL
uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
Confidence in the subchronic p-RfC for vinyl bromide is low, as described in Table 7.
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Table 7. Confidence Descriptors for the Subchronic p-RfC for
Vinyl Bromide (CASRN 593-60-2)
Confidence Categories
Designation
Discussion
Confidence in study
L
Confidence in the orincioal studv (Leone and Torkelson. 1970; Hazleton
Laboratories. 1967) is low. The studv examined a variety of endooints in
monkeys, rats, and rabbits after 6 mo of exposure and in rats after 3 wk of
exposure. However, only two exposure levels were tested, and the
monkey and rabbit portions of the study utilized small sample sizes. The
published paper included only limited description of results; much of the
data were available onlv from the unrmblished version (Hazleton
Laboratories. 1967) that was not peer-reviewed.
Confidence in database
L
Confidence in the database is low. The inhalation database for vinyl
bromide includes a 4-wk studv in rats (Leone and Torkelson. 1970); a
6-mo study in monkeys, rats, and rabbits, with a 3-wk interim sacrifice in
rats onlv (Leone and Torkelson. 1970); and a 2-vr cancer bioassav in rats,
with 6-. 12-. and 18-mo interim sacrifices (Benva et al.. 1982). Althoueh
published versions of all reports are available, they generally included
only limited descriptions of the results. Much of the data were available
onlv from the unrmblished versions (Himtinedon Research Center. 1979;
Dorato. 1978; EPL. 1978; Dow Chemical. 1969; Hazleton Laboratories.
1967). There are no reproductive or developmental toxicity studies
available by inhalation or oral exposure.
Confidence in
subchronic p-RfCa
L
Overall confidence in the subchronic p-RfC is low.
aThe overall confidence cannot be greater than the lowest entry in the table (low).
L = low; p-RfC = provisional reference concentration.
Derivation of Chronic Provisional Reference Concentration
A chronic p-RfC value is not derived because an inhalation reference concentration (RfC)
value is available on U.S. EPA's IRIS database (U.S. EPA. 2003). Table 8 summarizes the
p-RfCs derived for vinyl bromide. Of note, the IRIS RfC was derived using the chronic
inhalation study in rats from Benva et al. (1982).
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Table 8. Summary of Noncancer Reference Values for Vinyl Bromide (CASRN 593-60-2)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
(HEC)
UFc
Principal Study
Subchronic
p-RfD (mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
NDr
Subchronic
p-RfC (mg/m3)
Monkey/F
Increased
relative
liver weight
3 x 1Q-1
BMCL io
103.0
300
Leone and Torkelson
(1970): Hazleton
Laboratories (1967)
Chronic p-RfC
(mg/m3)
RfC value of 3 x io 3 me/m3 is available on IRIS (U.S. EPA. 2003). The value was derived
using the chronic inhalation study in rats from Benva et al. (1982).
BMCL = benchmark concentration lower confidence limit; F = female(s), HEC = human equivalent concentration;
IRIS = Integrated Risk Information System; NDr = not determined; POD = point of departure; p-RfC = provisional
reference concentration; p-RfD = provisional reference dose; RfC = inhalation reference concentration;
UFC = composite uncertainty factor.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Following U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, vinyl bromide is
"Likely to Be Carcinogenic to Humans" following inhalation exposure (see Table 9); there is
"Inadequate Information to Assess Carcinogenic Potential" following oral exposure
(see Table 9). No epidemiological studies or oral studies in animals are available to assess the
carcinogenic potential of vinyl bromide. The "Likely to Be Carcinogenic to Humans" descriptor
for vinyl bromide via the inhalation route is based on a single study in one species. Specifically,
in a 2-year inhalation bioassay in rats, vinyl bromide was carcinogenic in both males and females
(Benva et al.. 1982). The most observed tumor type was angiosarcoma, primarily in the liver,
with increased incidence in both sexes at all tested concentrations (>42 mg/m3). Increased
incidence of hepatocellular carcinoma and neoplastic nodules (combined) was also observed in
females at 42 mg/m3, and males and females at 1,080 mg/m3. Additionally, the incidence of
Zymbal gland squamous cell carcinoma was significantly increased in males at >1,080 mg/m3
and females at 5,402 mg/m3, and Zymbal gland papilloma incidence was significantly increased
in males at 5,402 mg/m3. The available evidence from Benva et al. (1982) is consistent with one
of the examples provided in the Cancer Guidelines (U.S. EPA. 2005) for the "Likely to Be
Carcinogenic to Humans " descriptor. The example states that supporting data for this descriptor
may include "an agent that has tested positive in animal experiments in more than one species,
sex, strain, site, or exposure route, with or without evidence of carcinogenicity in humans."
While the body of evidence is from a single study in a single species, the consistency of these
findings to related compounds (vinyl chloride and vinyl fluoride) increases the confidence in the
weight-of-evidence (WOE) descriptor (NIP. 2016; I ARC. 2008). Both vinyl chloride and vinyl
fluoride induce hepatic angiosarcomas in laboratory animals via the same proposed mechanism
as vinyl bromide (see "Mode-of-Action Discussion" below). Furthermore, epidemiological
evidence indicates increased risk of hepatic angiosarcoma in humans exposed to vinyl chloride.
The "Likely to Be Carcinogenic to Humans" descriptor for vinyl bromide via the inhalation
route is further supported by the fact that both Zymbal gland tumors and angiosarcomas are
considered rare tumors as discussed in the IRIS assessment for vinyl chloride (U.S. EPA. 2000).
Another example for the "Likely to Be Carcinogenic to Humans" descriptor from the Cancer
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Guidelines (U.S. EPA. 2005) is "a rare animal tumor response in a single experiment that is
assumed to be relevant to humans."
Table 9. Cancer WOE Descriptor for Vinyl Bromide
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation, or both)
Comments
"Carcinogenic to Humans"
NS
NA
No adequate human data are available.
"Likely to Be Carcinogenic
to Humans"
Selected
Inhalation
Vinyl bromide has been shown to
produce angiosarcomas
(predominantly in the liver),
hepatocellular carcinomas and
neoplastic nodules, and Zymbal
gland tumors in male and female
rats following inhalation exposure to
concentrations >42 mg/m3. Tumors
were first observed between
6-12 mo of exposure. Additionally,
angiosarcomas and Zymbal gland
tumors are considered rare tumors.
No adequate studies in other species
were located.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
Evidence of the carcinogenic potential
of vinyl bromide following inhalation
exposure supports a stronger
descriptor.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Oral
This descriptor is selected due to the
lack of any information on the
carcinogenicity of vinyl bromide by
oral exposure.
"Not Likely to Be
Carcinogenic to Humans"
NS
NA
The available data do not support this
descriptor.
NA = not applicable; NS = not selected; WOE = weight of evidence.
MODE-OF-ACTION DISCUSSION
The Guidelines for Carcinogenic Risk Assessment (U.S. EPA. 2005) define MO A ".. .as a
sequence of key events and processes, starting with interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation."
Examples of possible modes of carcinogenic action for any given chemical include
"mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell
proliferation, and immune suppression."
Hypothesis
Tumors associated with vinyl bromide exposure in rats, including angiosarcoma,
hepatocellular neoplasms, and Zymbal gland neoplasms, have a common genotoxic MO A (NTP.
2016. 2015; IARC. 2008; ACGIH. 2001; I ARC. 1999). Genotoxic events associated with vinyl
bromide include direct-acting mutagenicity (Ballerina et at.. 1996; Wagner et at.. 1992; Rotdan-
Ariona et at.. 1991; Lijinskv and Andrews. 1980; Bartsch et at.. 1979b). formation of DNA
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adducts (Guengerich et al.. 1981). and formation of RNA adducts (I.aib et al.. 1980; Ottenwalder
et al.. 1979). Studies using various metabolic inhibitors in hepatocytes indicate that
2-bromoethylene oxide is the primary DNA-binding agent, while 2-bromoacetaldehyde
preferably binds protein because of its slower DNA-binding kinetics (Guengerich. 1981;
Guengerich et al.. 1981). Based on analogy to vinyl chloride, the primary DNA adduct formed
by 2-bromoethylene oxide is expected to be 7-(2-oxoethyl)guanosine; the minor adduct,
N2,3-ethenoguanine, may also form (Swenberg et al.. 1992; Bolt et al.. 1981). Additionally,
based on further analogy to vinyl chloride as well as evidence following in vitro or in vivo
exposure to vinyl bromide, cyclic ethenodeoxyadenosine and ethenodeoxycytidine RNA adducts
would also readily form (N I P. 2016. 2015; Swenberg et al.. 1992; Bolt et al.. 1981; Laib et al..
1980; Ottenwalder et al.. 1979). Both 2-bromoethylene oxide and 2-bromoacetaldehyde have
been proposed to react with adenine and cytosine bases to form these etheno-RNA adducts
(N I P. 2016. 2015; IARC. 2008. 1999; Guengerich. 1981; Barbin et al.. 1975). Guengerich
(1981) proposed that 2-bromoacetaldehyde may have a greater contribution to DNA binding
away from the site of metabolism (i.e., the hepatocyte), including reticuloendothelial cells
associated with angiosarcomas.
Both DNA and RNA adducts expected following vinyl bromide exposure are considered
promutagenic. The 7-(2-oxoethyl)guanosine DNA adduct is considered chemically unstable and
can form potentially mutagenic abasic sites following spontaneous depurination, whereas the
more stable mutagenic cyclic etheno adducts can result in DNA miscoding by modifying
base-pairing sites (Swenberg et al.. 1992). Because etheno adducts have a longer half-life than
7-(2-oxoethyl)guanosine adducts, they have a greater capacity for accumulation over time.
Therefore, formation of promutagenic etheno adducts is considered the primary key event for
tumor formation following exposure to vinyl halides (including vinyl bromide) (NTP, 2016,
2015; IARC. 2008. 1999; Swenberg et al.. 1992).
Strength, Consistency, and Specificity of Association
Available studies indicate that vinyl bromide can form etheno RNA adducts in vitro and
in vivo (l.aib et al.. 1980; Ottenwalder et al.. 1979). Although the number of studies evaluating
this proposed MOA for vinyl bromide is limited, this MOA is supported by similarities in
reactive metabolites, adduct formation, and primary tumor type (hepatic angiosarcoma) to the
established human carcinogen, vinyl chloride (NTP. 2016. 2015; IARC. 2008; ACGIH. 2001;
IARC. 1999).
Temporal and Dose-Response Concordance
No studies have been identified that specifically evaluated both genotoxic events and
tumor development. However, the available in vivo genotoxicity studies reported formation of
promutagenic etheno adducts in the rat liver after a single 8-hour exposure to 250 ppm
(1,090 mg/m3). In the 2-year cancer bioassay, tumors first appeared between 6 and 12 months of
exposure to concentrations >1,080 mg/m3 (Huntingdon Research Center. 1979). Therefore,
etheno adduct formation is expected to occur prior to induction of tumors at relevant exposure
levels.
Biological Plausibility and Coherence
Formation of promutagenic, stable etheno RNA adducts is a proposed MOA for several
compounds, including alkenes, vinyl halides, and other vinyl monomers (Solomon. 1999).
Specifically, formation of etheno RNA adducts is a proposed common MOA for tumor formation
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following exposure to vinyl chloride, vinyl bromide, and vinyl fluoride (N I P. 2016). All
three vinyl halides cause angiosarcomas in animal bioassays and form similar DNA and RNA
adducts. Additionally, human studies have found an association between vinyl chloride exposure
and hepatic angiosarcomas (NIP. 2016). Therefore, this MO A is expected to be relevant to
human exposure.
Mode-of-Action Conclusions
Available evidence supports that formation of etheno DNA and RNA adducts by reactive
metabolites can occur following exposure to vinyl bromide. This proposed MOA is plausible
and consistent with proposed MO As for related vinyl halides (vinyl chloride and vinyl fluoride).
Based on human evidence for the related compound, vinyl chloride, the proposed MOA is
relevant to human exposure.
DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Derivation of Provisional Oral Slope Factor
Derivation of quantitative estimates of cancer risk following oral exposure to vinyl
bromide is precluded by the absence of repeated-dose oral data for this compound.
Derivation of Provisional Inhalation Unit Risk
One study in the inhalation database provided dose-response information for tumors
induced by vinyl bromide (Bcnva et at., 1982). This study found significantly increased
incidences of angiosarcomas, hepatocellular tumors, and Zymbal gland squamous cell
carcinomas. These data are shown in Table B-13.
Benchmark dose (BMD) modeling was performed for each of these tumor types
individually. Multistage cancer models in the U.S. EPA BMDS (Version 2.6) were fit to the
incidence data for each tumor. The benchmark response (BMR) used was 10% extra risk. The
HEC in mg/m3 was used as the dose metric. The MS Combo model was used to evaluate the
combined cancer risk of the multiple tumor types. MS Combo was run using the incidence data
for the individual tumor types and the polydegrees identified in the model runs for the individual
tumor types with adequate model fit. Modeling results are summarized in Table 10
(see additional BMD details in Appendix C).
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Table 10. Modeling Results Based on the Incidence of Tumors in S-D Rats Exposed to
Vinyl Bromide via Inhalation for up to 24 Months3
Tumor Endpoint
Selected Model
BMCio (HEC)
(mg/m3)
BMCLio (HEC)
(mg/m3)
Males
Angiosarcoma
Multistage cancer (l-degree)b
12
9.6
Total hepatocellular neoplasms
Multistage cancer (1-degree)0
240
130
Zymbal gland squamous cell carcinoma
Multistage cancer (1-degree)
270
210
Combined male tumors
MS Combod
11
9.0
Females
Angiosarcoma
Multistage cancer (l-degree)b
8.4
6.8
Total hepatocellular neoplasms
No models provided adequate fit
NDr
NDr
Zymbal gland squamous cell
carcinomas
Multistage cancer (1-degree)
1,000
620
Combined female tumors
MS Combod
8.3
6.7
a6enva etal. (1982).
bTwo highest concentrations dropped to achieve adequate fit.
°High concentration dropped to achieve adequate fit.
dAlthough angiosarcomas were observed in the liver, angiosarcomas are not specifically a liver tumor; therefore, it
is appropriate to combine this tumor type with hepatocellular neoplasms.
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 = concentration associated with 10% extra risk);
BMR = benchmark response; HEC = human equivalent concentration; NDr = not determined;
S-D = Sprague-Dawley.
The Multistage cancer (1-degree) model provided an adequate fit to the data for
angiosarcomas in males and females with the two highest concentrations dropped, total
hepatocellular neoplasms in males with the high concentration dropped, and Zymbal gland
squamous cell carcinomas in males females with the full data sets. Dropping of the
high-concentration data was necessary for certain tumor types because lower incidences were
observed at the highest concentration compared to the lower concentration groups, which the
study authors attributed to high mortality. No models provided adequate fit to the data for total
hepatocellular neoplasms (full data set or high concentration dropped) in females. Additional
concentrations were not dropped due to lack of significance of findings at the next lowest
concentration.
From the Multistage cancer models, the predicted benchmark concentrations associated
with 10% extra risk (BMCio), and their 95% benchmark concentration lower confidence limits
(BMCLio) for the individual tumor types ranged from 8.4 and 6.8 mg/m3 (HEC), respectively,
for angiosarcoma in females, to 270 and 210 mg/m3 (HEC), respectively, for Zymbal gland
squamous cell carcinoma in males. The combined tumor model for males resulted in BMCio and
BMCLio estimates of 11 and 9.0 mg/m3 (HEC), respectively. The combined tumor model
(angiosarcomas and Zymbal gland squamous cell carcinomas) for females resulted in BMCio and
BMCLio estimates of 8.3 and 6.7 mg/m3 (HEC), respectively. The lowest BMCLio value of
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6.7 mg/m3 (HEC), based on the combined angiosarcomas and Zymbal gland squamous cell
carcinomas in female rats was selected as the POD for deriving the provisional inhalation unit
risk (p-IUR).
Evidence of a genotoxic MOA for vinyl bromide tumorigenesis indicates that the p-IUR
for vinyl bromide should be derived using a linear approach. While there is evidence of
saturable pharmacokinetics in rats following inhalation exposure to vinyl bromide (Gargas and
Andersen. 1982; Andersen et al.. 1980; Filser and Bolt 1979). the two lowest exposure levels in
the study by Bcnva et al. (1982) (42 and 230 mg/m3), and therefore the 1 ow-concentration
extrapolation, are lower than exposure levels associated with saturation (>240 mg/m3) (Filser and
Bolt. 1979). Thus, based on mechanistic and toxicokinetic considerations, the p-IUR. for vinyl
bromide, based on the BMCLio (HEC) of 6.7 mg/m3 for combined angiosarcomas and Zymbal
gland squamous cell carcinomas in female rats exposed to vinyl bromide via inhalation for up to
24 months, was derived using a linear approach as follows:
p-IUR = BMR -h BMCLio (HEC)
= 0.1 6.7 mg/m3
= 1.5 x 10"2 (mg/m3)"1
Table 11 summarizes the cancer inhalation risk estimates derived.
Table 11. Summary of Cancer Risk Estimates for Vinyl Bromide (CASRN 593-60-2)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Risk Estimate
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)-1
Rat/F
Combined angiosarcomas and
Zymbal gland squamous cell
carcinomas
1.5 x 10-2
Bettva et al. (1982)
F = female(s); NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope
factor.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional reference doses (p-RfDs) or a provisional oral
slope factor (p-OSF) for vinyl bromide. Available information for this chemical is also
insufficient to support derivation of screening provisional toxicity values.
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APPENDIX B. DATA TABLES
Table B-l. Body-Weight Data (in grams) for Male Wistar Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 4 Weeks (7 Hours/Day, 5 Days/Week)3
Exposure Duration (d)b'c
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
43,763 (9,117.3)
0
281 ± 18
279 ± 20 (-0.7%)
2
290 ± 19
283 ± 21 (-2%)
5
305 ± 18
286 ± 21 (-6%)
10
316 ±22
293 ± 21 (-7%)
15
342 ± 22
313 ± 18* (-9%)
20
353 ±28
313 ±19** (-11%)
aLeong and Torkelson (1970).
bData are mean ± SEM; n= 10 controls, 5 exposed.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) control mean] x 100.
* Significantly different from control by Student's t-test (p < 0.05), as reported by the study authors.
**Significantly different from control by Student's t-test (p < 0.01), as reported by the study authors.
HECer = human equivalent concentration for extrarespiratory effects; SEM = standard error of the mean.
45
Vinyl bromide
-------
FINAL
September 2020
Table B-2. Select Body- and Organ-Weight Data for Charles River Rats Exposed to
Vinyl Bromide (CASRN 593-60-2) via Inhalation for 3 Weeks (7 Hours/Day,
5 Days/Week)3
Endpointb'c
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
1,121 (233.5)
2,126 (442.9)
Males
Body weight (g)
477 ± 46
482 ± 21 (+1%)
497 + 38 (+4%)
Liver
Absolute (g)
Relative (% BW)
15.32 ±2.08
3.24 ±0.70
14.43 ± 1.30 (-6%)
2.99 ± 0.22 (-8%)
16.27 + 2.54 (+6%)
3.26 + 0.32 (+0.6%)
Kidney
Absolute (g)
Relative (% BW)
3.25 ±0.52
0.573 ±0.140
2.99 ±0.17 (-8%)
0.622 ± 0.055 (+9%)
2.86 + 0.28 (-12%)
0.576 + 0.045 (+0.5%)
Heart
Absolute (g)
Relative (% BW)
1.26 ±0.15
0.266 ± 0.052
1.24 ±0.10 (-2%)
0.257 ± 0.026 (-3%)
1.19 + 0.08 (-6%)
0.242 + 0.027 (-9%)
Females
Body weight (g)
421 ± 83
349 ± 50 (-17%)
315 + 22 (-25%)
Liver
Absolute (g)
Relative (% BW)
11.81 ±0.58
2.90 ±0.64
13.09 ±2.47 (+11%)
3.74 ± 0.44 (+29%)
9.43 + 2.24 (-20%)
2.99 + 0.63 (+3%)
Kidney
Absolute (g)
Relative (% BW)
2.09 ±0.17
0.411 ±0.103
2.22 ± 0.32 (+6%)
0.639 ±0.091 (+56%)
1.71 + 0.15* (-18%)
0.542 + 0.029 (+32%)
Heart
Absolute (g)
Relative (% BW)
1.03 ±0.07
0.252 ±0.049
1.14±0.28 (+11%)
0.325 + 0.066 (+29%)
0.97 + 0.51 (-6%)
0.31 + 0.09 (+23%)
Ovary
Absolute (g)
Relative (% BW)
0.098 ± 0.022
0.024 ± 0.005
0.132 ±0.038 (-35%)
0.073 ± 0.0082* (+204%)
0.121 + 0.029 (+24%)
0.0385 + 0.0089* (+60%)
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bData are mean ± SD; n = 5/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by ANOVA (p < 0.05), as reported by the study authors.
ANOVA = analysis of variance; BW = body weight; HECer = human equivalent concentration for extrarespiratory
effects; SD = standard deviation.
46
Vinyl bromide
-------
FINAL
September 2020
Table B-3. Select Body- and Organ-Weight Data for Charles River Rats Exposed to
Vinyl Bromide (CASRN 593-60-2) via Inhalation for 6 Months (7 Hours/Day,
5 DaysAVeek)3
Endpointb'c
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
1,121 (233.5)
2,126 (442.9)
Males
Body weight (g)
606 ± 70
589 ± 61 (-3%)
581 ± 48 (-4%)
Liver
Absolute (g)
Relative (% BW)
17.80 ±3.41
2.93 ±0.35
19.35 ±3.36* (+9%)
3.27 ±0.35* (+12%)
17.79 ±2.90 (-0.1%)
3.05 ± 0.38 (+4%)
Kidney
Absolute (g)
Relative (% BW)
4.06 ±0.50
0.671 ±0.063
3.95 ± 0.44 (-3%)
0.672 ±0.050 (+0.1%)
3.81 ± 0.47 (-6%)
0.656 ± 0.073 (-2%)
Heart
Absolute (g)
Relative (% BW)
1.77 ±0.24
0.295 ± 0.042
1.96 ±0.39 (+11%)
0.332 ± 0.057* (+13%)
1.72 ±0.22 (-3%)
0.298 ± 0.038 (+1%)
Females
Body weight (g)
372 ± 46
357 ± 39 (-4%)
347 ± 37 (-7%)
Liver
Absolute (g)
Relative (% BW)
12.26 ±2.21
3.29 ±0.38
11.50 ± 1.88 (-6%)
3.20 ±0.25 (-3%)
11.89 ± 1.62 (-3%)
3.43 ± 0.43 (+4%)
Kidney
Absolute (g)
Relative (% BW)
2.65 ±0.31
0.717 ±0.089
2.56 ± 0.45 (-3%)
0.720 ±0.124 (+0.4%)
2.68 ± 0.33 (+1%)
0.778 ±0.126 (+9%)
Heart
Absolute (g)
Relative (% BW)
1.26 ±0.26
0.340 ±0.071
1.39 ±0.32 (+10%)
0.396 ±0.104* (+17%)
1.26 ±0.15 (+0%)
0.363 ± 0.054 (+7%)
Ovary
Absolute (g)
Relative (% BW)
0.134 ±0.057
0.0361d± 0.0161
0.133 ±0.033 (-0.7%)
0.0374 ± 0.0088 (+4%)
0.113 ±0.039 (-16%)
0.0326 ±0.0116 (-10%)
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bData are mean ± SD; n = 20-25/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
dReported as 0.361 g; however, based on SD values, values reported in other groups, and lack of significant
difference, it is assumed that this should be 0.0361 g.
* Significantly different from control by ANOVA (p < 0.05), as reported by the study authors.
ANOVA = analysis of variance; BW = body weight; HECer = human equivalent concentration for extrarespiratory
effects; SD = standard deviation.
47
Vinyl bromide
-------
FINAL
September 2020
Table B-4. Select Body- and Organ-Weight Data for Cynomolgus Monkeys Exposed to
Vinyl Bromide (CASRN 593-60-2) via Inhalation for 6 Months (7 Hours/Day,
5 DaysAVeek)3
Endpointb'c
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
1,121 (233.5)
2,126 (442.9)
Males
Body weight (kg)
3.65 ±0.354
3.59 ±0.0173 (-2%)
2.75 + 0.910 (-25%)
Liver
Absolute (g)
Relative (% BW)
63.4 ±4.31
1.75 ±0.283
62.5 ± 2.27 (-1%)
1.74 ±0.0529 (-0.6)
50.2+12.1 (-21%)
1.88 + 0.281 (+7%)
Kidney
Absolute (g)
Relative (% BW)
14.4 ±0.424
0.396 ±0.0269
12.6 ± 1.59 (—13%)
0.350 ±0.0461 (-12%)
10.8 + 1.82 (-25%)
0.411 +0.0855 (+4%)
Spleen
Absolute (g)
Relative (% BW)
4.44 ± 1.94
0.125 ±0.065
6.05 ± 1.22 (+36%)
0.169 ±0.0340 (+35%)
4.33 + 1.10 (-3%)
0.175 + 0.087 (+40%)
Thyroid
Absolute (g)
Relative (% BW)
0.405 ± 0.0778
0.0112 ±0.00320
0.427 ± 0.0895 (+5%)
0.0119 + 0.00254 (+6%)
0.257 + 0.0666 (-37%)
0.00973 + 0.00222 (-13%)
Females
Body weight (kg)
2.63 ±0.512
2.30 ± 0.260 (-13%)
2.53+0.911 (-4%)
Liver
Absolute (g)
Relative (% BW)
61.1 ± 7.31
2.40 ±0.574
67.5 ± 15.9 (+10%)
2.91+ 0.420 (+21%)
69.7 + 29.5 (+14%)
2.72 + 0.402 (+13%)
Kidney
Absolute (g)
Relative (% BW)
12.1 ± 1.59
0.465 ±0.0326
11.4 + 2.38 (-6%)
0.497+ 0.0816 (+7%)
11.9 + 3.62 (-2%)
0.477 + 0.0360 (+3%)
Spleen
Absolute (g)
Relative (% BW)
4.91 ± 1.75
0.193 ±0.0700
5.45 + 1.73 (+11%)
0.234 + 0.0542 (+21%)
6.51 + 1.08 (+33%)
0.268 + 0.0480 (+39%)
Thyroid
Absolute (g)
Relative (% BW)
0.466 ±0.153
0.0175 ±0.00288
0.303 + 0.0431 (-35%)
0.0132 + 0.000757 (-25%)
0.295 + 0.124 (-37%)
0.0115 + 0.000764 (-34%)
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bData are mean ± SD; n = 2-4/group; means and SDs calculated for this review from individual animal data. The
study authors stated that "statistical analyses showed that the differences were not significant."
°Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
B W = body weight; HECer = human equivalent concentration for extrarespiratory effects; SD = standard deviation.
48
Vinyl bromide
-------
FINAL
September 2020
Table B-5. Select Organ Weights for Male S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6 or 12 Months (6 Hours/Day, 5 DaysAVeek)3
Endpointb'c
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
Body weight (g)
6 mo
12 mo
522 ± 19.8
546 ±28.3
488 ± 17.7
(-7%)
575 ±28.3
(+5%)
506+ 17.7
(-3%)
606+ 19.0
(+11%)
545+ 17.9
(+4%)
592+ 18.2
(+8%)
542 + 51.3
(+4%)
597 + 23.0
(+9%)
Absolute liver weight (g)
6 mo
12 mo
11.5±
0.243
12.9 ±
0.930
13.3 ±0.872
(+16%)
12.9 ±0.785
(+0%)
13.6 + 0.872**
(+18%)
15.3 + 0.756
(+19%)
16.8+ 1.10**
(+46%)
15.4 + 0.853
(+20%)
13.6+1.04
(+18%)
16.3 + 0.848**
(+26%)
Relative liver weight (% B W)
6 mo
12 mo
2.21 ±
0.046
2.33 ±
0.083
2.73 ±0.115*
(+24%)
2.25 ±0.106
(-3%)
2.68 + 0.123*
(+21%)
2.52 + 0.080
(+8%)
3.07 + 0.127*
(+39%)
2.60 + 0.120
(+12%)
2.54 + 0.132
(+15%)
2.71 + 0.063*
(+16%)
Absolute kidney weight (g)
6 mo
12 mo
2.8 ±
0.093
3.0 ±0.23
3.1±0.22
(+11%)
3.3 + 0.17
(+10%)
2.8 + 0.25
(+0%)
3.8 + 0.18**
(+27%)
3.4 + 0.18**
(+21%)
3.6 + 0.37
(+20%)
3.2 + 0.21
(+14%)
3.6 + 0.19**
(+20%)
Relative kidney weight (% BW)
6 mo
12 mo
0.530 ±
0.0155
0.56 ±
0.036
0.667 + 0.0382*
(+26%)
0.58 + 0.025
(+4%)
0.560 + 0.037
(+6%)
0.62 + 0.025
(+11%)
0.626 + 0.0147
* (+18%)
0.62 + 0.075
(+11%)
0.591 + 0.0246
(+12%)
0.59 + 0.023
(+5%)
Absolute spleen weight (g)
6 mo
12 mo
0.4 ±0.07
0.53 ±
0.116
0.7 + 0.2
(+75%)
0.58 + 0.074
(+9%)
0.4 + 0.05
(+0%)
1.0 + 0.077**
(+89%)
0.6 + 0.08**
(+50%)
0.75 + 0.131
(+42%)
0.8 + 0.07**
(+100%)
0.83 + 0.111
(+57%)
Relative spleen weight (% B W)
6 mo
12 mo
0.065 ±
0.0100
0.097 ±
0.0202
0.151+0.0315*
(+132%)
0.103 + 0.0129
(+6%)
0.084 + 0.0084
(+29%)
0.166 + 0.0138*
(+71%)
0.114 + 0.0136
(+75%)
0.129 + 0.0243
(+33%)
0.152 + 0.0091*
(+134%)
0.143 + 0.0223
(+47%)
a6enva etal. (1982): Himtingdon Research Center (1979).
bData are mean ± SEM (variance data only reported for relative organ weights by the study authors; SEM
calculated for body weight and absolute organ weights for this review); n = 4-10/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Mann-Whitney U test or Student's t-test (p < 0.05), as reported by the
study authors for relative organ weights (statistical analysis not reported by the study authors for body weight or
absolute organ weights).
**Significantly different from control by Student's /-test (p < 0.05), as calculated for this review for body weight
and absolute organ weights.
BW = body weight; HECEr = human equivalent concentration for extrarespiratory effects; S-D = Sprague-Dawley;
SEM = standard error of the mean.
49
Vinyl bromide
-------
FINAL
September 2020
Table B-6. Select Organ Weights for Female S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6 or 12 Months (6 Hours/Day, 5 DaysAVeek)3
Endpointb'c
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
Body weight (g)
6 mo
12 mo
293 ± 14.5
360 ± 14.3
282 ± 17.9 (-4%)
319 ± 10.7**
(-11%)
308 ± 7.43 (+5%)
348+ 13.5 (-3%)
268 + 6.38
(-9%)
333 + 8.43
(-8%)
270 + 8.32
(-8%)
333 + 12.0
(-8%)
Absolute liver weight (g)
6 mo
12 mo
7.3 ±0.48
8.9 ±0.50
7.8 ±0.18 (+7%)
8.3 ± 0.24 (-7%)
8.4 ±0.17
(+15%)
9.9 + 0.51
(+11%)
7.2 + 0.28
(-1%)
9.0 + 0.54
(+1%)
7.7 + 0.45
(+6%)
9.5 + 0.92
(+6%)
Relative liver weight (% B W)
6 mo
12 mo
2.50 ±
0.107
2.48 ±
0.083
2.83 ±0.259
(+13%)
2.61 ±0.094
(+5%)
2.72 + 0.083
(+9%)
2.86 + 0.118
(+15%)
2.68 + 0.062
(+7%)
2.71 + 0.157
(+9%)
2.88 + 0.195
(+15%)
2.82 + 0.207
(+14%)
Absolute kidney weight (g)
6 mo
12 mo
1.8 ±0.21
2.5 ±0.19
2.3 ±0.080
(+28%)
2.1 ±0.079**
(-16%)
2.0 + 0.068
(+11%)
2.5 +0.18 (+0%)
1.6 + 0.073
(-11%)
1.9 + 0.16**
(-24%)
1.8 + 0.024
(+0%)
2.1+0.14
(-16%)
Relative kidney weight (% BW)
6 mo
12 mo
0.61 ±
0.050
0.71 ±
0.051
0.82 ±0.066*
(+34%)
0.65 ± 0.032
(-9%)
0.66 + 0.016
(+8%)
0.70 + 0.032
(-1%)
0.61 + 0.034
(+0%)
0.58 + 0.045
(-18%)
0.69 + 0.014
(+13%)
0.63 + 0.038
(-11%)
Absolute spleen weight (g)
6 mo
12 mo
0.4 ±0.05
0.6 ±0.05
0.7 ±0.08**
(+75%)
0.5 ±0.03
(-17%)
0.6 + 0.1 (+50%)
0.6 + 0.1 (+0%)
0.3 + 0.02
(-25%)
0.6 + 0.08
(+0%)
0.5 + 0.02
(+25%)
1.2 + 0.51
(+100%)
Relative spleen weight (% B W)
6 mo
12 mo
0.145 ±
0.0165
0.1601 ±
0.01165
0.252 ±0.0327*
(+74%)
0.1618 + 0.01142
(+1%)
0.181 + 0.0352
(+25%)
0.1808 + 0.02429
(+13%)
0.127 + 0.00
79 (-12%)
0.1648 +
0.02148
(+3%)
0.193 + 0.0072*
(+33%)
0.3417 + 0.1393
(+113%)
a6enva etal. (1982): Himtingdon Research Center (1979).
bData are mean ± SEM (variance data only reported for relative organ weights by the study authors; SEM
calculated for body weight and absolute organ weights for this review); n = 5-10/group.
°Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control Mann-Whitney U test (p < 0.05), as reported by the study authors for relative
organ weights (statistical analysis not reported by the study authors for body weight or absolute organ weights).
**Significantly different from control by Student's /-test (p < 0.05), conducted for this review for body weight and
absolute organ weights.
BW = body weight; HECer = human equivalent concentration for extrarespiratory effects; S-D = Sprague-Dawley;
SEM = standard error of the mean.
50
Vinyl bromide
-------
FINAL
September 2020
Table B-7. Hematological Data for Male S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6,12, or 18 Months (6 Hours/Day, 5 DaysAVeek)3
Concentration Group, Analytical Concentration in mg/m3 (HECer)
Endpointb'c
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
Hct (%)
6 mo
41.0 ±2.5
34.0 ±2.1
42.0 + 0.9
42.0 + 0.7
43.0+1.4
(-17%)
(+2%)
(+2%)
(+5%)
12 mo
37.0 ± 1.4
35.0 ± 1.0
39.0 + 0.5
39.0 + 0.7
34.0 + 0.9
(-5%)
(+5%)
(+5%)
(-8%)
18 mo
38.0 ± 1.4
36.0 ±2.0
37.0 + 0.8
37.0+1.2
32.0+1.4*
(-5%)
(-3%)
(-3%)
(-16%)
Hb (%)
6 mo
14.00 ±0.67
11.40 ±0.76
14.50 + 0.39
14.10 + 0.12
14.20 + 0.59
(-19%)
(+10%)
(+0.7%)
(+1%)
12 mo
12.80 ±0.57
11.40 ±0.28*
13.20 + 0.17
12.80 + 0.28
11.00 + 0.28*
(-11%)
(+3%)
(+0%)
(-14%)
18 mo
11.80 ±0.49
11.40 ±0.69
12.30 + 0.29
12.10 + 0.35
10.70 + 0.51
(-3%)
(+4%)
(+3%)
(-9%)
RBC count (106/mm3)
6 mo
7.32 ±0.40
5.86 ±0.32
7.38 + 0.08
7.49 + 0.21
7.56 + 0.22
(-20%)
(+0.8%)
(+2%)
(+3%)
12 mo
6.56 ±0.29
6.40 ± 0.20
6.90 + 0.14
6.16 + 0.15
5.70 + 0.23*
(-2%)
(+5%)
(-6%)
(-13%)
18 mo
6.46 ± 0.27
6.17 ±0.37
6.65 + 0.15
6.94 + 0.22
5.91 + 0.26
(-5%)
(+3%)
(+7%)
(-9%)
MCV (|im3)
6 mo
55.37 ±0.50
57.32 ±0.97
56.19 + 0.91
56.19+1.29
56.90 + 0.70
(+4%)
(+2%)
(+2%)
(+3%)
12 mo
56.80 ±0.91
54.80 ±0.74
56.20 + 0.45
62.80+ 1.28*
60.10+ 1.26*
(-4%)
(-1%)
(+11%)
(+6%)
18 mo
58.50 ±0.82
58.70 ± 1.19
56.30 + 0.55
53.90 + 0.46*
54.90 + 0.64*
(+0.3%)
(-4%)
(-8%)
(-6%)
WBC count (103/mm3)
6 mo
4.70 ± 0.42
7.50 ± 1.47
4.50 + 0.70
4.60 + 0.45
7.10 + 0.84
(+60%)
(-4%)
(-2%)
(+51%)
12 mo
4.90 ±0.71
4.60 ±0.61
4.70 + 0.66
7.60 + 2.07
7.80 + 0.84*
(-6%)
(-4%)
(+55%)
(+59%)
18 mo
6.90 ±0.71
7.00±1.85
6.80 + 0.56
8.70 + 2.33
11.50 + 2.02
(+1%)
(-1%)
(+26%)
(+67%)
a6enva etal. (1982).
bData are mean ± SEM; n = 5-10/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Mann-Whitney U test or Student's t-test (p < 0.05), as reported by the
study authors.
Hb = hemoglobin; Hct = hematocrit; HECer = human equivalent concentration for extrarespiratory effects;
MCV = mean corpuscular volume; RBC = red blood cell; S-D = Sprague-Dawley; SEM = standard error of the
mean; WBC = white blood cell.
51
Vinyl bromide
-------
FINAL
September 2020
Table B-8. Hematological Data for Female S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6,12, or 18 Months (6 Hours/Day, 5 DaysAVeek)3
Concentration Group, Analytical Concentration in mg/m3 (HECer)
Endpointb'c
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
Hct (%)
6 mo
37.0 ±0.7
40.0 ±0.5
39.0±0.7
38.0+ 1.5
41.0+ 1.5
(+8%)
(+5%)
(+3%)
(+11%)
12 mo
39.0 ±0.8
39.0 ±0.9
36.0+ 1.3
36.0+ 1.3
35.0+ 1.7
(+0%)
(-8%)
(-8%)
(-10%)
18 mo
41.0 ±0.8
37.0 ±3.2
36.0+ 1.7
36.0 + 1.8*
27.0+1.7*
(-10%)
(-12%)
(-12%)
(-34%)
Hb (%)
6 mo
13.10 ±0.26
13.80 ±0.25
13.90 + 0.14
13.60 + 0.46
13.90 + 0.39
(+5%)
(+6%)
(+4%)
(+6%)
12 mo
13.30 ±0.31
12.70 ±0.28
12.30 + 0.51
12.30 + 0.56
11.50 + 0.65*
(-5%)
(-8%)
(-8%)
(-14%)
18 mo
12.80 ±0.18
11.90 ± 1.12
11.80 + 0.06
12.10 + 0.54
9.30 + 0.58*
(-7%)
(-8%)
(-6%)
(-27%)
RBC count (106/mm3)
6 mo
6.74 ±0.12
6.77 ±0.13
6.32 + 0.13
6.63 + 0.20
6.94 + 0.23
(+0.4%)
(-6%)
(-2%)
(+3%)
12 mo
6.41 ±0.17
6.71 ±0.21
6.00 + 0.27
5.87 + 0.28
5.60 + 0.32
(+5%)
(-6%)
(-8%)
(-13%)
18 mo
6.38 ±0.12
6.02 ±0.57
5.84 + 0.32
6.09 + 0.31
4.77 + 0.36*
(-6%)
(-9%)
(-5%)
(-25%)
MCV (|im3)
6 mo
55.21 ±0.40
58.49 ±0.64
61.11 + 0.41
56.64 + 0.79
58.54+ 1.58*
(+6%)
(+11%)
(+3%)
(+6%)
12 mo
60.50 ±0.97
58.00 ± 1.41
60.30 + 0.97
62.00+ 1.25
62.60+ 1.66
(-4%)
(-0.3%)
(+3%)
(+4%)
18 mo
64.10 ± 1.39
62.40 ±2.19
62.80+ 1.73
59.90 + 0.89*
57.60 + 3.33*
(-3%)
(-2%)
(-7%)
(-10%)
WBC count (103/mm3)
6 mo
1.90 ±0.18
3.10 ± 0.18*
3.20 + 0.50
5.20 + 2.00
4.10 + 0.30*
(+63%)
(+68%)
(+174%)
(+116%)
12 mo
2.30 ±0.27
2.30 ±0.22
2.00 + 0.34
3.40+1.43
14.50 + 8.01
(+0%)
(-13%)
(+48%)
(+530%)
18 mo
3.80 ±0.28
5.60 ±2.28
5.20 + 0.86
4.80 + 0.70
4.00+1.41
(+47%)
(+37%)
(+26%)
(+5%)
a6enva etal. (1982).
bData are mean ± SEM; n = 5-10/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Mann-Whitney U test or Student's t-test (p < 0.05), as reported by the
study authors.
Hb = hemoglobin; Hct = hematocrit; HECer = human equivalent concentration for extrarespiratory effects;
MCV = mean corpuscular volume; RBC = red blood cell; S-D = Sprague-Dawley; SEM = standard error of the
mean; WBC = white blood cell.
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Table B-9. Serum Chemistry Data for Male S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6, 12, or 18 Months (6 Hours/Day, 5 DaysAVeek)3
Concentration Group, Analytical Concentration in mg/m3 (HECer)
Endpointb'c
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
BUN (mU/mL)
6 mo
18.0 ± 1.3
2.70 ± 1.8*
17.0 ±0.7
16.0 ± 1.0
18.0 ± 1.5
(-85%)
(-6%)
(-11%)
(+0%)
12 mo
24.0 ± 1.2
27.0 ± 1.4
31.0 ± 1.1*
32.0 ±2.8*
28.0 ±3.2
(+13%)
(+29%)
(+33%)
(+17%)
18 mo
20.0 ± 1.1
22.0 ±2.2
19.0 ±0.8
19.0 ±0.9
15.0 ±0.8*
(+10%)
(-5%)
(-5%)
(-25%)
ALP (mU/mL)
6 mo
189.0 ±9.2
182.0 ±39.8
234.0 ± 11.9*
192.0 ± 18.0
286.0 ±39.8
(-4%)
(+24%)
(+2%)
(+51%)
12 mo
194.0 ± 11.8
233.0 ± 19.9
195.0 ± 10.4
233.0 ±39.6
290.0 ±73.9
(+20%)
(+0.5%)
(+20%)
(+50%)
18 mo
185.0 ± 14.7
261.0 ±56.1
166.0 ± 14.8
280.0 ± 60.6
266.0 ±33.1*
(+41%)
(-10%)
(+51%)
(+44%)
AST (mU/mL)
6 mo
109.0 ± 14.4
378.0 ± 161.9*
89.0 ±7.4
113.0 ± 21.5
111.0 ± 11.8
(+247%)
(-18%)
(+4%)
(+2%)
12 mo
144.0 ± 15.8
116.0 ± 12.4
108.0 ± 16.2
119.0 ± 12.7
138.0 ± 12.5
(-19%)
(-25%)
(-17%)
(-4%)
18 mo
96.0 ±7.8
129.0 ± 17.7
89.0 ±9.3
144.0 ± 12.6*
172.0 ±55.6
(+34%)
(-7%)
(+50%)
(+79%)
LDH (mU/mL)
6 mo
318.0 ±38.2
1,600.0 ± 1134
331.0 ±49.7
338.0 ± 128.2
1,127.0 + 274.9*
(+403%)
(+4%)
(+6%)
(+254%)
12 mo
434.0 ± 142.3
483.0 ±87.2
447.0 ± 103.9
320.0 ±98.3
784.0 + 93.3
(+11%)
(+3%)
(-26%)
(+81%)
18 mo
746.0 ± 183.0
921.0 ± 162.8
347.0 ±78.2
1,360.0 ±231.0
384.0 + 73.1
(+24%)
(-54%)
(+82%)
(-49%)
a6enva etal. (1982).
bData are mean ± SEM; n = 5-10/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Student's t-test (p < 0.05), as reported by the study authors.
ALP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; HECer = human
equivalent concentration for extrarespiratory effects; LDH = lactate dehydrogenase; S-D = Sprague-Dawley;
SEM = standard error of the mean.
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Table B-10. Serum Chemistry Data for Female S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6,12, or 18 Months (6 Hours/Day, 5 DaysAVeek)3
Concentration Group, Analytical Concentration in mg/m3 (HECer)
Endpointb'c
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
BUN (mU/mL)
6 mo
18.0 ±0.2
18.0 ± 1.3
18.0+ 1.1
16.0+ 1.5
18.0+ 1.2
(+0%)
(+0%)
(-11%)
(+0%)
12 mo
26.0 ± 1.3
25.0 ± 1.0
32.0 + 2.4
33.0+1.9*
28.0 + 2.4
("4%)
(+23%)
(+27%)
(+8%)
18 mo
20.0 ±2.0
22.0 ±3.3
20.0 + 2.6
23.0 + 2.0
16.0 + 0.7*
(+10%)
(+0%)
(+15%)
(-20%)
ALP (mU/mL)
6 mo
140.0 ± 16.4
118.0 ± 9.1
152.0 + 20.3
140.0+12.9
128.0 + 9.1
(-16%)
(+9%)
(+0%)
(-9%)
12 mo
124.0 ±6.3
98.0 ±7.7*
119.0+ 11.4
185.0 + 43.7
208.0 + 56.1*
(-21%)
("4%)
(+49%)
(+68%)
18 mo
157.0 ±20.9
168.0 ±30.1
151.0 + 20.9
165.0+ 15.5
137.0+ 12.5
(+7%)
("4%)
(+5%)
(-13%)
AST (mU/mL)
6 mo
123.0 ± 10.2
87.0 ±8.2
88.0 + 7.0*
97.0+12.4
83.0 + 0.6*
(-29%)
(-29%)
(-21%)
(-33%)
12 mo
93.0 ± 10.9
91.0 ±9.7
116.0+ 17.1
104.0+ 11.7
121.0 + 23.9
(-2%)
(+25%)
(+12%)
(+30%)
18 mo
82.0 ±5.3
124.0 ±23.4
92.0+13 3
123.0+ 19.0
115.0 + 23.5
(+51%)
(+12%)
(+50%)
(+40%)
LDH (mU/mL)
6 mo
174.0 ±41.1
216.0 ±77.6
187.0 + 35.8
531.0 + 133.3*
515.0 + 91.0*
(+24%)
(+8%)
(+205%)
(+196%)
12 mo
234.0 ±34.7
296.0±53.8
349.0 + 64.7
247.0 + 71.2
640.0+ 114.7*
(+27%)
(+49%)
(+6%)
(+174%)
18 mo
188.0 ±24.1
723.0 + 238.3*
227.0 + 358
868.0+ 190.9*
604.0+ 179.3
(+285%)
(+21%)
(+362%)
(+221%)
a6enva etal. (1982).
bData are mean ± SEM; n = 5-10/group.
0Value in parentheses is % change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control by Student's t-test (p < 0.05), as reported by the study authors.
ALP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; HECer = human
equivalent concentration for extrarespiratory effects; LDH = lactate dehydrogenase; S-D = Sprague-Dawley;
SEM = standard error of the mean.
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Table B-ll. Non-neoplastic Liver Lesions in Male S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months (6 Hours/Day, 5 DaysAVeek)3
Endpointb
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
Eosinophilic foci
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
1/10 (10%)
NA
14/74 (19%)
NE
2/10 (20%)
NA
22/52* (42%)
1/10 (10%)
8/10* (80%)
NA
11/28* (39%)
0/10 (0%)
6/10 (60%)
NA
1/6 (17%)
1/10 (10%)
3/10 (30%)
1/19 (5%)
NA
Basophilic foci
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
1/10 (10%)
0/10 (0%)
NA
9/74 (12%)
NE
1/10 (10%)
NA
16/52* (31%)
1/10 (10%)
5/10* (50%)
NA
11/28* (39%)
0/10 (0%)
6/10* (60%)
NA
0/6 (0%)
1/10 (10%)
6/10* (60%)
5/19** (26%)
NA
Focal hepatocyte hypertrophy
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
0/10 (0%)
NA
NR
NE
4/10 (40%)
NA
NR
0/10 (0%)
8/10* (80%)
NA
NR
0/10 (0%)
9/10* (90%)
NA
NR
0/10 (0%)
10/10* (100%)
NR
NA
Peliosis
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
0/10 (0%)
NA
NR
NE
3/10 (30%)
NA
NR
0/10 (0%)
5/10* (50%)
NA
NR
0/10 (0%)
6/10* (60%)
NA
NR
0/10 (0%)
4/10 (40%)
NR
NA
a6enva etal. (1982): Ethyl Corporation (1979): Huntingdon Research Center (1979): EPL (1978).
bValues denote number of animals showing changes total number of animals examined (% incidence).
°A11 surviving rats in 5,402-mg/m3 group were sacrificed at 18 months due to high group mortality (>50%).
* Significantly increased compared with control by Fisher's exact test (p < 0.05), conducted for this review.
**Combined 18-month interim and terminal data are significantly different from interim 18-month control data by
Fisher's exact test (p < 0.05), conducted for this review.
HECer = human equivalent concentration for extrarespiratory effects; NA = not applicable; NE = not examined;
NR = not reported; S-D = Sprague-Dawley.
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Table B-12. Non-neoplastic Liver Lesions in Female S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months (6 Hours/Day, 5 DaysAVeek)3
Endpointb
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)
Eosinophilic foci
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
1/10 (10%)
NA
3/47 (6%)
NE
1/10 (10%)
NA
4/48 (8%)
1/10 (10%)
2/10 (20%)
NA
2/67 (3%)
1/10 (10%)
4/10 (40%)
NA
2/83 (2%)
0/10 (0%)
0/10 (0%)
1/43 (2%)
NA
Basophilic foci
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
0/10 (0%)
NA
2/47 (4%)
NE
2/10 (20%)
NA
10/48* (21%)
0/10 (0%)
4/10 (40%)
NA
7/67 (10%)
2/10 (20%)
4/10 (40%)
NA
5/83 (6%)
2/10 (20%)
3/10 (30%)
0/43 (0%)
NA
Focal hepatocyte hypertrophy
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
0/10 (0%)
NA
NR
NE
3/10 (30%)
NA
NR
0/10 (0%)
5/10* (50%)
NA
NR
0/10 (0%)
8/10* (80%)
NA
NR
0/10 (0%)
6/10* (60%)
NR
NA
Peliosis
12-mo interim sacrifice
18-mo interim sacrifice
18-mo terminal sacrifice0
24-mo terminal sacrifice
0/10 (0%)
0/10 (0%)
NA
NR
NE
5/10* (50%)
NA
NR
0/10 (0%)
4/10 (40%)
NA
NR
0/10 (0%)
3/10 (30%)
NA
NR
0/10 (0%)
0/10 (0%)
NR
NA
a6enva etal. (1982): Ethyl Corporation (1979): Huntingdon Research Center (1979): EPL (1978).
bValues denote number of animals showing changes total number of animals examined (% incidence).
°A11 surviving rats in 5,402-mg/m3 group were sacrificed at 18 months due to high mortality (>50%).
* Significantly increased compared with control by Fisher's exact test (p < 0.05), conducted for this review.
HECer = human equivalent concentration for extrarespiratory effects; NA = not applicable; NE = not examined;
NR = not reported; S-D = Sprague-Dawley.
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Table B-13. Select Neoplastic Lesions in S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months (6 Hours/Day, 5 DaysAVeek)3
Endpointb
Concentration Group, Analytical Concentration in mg/m3 (HECer)
0
42 (7.5)
230 (41)
1,080 (193)
5,402 (964.6)c
Males
Angiosarcoma11
0/144 (0%)
7/120* (6%)
36/120* (30%)
61/120* (51%)
43/120* (36%)
Hepatocellular carcinoma
3/143 (2%)
1/103 (1%)
7/119(6%)
9/120 (8%)
3/119(3%)
Hepatic neoplastic nodules
1/143 (0.7%)
4/103 (4%)
3/119(3%)
4/120 (3%)
2/119(2%)
Total hepatocellular neoplasms
4/143 (3%)
5/103 (5%)
10/119 (8%)
13/120* (11%)
5/119(4%)
Zymbal gland squamous cell
carcinoma
2/142 (1%)
1/99 (1%)
1/112 (0.9%)
13/114* (11%)
35/116* (30%)
Zymbal gland papilloma
0/142 (0%)
0/99 (0%)
1/112 (0.9%)
3/114(3%)
5/116* (4%)
Females
Angiosarcoma11
1/144 (0.7%)
10/120* (8%)
50/120* (42%)
61/120* (51%)
41/120* (34%)
Hepatocellular carcinoma
4/142 (3%)
6/101(6%)
3/113 (3%)
11/118 (9%)
4/112(4%)
Hepatic neoplastic nodules
3/142 (2%)
12/101 (12%)
9/113 (8%)
10/118 (8%)
5/112(4%)
Total hepatocellular neoplasms
7/142 (5%)
18/101* (18%)
12/113 (11%)
21/118* (18%)
9/112(8%)
Zymbal gland squamous cell
carcinoma
0/139 (0%)
0/99 (0%)
3/113 (3%)
2/119(2%)
11/114* (10%)
Zymbal gland papilloma
0/139 (0%)
0/99 (0%)
0/113 (0%)
0/119(0%)
3/114(3%)
a6enva etal. (1982).
bValues denote number of animals showing changes total number of animals examined (% incidence); the
denominator includes terminal sacrifice, interim sacrifices, and all animals found dead or sacrificed moribund.
°A11 surviving rats in this group sacrificed at 18 months due to high mortality (>50%).
dThe majority of angiosarcomas were observed in the liver; occasional incidences were observed in lung, spleen,
nasal cavity, and mesentery.
* Significantly different from control by Yates-corrected x2 test (p < 0.05), as reported by the study authors.
HECer = human equivalent concentration for extrarespiratory effects; S-D = Sprague-Dawley.
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR CONTINUOUS NONCANCER DATA
Benchmark dose (BMD) modeling of continuous data is conducted with U.S. EPA's
Benchmark Dose Software (BMDS, Version 2.7). All continuous models available within the
software are fit using a benchmark response (BMR) of 1 standard deviation (SD) relative risk or
10% extra risk when a biologically determined BMR is available (e.g., BMR 10% relative
deviation [RD] for body weight based on a biologically significant weight loss of 10%), as
outlined in the Benchmark Dose Technical Guidance (U.S. EPA, 2012b). An adequate fit is
judged based on the x2 goodness-of-fit p-walue (p > 0.1), magnitude of the scaled residuals near
the BMR, and visual inspection of the model fit. In addition to these three criteria forjudging
adequacy of model fit, a determination is made as to whether the variance across dose groups is
homogeneous. If a homogeneous variance model is deemed appropriate based on the statistical
test provided by BMDS (i.e., Test 2), the final BMD results are estimated from a homogeneous
variance model. If the test for homogeneity of variance is rejected (p < 0.1), the model is run
again while modeling the variance as a power function of the mean to account for this
nonhomogeneous variance. If this nonhomogeneous variance model does not adequately fit the
data (i.e., Test 3;p<0. 1), the data set is considered unsuitable for BMD modeling. Among all
models providing adequate fit, the lowest benchmark dose lower confidence limit/benchmark
concentration lower confidence limit (BMDL/BMCL) is selected if the BMDL/BMCL estimates
from different models vary >threefold; otherwise, the BMDL/BMCL from the model with the
lowest Akaike's information criterion (AIC) is selected as a potential POD from which to derive
the oral reference dose/inhalation reference concentration (RfD/RfC).
BMD MODELING TO IDENTIFY POTENTIAL POINTS OF DEPARTURE FOR THE
DERIVATION OF A SUBCHRONIC PROVISIONAL REFERENCE
CONCENTRATION
As discussed in the body of the report under "Derivation of Subchronic Provisional
Reference Concentration," the most sensitive treatment-related changes due to inhalation
exposure of vinyl bromide were reported in male and female monkeys from the (Leong and
Torkelson. 1970; Hazleton Laboratories. 1967) study and are presented in Table B-4. Endpoints
selected to determine potential PODs for the subchronic provisional reference concentration
(p-RfC) using BMD analysis were as follows: (1) decreased body weight in male monkeys,
(2) increased absolute liver weight in female monkeys, and (3) increased relative liver weight in
female monkeys.
Model Predictions for Decreased Body Weight in Male Monkeys Treated with Vinyl
Bromide via Inhalation for 6 Months
The procedure outlined above for continuous data was applied to the data for decreased
body weight in male monkeys treated with vinyl bromide via inhalation for 6 months (Leong and
Torkelson. 1970; Hazleton Laboratories. 1967). Table C-l summarizes the BMD modeling
results. Neither the constant nor the nonconstant variance models provided adequate fit to the
variance data; thus, these data were not suitable for BMD modeling.
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Table C-l. Modeling Results for Decreased Body Weight in Male Monkeys Administered Vinyl Bromide (CASRN 593-60-2) via
Inhalation for 6 Months3*
Model
Test for Significant
Difference />-Valueb
Variance
/>-Valuce
Means
/>-Valuce
Scaled Residuals
for Dose Groupd
AIC
BMCio
(mg/m3)
BMCLio
(mg/m3)
Nonconstant variance
Exponential (Model 2)e
<0.0001
0.1118
<0.0001
0.9085
2.056236
285.973
124.009
Exponential (Model 3)e
<0.0001
0.1118
NDr
1.25 x 10-5
-2.021505
420.064
274.274
Exponential (Model 4)e
<0.0001
0.1118
<0.0001
0.9085
2.056236
285.973
107.147
Exponential (Model 5)e
<0.0001
NDr
NDr
NDr
NDr
NDr
NDr
Hill6
<0.0001
NDr
NDr
NDr
NDr
NDr
NDr
Lineal
<0.0001
0.1118
<0.0001
0.937
1.845925
276.649
133.891
Polynomial (2-degree/
<0.0001
0.1118
0.0002728
0.666
-1.10378
306.487
224.891
Polynomial (3-degree/
<0.0001
0.1118
0.0006902
0.311
-2.836675
331.014
270.064
Power6
<0.0001
0.1118
0.001308
1.30 x 10-5
-4.021509
421.965
276.516
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals at concentrations closest to BMC.
Tower restricted to >1.
Coefficients restricted to be negative.
*No model was selected. Neither the constant nor nonconstant variance models provide adequate fit to the variance data.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = benchmark concentration 10% extra risk; BMCLio = 95% benchmark concentration
lower confidence limit; NDr = not determined.
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Model Predictions for Increased Absolute Liver Weight in Female Monkeys Treated with
Vinyl Bromide via Inhalation for 6 Months
The procedure outlined above for continuous data was applied to the data for increased
absolute liver weight in female monkeys treated with vinyl bromide via inhalation for 6 months
(Leong and Torkelson. 1970; Hazleton Laboratories. 1967). Table C-2 summarizes the BMD
modeling results. Neither the constant nor the nonconstant variance models provided adequate
fit to the variance data; thus, these data were not suitable for BMD modeling.
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Table C-2. Modeling Results for Increased Absolute Liver Weight in Female Monkeys Administered Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6 Months3*
Model
Test for Significant
Difference />-Valueb
Variance
/>-Valuce
Means
/>-Valuce
Scaled Residuals
for Dose Groupd
AIC
BMCio
(mg/m3)
BMCLio
(mg/m3)
Nonconstant variance
Exponential (Model 2)e
0.1866
0.3394
NDr
0.1416
67.27368
270.519
98.8017
Exponential (Model 3)e
0.1866
0.3394
NDr
0.1416
67.27368
270.519
98.8017
Exponential (Model 4)e
0.1866
0.3394
NDr
0.2317
73.45937
137.851
0.00414018
Exponential (Model 5)e
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Hill6
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Lineal
0.1866
0.3422
<0.0001
0.126
67.266113
265.999
87.3691
Polynomial (2-degree/
0.1866
0.3422
<0.0001
0.126
67.266113
265.999
87.3691
Polynomial (3-degree/
0.1866
0.3422
<0.0001
0.126
67.266113
265.994
87.3691
Power6
0.1866
0.3394
<0.0001
0.126
67.266113
265.998
87.3691
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals at concentrations closest to BMC.
Tower restricted to >1.
Coefficients restricted to be negative.
*No model was selected. Neither the constant nor nonconstant variance models provide adequate fit to the variance data.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = benchmark concentration 10% extra risk; BMCLio = 95% benchmark concentration
lower confidence limit; NDr = not determined.
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Model Predictions for Increased Relative Liver Weight in Female Monkeys Treated with
Vinyl Bromide via Inhalation for 6 Months
The procedure outlined above for continuous data was applied to the data for increased
relative liver weight in female monkeys treated with vinyl bromide via inhalation for 6 months
(Leong and Torkelson. 1970; Hazleton Laboratories. 1967). The BMD modeling results are
summarized in Table C-3 and Figure C-l. The constant variance model provided adequate fit to
the variance data, and adequate fit to the means was provided by all models except for the
Exponential 4 and 5 models and the Hill model. The BMCLs for the models providing adequate
fit are sufficiently close (i.e., differ by
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Table C-3. Modeling Results for Increased Relative Liver Weight in Female Monkeys Administered Vinyl Bromide
(CASRN 593-60-2) via Inhalation for 6 Months3
Model
Test for Significant
Difference />-Valucb
Variance
/>-Valuce
Means
/>-Valuce
Scaled Residuals
for Dose Groupd
AIC
BMCio
(mg/m3)
BMCLio
(mg/m3)
Constant variance
Exponential (Model 2)e
0.5182
0.6817
0.2367
0.9532
-0.5308398
322.982
121.181
Exponential (Model 3)e
0.5182
0.6817
0.2367
0.9532
-0.5308398
322.982
121.181
Exponential (Model 4)e
0.5182
0.6817
NDr
-4.01 x 10~7
0.3891677
9.14818
0.0159053
Exponential (Model 5)e
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Hill6
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Lineal*
0.5182
0.6817
0.2442
0.937
-0.574912
304.929
103.006
Polynomial (2-degree/*
0.5182
0.6817
0.2442
0.937
-0.574912
304.929
103.006
Polynomial (3-degree/*
0.5182
0.6817
0.2442
0.937
-0.574912
304.929
103.006
Power6*
0.5182
0.6817
0.2442
0.937
-0.574912
304.929
103.006
aLeong and Torkelson (1970): Hazleton Laboratories (1967).
bValues >0.05 fail to meet conventional goodness-of-fit criteria.
°Values <0.10 fail to meet conventional goodness-of-fit criteria.
dScaled residuals at concentrations closest to BMC.
Tower restricted to >1.
Coefficients restricted to be negative.
* Selected model. Lowest AIC among models that provided an adequate fit.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = benchmark concentration 10% extra risk; BMCLio = 95% benchmark concentration
lower confidence limit; NDr = not determined.
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Linear Model, with BMR of 0.1 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
Figure C-l. Linear Model for Increased Relative Liver Weight in Female Monkeys Treated
with Vinyl Bromide (CASRN 593-60-2) via Inhalation for 6 Months (Leong and Torkelson,
1970; Hazleton Laboratories, 1967)
Text Output for Figure C-l:
Polynomial Model. (Version: 2.21; Date: 03/14/2017)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/1in_increasedrelliverfm_vb_Lin-ConstantVariance-
BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/1in_increasedrelliverfm_vb_Lin-ConstantVariance-
BMR10.pit
Wed Jan 08 15:19:32 2020
BMDS Model Run
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*dose/s2 + ...
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
Signs of the polynomial coefficients are not restricted
A constant variance model is fit
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Total number of dose groups = 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
Default Initial Parameter Values
alpha = 0.237777
rho = 0 Specified
beta_0 = 2.50747
beta 1 = 0.000750437
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -rho
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
alpha beta_0 beta_l
alpha 1 7.7e-010 2.1e-009
beta_0 7.7e-010 1 -0.74
beta 1 2.le-009 -0.74 1
Parameter Estimates
Interval
Variable
Limit
alpha
0.357696
beta_0
2.886
beta_l
0.00228145
95.0% Wald Confidence
Estimate Std. Err. Lower Conf. Limit Upper Conf.
0.190617 0.0852463 0.0235369
2.48372 0.20525 2.08143
0.000814523 0.000748446 -0.000652404
Table of Data and Estimated Values of Interest
Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 4 2.4 2.48 0.574 0.437 -0.383
233.5 3 2.91 2.67 0.42 0.437 0.937
442.9 3 2.72 2.84 0.402 0.437 -0.494
Model Descriptions for likelihoods calculated
Model A1: Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
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Model A2 : Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)^2
Model A3: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma^2
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)
3.965494
4.348674
3.965494
3.287456
2.727796
# Param's
4
6
4
3
2
AIC
0. 069012
3.302651
0. 069012
-0.574912
-1.455593
Test 1:
Test
Test
Test
Explanation of Tests
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
3.24176
0.766361
0.766361
1.35608
0.5182
0.6817
0.6817
0.2442
The p-value for Test 1 is greater than .05. There may not be a
diffence between responses and/or variances among the dose levels
Modelling the data with a dose/response curve may not be appropriate
The p-value for Test 2 is greater than .1.
model appears to be appropriate here
A homogeneous variance
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
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Relative deviation
Confidence level = 0.95
BMD = 304.929
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BMDL = 103.006
BMDU = 1.9616e+009
MODELING PROCEDURE FOR CANCER DATA
The model-fitting procedure for dichotomous cancer incidence is as follows. The
Multistage cancer model in the U.S. EPA's Benchmark Dose Software (BMDS; Version 2.6) is
fit to the incidence data using the extra risk option. The Multistage cancer model is run for all
polynomial degrees up to n - 1 (where n is the number of dose/concentration groups including
control). An adequate model fit is judged by three criteria: (1) goodness-of-fit p-value
(p < 0.05), (2) visual inspection of the dose-response curve, and (3) scaled residual at the data
point (except the control) closest to the predefined benchmark response (BMR) (absolute
value <2.0). Among all of the models providing adequate fit to the data, the benchmark dose
lower confidence limit (BMDL) or BMCL for the model with the lowest Akaike's information
criterion (AIC) is selected as the point of departure (POD), if the BMDL/BMCLs are sufficiently
close (threefold),
model-dependence is indicated, and the model with the lowest reliable BMDL/BMCL is
selected. In accordance with U.S. EPA (2012b) and U.S. EPA (2005) guidance, benchmark dose
(BMD) or concentration (BMC) and BMDL/BMCL values associated with an extra risk of 10%
are calculated, which should be within the observable range of increased risk in a cancer
bioassay. Modeling is performed for each individual tumor type with at least a statistically
significant trend. Where applicable, the MS Combo model is used to evaluate the combined
cancer risk of multiple tumor types. MS Combo is run using the incidence data for the individual
tumor types and the polynomial degrees identified in the model runs for the individual tumor
types.
Dropping the High Dose/Concentration
In the absence of a mechanistic understanding of the biological response to a toxic agent,
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 at low
doses/concentrations. Such exposures, however, can have a strong effect on the shape of the
fitted model in the low-dose/concentration region of the dose-response curve. Thus, if lack of fit
is due to characteristics of the dose-response data for high doses/concentrations, then the
Benchmark Dose Technical Guidance document allows for data to be adjusted by eliminating the
high-dose/concentration group (U.S. EPA. 2012b). Because the focus of BMD/BMC analysis is
on the low-dose/concentration regions of the response curve, elimination of the
high-dose/concentration group may be reasonable for certain data sets.
BMD MODELING TO IDENTIFY POTENTIAL POINTS OF DEPARTURE FOR THE
DERIVATION OF A PROVISIONAL INHALATION UNIT RISK
Six data sets from one study provided dose-response information for carcinogenicity of
vinyl bromide, including incidence of angiosarcoma, hepatocellular tumors (combined), and
Zymbal gland squamous cell carcinomas in males and females (Bcnva et al.. 1982). These data
are shown in Table B-13. The data sets modeled include all animals in the study, including
6-month interim sacrifices (5/sex/group), 12- and 18-month interim sacrifices (10/sex/group per
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time point), and terminal sacrifices (18 months for high-concentration group, 24 months for
remaining groups), as well as all animals that died or were sacrificed moribund during the study.
Increased Incidence of Angiosarcoma in Male S-D Rats Exposed to Vinyl Bromide via
Inhalation for up to 24 Months
The procedure outlined above for dichotomous cancer data was applied to the data for
increased incidence of angiosarcoma in male rats exposed to vinyl bromide via inhalation
6 hours/day, 5 days/week, for up to 24 months (Benva et al.. 1982). The data are shown in
Table B-13. Table C-4 summarizes the BMD modeling results. The Multistage models did not
provide statistical fit to the full data set. The characteristics of the dose-response data for high
concentrations affected the shape of the model in the low-concentration region of the
dose-response curve; therefore, the highest concentration was dropped from the modeled data
set. With the highest concentration dropped, the Multistage models still did not provide
statistical fit. With the two highest concentrations dropped, the Multistage models provided
adequate statistical fit to the data. The 10% benchmark concentration lower confidence limit
(BMCLio) values were sufficiently close (
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Table C-4. BMD Modeling Results for Incidence of Angiosarcoma in Male S-D Rats Exposed to Vinyl Bromide (CASRN 593-60-2)
via Inhalation for up to 24 Months3
Model
DF
x2
X2 Goodness-of-Fit
/>-Valucb
Scaled Residual at
Concentration Nearest
BMC
AIC
BMCio
(mg/m3, HEC)
BMCLio
(mg/m3, HEC)
Full data set
Multistage cancer (1-degree)0
3
110.41
0
7.29
648.054
191.985
141.434
Multistage cancer (2-degree)0
3
110.41
0
7.29
648.054
191.985
141.434
Multistage cancer (3-degree)0
3
110.41
0
7.29
648.054
191.985
141.434
Multistage cancer (4-degree)°
3
110.41
0
7.29
648.054
191.985
141.434
High concentration dropped
Multistage cancer (1-degree)0
3
18.37
0.0004
1.329
384.804
21.6774
18.4577
Multistage cancer (2-degree)0
3
18.37
0.0004
1.329
384.804
21.6774
18.4577
Multistage cancer (3-degree)0
3
18.37
0.0004
1.329
384.804
21.6774
18.4577
Two highest concentrations dropped
Multistage cancer (1-degree)0*
2
0.04
0.9805
-0.18
202.013
12.2813
9.64194
Multistage cancer (2-degree)0
1
0
1
0
203.973
12.9663
9.65864
a6enva etal. (1982).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
*Selected model. The Multistage models did not provide statistical fit to the full data set, or the data set with the highest concentration dropped. With two highest
concentrations dropped, both models provided adequate fit. The BMCLs were sufficiently close (within threefold), so the model with the lower AIC was selected
(1-degree Multistage).
AIC = Akaike's information criterion; 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 = concentration associated with 10% extra risk); BMD = benchmark dose; BMR = benchmark response;
DF = degree(s) of freedom; HEC = human equivalent concentration; S-D = Sprague-Dawley.
69
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Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
14:56 03/27 2018
Figure C-2. Fit of the Multistage (1-Degree) Model (Two Highest Concentrations Dropped)
to Data for Incidence of Angiosarcoma in Male S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months (Benya et al., 1982)
Text Output for Figure C-2:
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbromide/Angiosarcoma/male/msc_angiomale2HDD_Mscl-BMR10.(d)
Gnuplot Plotting File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbromide/Angiosarcoma/male/msc_angiomale2HDD_Mscl-BMR10.pit
Tue Mar 27 14:56:36 2018
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
70
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Dependent variable = Effect
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0
Beta(1) = 0.00874614
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Beta(1)
Beta (1) 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
Background 0 NA
Beta(1) 0.00857893 0.00131396 0.00600361 0.0111542
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
Full model
Fitted model
Reduced model
AIC:
Log(likelihood) # Param's Deviance Test d.f. P-value
-99.9865 3
-100.007 1 0.0401331 2 0.9801
-134.643 1 69.3134 2 <.0001
202.013
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
7.5000
41.0000
0.0000
0.0623
0.2965
0.000 0.000 144.000
7.478 7.000 120.000
35.584 36.000 120.000
Chi^2 = 0.04 d.f. = 2
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
P-value = 0.98 05
0. 000
-0.180
0. 083
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BMD
12.2813
BMDL
9.64194
BMDU
15.9724
Taken together, (9.64194, 15.9724) is a 90 % two-sided confidence
interval for the BMD
Cancer Slope Factor
0.0103714
Increased Incidence of Angiosarcoma in Female S-D Rats Exposed to Vinyl Bromide via
Inhalation for up to 24 Months
The procedure outlined above for dichotomous cancer data was applied to the data for
increased incidence of angiosarcoma in female rats exposed to vinyl bromide via inhalation
6 hours/day, 5 days/week, for up to 24 months (Benva et al.. 1982). The data are shown in
Table B-13. Table C-5 summarizes the BMD modeling results. The Multistage models did not
provide statistical fit to the full data set. The characteristics of the dose-response data for high
concentrations affected the shape of the model in the low-concentration region of the
dose-response curve; therefore, the highest concentration was dropped from the modeled data
set. With the highest concentration dropped, the Multistage models, again, did not provide
statistical fit. With the two highest concentrations dropped, only the 1-degree Multistage model
provided adequate statistical fit to the data. Figure C-3 shows the fit of the 1-degree Multistage
model to the data. Based on HECs, the BMCio and BMCLio for angiosarcoma in female rats
were 8.4 and 6.8 mg/m3, respectively.
72
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Table C-5. BMD Modeling Results for Incidence of Angiosarcoma in Female S-D Rats Exposed to Vinyl Bromide (CASRN 593-60-2)
via Inhalation for up to 24 Months3
Model
DF
x2
X2 Goodness-of-Fit
/>-Valucb
Scaled Residual at
Concentration Nearest
BMC
AIC
BMCio
(mg/m3, HEC)
BMCLio
(mg/m3, HEC)
Full data set
Multistage cancer (1-degree)0
3
119.92
0
6.364
701.49
272.651
185.106
Multistage cancer (2-degree)0
3
119.92
0
6.364
701.49
272.651
185.106
Multistage cancer (3-degree)0
3
119.92
0
6.364
701.49
272.651
185.106
Multistage cancer (4-degree)°
3
119.92
0
6.364
701.49
272.651
185.106
Highest concentration dropped
Multistage cancer (1-degree)0
2
41.08
0
0.638
451.889
20.5342
17.0289
Multistage cancer (2-degree)0
2
41.08
0
0.638
451.889
20.5342
17.0289
Multistage cancer (3-degree)0
2
41.08
0
0.638
451.889
20.5342
17.0289
Two highest concentrations dropped
Multistage cancer (1-degree)0*
1
0.27
0.6017
-0.467
248.061
8.37103
6.76577
Multistage cancer (2-degree)0
0
0
NA
0
249.78
9.73228
6.84033
a6enva etal. (1982).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
*Selected model. The Multistage models did not provide statistical fit to the full data set or the data set with the highest concentration dropped. With the two highest
concentrations dropped, only the 1-degree multistage model provided adequate fit.
AIC = Akaike's information criterion; 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 = concentration associated with 10% extra risk); BMD = benchmark dose; BMR = benchmark response;
DF = degree(s) of freedom; HEC = human equivalent concentration; NA = not applicable; S-D = Sprague-Dawley.
73
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Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
23:05 03/27 2018
Figure C-3. Fit of the Multistage (1-Degree) Model (Two Highest Concentrations Dropped)
to Data for Incidence of Angiosarcoma in Female S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months (Benya et al., 1982)
Text Output for Figure C-3:
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbromide/Angiosarcoma/female/msc_angiofemale2HDD_Mscl-BMR10.(d)
Gnuplot Plotting File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbroniide/Angiosarcoma/female/msc_angiofemale2HDD_Mscl-BMR10.pit
Tue Mar 27 23:05:24 2018
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
74
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Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0
Beta(1) = 0.0131334
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
1 -0.15
-0.15 1
Parameter Estimates
Background
Beta(1)
95.0% Wald Confidence Interval
Variable
Background
Beta(1)
Estimate
0.00637629
0.0125863
Std. Err.
0.00628501
0.00169542
Lower Conf. Limit
-0.0059421
0.00926336
Upper Conf. Limit
0.0186947
0.0159093
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood) # Param's Deviance Test d.f. P-value
-121.89
-122.03
-168.102
248.061
0.281245
92.4238
0.5959
<.0001
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
7.5000
41.0000
0.0064
0.0959
0.4069
0.918
11.506
48.831
1.000
10.000
50.000
144.000
120.000
120.000
0. 086
-0.467
0.217
Chi^2 = 0.27 d.f. = 1
Benchmark Dose Computation
P-value = 0.6017
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
8 .37103
6.76577
10.556
Taken together, (6.76577, 10.556 ) is a 90
two-sided confidence
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interval for the BMD
Cancer Slope Factor = 0.0147803
Increased Incidence of Hepatocellular Neoplasms in Male S-D Rats Exposed to Vinyl
Bromide via Inhalation for up to 24 Months
The procedure outlined above for dichotomous cancer data, was applied to the data for
increased incidence of hepatocellular neoplasms in male rats exposed to vinyl bromide via
inhalation 6 hours/day, 5 days/week, for up to 24 months (Benva et al.. 1982). The data are
shown in Table B-13. Table C-6 summarizes the BMD modeling results. The Multistage
models did not provide statistical fit to the full data set. The characteristics of the dose-response
data for high concentrations affected the shape of the model in the low-concentration region of
the dose-response curve; therefore, the highest concentration was dropped from the data set.
With the highest concentration dropped, all models converged on the 1-degree Multistage model
and provided an adequate fit. Figure C-4 shows the fit of the 1-degree Multistage model to the
data. Based on HECs, the BMCio and BMCLio for hepatocellular neoplasms in male rats were
240 and 130 mg/m3, respectively.
76
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Table C-6. BMD Modeling Results for Incidence of Hepatocellular Neoplasms in Male S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months3
Model
DF
x2
X2 Goodness-of-Fit
/>-Valucb
Scaled Residual at
Concentration Nearest
BMC
AIC
BMC io
(mg/m3, HEC)
BMCLio
(mg/m3, HEC)
Full data set
Multistage cancer (1-degree)0
4
9.51
0.0496
NA
280.342
NA
NA
Multistage cancer (2-degree)0
4
9.51
0.0496
NA
280.342
NA
NA
Multistage cancer (3-degree)0
4
9.51
0.0496
NA
280.342
NA
NA
Multistage cancer (4-degree)°
4
9.51
0.0496
NA
280.342
NA
NA
High concentration dropped
Multistage cancer (1-degree)0*
2
2.21
0.3306
-0.372
233.652
241.299
131.437
Multistage cancer (2-degree)0
2
2.21
0.3306
-0.372
233.652
241.299
131.437
Multistage cancer (3-degree)0
2
2.21
0.3306
-0.372
233.652
241.299
131.437
a6enva etal. (1982).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
*Selected model. The Multistage models did not provide statistical fit to the full data set. With highest concentration dropped, the 1-degree Multistage model provided
adequate fit to the data. The higher degree polynomial models took the form of the 1-degree model.
AIC = Akaike's information criterion; 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 = concentration associated with 10% extra risk); BMD = benchmark dose; BMR = benchmark response;
DF = degree(s) of freedom; HEC = human equivalent concentration; NA = not applicable (e.g., BMD computation failed); S-D = Sprague-Dawley.
77
Vinyl bromide
-------
FINAL
September 2020
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
23:51 03/27 2018
Figure C-4. Fit of the Multistage (1-Degree) Model (Highest Concentration Dropped) to
Data for Incidence of Hepatocellular Neoplasms in Male S-D Rats Exposed to Vinyl
Bromide (CASRN 593-60-2) via Inhalation for up to 24 Months (Benya et al., 1982)
Text Output for Figure C-4:
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbroniide/hepatictumor/msc_heptumormaleHDD_Mscl-BMR10.(d)
Gnuplot Plotting File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbroniide/hepatictumor/msc_heptumormaleHDD_Mscl-BMR10.pit
Tue Mar 27 23:51:47 2018
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
78
Vinyl bromide
-------
FINAL
September 2020
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0.046367
Beta(1) = 0.000375425
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
1 -0.54
-0.54 1
Parameter Estimates
Background
Beta(1)
95.0% Wald Confidence Interval
Variable
Background
Beta(1)
Estimate
0.0419259
0.000436638
Std. Err.
0. 0126693
0.000201586
Lower Conf. Limit
0. 0170945
4 .15369e-005
Upper Conf. Limit
0.0667572
0.00083174
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood) # Param's Deviance Test d.f. P-value
-113.748
-114.826
-117.91
233.652
2.15674
8.32362
0.3402
0.03978
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
7.5000
41.0000
193.0000
0.0419
0.0451
0. 0589
0.1194
5.995
4 . 641
7.012
14.323
4.000
5.000
10.000
13.000
143.000
103.000
119.000
120.000
-0.833
0.171
1.163
-0.372
Chi^2 = 2.21 d.f. = 2
Benchmark Dose Computation
P-value = 0.3306
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
241.299
131.437
781.464
79
Vinyl bromide
-------
FINAL
September 2020
Taken together, (131.437, 781.464) is a 90 % two-sided confidence
interval for the BMD
Cancer Slope Factor = 0.000760821
Increased Incidence of Hepatocellular Neoplasms in Female S-D Rats Exposed to Vinyl
Bromide via Inhalation for up to 24 Months
The procedure outlined above for dichotomous cancer data was applied to the data for
increased incidence of hepatocellular neoplasms in female rats exposed to vinyl bromide via
inhalation 6 hours/day, 5 days/week, for up to 24 months (Benva et al.. 1982). The data are
shown in Table B-13. Table C-7 summarizes the BMD modeling results. The Multistage
models did not provide statistical fit to the full data set. The characteristics of the dose-response
data for high concentrations affected the shape of the model in the low-concentration region of
the dose-response curve; therefore, the highest concentration was dropped from the modeled data
set. With the highest concentration dropped, the Multistage models, again, did not provide
statistical fit. No further concentrations could be dropped from the data set because there was no
statistical significance at the next highest concentration; therefore, no model was selected.
80
Vinyl bromide
-------
FINAL
September 2020
Table C-7. BMD Modeling Results for Incidence of Hepatocellular Neoplasms in Female S-D Rats Exposed to Vinyl Bromide
(CASRN 593-60-2) via Inhalation for up to 24 Months3
Model
DF
x2
X2 Goodness-of-Fit
/>-Valucb
Scaled Residual at
Concentration Nearest
BMC
AIC
BMCio
(mg/m3, HEC)
BMCLio
(mg/m3, HEC)
Full data set
Multistage cancer (1-degree)0
4
16.07
0.0029
NA
418.626
NA
NA
Multistage cancer (2-degree)0
4
16.07
0.0029
NA
418.626
NA
NA
Multistage cancer (3-degree)0
4
16.07
0.0029
NA
418.626
NA
NA
Multistage cancer (4-degree)°
4
16.07
0.0029
NA
418.626
NA
NA
High concentration dropped
Multistage cancer (1-degree)0
2
10.61
0.005
-0.055
351.64
209.9
109.954
Multistage cancer (2-degree)0
2
10.61
0.005
-0.055
351.64
209.9
109.954
Multistage cancer (3-degree)0
2
10.61
0.005
-0.055
351.64
209.9
109.954
a6enva etal. (1982).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
AIC = Akaike's information criterion; 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 = concentration associated with 10% extra risk); BMD = benchmark dose; BMR = benchmark response;
DF = degree(s) of freedom; HEC = human equivalent concentration; NA = not applicable (e.g., BMD computation failed); S-D = Sprague-Dawley.
81
Vinyl bromide
-------
FINAL
September 2020
Increased Incidence of Zymbal Gland Carcinomas in Male S-D Rats Exposed to Vinyl
Bromide via Inhalation for up to 24 Months
The procedure outlined above for dichotomous cancer data was applied to the data for
increased incidence of Zymbal gland carcinomas in male rats exposed to vinyl bromide via
inhalation 6 hours/day, 5 days/week, for up to 24 months (Benva et al.. 1982). The data are
shown in Table B-13. Table C-8 summarizes the BMD modeling results. The Multistage
models all converged on the 1-degree Multistage model and provided statistical fit to the data.
Figure C-5 shows the fit of the 1-degree Multistage model to the data. Based on HECs, the
BMCio and BMCLio for Zymbal gland carcinomas in male rats were 270 and 210 mg/m3,
respectively.
Table C-8. BMD Modeling Results for Incidence of Zymbal Gland Carcinomas in Male
S-D Rats Exposed to Vinyl Bromide (CASRN 593-60-2) via Inhalation for
up to 24 Months3
Model
DF
X2
X2 Goodness-of-Fit
/>-Valucb
Scaled Residual at
Concentration
Nearest BMC
AIC
BMCio
(mg/m3,
HEC)
BMCLio
(mg/m3,
HEC)
Full data set
Multistage cancer
(1-degree)0*
3
3.33
0.344
1.282
274.156
272.836
213.703
Multistage cancer (2-degree)0
3
3.33
0.344
1.282
274.156
272.836
213.703
Multistage cancer (3-degree)0
3
3.33
0.344
1.282
274.156
272.836
213.703
Multistage cancer (4-degree)°
3
3.33
0.344
1.282
274.156
272.836
213.703
a6enva ct al. (1982).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
* Selected model. The 1-degree Multistage model provided adequate fit to the data. The higher degree polynomial
models took the form of the 1-degree model.
AIC = Akaike's information criterion; 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 = concentration associated with 10% extra risk); BMD = benchmark dose; BMR = benchmark response;
DF = degree(s) of freedom; HEC = human equivalent concentration; S-D = Sprague-Dawley.
82
Vinyl bromide
-------
FINAL
September 2020
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
dose
08:56 03/28 2018
Figure C-5. Fit of the Multistage (1-Degree) Model to Data for Incidence of Zymbal Gland
Carcinomas in Male S-D Rats Exposed to Vinyl Bromide (CASRN 593-60-2) via Inhalation
for up to 24 Months (Benya et al., 1982)
Text Output for Figure C-5:
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbroniide/zymbaltumor/male/msc_zymbaltumormale_Mscl-BMR10.(d)
Gnuplot Plotting File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbromide/zymbaltumor/male/msc_zymbaltumormale_Mscl-BMR10.pit
Wed Mar 28 08:56:32 2018
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
83
Vinyl bromide
-------
FINAL
September 2020
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 5
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0.0150035
Beta(1) = 0.000363103
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
1 -0.24
-0.24 1
Background
Beta(1)
Parameter Estimates
95.0% Wald Confidence Interval
Variable
Background
Beta(1)
Estimate
0.0101462
0.000386168
Std. Err.
0. 0060259
6.04509e-005
Lower Conf. Limit
-0.00166437
0.000267687
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f.
-133.299 5
-135.078 2 3.5572 3
-175.29 1 83.9811 4
Upper Conf. Limit
0.0219567
0.00050465
P-value
AIC: 274.156
Goodness of Fit
Dose Est._Prob. Expected Observed
Size
0.0000
7.5000
41.0000
193.0000
964.6000
0.0101
0.0130
0.0257
0.0812
0.3180
1.441
1.288
2.878
9.261
36.886
2.000
1.000
1.000
13.000
35.000
142.000
99.000
112.000
114.000
116.000
Chi^2 = 3.33 d.f. = 3
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 272.836
P-value = 0.3440
0.3134
<.0001
Scaled
Residual
0. 468
-0.255
-1.121
1.282
-0.376
84
Vinyl bromide
-------
FINAL
September 2020
BMDL = 213.703
BMDU = 358.816
Taken together, (213.703, 358.816) is a 90 % two-sided confidence
interval for the BMD
Cancer Slope Factor = 0.000467939
Increased Incidence of Zymbal Gland Carcinomas in Female S-D Rats Exposed to Vinyl
Bromide via Inhalation for up to 24 Months
The procedure outlined above for dichotomous cancer data was applied to the data for
increased incidence of Zymbal gland carcinomas in female rats exposed to vinyl bromide via
inhalation 6 hours/day, 5 days/week, for up to 24 months (Benva et al.. 1982). The data are
shown in Table B-13. Table C-9 summarizes the BMD modeling results. The Multistage
models all converged on a 1-degree Multistage model and provided statistical fit to the data.
Figure C-6 shows the fit of the 1-degree Multistage model to the data. Based on HECs, the
BMCio and BMCLio for Zymbal gland carcinomas in female rats were 1,000 and 620 mg/m3,
respectively.
Table C-9. BMD Modeling Results for Incidence of Zymbal Gland Carcinomas in Female
S-D Rats Exposed to Vinyl Bromide (CASRN 593-60-2) via Inhalation for
up to 24 Months3
Scaled Residual
BMCio
BMCLio
X2 Goodness-of-Fit
at Concentration
(mg/m3,
(mg/m3,
Model
DF
x2
/>-Valucb
Nearest BMC
AIC
HEC)
HEC)
Full data set
Multistage cancer (1-degree)0*
3
6.39
0.0943
-0.13
129.603
995.207
621.746
Multistage cancer (2-degree)0
3
6.39
0.0943
-0.13
129.603
995.207
621.746
Multistage cancer (3-degree)0
3
6.39
0.0943
-0.13
129.603
995.206
621.746
Multistage cancer (4-degree)°
3
6.39
0.0943
-0.13
129.603
995.206
621.746
a6enva ct al. (1982).
bValues <0.1 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
* Selected model. The 1-degree Multistage model provided adequate fit to the data. The higher degree polynomial
models took the form of the 1-degree model.
AIC = Akaike's information criterion; 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 = concentration associated with 10% extra risk); BMD = benchmark dose; BMR = benchmark response;
DF = degree(s) of freedom; HEC = human equivalent concentration; S-D = Sprague-Dawley.
85
Vinyl bromide
-------
FINAL
September 2020
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.15
0 " w
BMpL
^MD
0
200
400
600
800
1000
dose
09:13 03/28 2018
Figure C-6. Fit of the Multistage (1-Degree) Model to Data for Incidence of Zymbal Gland
Carcinomas in Female S-D Rats Exposed to Vinyl Bromide (CASRN 593-60-2) via
Inhalation for up to 24 Months (Benya et al., 1982)
Text Output for Figure C-6:
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbromide/zymbaltumor/female/msc_zymbaltumorfemale_Mscl-BMR10.(d)
Gnuplot Plotting File: C:/Users/rhoades/Desktop/PTV
BMDS/vinylbromide/zymbaltumor/female/msc_zymbaltumorfemale_Mscl-BMR10.pit
Wed Mar 28 09:13:21 2018
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 5
Total number of records with missing values = 0
-betal*doseAl) ]
86
Vinyl bromide
-------
FINAL
September 2020
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0.00516248
Beta (1) = 9.90359e-005
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Background 1 -0.47
Beta (1) -0.47 1
Parameter Estimates
Interval
Variable
Limit
Background
0.0128514
Beta(1)
0.00017175
95.0% Wald Confidence
Estimate Std. Err. Lower Conf. Limit Upper Conf.
0.00339121 0.00482674 -0.00606902
0.000105868 3.3614e-005 3.99857e-005
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-60.1739
-62.8015
-73.3358
# Param's
5
2
1
Deviance Test d.f.
5 .25528
26.3238
P-value
0.154
<.0001
AIC:
129.603
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000 0.0034 0.471
7.5000 0.0042 0.414
41.0000 0.0077 0.871
193.0000 0.0235 2.802
964.6000 0.1001 11.416
Chi^2 = 6.39 d.f. =3 P
0.000 139.000 -0.688
0.000 99.000 -0.645
3.000 113.000 2.290
2.000 119.000 -0.485
11.000 114.000 -0.130
value = 0.0943
Benchmark Dose Computation
87
Vinyl bromide
-------
FINAL
September 2020
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 995.2 07
BMDL = 621.74 6
BMDU = 1813.35
Taken together, (621.746, 1813.35) is a 90 % two-sided confidence
interval for the BMD
Cancer Slope Factor = 0.000160837
BMD Model Output for MS Combo Model of Tumors in Male S-D Rats Exposed to
Vinyl Bromide via Inhalation:
MS_COMBO. (Version: 1.10; Date: 01/29/2017)
Input Data File: C:\Users\rhoades\Desktop\PTV
BMDS\vinylbromide\MScombo\MScomboMale.(d)
Gnuplot Plotting File: C:\Users\rhoades\Desktop\PTV
BMDS\vinylbromide\MScombo\MScomboMale.pit
Wed Mar 28 16:51:14 2018
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = angiomale2HDD.dax
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0
Beta(1) = 0.00874614
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
88
Vinyl bromide
-------
FINAL
September 2020
Beta(1)
Beta(1)
Variable
Background
Beta(1)
Parameter Estimates
Estimate
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
0
0.00857892 *
* - Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f. P-value
-99.9865
-100.007
-134.643
0.0401331
69.3134
202.013
Log-likelihood Constant
Dose
Est. Prob.
95 .577776546820544
Goodness of Fit
Expected Observed Size
0.0000
7.5000
41.0000
0.0000
0.0623
0.2965
0.000
7.478
35 .584
0.000
7.000
36.000
144.000
120.000
120.000
Chi^2 = 0.04 d.f. = 2
Benchmark Dose Computation
P-value = 0.98 05
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
12.2813
9.64194
15.9724
0.9801
<.0001
Scaled
Residual
0. 000
-0.180
0. 083
Taken together, (9.64194, 15.9724) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor =
0.0103714
MS_COMBO. (Version: 1.10; Date: 01/29/2017)
Input Data File: C:\Users\rhoades\Desktop\PTV
BMDS\vinylbromide\MScombo\MScomboMale.(d)
Gnuplot Plotting File: C:\Users\rhoades\Desktop\PTV
BMDS\vinylbromide\MScombo\MScomboMale.pit
Wed Mar 28 16:51:14 2018
BMDS Model Run
89
Vinyl bromide
-------
FINAL
September 2020
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = heptumormaleHDD.dax
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0.046367
Beta(1) = 0.000375425
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Background 1 -0.62
Beta (1) -0.62 1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Estimate
0.0419259
0.000436638
Std. Err.
* - Indicates that this value is not calculated.
Analysis of Deviance Table
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Model
Full model
Fitted model
Reduced model
Log(likelihood) # Param's Deviance Test d.f. P-value
-113.748
-114.826
-117.91
2.15674
8 .32362
0.3402
0.03978
AIC:
233.652
Log-likelihood Constant
Dose
Est. Prob.
106.22823536283573
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
7.5000
41.0000
0.0419
0. 0451
0.0589
5.995
4 . 641
7.012
4.000
5.000
10.000
143.000
103.000
119.000
-0. 833
0.171
1.163
90
Vinyl bromide
-------
FINAL
September 2020
193.0000 0.1194 14.323 13.000 120.000 -0.372
Chi^2 = 2.21 d.f. = 2 P-value = 0.3306
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 2 41.299
BMDL = 131.437
BMDU = 781.464
Taken together, (131.437, 781.464) is a 90 % two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.000760821
MS_COMBO. (Version: 1.10; Date: 01/29/2017)
Input Data File: C:\Users\rhoades\Desktop\PTV
BMDS\vinylbromide\MScombo\MScomboMale.(d)
Gnuplot Plotting File: C:\Users\rhoades\Desktop\PTV
BMDS\vinylbromide\MScombo\MScomboMale.pit
Wed Mar 28 16:51:14 2018
BMDS Model Run
Vinyl bromide
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = zymbaltumormale.dax
Total number of observations = 5
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
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
Background = 0.0150035
Beta(1) = 0.000363103
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Background 1 -0.51
91
-------
FINAL
September 2020
Beta(1)
-0.51
Parameter Estimates
Variable
Background
Beta(1)
Estimate
0.0101462
0.000386168
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-133.299
-135.078
-175.29
# Param's Deviance Test d.f.
5
2 3.5572 3
1 83.9811 4
P-value
0.3134
<.0001
274.156
Log-likelihood Constant
Dose
Est. Prob.
125.34195557204099
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
7.5000
41.0000
193.0000
964.6000
0.0101
0.0130
0.0257
0.0812
0.3180
1.441
1.288
2.878
9.261
36.886
2.000
1.000
1.000
13.000
35.000
142.000
99.000
112.000
114.000
116.000
0. 468
-0.255
-1.121
1.282
-0.376
Chi^2 = 3.33 d.f. = 3
Benchmark Dose Computation
P-value = 0.3440
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
272.836
213.703
358.816
Taken together, (213.703, 358.816) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor = 0.000467939
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -34 9.91057237 691183
Combined Log-likelihood Constant 327.14796748169726
Benchmark Dose Computation
Specified effect = 0.1
92
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Risk Type = Extra risk
Confidence level = 0.95
BMD = 11.2065
BMDL = 8.94843
BMDU = 14.2621
Multistage Cancer Slope Factor = 0.0111751
BMD Model Output for MS Combo Model of Tumors in Female S-D Rats Exposed to
Vinyl Bromide via Inhalation.
MS_COMBO. (Version: 1.9; Date: 05/20/2014)
Input Data File: C:\Users\adavislO\OneDrive - Environmental
Protection Agency
(EPA)\adavisl0\_BMDS_Modeling_Results\BMDS2 601\Data\vinyl_bromide\female_m
scombo.(d)
Gnuplot Plotting File: C:\Users\adavislO\OneDrive - Environmental
Protection Agency
(EPA)\adavisl0\_BMDS_Modeling_Results\BMDS2 601\Data\vinyl_bromide\fo
Thu Jan 16 05:50:47 2020
BMDS Model Run
The form of the probability function is:
P [response] = background + (1-background)*[1-EXP(
-betal*doseAl)]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = angio_f_2hdd.dax
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 50 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
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Default Initial Parameter Values
Background = 0
Beta(1) = 0.0131334
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Background
Beta (1)
1
-0 .57
-0 . 57
1
Parameter Estimates
Confidence Interval
Variable
Upper Conf. Limit
Background
¦k
Beta(1)
Estimate
0.00637629
0.0125863
Std. Err.
95.0% Wald
Lower Conf. Limit
* - Indicates that this value is not calculated.
Model
value
Full model
Fitted model
0 . 5959
Reduced model
<.0001
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f.
-121.89
-122 .03
-168.102
0.281245
92 . 4238
AIC: 248.061
Log-likelihood Constant
116.25058964456983
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
Scaled
Residual
0.0000
7 . 5000
41.0000
0.0064
0.0959
0.4069
0 . 918
11.506
48.831
1.000
10.000
50.000
144.000
120 . 000
120.000
0.086
-0 .467
0 .217
ChiA2 = 0.27
d.f. = 1
P-value = 0.6017
94
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Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 8.37104
BMDL = 6.76577
BMDU = 10.556
Taken together, (6.76577, 10.556 ) is a 90 % two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.0147803
MS_COMBO. (Version: 1.9; Date: 05/20/2014)
Input Data File: C:\Users\adavislO\OneDrive - Environmental
Protection Agency
(EPA)\adavisl0\_BMDS_Modeling_Results\BMDS2 601\Data\vinyl_bromide\female_m
scombo.(d)
Gnuplot Plotting File: C:\Users\adavislO\OneDrive - Environmental
Protection Agency
(EPA)\adavisl0\_BMDS_Modeling_Results\BMDS2 601\Data\vinyl_bromide\fo
Thu Jan 16 05:50:47 2020
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl)]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Data file name = zymbal_f_full.dax
Total number of observations = 5
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
95
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Maximum number of iterations = 50 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.00516248
Beta(1) = 9.90359e-005
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Background 1 -0.55
Beta(1) -0.55 1
Parameter Estimates
95.0% Wald
Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit
Upper Conf. Limit
Background 0.00339121 * *
¦k
Beta(1) 0.000105868 * *
¦k
* - Indicates that this value is not calculated.
Model
value
Full model
Fitted model
0 .154
Reduced model
<.0001
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f.
P-
-60.1739
-62.8015
-73.3358
5.25528
26.3238
AIC :
129 . 603
Log-likelihood Constant
55.318204505968403
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
96
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0.0000
7 . 5000
41.0000
193.0000
964.6000
ChiA2 = 6.39
0 .0034
0.0042
0 .0077
0.0235
0.1001
0 . 471
0 . 414
0.871
2.802
11.416
0 .000
0 .000
3 .000
2 .000
11.000
139.000
99.000
113.000
119 .000
114.000
-0.688
-0.645
2 .290
-0.485
-0 .130
d.f. = 3
P-value = 0.0943
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
BMDU =
0 .1
Extra risk
0 . 95
995.207
621.746
1813.35
Taken together, (621.746, 1813.35) is a 90
interval for the BMD
Multistage Cancer Slope Factor = 0.000160837
two-sided confidence
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -184.83199235072126
Combined Log-likelihood Constant 171.56879415053822
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
0 .1
Extra risk
0 . 95
8 .30122
6.71988
Multistage Cancer Slope Factor =
0 .0148812
97
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