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EPA/690/R-17/004
FINAL
09-21-2017
Provisional Peer-Reviewed Toxicity Values for
1 -Bromo-3 -fluorobenzene
(CASRN 1073-06-9)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Scott C. Wesselkamper, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Elizabeth Owens, PhD
National Center for Environmental Assessment, Cincinnati, OH
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the EPA Office
of Research and Development's National Center for Environmental Assessment, Superfund
Health Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 5
DERIVATION 01 PROVISIONAL VALUES 8
DERIVATION 01 ORAL REFERENCE DOSES 9
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 9
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 10
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 10
APPENDIX A. SCREENING PROVISIONAL VALUES 11
APPENDIX B. REFERENCES 36
in
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COMMONLY USED ABBREVIATIONS AND ACRONYMS1
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic
Industrial Hygienists
erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
7V-acetyl-P-D-glucosaminidase
AR
androgen receptor
NCEA
National Center for Environmental
AST
aspartate aminotransferase
Assessment
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NOAEL
no-observed-adverse-effect level
Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity
number
relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPN
chronic progressive nephropathy
RGDR
regional gas dose ratio
CYP450
cytochrome P450
RNA
ribonucleic acid
DAF
dosimetric adjustment factor
SAR
structure activity relationship
DEN
diethylnitrosamine
SCE
sister chromatid exchange
DMSO
dimethylsulfoxide
SD
standard deviation
DNA
deoxyribonucleic acid
SDH
sorbitol dehydrogenase
EPA
Environmental Protection Agency
SE
standard error
ER
estrogen receptor
SGOT
serum glutamic oxaloacetic
FDA
Food and Drug Administration
transaminase, also known as AST
FEVi
forced expiratory volume of 1 second
SGPT
serum glutamic pyruvic transaminase,
GD
gestation day
also known as ALT
GDH
glutamate dehydrogenase
SSD
systemic scleroderma
GGT
y-glutamyl transferase
TCA
trichloroacetic acid
GSH
glutathione
TCE
trichloroethylene
GST
glutathione-S-transferase
TWA
time-weighted average
Hb/g-A
animal blood-gas partition coefficient
UF
uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFa
interspecies uncertainty factor
HEC
human equivalent concentration
UFc
composite uncertainty factor
HED
human equivalent dose
UFd
database uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFl
LOAEL-to-NOAEL uncertainty factor
IVF
in vitro fertilization
UFS
subchronic-to-chronic uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level
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
l-BROMO-3-FLUOROBENZENE (CASRN 1073-06-9)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by at least two National Center for
Environment Assessment (NCEA) scientists and an independent external peer review by at least
three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data
or methodologies that might impact the toxicity values or characterization of potential for
adverse human-health effects and are revised as appropriate. Questions regarding nomination of
chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency
(EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-
science).
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 EPA
Office of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical
Support Center (513-569-7300).
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INTRODUCTION
l-Bromo-3-fluorobenzene, CASRN 1073-06-9, belongs to the class of compounds known
as aryl halides. l-Bromo-3-fluorobenzene is used as an intermediate in agrochemical production
(PTG, 2013). It is listed on U.S. EPA's Toxic Substances Control Act's public inventory (U.S.
EPA. 2017b) and Canada's Non-Domestic Substances List (NDSL) (Environment Canada. 2015)
but it is not registered with Europe's Registration, Evaluation, Authorisation and Restriction of
Chemicals (REACH) program (ECHA. 2017).
l-Bromo-3-fluorobenzene can be produced in a stepwise process. First, an isomeric
mixture of bromofluorobenzenes is produced by the bromination of fluorobenzene. The isomers
are then reacted with benzene in the presence of a Friedel-Crafts catalyst to isolate the
meta-substituted l-bromo-3-fluorobenzene (Tolevesi and Ontario. 1967).
The empirical formula for l-bromo-3-fluorobenzene is Cel^BrF. The chemical structure
is shown in Figure 1. Table 1 summarizes the physicochemical properties of
l-bromo-3-fluorobenzene. The compound is a flammable, colorless liquid at room temperature
(NQAA. 2015) with an estimated high vapor pressure that indicates it is likely to exist as a vapor
in the atmosphere. Given its vapor pressure and estimated Henry's law constant, it is likely to
volatilize from either dry or moist soil surfaces, and from water surfaces. The estimated low
water solubility and moderate soil adsorption coefficient for l-bromo-3-fluorobenzene indicate
that it will have low to moderate potential to leach to groundwater or undergo runoff after a rain
event. Volatilization to the atmosphere is likely to be the main transport pathway.
l-Bromo-3-fluorobenzene was shown to undergo photohydrolysis in dilute aqueous solution with
a measured rate constant of 0.016/minute, which corresponds to a half-life of 44 minutes, when
irradiated with ultraviolet light at wavelengths ranging from 250-350 nm (Peljnenburg et al..
1992).
Br
F
Figure 1. l-Bromo-3-fluorobenzene Structure
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Table 1. Physicochemical Properties of l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Property (unit)
Value
Physical state
Liquid
Boiling point (ฐC)
150a
Melting point (ฐC)
-8b
Density (g/cm3)
1.594ฐ
Vapor pressure (mm Hg at 25 ฐC)
4.0 (estimated)3
pH (unitless)
NV
pKa (unitless)
NV
Solubility in water (mg/L at 25 ฐC)
378a
Octanol-water partition coefficient (log Kow)
2.92a
Henry's law constant (atm-m3/mol at 25ฐC)
6.3 x 10 3 (estimated)3
Soil adsorption coefficient Koc (L/kg)
380 (estimated)3
Atmospheric OH rate constant (cm3/molecule-sec at 25ฐC)
1.5 x 10-12 (estimated)3
Atmospheric half-life (d)
7 (estimated)3
Relative vapor density (air = 1)
6.03d
Molecular weight (g/mol)
1753
Flash point (ฐC)
46ฐ
"U.S. EPA (2012b).
bAlfa Aesar (2017).
cSigma-Aldrich (2017).
dFisher Scientific (2008).
NV = not available.
No toxicity values for l-bromo-3-fluorobenzene are available from U.S. EPA or other
agencies/organizations, as shown in Table 2.
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Table 2. Summary of Available Toxicity Values for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Source3
Value
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2017a)
HEAST
NV
NA
U.S. EPA (201 la)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2017)
IPCS
NV
NA
IPCS (2017); WHO (2017)
Cal/EPA
NV
NA
Cal/EPA (2014): Cal/EPA (2017a): Cal/EPA (2017b)
OSHA
NV
NA
OSHA (2006); OSHA (2011)
NIOSH
NV
NA
NIOSH (2016}
ACGIH
NV
NA
ACGIH (2016)
Cancer
IRIS
NV
NA
U.S. EPA (2017a)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2017)
Cal/EPA
NV
NA
Cal/EPA (2011): Cal/EPA (2017a): Cal/EPA (2017b)
ACGIH
NV
NA
ACGIH (2016)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = 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.
NA = not applicable; NV = not available.
Non-date-limited literature searches were conducted in November 2015 and updated in
June 2017 for studies relevant to the derivation of provisional toxicity values for
l-bromo-3-fluorobenzene (CASRN 1073-06-9). Searches were conducted using U.S. EPA's
Health and Environmental Research Online (HERO) database of scientific literature. HERO
searches the following databases: PubMed, ToxLine (including TSCATS1), and Web of Science.
The following databases were searched outside of HERO for health-related data: American
Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and
Disease Registry (ATSDR), California Environmental Protection Agency (Cal/EPA), U.S. EPA
Integrated Risk Information System (IRIS), U.S. EPA Health Effects Assessment Summary
Tables (HEAST), U.S. EPA Office of Water (OW), U.S. EPA TSCATS2/TSCATS8e, National
Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), and
Occupational Safety and Health Administration (OSHA).
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
As shown in Tables 3 A and 3B, there are no potentially relevant short-term-, subchronic-,
or chronic-duration studies or developmental or reproductive toxicity studies of
l-bromo-3-fluorobenzene in humans or animals exposed by oral or inhalation routes. In
addition, no data on acute toxicity or genotoxicity were identified for this compound.
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Table 3A. Summary of Potentially Relevant Noncancer Data for l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Number of Male/Female, Strain, Species, Study
Category
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
NOAEL
LOAEL
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level.
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Table 3B. Summary of Potentially Relevant Cancer Data for l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
ND = no data.
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A single study examining the Phase II metabolism of l-bromo-3-fluorobenzene (as part
of a series of 3-halofluorobenzenes) was identified. Soffers et al. (1994) administered a single
gavage dose of 500 |imol/kg l-bromo-3-fluorobenzene (purity not reported) in olive oil to male
Wistar rats and collected urine for the first 24 hours after dosing. Urine samples were
enzymatically treated to hydrolyze sulfate and glucuronide conjugates, and then analyzed by 19F
nuclear magnetic resonance (NMR). Urinary recovery of fluorine was 78% of the administered
dose after exposure to l-bromo-3-fluorobenzene. Metabolites identified in the urine included the
sulfate and glucuronide conjugates of 4-bromo-2-fluorophenol; the sulfate conjugate represented
-8% of the total fluorine intensity in the urine, while the glucuronide represented <2%. The
primary metabolites in the urine (which apparently represented -90% of the excreted fluorine)
were not identified, but the authors suggested that these most likely were products of glutathione
(GSH) conjugation pathways (Soffers et al, 1994). In vitro experiments in which rat liver
microsomes were incubated with l-bromo-3-fluorobenzene (0.5, 1.0, or 2.0 mM) showed
dose-dependent formation of 4-bromo-2-fluorophenol (Soffers et al.. 1994).
DERIVATION OF PROVISIONAL VALUES
The lack of repeated-dose toxicity data in humans or animals precludes derivation of
subchronic or chronic provisional reference doses (p-RfDs) or provisional reference
concentrations (p-RfCs) for l-bromo-3-fluorobenzene. However, screening subchronic and
chronic p-RfDs and a screening subchronic p-RfC are derived based on data for structurally
similar compounds (see Appendix A).
Tables 4 and 5 present summaries of noncancer and cancer references values,
respectively.
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Table 4. Summary of Noncancer Reference Values for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Toxicity Type
(units)
Species/Sex
Critical Effects
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Screening
subchronic
p-RfD
(mg/kg-d)
Rat/M
Increased relative
liver weight
(liver:body-weight
ratio) and hepatic
microsomal enzyme
induction
3 x 1(T3
NOAEL
(HED)
1
(based on
surrogate)
300
Carlson and
Tardiff (1977)
Screening
chronic p-RfD
(mg/kg-d)
Rat/M
Increased relative
liver weight
(liver:body-weight
ratio) and hepatic
microsomal enzyme
induction
3 x 1(T4
NOAEL
(HED)
1
(based on
surrogate)
3,000
Carlson and
Tardiff (1977)
Screening
subchronic
p-RfC (mg/m3)
Rat/M
Centrilobular
hepatocyte
enlargement
3 x 10-2
BMCLio
(HEC)
8.9
(based on
surrogate)
300
Safepharm Labs,
Ltd. (1993) as
cited in U.S. EPA
(2011b)
Chronic p-RfC
(mg/m3)
NDr
BMCLio = 10% benchmark concentration lower confidence limit; HEC = human equivalent concentration;
HED = human equivalent dose; M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level;
p-RfC = provisional reference concentration; p-RfD = provisional reference dose; POD = point of departure;
UFC = composite uncertainty factor.
Table 5. Summary of Cancer Reference Values for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
DERIVATION OF ORAL REFERENCE DOSES
There are no relevant data on the effects of l-bromo-3-fluorobenzene in humans or
animals exposed orally. However, screening subchronic and chronic p-RfD values are derived
based on data for structurally similar compounds (see Appendix A).
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
There are no relevant data on the effects of l-bromo-3-fluorobenzene in humans or
animals exposed by inhalation. However, a screening subchronic p-RfC value is derived based
on data for structurally similar compounds (see Appendix A).
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CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No relevant data are available. Under the U.S. EPA Guidelines for Carcinogen Risk
Assessment (U.S. EPA. 2005). there is "Inadequate Information to Assess the Carcinogenic
Potential" of l-bromo-3-fluorobenzene following both oral and inhalation exposure as shown in
Table 6.
Table 6. Cancer WOE Descriptor for l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
There are no human carcinogenicity data
identified to support this descriptor.
"Likely to Be Carcinogenic to
Humans "
NS
NA
There are no animal carcinogenicity
studies identified to support this
descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No adequate chronic-duration animal
cancer bioassays are available.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No studies are available assessing the
carcinogenic potential of
l-bromo-3-fluorobenzene in humans
or animals following oral or inhalation
exposure.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
No evidence of noncarcinogenicity is
available.
NA = not applicable; NS = not selected; WOE = weight of evidence.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of quantitative estimates of cancer risk for l-bromo-3-fluorobenzene is
precluded by the absence of carcinogenicity data.
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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 toxicity values for l-bromo-3-fluorobenzene.
However, information is available for this chemical which, although insufficient to support
derivation of a provisional toxicity value under current guidelines, may be of limited use to risk
assessors. In such cases, the Superfund Health Risk Technical Support Center summarizes
available information in an appendix and develops a "screening value." Appendices receive the
same level of internal and external scientific peer review as the PPRTV documents to ensure
their appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
value presented in the body of the assessment. Questions or concerns about the appropriate use
of screening values should be directed to the Superfund Health Risk Technical Support Center.
APPLICATION OF AN ALTERNATIVE SURROGATE APPROACH
The surrogate approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for surrogate analysis are presented in Wang et al. (2012).
Three types of potential surrogates (structural, metabolic, and toxicity-like) are identified to
facilitate the final surrogate chemical selection. The surrogate approach may or may not be
route-specific or applicable to multiple routes of exposure. All information was considered
together as part of the final weight-of-evidence (WOE) approach to select the most suitable
surrogate both toxicologically and chemically.
Structural Surrogates (Structural Analogs)
Initial surrogate searches focused on identifying structurally similar chemicals with oral
and/or inhalation toxicity values from the Integrated Risk Information System (IRIS), PPRTV,
Agency for Toxic Substances and Disease Registry (ATSDR), or California Environmental
Protection Agency (Cal/EPA) databases to take advantage of the well-characterized
chemical-class information. This search did not identify any candidate analogs containing both
fluorine and bromine substituents on a benzene ring, as in the case of the target chemical
(including potential surrogates containing other substituents on the ring such as a methyl group);
the available analogs contain either fluorine or bromine. Under Wane et al. (2012). structural
similarity for analogs is typically evaluated using U.S. EPA's DSSTox database (DSSTox. 2016)
and the National Library of Medicine's (NLM's) ChemlDplus database (ChemlDplus. 2017). At
the time this PPRTV assessment was developed, however, DSSTox was not available to the
public. In lieu of DSSTox scores, the Organisation for Economic Co-operation and
Development (OECD) toolbox was used to calculate structural similarity using the Tanimoto
method (the same quantitative method used by ChemlDplus and DSSTox). Table A-l
summarizes the analogs' physicochemical properties and similarity scores.
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Table A-l. Comparison of Physicochemical Properties for l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Analogs3
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Structure
prB'
F
a'
a"
JO*
lYr
CASRN
1073-06-9
462-06-6
108-86-1
106-37-6
615-54-3
Molecular weight
175
96
157
236
315
DSSTox similarity score (%)b
100
NV
NV
NV
NV
ChemlDplus similarity score (%)ฐ
100
<50
<50
<50
52
OECD toolbox similarity score (%)d
100
33
33
26
26
Melting point (ฐC)
-8
-42.2
-30.6
87.3
44.5
Boiling point (ฐC)
150
84.7
156
218.5
275
Vapor pressure (mm Hg at 25ฐC)
4.0 (estimated)15
7.72 x 101
4.18
5.75 x 10-2
4.8 x 10~3 (estimated)
Henry's law constant (atm-m3/mole at 25ฐC)
6.3 x 10 3 (estimated)13
6.25 x 10-3
2.47 x lO-3
8.9 x 10-4
3.9 x 10 4 (estimated)
Water solubility (mg/L)
378
1,540 (at 30ฐC)
446 (at 30ฐC)
20
4.9
Log Kow
2.92
2.27
2.99
3.79
4.66 (estimated)
pKa
NA
NA
NA
NA
NA
'Data were gathered from PHYSPROP for each respective compound unless otherwise specified (U.S. HPA. 2012b).
bDSSTox (2016).
ฐChemIDplus Advanced, similarity scores (ChemlDplus. 20171.
dOECD (2016).
NA = not applicable; NV = not available; OECD = Organisation for Economic Co-operation and Development.
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Physicochemical properties indicate that l-bromo-3-fluorobenzene and all candidate
surrogates are likely to be bioavailable by oral and inhalation routes (based on water solubility
and vapor pressure). In addition, relatively high octanol-water partition coefficient (log Kow)
values suggest that, after systemic absorption, these compounds will exhibit an affinity for
adipose tissue. The target and candidate surrogate compounds are all neutral compounds and
will not ionize. Although the di- and tribromobenzenes are solids at room temperature, the
relatively minor differences in physicochemical properties between the candidate surrogates and
the target compound does not preclude any of the surrogates from further consideration.
ChemlDplus similarity scores for the candidate surrogates were <50%, except for
1,2,4-tribromobenzene (52%). Low similarity scores (2633%) were obtained using the OECD
toolbox. The low similarity scores for the candidate surrogates are likely related to the limited
number of structural descriptors available for these compounds. Structural similarity metrics use
a variety of structural descriptors to calculate similarity (although the nature of the descriptors
may vary across different tools). Similarity scores calculated for compounds with few structural
descriptors will be disproportionately influenced by changes in, or absence of, a single
descriptor, while these same changes have relatively lower impact on similarity scores for
compounds with many descriptors. Thus, similarity scores may be of limited use when
comparing surrogates with relatively simple structures such as those evaluated in this
assessment.
Despite the low similarity scores, examination of the structural features demonstrates that
the available candidate surrogates all share a benzene ring with one or more bromine or fluorine
substituents. Moreover, they all contain at least one set of adjacent hydrogen atoms on the
aromatic ring which, as indicated in the subsequent section, suggests that they all have the
potential to follow the same first step in their metabolic transformation. Thus, all of these
analogs may be considered potential structural surrogates.
Metabolic Surrogates
Oral toxicokinetic data are available for l-bromo-3-fluorobenzene and the candidate
surrogates (see Table A-2). There were no data on inhalation toxicokinetics of
l-bromo-3-fluorobenzene or the candidate surrogate compounds.
13
1 -Bromo-3 -fluorob enzene
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Table A-2. Comparison of Available ADME Data for l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
CASRN 1073-06-9
CASRN 462-06-6
CASRN 108-86-1
CASRN 106-37-6
CASRN 615-54-3
Cr*
F
a'
a*
XT
jOCb'
Absorption
78% in rats exposed orally based
on urinary excretion in the first
24 hr postdosing
83% in rats exposed orally
based on urinary excretion
in the first 24 hr
postdosing
60-70% in rats, mice, and rabbits exposed
orally (based on elimination of metabolites
via urine)
24-40% in rats, mice, and
rabbits exposed orally (based on
elimination of metabolites via
urine)
ND
Distribution
ND
ND
In rats exposed i.p., highest bromobenzene
concentrations in:
Fat
Liver, kidney, brain, muscle, heart,
blood, seminal fluid
Bromophenol metabolites highest in
kidney, lungs, and blood
In rats exposed i.p., highest
1,4-dibromobenzene
concentrations in:
Fat
Muscle
Adrenals
Sciatic nerve
ND
14
1 -Bromo-3 -fluorob enzene
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Table A-2. Comparison of Available ADME Data for l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Metabolites
Rats exposed orallv
Rats exposed orallv
Rats. mice, and rabbits exposed orallv
Rats and mice exposed orallv
Rats exposed orallv
Urinary (% of urinary fluorine):
Urinary (as sulfate and
Urinary (% dose):
Urinary (% dose):
ND
Unidentified metabolites
glucuronide conjugates, in
4-Bromophenyl mercapturic acid
Phenol,
(-90%)
descending order of
(35-38%)
2,5-dibromo- (23-39%)
Rabbits exposed i.p.
4-Bromo-2-fluorophenyl-
abundance):
Phenol, 3-bromo- (9-23%)
Phenol, 3-bromo- (0.6-1.0%)
Urinary (ether extractable
sulfate (~8%)
Phenol, 4-fluoro-
Phenol, 4-bromo- (3-13%)
Phenol, 2-bromo- (0.2-0.3%)
metabolites):
4-Bromo-2-fluorophenyl-
Phenol, 2-fluoro-
Phenol, 2-bromo- (3-12%)
Phenol, 2,4,5-tribromo-
glucuronide (<2%)
Phenol, 3-fluoro-
Bromobenzene (1.2%)
Rabbits exposed i.p.
Phenol, 2,4,6-tribromo-
Unidentified metabolites
Urinary (ether extractable
Study authors suggested that the
1,2-Benzenediol,
Similar in rabbits; higher 2-bromophenol
metabolites):
Third tribromophenol not
unidentified metabolites may be
4-fluoro-
(12.1%) and lower 3- and 4-bromophenol
Phenol, 2,4-dibromo-
identified
products of GSH conjugation
1,2-Benzenediol,
(8.8 and 3.1%, respectively) in mice
Phenol, 2,5-dibromo-
pathways.
3-fluoro-
Rabbits exposed orallv
Rats exposed i.p.
Rat liver microsomes
Study authors suggested
Urinary (% dose):
Urinary (% urinary
4-Bromo-2-fluorophenol
that the unidentified
Sulfate conjugate (37%)
radioactivity):
metabolites may be
Glucuronide conjugate (40%)
Phenol, 2,5-dibromo- (84%)
mercapturic acids or other
Mercapturic acid (21%)
1,4-dibromobenzene (5.3%)
sulfur-containing
Benzenethiol,
metabolites
28% of the sulfate and glucuronide
2,5-dibromo- (4.6%)
conjugates consisted of catechol derivatives
Bromophenol (isomer not
Rabbits exposed orallv
identified; 1.9%)
Urinary (% dose):
Rabbits exposed i.p.
Methylated benzenethiol,
Sulfate conjugate (21%)
Urinary (ether extractable metabolites):
2,5-dibromo- (0.8%)
Glucuronide conjugate
Phenol, 4-bromo-
(10%)
Phenol, 3-bromo-
Two additional metabolites
Mercapturic acid (1.6%)
containing ethylmercapto groups
Rats exposed i.v. or i.p.
and free mercapto groups in
Urinary (% urinary radioactivity):
addition to methyl mercapto
Bromophenyl mercapturic acid
group already on ring (2.6 and
(48-70%)
0.5%)
Phenol, 4-bromo- (18-37%)
1,2-Benzenediol, bromo- (4-6%)
15
1 -Bromo-3 -fluorob enzene
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Table A-2. Comparison of Available ADME Data for l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Continued:
Continued:
Continued:
Continued:
Continued:
12% of the sulfate and
glucuronide conjugates
consisted of catechol
derivatives
Bromophenyldihydrodiol (4%)
Phenol, 2-bromo- (3-4%)
PB-induced rats cxooscd i.D.
Urinary (% ether extractable metabolites):
Phenol, 3-bromo- (44%)
Phenol, 4-bromo- (38%)
1,2-Benzenediol, 4-bromo- (18%)
Dihydrodiol (4%)
-57% of the urinary radioactivity was not
ether extractable; the study authors
indicated that this fraction likely consisted
of mercapturic acids and premercapturic
acids.
PB-induced rat liver microsomes (% total)
Phenol, 4-bromo- (58%)
1,2-Benzenendiol, 4-bromo- (24%)
3,5-Cyclohexadiene-l,2-diol,
4-bromo- (17%)
PB-induced rat heratocvtes (% total)
3,5-Cyclohexadiene-l,2-diol,
4-bromo- (25-55%)
Phenol, 4-bromo- (12-60%)
1,2-Benzenediol, 4-bromo- (8-22%)
3,5-Cyclohexadiene-l,2-diol,
3-bromo- (3-12%)
Phenol, 3-bromo- (3-4%)
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Table A-2. Comparison of Available ADME Data for l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Excretory pattern
Rats cxooscd orallv
Rats cxooscd orallv
Rats, rabbits, and mice cxooscd orallv
Rats and mice cxooscd orallv
ND
(% dose in 24 hr):
Urine: 78%
Feces: ND
(% dose in 24 hr):
Urine: 83%
Feces: ND
(% dose):
Urine: 60-71%
Feces: ND
(% dose):
Urine: 24-40%
Feces: ND
Rats exoosed i.o.
(% dose in 72 hr):
Urine: 30%
Feces: 3.6%
Sources
Soffers et al. (1994)
Koerts et al. (1997); Azouz
et al. (1953. 1952)
Miller et al. (1990); Oeino (1984); Ruzo et
al. (1976); Zamraelione et al. (1973);
Azouz etal. (1953. 1952)
Szvmanska et al. (2002); Oeino
(1984): Ruzo etal. (1976)
Ruzo et al. (1976)
ADME = absorption, distribution, metabolism, and excretion; GSH = glutathione; i.p. = intraperitoneal; i.v. = intravenous; ND = no data; PB = phenobarbital.
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1 -Bromo-3 -fluorob enzene
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After oral exposure, 78% of l-bromo-3-fluorobenzene, 60-70% of bromobenzene, and
24-40% of 1,4-dibromobenzene is absorbed (Soffers et al.. 1994; Ogino. 1984; Ru/.o et al..
1976); no data are available on the other candidates. Studies examining systemic distribution in
rats after intraperitoneal (i.p.) exposure indicate that bromobenzene and 1,4-dibromobenzene are
both deposited at highest concentrations in the fat (Ru/.o et al.. 1976). No information on the
distribution of l-bromo-3-fluorobenzene or the other candidate surrogates was located; however,
given that l-bromo-3-fluorobenzene has a lower log Kow value and higher water solubility than
the di- and tribromobenzenes, its partitioning to fat is expected to be lower.
After oral exposure, l-bromo-3-fluorobenzene, fluorobenzene, and bromobenzene are
primarily excreted via the urine; urinary excretion is also the primary pathway after i.p. exposure
to 1,4-dibromobenzene. Excretion information is not available for 1,2,4-tribromobenzene.
l-Bromo-3-fluorobenzene and all of the candidate surrogates are initially metabolized via
cytochrome P450 (CYP450) isozymes to phenolic derivatives. The phenolic compounds may be
excreted unchanged, further hydroxylated to yield benzenediols (catechols) and/or quinones, or
conjugated with sulfate or glucuronide. Available data suggest that, for fluorobenzene, sulfate
and glucuronide conjugation play major roles in the Phase II metabolism (Koerts et al.. 1997),
while glutathione (GSH) conjugation of electrophilic intermediates appears to play a minor role
(Azouz et al.. 1953. 1952). In contrast, GSH conjugation represents a significant pathway for
bromobenzene [reviewed by I .an and Monks (1997)1. Soffers et al. (1994) hypothesized that
products of GSH conjugates might account for the unidentified metabolites (representing -90%
of total urinary fluorine) in their study of l-bromo-3-fluorobenzene, but these metabolites cannot
be definitively identified (see Figure A-l). Conjugation reactions for metabolites of
1,4-dibromobenzene and 1,2,4-tribromobenzene have not been well established; however, data
showing limited excretion of mercapturic acids (formed via GSH conjugates) after exposure to
these compounds (discussed further below) suggest a small role for GSH conjugation.
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1 -Bromo-3 -fluorob enzene
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ir
F
l-Bromo-3-fluorobenzene
osc
Unknown (~90%)
Br
Bi
Br
4-Bromo- 2-fluorophenylsulfate (~8%)
4-Bromo-2-fluorppheaylglucuronide (<2%)
Figure A-l. Putative Metabolism of l-Bromo-3-fluorobenzene
[based on Soffers et al. (1994)1
Bromobenzene metabolites are largely excreted as mercapturic acids (Miller et al.. 1990;
Qui no. 1984; Zampaglione et al. 1973). primarily 4-bromophenyl mercapturic acid resulting
from GSH conjugation of a 3,4-epoxide intemiediate (U.S. EPA. 2009). In addition, as noted
above, Soffers et al. (1994) suggested that the primary metabolites of 1 -bromo-3-fluorobenzene,
which were not definitively identified, might be products of GSH conjugation (i.e., mercapturic
acids). In contrast, mercapturic or premercapturic acids, when they were reported, occurred in
smaller quantities (<10% of administered dose when quantified) in the urine of animals exposed
to fluorobenzene, 1,4-dibromobenzene, and 1,2,4-tribromobenzene. In a comparative
metabolism study (Qgino. 1984). mercapturic acid derivatives were the major urinary
metabolites of bromobenzene (35-38% of dose) in rats, mice, and rabbits exposed orally, while
no mercapturic acid derivatives were recovered after exposure of rats or mice to 1,3- or
1,4-dibromobenzene. 1,2,4-Tribromobenzene was not tested in the study by Qgino (1984);
however, a mercapturic acid derivative representing a small fraction of the administered dose
was measured in the urine of rats exposed to its isomer, 1,3,5-tribromobenzene. No mercapturic
acids were observed in the urine of rabbits exposed i.p. to bromobenzene, 1,4-dibromobenzene,
or 1,2,4-tribromobenzene (Ru/.o et al.. 1976); however, it is not clear that the analytical methods
used by the study authors would have identified these metabolites. Mercapturic acid derivatives
of 1,4-dibromobenzene were tentatively identified in rat urine after i.p. exposure (S/vmanska et
al.. 2002). but these compounds constituted a small fraction of the excreted metabolites. In an
early study, Azouz et al. (1952) observed a small quantity of mercapturic acid metabolites (1.6%
of dose) in the urine of rabbits exposed orally to fluorobenzene; by comparison, 21% of the
administered dose of bromobenzene was excreted as mercapturic acids in this study. Koerts et
al. (1997) hypothesized that unidentified metabolites detected in small quantities in the urine of
rats exposed to fluorobenzene might be mercapturic acids or other sulfur-containing metabolites,
but these metabolites cannot be definitively identified.
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Phenolic metabolites that are not conjugated and/or excreted may be further hydroxylated
to form benzenediol metabolites and/or reactive quinone intermediates. Benzenediol derivatives
have been observed in the urine of rats and rabbits exposed to fluorobenzene and bromobenzene
(Koerts et aL 1997; Miller et al.. 1990; Zampaglione et al.. 1973; Azouz et al.. 1953).
Hydroxylated phenolic derivatives of 1,4-dibromobenzene and 1,2,4-tribromobenzene are
plausible, but have not been reported in available studies (Szvmanska et al, 2002; Ogino, 1984;
Ruzo et al. 1976). If formed, these metabolites are expected to occur in much lower quantities
after exposure to 1,4-dibromobenzene or 1,2,4-tribromobenzene due to steric hindrance exerted
by the bromines. Koerts et al. (1997) reported that steric hindrance of CYP450 attack on
adjacent ring positions was significant for bromine. Steric hindrance of hydroxylation exerted by
para-positioned bromines may explain the lower excretion of 1,4-dibromobenzene compared
with l-bromo-3-fluorobenzene and bromobenzene.
Debromination is an additional metabolic step for the higher brominated compounds.
Debromination of 1,4-dibromobenzene or its metabolites was apparent from the detection of
small quantities of monobromophenols in the urine of orally exposed mice and rats (Ogino.
1984). While debromination products were not seen in the single study of
1,2,4-tribromobenzene (Ruzo et al.. 1976). these products were seen in rats and mice exposed
orally to the related compound, 1,3,5-tribromobenzene (Ogino. 1984). Compounds excreted in
urine after exposure to 1,3,5-tribromobenzene primarily consisted of the parent compound
(14-15% of dose), 2,4,6-tribromophenol (13-14%), 3,5-dibromophenol (11-18%),
2-hydroxy-3,5 -dibromothiophenyl-1 -methyl (14-19%), 2-hydroxy-3,5 -dibromothiophenyl-
1-methyloxide (79%), and 3,5-dibromopheny 1 mercapturic acid (6-7%) (Ogino. 1984). Thus,
for 1,3,5-tribromobenzene, the majority of urinary metabolites had undergone debromination.
No evidence for debromination was seen in studies of animals exposed to bromobenzene (Miller
et al.. 1990; Ogino. 1984; Ruzo et al.. 1976; Zampaglione et al.. 1973) or
1 -bromo-3-fluorobenzene (Suffers et al.. 1994).
In summary, the metabolism of l-bromo-3-fluorobenzene and each of the candidate
surrogates begins with ring hydroxylation via CYP450s followed by excretion, sulfate or
glucuronide conjugation, or further ring hydroxylation. The higher brominated candidates may
also undergo debromination. Data in several species indicate that bromobenzene metabolism to
mercapturic acid derivatives likely occurs via an epoxide intermediate that is conjugated with
GSH. In addition, sulfate and glucuronide conjugates represented a small quantity of excreted
fluorine in the urine of rats exposed to the l-bromo-3-fluorobenzene target chemical, leading
Suffers et al. (1994) to postulate that the primary metabolites might reflect GSH conjugation.
Importantly, however, the identity of these metabolites cannot be definitively determined. In
contrast, data on fluorobenzene, 1,4-dibromobenzene, and 1,2,4-tribromobenzene do not indicate
the formation of significant quantities of mercapturic acid derivatives, suggesting that GSH
conjugation of these compounds may be more limited. In light of the common Phase I metabolic
pathways, as well as the uncertainties surrounding potential similarities in excreted Phase II
metabolites, bromobenzene, fluorobenzene, 1,4-dibromobenzene, and 1,2,4-tribromobenzene are
all considered to be reasonable metabolic surrogates.
Toxicity-Like Surrogates
There are no oral toxicity data for l-bromo-3-fluorobenzene or fluorobenzene. Table A-3
summarizes the available subchronic and chronic oral toxicity values for bromobenzene,
1,4-dibromobenzene, and 1,2,4-tribromobenzene. As the table shows, the liver is the target
20
1 -Bromo-3 -fluorob enzene
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organ for all of the brominated candidate surrogates, but kidney effects have also been seen at
higher doses of bromobenzene and 1,4-dibromobenzene. While there are no repeated-dose oral
data for fluorobenzene, the liver is also the target organ in the single available repeated-exposure
study of fluorobenzene administered via inhalation (see Table A-4).
There are no inhalation toxicity data for l-bromo-3-fluorobenzene. Among the candidate
surrogates, only fluorobenzene and bromobenzene have inhalation toxicity values, as shown in
Table A-4. As with the oral toxicity data, the available inhalation toxicity data confirm the liver
as the primary target organ after exposure to the candidate surrogates.
The mode of action (MOA) for bromobenzene hepatotoxicity has been well studied, and
is believed to be mediated by reactive metabolites. U.S. EPA (2009) suggested that some or all
of the following intermediates may be involved in bromobenzene-induced hepatotoxicity: the
3,4-epoxide, the 2,3-epoxide, the oxide derivatives of 2- or 3-bromophenol,
4-bromophenol-5,6-oxide, 1,4-benzoquinone, 4-bromo-o-quinone, 2-bromo-/>quinone, or
reactive oxygen species resulting from redox cycling of 2-broino-p-catechol,
4-bromo-o-catechol, and/or the bromoquinones. Although there is support for the importance of
the 3,4-epoxide, the relative importance of the other metabolites is not known (U.S. EPA, 2009).
Molecular mechanisms proposed to be involved include decreased hepatocyte oxygen uptake and
adenosine triphosphate (ATP) depletion, altered calcium homeostasis, and GSH depletion (U.S.
EPA, 2009). Information on the hepatotoxic MOA(s) for fluorobenzene, 1,4-dibromobenzene,
and 1,2,4-tribromobenzene was not available.
As shown in Table A-3, liver pathology findings in studies of the candidate surrogates
were remarkably consistent: the critical effect was generally hepatocyte swelling/cytomegaly,
associated with increased liver weight and induction of hepatic enzymes; at higher doses of
bromobenzene (400 mg/kg-day) and 1,2,4-tribromobenzene (25 mg/kg-day), hepatocyte
vacuolation and necrosis were reported in rats. At higher doses of bromobenzene and
1,4-dibromobenzene (100-500 mg/kg-day), renal effects were seen; available studies of
1,2,4-tribromobenzene (Dodd et al 2012: Carlson and Tardiff. 1977) did not evaluate potential
kidney effects.
In summary, all of the structurally related candidate surrogates exhibit remarkably similar
acute toxicity potencies, target organ toxicity, effect levels (human equivalent doses [HEDs]) for
repeated-dose oral toxicity, and resultant histopathological lesions, supporting the inference that
l-bromo-3-fluorobenzene is hepatotoxic too. However, in the absence of repeated-exposure
toxicity data for l-bromo-3-fluorobenzene, there is no information with which to identify or rule
out candidate surrogates based on toxicity comparisons.
21
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Table A-3. Comparison of Available Subchronic and Chronic Oral Toxicity Data for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
1-Bromo-
3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
CASRN
460-00-4
462-06-6
108-86-1
106-37-6
615-54-3
Structure
F
a'
a*
.XT*
lYr
POD (mg/kg-d)
NA
NA
24.1
10
5
POD (HED)
mg/kg-da
NA
NA
3.51b
2ฐ
lc
POD type
NA
NA
BMDLio
NOAEL
NOAEL
Subchronic UFC
NA
NA
1,000 (UFa x UFd x UFh)
NA
NA
Subchronic RfD
(mg/kg-d)
NA
NA
2 x 102
NA
NA
Chronic UFC
NA
NA
3,000 (UFa x UFd x UFh x UFs)
1,000 (UFa x UFh x UFs)
1,000 (UFa x UFh x UFs)
Chronic RfD
(mg/kg-d)
NA
NA
8 x 10-3
1 x 10-2
5 x 10-3
Critical effects
NA
NA
Hepatocellular cytomegaly
Increased relative liver weight
(liver:body-weight ratio) and hepatic
microsomal enzyme induction
Increased relative liver
weight (liver:body-weight
ratio) and hepatic
microsomal enzyme
induction
22
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Table A-3. Comparison of Available Subchronic and Chronic Oral Toxicity Data for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
1-Bromo-
3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Other effects
NA
NA
Mortality (600 mg/kg-d) and
reduced body weight
(>400 mg/kg-d) in males; increased
absolute and relative liver weight
(>50 mg/kg-d); increased serum
SDH (>200 mg/kg-d); additional
liver histopathology (necrosis
[>400 mg/kg-d], mineralization
[>400 mg/kg-d], inflammation
[600 mg/kg-d]).
NA
NA
Species (strain)
NA
NA
Mouse (B6C3F0
Rat (S-D)
Rat (S-D)
Duration
NA
NA
90 d
90 d
90 d
Route (method)
NA
NA
Oral (gavage)
Oral (gavage)
Oral (gavage)
23
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Table A-3. Comparison of Available Subchronic and Chronic Oral Toxicity Data for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
1-Bromo-
3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Notes
NA
NA
In a subchronic-duration rat study,
clinical signs included mortality,
emaciation, tremors, ataxia,
hypoactivity, and ocular discharge
(600 mg/kg-d); reduced body weight
(>400 mg/kg-d); increased absolute
and relative liver and kidney weights
(>50 mg/kg-d); increased serum
enzymes (ALT [400 mg/kg-d], AST
[400 mg/kg-d], SDH [100 mg/kg-d];
no dose-response relationship); liver
histopathology (cytomegaly
[>200 mg/kg-d], necrosis
[>400 mg/kg-d], mineralization
[600 mg/kg-d], inflammation
[>200 mg/kg-d]); and kidney
histopathology (brown staining of
cytoplasm [400 mg/kg-d])
INTP (1985b) as cited in U.S. EPA
(2009)1.
In 28-d rat gavage study published in Japanese
with Enslish tables (JECDB. 2015a. b).
increased total cholesterol (>100 mg/kg-d),
triglycerides (500 mg/kg-d), bilirubin
(>100 mg/kg-d), BUN (500 mg/kg-d), and
GGT (500 mg/kg-d) seen in males; increased
total protein, albumin, ALT, total cholesterol,
triglycerides seen in females (500 mg/kg-d);
decreased prothrombin time (>20 mg/kg-d)
and increased activated partial thromboplastin
time (500 mg/kg-d); increased absolute and
relative liver and kidney weights
(>100 mg/kg-d); hepatocellular swelling
(>100 mg/kg-d); renal histopathology
(eosinophilic bodies in proximal tubule
[>20 mg/kg-d; no dose-response relationship],
hyaline droplets in proximal tubular
epithelium [>100 mg/kg-d], dilatation of
glomerular capillary [>100 mg/kg-d]); and
vacuolization of mucosal epithelium in small
intestine and in cortical cells of adrenal glands
(500 mg/kg-d).
The study authors identified a NOEL of
4 mg/kg-d. In a combined
reproduction/developmental toxicity study
(JECDB. 2015a. b). male dud bodv weight
was decreased at 100 mg/kg; there were no
other significant findings apart from liver
toxicity at 100 mg/kg.
Doddetal. (2012)
published a 13-wk study of
1,2,4-tribromobenzene in
rats exposed by gavage;
effects included increased
liver weight
(>10 mg/kg-d), increased
incidence and severity of
centrilobular cytoplasmic
alteration (>5 mg/kg-d; not
considered to be
toxicologically relevant by
study authors), hepatocyte
hypertrophy
(>10 mg/kg-d), and
hepatocyte vacuolation
(>25 mg/kg-d).
Source
NA
NA
NTP (1985b) as cited in U.S. EPA
(2009)
Carlson and lard iff (1977)
Carlson and Tardiff (1977)
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Table A-3. Comparison of Available Subchronic and Chronic Oral Toxicity Data for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
1-Bromo-
3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Acute toxicity
Rat oral LD5o
(mg/kg)
2,700
4,399
2,383
ND
ND
Toxicity target
Tremor, changes
in motor activity,
ataxia, weight
loss (Haskell
Laboratories.
1985b")
NR
(CliemlDolus.
2016b)
Gastrointestinal
hypermotility/diarrhea;
chromodacrvorrhea (ChemlDnlus.
ND
ND
2016a)
'Following U.S. EPA (2011c) guidance, candidate surrogate PODs were converted to HEDs through the application of a DAF. DAFs are calculated as follows:
DAF = (BW14 BWh1/4), where BWa = animal body weight and BWh = human body weight. For all DAF calculations, a reference human body weight (BWh) of 70 kg
(U.S. EPA. 19881 was used.
' DAF was calculated using reference body weight (BW) for male B6C3Fi mice following subchronic-duration exposure (U.S. EPA. 19881.
DAF was calculated using reference body weight (BW) for male S-D rats following subchronic-duration exposure (U.S. EPA. 19881.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMDLio = 10% benchmark dose lower confidence limit; BUN = blood urea nitrogen; BW = body
weight; DAF = dosimetric adjustment factor; GGT = y-glutamyl transferase; HED = human equivalent dose; LD5o = median lethal dose; NA = not applicable; ND = no
data; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect level; NR = not reported; POD = point of departure; RfD = reference dose;
S-D = Sprague-Dawley; SDH = sorbitol dehydrogenase; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
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Table A-4. Comparison of Available Subchronic and Chronic Inhalation Toxicity Data for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Trib ro mo benzene
CASRN
460-00-4
462-06-6
108-86-1
106-37-6
615-54-3
Structure
F
a'
a*
jor
XYr
POD (mg/m3)
NA
8.9
63
NA
NA
POD type
NA
BMCLio (HEC)
BMCLio (HEC)
NA
NA
Subchronic UFC
NA
300 (UFa x UFd x UFh)
300 (UFa x UFd x UFh)
NA
NA
Subchronic RfC
(mg/m3)
NA
3 x 10 2 (screening value because
principal study is unpublished)
2 x 10-1
NA
NA
Chronic UFC
NA
NA
1,000 (UFa x UFd x UFh x UFs)
NA
NA
Chronic RfC
(mg/m3)
NA
NA
6 x 10-2
NA
NA
Critical effects
NA
Centrilobular hepatocyte
enlargement
Hepatocellular cytomegaly
NA
NA
Other effects
NA
Clinical signs (hunched posture and
piloerection) (>375 mg/m3);
increased absolute and relative liver
weights (>375 mg/m3); increased
relative kidney weight
(1,560 mg/m3); eosinophilic
droplets in renal proximal tubular
epithelium (>375 mg/m3);
basophilic or dilated tubules
(1,560 mg/m3)
Increased relative liver weight
(>642 mg/m3)
NA
NA
Species (strain)
NA
Rat (S-D)
Mouse (B6C3Fi)
NA
NA
Duration
NA
28 d
90 d
NA
NA
Route (method)
NA
Inhalation (vapor)
Inhalation (vapor)
NA
NA
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Table A-4. Comparison of Available Subchronic and Chronic Inhalation Toxicity Data for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9) and Candidate Surrogates
l-Bromo-3-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Notes
NA
NA
In a subchronic-duration rat
study, renal cortical tubular
regeneration without
degeneration or necrosis
(1,926 mg/m3) [NTP (1985b) as
cited in U.S. EPA (2009)1
NA
NA
Source
NA
Safepharm Labs, Ltd. (1993) as
cited in U.S. EPA (20 lib)
NTP (1985b) as cited in U.S.
EPA (2009)
NA
NA
Acute toxicity
Rat inhalation
LC50 (mg/m3)
18,000 (4 hr)
26,908 (duration not specified)
20,411 (duration not specified)
ND
ND
Toxicity target
Tremor, changes in motor
activity, red nasal
discharge, darkened eyes,
and dyspnea
NR
NR
ND
ND
Source
Haskell Laboratories
ChemlDnlus (2016b)
ChemlDnlus (2016a)
NA
NA
(1985a)
BMCLio = 10% benchmark concentration lower confidence limit; HEC = human equivalent concentration; LC50 = median lethal concentration; NA = not applicable;
ND = no data; NR = not reported; POD = point of departure; RfC = reference concentration; S-D = Sprague-Dawley; UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
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Weight-of-Evidence Approach
A WOE approach is used to evaluate information from potential candidate surrogates as
described by Wang et al. (2012). Commonalities in structural/physicochemical properties,
toxicokinetics, metabolism, toxicity, or MOA between potential surrogates and chemical(s) of
concern are identified. Emphasis is given to toxicological and/or toxicokinetic similarity over
structural similarity. Surrogate candidates are excluded if they do not have commonality or
demonstrate significantly different physicochemical properties and toxicokinetic profiles that set
them apart from the pool of potential surrogates and/or chemical(s) of concern. From the
remaining potential surrogates, the most appropriate surrogate (most biologically or
toxicologically relevant analog chemical) with the highest structural similarity and/or most
conservative toxicity value is selected.
Similarity scores for the particular set of aryl halide compounds examined in this PPRTV
assessment may be of limited use due to the small number of structural descriptors, so this
information was not used to select among the potential candidate surrogates. The available data
suggest commonalities in the toxicokinetics of the l-bromo-3-fluorobenzene target chemical and
the four candidate surrogates. Among those compounds with toxicokinetic data, all are absorbed
after oral exposure and primarily excreted in the urine. Available in vivo data on the metabolism
of l-bromo-3-fluorobenzene and the candidate surrogates confirmed that the major Phase I
pathway for all of the compounds is ring hydroxylation via CYP450s. However, several
uncertainties remain regarding the importance of Phase I and Phase II metabolism in toxicity, as
well as the specific metabolite(s) that are responsible for the observed liver effects of the
brominated benzene compounds (discussed below). Toxicity data on the structurally related
candidate surrogates confirm the liver as the target organ for all candidates; however, the lack of
repeated-dose toxicity data on l-bromo-3-fluorobenzene precludes identifying one or more of the
candidates as a better "toxicity-like" surrogate (i.e., a surrogate that exhibits similar target organ
toxicity as l-bromo-3-fluorobenzene).
Given the absence of data on the toxicity of l-bromo-3-fluorobenzene, as well as
remaining questions regarding the specific metabolite(s) responsible for the remarkably similar
liver effects and effect levels (HEDs) observed across the brominated benzene compounds, it is
prudent to select the most health-protective option among the candidate surrogates. Thus,
1,2,4-tribromobenzene was selected as the surrogate for deriving a screening chronic provisional
reference dose (p-RfD) for l-bromo-3-fluorobenzene because its point of departure (POD)
(a no-observed-adverse-effect level [NOAEL] [HED] of 1 mg/kg-day) is lower than the PODs
(HEDs) for bromobenzene and 1,4-dibromobenzene. A subchronic p-RfD derived by the EPA is
not available for 1,2,4-tribromobenzene; however, the study upon which the chronic IRIS RfD
was based (Carlson and Tardiff, 1977) was of subchronic duration and could be used to derive a
screening subchronic p-RfD for l-bromo-3-fluorobenzene.
Subchronic and chronic provisional reference concentrations (p-RfCs) are available for
bromobenzene, and a subchronic p-RfC is available for fluorobenzene; neither of the other
candidate surrogates has an inhalation toxicity value. Thus, based on the WOE approach
described above, fluorobenzene is selected as the surrogate for deriving a subchronic p-RfC for
l-bromo-3-fluorobenzene because the subchronic POD (10% benchmark concentration lower
confidence limit human equivalent concentration [BMCLio (HEC)] of 8.9 mg/m3) is lower than
the POD for bromobenzene (see Table A-4). The choice of fluorobenzene as the surrogate for
deriving a screening subchronic p-RfC precludes the derivation of a screening chronic p-RfC for
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l-bromo-3-fluorobenzene, as the only available study of exposure to fluorobenzene is a 28-day
study, and it is imprudent to extrapolate a chronic value from a 28-day study in the absence of
chronic-duration toxicity information for either the target chemical or the chosen surrogate.
ORAL TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Dose
Based on the overall WOE approach presented in this PPRTV assessment,
1,2,4-tribromobenzene is selected as the surrogate for l-bromo-3-fluorobenzene for deriving a
screening subchronic p-RfD. The study used for the U.S. EPA (2004) chronic RfD for
1,2,4-tribromobenzene is a 90-day rat study and thus suitable for use in deriving a screening
subchronic p-RfD. U.S. EPA (2004) described the study as follows:
Six male rats/group were dosed daily with 0, 2.5, 5 or 10 mg
1,2,4-tribromobenzene (TBB)/kg bw for 45 or 90 days. TBB was administered in
corn oil p.o. as 0.1% of body weight. Controls received corn oil only. Animals
were sacrificed at 45 or 90 days or after an additional 30-day recovery period
after 90-days of treatment. Body weight, liver weight, and hepatic microsomal
enzyme activity were measured. Liver-to-body weight ratios were increased
12-16% over controls for the rats treated at 10 mg/kg/day. Liver enzyme
activities were 1.4- to 3-fold that of controls for the same group. Full recovery to
baseline enzyme activity was observed after the 30-day recovery period;
liver-to-body weight ratios were only 7% greater than the control values. Similar
results were reported by Carlson (1979) in a follow-up study. Although no overt
liver toxicity was demonstratedfor TBB, bromobenzene mixtures at higher doses
cause acute hepatic necrosis. The mechanism of bromobenzene toxicity has been
studied in detail and involves conversion of the parent compound to toxic
intermediates by hepatic microsomal enzymes. Induction of these enzymes can
potentiate the toxicity of bromobenzenes and other similarly-activated
compounds.
The critical effects in this study were increased relative liver weight and hepatic
microsomal enzyme induction; the NOAEL (HED) of 1 mg/kg-day is used as the POD for
1,2,4-tribromobenzene (U.S. EPA, 2004). U.S. EPA (2014) performed an updated literature
search (2004-2013) for 1,2,4-tribromobenzene and identified an additional sub chronic-duration
study by Dodd et al. (2012). In that study, 10 male Sprague-Dawley (S-D) rats/dose were
exposed by gavage (7 days/week) to 1,2,4-tribromobenzene (>97% purity) in corn oil at doses of
0, 2.5, 5, 10, 25, or 75 mg/kg-day for one of the following durations: 5 days, 2 weeks, 4 weeks,
or 13 weeks. Apart from mortality and clinical signs of toxicity, the only endpoints evaluated
were related to the liver (serum chemistry and liver weight and histopathology). For the 13-week
experiment, Dodd et al. (2012) identified a NOAEL of 5 mg/kg-day based on increased liver
weight and increased incidence of hepatocyte hypertrophy at 10 mg/kg-day. The NOAEL and
lowest-observed-adverse-effect level (LOAEL) from this study are identical to those in the
Carlson and Tardiff (1977) study used as the POD in the IRIS assessment of
1,2,4-tribromobenzene, providing support for the continued use of the POD from the Carlson and
Tardiff (1977) study. The POD was not adjusted for molecular-weight differences in the
derivation of the l-bromo-3-fluorobenzene provisional toxicity value because the
molecular-weight difference between the two compounds is less than twofold (Wang et al..
2012). Furthermore, because the current practice is to only adopt existing PODs, benchmark
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dose (BMD) modeling is not performed when applying the alternative surrogate approach (Wane
et aL 2012) in PPRTV assessments.
The NOAEL of 5 mg/kg-day is converted to an HED according to current U.S. EPA
(2011c) guidance. In Recommended Use of Body Weight4 as the Default Method in Derivation
of the Oral Reference Dose (U.S. EPA. 2011c). the Agency endorses a hierarchy of approaches
to derive human equivalent oral exposures from data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches may
include using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, EPA endorses body-weight scaling to the 3/4 power
(i.e., BW3/4) as a default to extrapolate toxicologically equivalent doses of orally administered
agents from all laboratory animals to humans for deriving an RfD under certain exposure
conditions. More specifically, the use of BW3/4 scaling for deriving an RfD is recommended
when the observed effects are associated with the parent compound or a stable metabolite but not
for portal-of-entry effects.
A validated human physiologically based pharmacokinetic (PBPK) model for
1,2,4-tribromobenzene is not available for use in extrapolating doses from animals to humans.
The selected POD is based on increased relative liver weight and hepatic microsomal enzyme
induction, which is not a portal-of-entry effect. Therefore, scaling by BW3/4 is relevant for
deriving HEDs for this effect.
Following U.S. EPA (2011c) guidance, the POD for increased relative liver weight and
hepatic microsomal enzyme induction in male rats is converted to an HED by applying a
dosimetric adjustment factor (DAF) derived as follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a reference BWa of 0.267 kg for S-D rats following subchronic-duration exposure
and a reference BWh of 70 kg for humans (U.S. EPA. 1988). the resulting DAF is 0.25.
Applying this DAF to the NOAEL of 5 mg/kg-day yields a POD (HED) as follows:
POD (HED) = NOAEL (mg/kg-day) x DAF
= 5 mg/kg-day x 0.25
= 1 mg/kg-day
For the derivation of the screening subchronic p-RfD for l-bromo-3-fluorobenzene, a
composite uncertainty factor (UFc) of 300 is applied, based on a 3-fold uncertainty factor value
for interspecies extrapolation (UFa, reflecting use of a dosimetric adjustment) and 10-fold
uncertainty factor values for both intraspecies variability (UFh) and database deficiencies (UFd,
reflecting lack of any repeated-exposure toxicity information for l-bromo-3-fluorobenzene).
The screening subchronic p-RfD for l-bromo-3-fluorobenzene is derived as follows:
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1 -Bromo-3 -fluorob enzene
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Screening Subchronic p-RfD = Surrogate POD (HED) ^ UFc
= 1 mg/kg-day ^-300
= 3 x 10"3 mg/kg-day
Table A-5 summarizes the uncertainty factors for the screening subchronic p-RfD for
l-bromo-3-fluorobenzene.
Table A-5. Uncertainty Factors for the Screening Subchronic p-RfD for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
UF
Value
Justification
UFa
3
A UFa of 3 (10ฐ5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following l-bromo-3-fluorobenzene exposure.
The toxicokinetic uncertainty has been accounted for by calculating an HED through application of a
DAF as outlined in the EPA's Recommended Use of Body Weight3/4 as the Default Method in
Derivation of the Oral Reference Dose ('U.S. EPA. 20110).
UFd
10
A UFd of 10 is applied to account for the absence of toxicity data for 1-bromo-3-fluorobenzene.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of 1-bromo-3-fluorobenzene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because a subchronic-duration study was selected as the principal study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
DAF = dosimetric adjustment factor; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose;
UF = uncertainty factor; UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database
uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Dose
1,2,4-Tribromobenzene is also selected as the surrogate for l-bromo-3-fluorobenzene for
derivation of a screening chronic p-RfD. The IRIS chronic RfD for 1,2,4-tribromobenzene was
based on the 90-day rat study described in the "Derivation of a Screening Subchronic Provisional
Dose" section [Carlson and Tardiff (1977) as cited in U.S. EPA (2014)1. In deriving the
screening chronic p-RfD for l-bromo-3-fluorobenzene, the uncertainty factors used for the
screening subchronic p-RfD (UFa of 3, UFh of 10, and UFd of 10) are applied, and a
subchronic-to-chronic uncertainty factor (UFs) of 10 is applied to account for extrapolation from
a subchronic to a chronic duration. Thus, the screening chronic p-RfD for
l-bromo-3-fluorobenzene is derived using a UFc of 3,000.
Screening Chronic p-RfD = Surrogate POD (HED) ^ UFc
= 1 mg/kg-day ^ 3,000
= 3 x 10"4 mg/kg-day
Table A-6 summarizes the uncertainty factors for the screening chronic p-RfD for
l-bromo-3-fluorobenzene.
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Table A-6. Uncertainty Factors for the Screening Chronic p-RfD for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
UF
Value
Justification
UFa
3
A UFa of 3 (10ฐ5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following l-bromo-3-fluorobenzene exposure.
The toxicokinetic uncertainty has been accounted for by calculating an HED through application of a
DAF as outlined in the EPA's Recommended Use of Body Weight4 as the Default Method in
Derivation of the Oral Reference Dose (U.S. EPA. 201 lc).
UFd
10
A UFd of 10 is applied to account for the absence of toxicity data for l-bromo-3-fluorobenzene.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of l-bromo-3-fluorobenzene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because a subchronic-duration study was selected as the principal study.
UFC
3,000
Composite UF = UFA x UFD x UFH x UFL x UFS.
DAF = dosimetric adjustment factor; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD= provisional reference dose;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database
uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
INHALATION TOXICITY VALUES
Derivation of Screening Subchronic Provisional Reference Concentration
Based on the overall WOE approach presented in this PPRTV assessment, fluorobenzene
is selected as the surrogate for l-bromo-3-fluorobenzene for deriving a screening subchronic
p-RfC. The study used for the U.S. EPA (2011b) screening subchronic p-RfC for fluorobenzene
was a 28-day rat study. As stated above, the choice of fluorobenzene as the surrogate for
deriving a screening subchronic p-RfC precludes deriving a screening chronic p-RfC for
l-bromo-3-fluorobenzene, as the only available study of exposure to fluorobenzene is the
aforementioned 28-day study, and it is imprudent to extrapolate a chronic value from a 28-day
study in the absence of chronic-duration toxicity information for either the target chemical or the
chosen surrogate. U.S. EPA (2011b) described the study as follows:
In an unpublished, Good Laboratory Practice (GLP)-certified, subacute
inhalation toxicity study, Safepharm Labs, Ltd. (1993) exposed groups of 10
Sprague-Daw ley rats (5 per gender) per dose to concentrations of 0.4, 1.5, and
6.0 mg/L fluorobenzene (purity not reported) for 6 hours/day, 7 days a week, for
28 days. The study authors exposed a control group of five animals per sex to air
only. The test substance was kept in glass flasks that were held in water baths at
20ฐC. Compressed air was passed through a water trap and respiratory quality
filters before entering the system. The main air supply went through a tangential
channel at the top of each exposure chamber. Some of this air was bubbled
through the test substance before reaching the exposure chamber, which had a
volume of approximately 30 L. Temperature and relative humidity were
measured daily, and oxygen levels were measured weekly. Concentration of the
test substance was measured daily. Mean atmospheric concentrations of
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fluorobenzene were calculated as 0, 0.37, 1.50, and 6.24 mg/L for the 0-, 0.4-,
1.5-, and 6.0-mg/L-dose groups, respectively. The corresponding exposure
concentrations adjusted for continuous exposure in Sprague-Daw ley rats are 0,
92.5, 375, and 1560 mg/m3. During exposure, rats were individually restrained
by a polycarbonate tube, and only the nose was exposed to the test atmosphere.
Animals were gradually acclimatized to the restraint procedure, and during the
study period, they were rotated to account for any variation within the chambers.
Rats were monitored throughout each exposure periodfor changes in
appearance, respiration, and behavior.
Clinical observations were noted before each exposure period and after
removal from the test chambers. Body weight was measured at Days 0, 7, 14, 21,
and 28; food consumption was measured weekly; and water consumption was
initially inspected and then measured daily from Day 15 onward. Home cage,
open field, and neurotoxicity functional observations were completed the day
before initial dosing and then on Days 13 and 14 for females and Days 27 and 28
for males. Hematology and blood chemistry were analyzed prior to necropsy on
Day 29; no fasting occurred before samples were taken. Urine samples following
2 weeks postdosing were also collected over a period of approximately 16 hours
while rats were kept in metabolism cages. Animals were fasted, with water
provided. Hematology measurements and calculations were performed, including
hematocrit, hemoglobin, erythrocyte count, total leukocyte count, differential
leukocyte count, platelet count, mean corpuscular hemoglobin, mean corpuscular
volume, and mean corpuscular hemoglobin concentration. Blood chemistry
calculations or measurements were done for blood urea, total protein, albumin,
albumin/globulin ratio, sodium, potassium, chloride, calcium, inorganic
phosphorus, creatinine, alkaline phosphatase, alanine aminotransferase,
aspartate aminotransferase, glucose, and total bilirubin. In urine, researchers
measured volume, specific gravity, pH, protein, glucose, ketones, bilirubin,
urobilinogen, reducing substances, and blood, as well as microscopic
examination of sediment. At the study's end, all animals were necropsied; organ
weights and relative organ weights were calculatedfor adrenals, brain, heart,
kidneys, liver, lungs, ovaries, pituitary, spleen, and testes (including
epididymides). Samples of approximately 35 tissues were collected, including
adrenals, aorta, bone and bone marrow, brain, cecum, kidneys, larynx, liver,
lungs, lymph nodes, mammary gland, muscle, nasal cavity, esophagus, ovaries,
pancreas, pituitary, prostate, rectum, salivary glands, sciatic nerve, seminal
vesicles, skin, spinal cord, spleen, stomach, testes with epididymides, thymus,
thyroid/parathyroid, trachea, urinary bladder, and uterus. All preserved tissues
from control and high-dose groups were stained and preparedfor microscopic
examinations. Lungs, gross lesions, liver, and kidneys from the other dose groups
were examined as well. Samples of the sternum bone and the teeth were taken
from each rat and pooled to analyze for fluoride.
Data were analyzed to yield group means and standard deviations, where
necessary. Absolute and relative organ weights and hematological and blood
chemistry parameters were analyzed using one-way analysis of variance
incorporating the F-max test for homogeneity variance. Data with heterogeneous
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variance were tested using the Kruskal-Wallis analysis of variance and
Mann-Whitney U-test.
There was no mortality during the study. Red/brown staining of the
exterior body and wetness of the fur were seen in all groups. The study authors
concluded that these observations were a result of restraint. Hunched posture
andpiloerection were seen at the 375- and 1560-mg/m3 doses. Incidence
increased with progression of the study, and by Day 24, all animals exposed to a
concentration of 1560 mg/m3 showed these behaviors. Animals exposed to 375
mg/m3 showed these signs from Day 21 and continuing through the study. Rats
did not show any significant signs of neurotoxicity. There were no significant
adverse effects indicated by body weight, food or water consumption, hematology,
blood chemistry, or urine composition. Necropsies revealed no treatment-related
macroscopic abnormalities. The males exposed to 375 and 1560 mg/m3 (medium
and high exposures) experienced significant (p < 0.01) increases in absolute
(126-129%) and relative (115 125%) liver weights; relative liver weight was
also elevated (113%) in the high-dose female group (see Tables B.l andB.2).
Relative kidney weight was also significantly increased in the high-dose male
group. There were no effects detected in the low-dose group. The results of the
histopathology examination of tissues from the control and high-dose animals
showed irregularities in the high-dose males consisting of hepatocyte
enlargement in the centrilobular liver and abnormal quantities of eosinophilic
material in the renal proximal tubular epithelium as well as groups of
basophilic/dilated tubules (see Table B.3). Other adaptive kidney changes were
reported, including hydrocarbon nephropathy in males in all dose groups.
Eosinophilic droplets were seen in the tubular epithelium of the kidneys of male
rats at the medium and high doses. This was noted as a treatment-related effect,
typical of hydrocarbon administration. There were no treatment-related
respiratory effects found. Additionally, a substantial increase in fluoride was
measured in teeth and sternum samples from all groups (see Table B.4).
Authors established a NOAEL of 0.3 7-mg/L (NOAELadj of 92.5-mg/m3)
fluorobenzene, based on the lack of treatment-related adverse effects at this dose
level. A LOAELadj of375 mg/m3 is identified based on increased liver weight
(absolute and relative) in male rats, which is supported by an increase in
incidence of centrilobular hepatocyte enlargement at the higher dose. Although
an increase in relative kidney weight, supported by histopathology changes, was
observed in treated animals, the effects were only significant in the high-dose
group (1560 mg/m3), making the liver a more sensitive indicator of exposure.
This study is GLP certified, and the procedures were based on guideline
recommendations Method B8, Annex V of the European Economic Community
(EEC) Commission Directive 84/449/EEC, and Organisation for European
Economic Co-operation (OECD) Guideline 412 (OECD, 1997). Despite the lack
ofpeer review and the shortness in exposure duration, the quality of the study
supports its use in the derivation of a screening subchronic p-RfC.
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The critical effect in this study was centrilobular hepatocyte enlargement (U.S. EPA.
2011b). U.S. EPA (2011b) used a BMCLio (HEC) of 8.9 mg/m3, obtained by modeling the
incidences of centrilobular hepatocyte enlargement in male rats, for the POD. The POD was not
adjusted for molecular-weight differences in the derivation of the l-bromo-3-fluorobenzene
provisional toxicity value because the molecular-weight difference between the two compounds
is less than twofold (Wang et al, 2012).
In deriving a screening p-RfC for l-bromo-3-fluorobenzene, a UFc of 300 is applied,
based on a 3-fold uncertainty factor value for UFa (reflecting use of a dosimetric adjustment) and
10-fold uncertainty factor values for both UFh and UFd (reflecting lack of any repeated-exposure
toxicity information for l-bromo-3-fluorobenzene). The screening subchronic p-RfC for
l-bromo-3-fluorobenzene is derived as follows:
Screening Subchronic p-RfC = Surrogate POD (HEC) ^ UFc
= 8.9 mg/m3 ^ 300
= 3 x 10"2 mg/m3
Table A-7 summarizes the uncertainty factors for the screening subchronic p-RfC for
l-bromo-3-fluorobenzene.
Table A-7. Uncertainty Factors for the Screening Subchronic p-RfC for
l-Bromo-3-fluorobenzene (CASRN 1073-06-9)
UF
Value
Justification
UFa
3
A UFa of 3 (10ฐ5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following 1-bromo-3-fluorobenzene exposure.
The toxicokinetic uncertainty has been accounted for by calculating a HEC.
UFd
10
A UFd of 10 is applied to account for the absence of toxicity data for 1-bromo-3-fluorobenzene.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of 1-bromo-3-fluorobenzene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMCLio.
UFS
1
A UFS of 1 is applied because a 28-d study was selected as the principal study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCLio = 10% 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; UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty
factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
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