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EPA/690/R-17/005
FINAL
09-25-2017
Provisional Peer-Reviewed Toxicity Values for
1 -Bromo-4-fluorobenzene
(CASRN 460-00-4)
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
Lucina E. Lizarraga, 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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1 -Bromo-4-fluorobenzene

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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
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	8
Acute Animal Toxicity Studies	8
Genotoxicity Studies	8
DERIVATION 01 PROVISIONAL VALUES	9
DERIVATION OF ORAL REFERENCE DOSES	10
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	10
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.
iv	l-Bromo-4-fluorobenzene

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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1-BROMO-4-FLUOROBENZENE (CASRN 460-00-4)
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).
1
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INTRODUCTION
l-Bromo-4-fluorobenzene, CASRN 460-00-4, belongs to the class of compounds known
as aryl halides. l-Bromo-4-fluorobenzene is used as an intermediate in agrochemical production,
in organic reactions, such as the preparation of Grignard reagents, and in the production of a
variety of therapeutic drugs. It is also used as an internal standard in gas chromatography-mass
spectrometry for the analytical determination of volatile organic compounds (VOCs) in various
media (NTP, 2005). It is listed on U.S. EPA's Toxic Substances Control Act's public inventory
(U.S. EPA 2017bI listed as a high production volume (HPV) chemical in the United States and
Europe under the EPA's HPV Challenge Program and Organization for Economic Co-operation
and Development (OECD) (NTP, 2005), and registered with Europe's Registration, Evaluation
Authorisation and Restriction of Chemicals (REACH) program (ECHA 2017).
l-Bromo-4-fluorobenzene has been commercially produced by the reaction of
fluorobenzene with bromine in the presence of a catalyst (NTP. 2005). As an HPV chemical,
l-bromo-4-fluorobenzene has an annual production volume of over 2 million pounds in Europe
and 1 million pounds in the United States (NTP. 2005).
The empirical formula for l-bromo-4-fluorobenzene is CfiFUBrF. The chemical structure
is shown in Figure 1. Table 1 summarizes the physicochemical properties of
l-bromo-4-fluorobenzene. The compound is a flammable, colorless liquid at room temperature
(NOAA. 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-4-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.
Br
Figure 1. l-Bromo-4-fluorobenzene Structure
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Table 1. Physicochemical Properties of l-Bromo-4-fluorobenzene (CASRN 460-00-4)
Property (unit)
Value
Physical state
Liquid
Boiling point (°C)
151.53
Melting point (°C)
-17.43
Density (g/cm3)
1.604 (at 20°C)b
Vapor pressure (mm Hg at 25 °C)
3.7 (estimated)3
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mg/L at 25 °C)
270 (estimated)3
Octanol-water partition coefficient (log Kow)
3.083
Henry's law constant (atm-m3/mol at 25°C)
6.3 x 10 3 (estimated)3
Soil adsorption coefficient Koc (L/kg)
380 (estimated)3
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
7 x 10 13 (estimated)3
Atmospheric half-life (d)
15 (estimated)3
Relative vapor density (air = 1)
NV
Molecular weight (g/mol)
1753
Flash point (°C)
60b
"U.S. EPA (2012b).
bAlfa Aesar (2017).
NA = not applicable; NV = not available.
No toxicity values for l-bromo-4-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-4-fluorobenzene (CASRN 460-00-4)
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-4-fluorobenzene (CASRN 460-00-4). 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-4-fluorobenzene in humans or animals exposed by oral or inhalation routes.
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Table 3A. Summary of Potentially Relevant Noncancer Data for l-Bromo-4-fluorobenzene (CASRN 460-00-4)

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.
6
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Table 3B. Summary of Potentially Relevant Cancer Data for l-Bromo-4-fluorobenzene (CASRN 460-00-4)
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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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Available data regarding the toxicity of l-bromo-4-fluorobenzene consist of an
acute-duration oral lethality study, two acute-duration inhalation toxicity studies, and a mouse
lymphoma cell mutation assay, all described below.
Acute Animal Toxicity Studies
One acute oral lethality study was located (Haskell Laboratories. 1985b). Groups of
10 male Sprague-Dawley (S-D) rats were administered a single dose of 1,000, 2,000, 3,000, or
5,000 mg/kg of l-bromo-4-fluorobenzene (-98% purity) in corn oil via gavage and sacrificed
after a 14-day observation period. The median lethal dose (LD50) was 2,700 mg/kg
(95% confidence interval [CI]: 2,200-3,200 mg/kg). At nonlethal doses (specific levels not
reported), tremors, limpness, and weight loss (3—19%) were observed 1-2 days after dosing. At
lethal doses, death occurred within 3 days of dosing, preceded by tremors, absence of righting
and/or grasping reflex, limpness, ataxia, lung noise, clear ocular discharge, and body-weight loss
(8-21%). No other endpoints (e.g., gross or histological pathology) were examined. NTP
(2005)	reported additional rat LD50 values of 2,248 and 3,788 mg/kg, citing an abstract from the
TOXCENTER database; a source and/or confirmation of these values was not located.
Two acute inhalation studies were found (Huntingdon Research Center. 1987; Haskell
Laboratories. 1985a). Groups of 10 male S-D rats were exposed (whole-body) to 7.1, 14, 19, 22,
or 26 mg/L (or 7,100, 14,000, 19,000, 22,000, or 26,000 mg/m3) l-bromo-4-fluorobenzene
(purity not reported) for 4 hours and sacrificed after a 14-day observation period (Haskell
Laboratories, 1985a). A control group received clean air only for 4 hours. The median lethal
concentration (LCso)was 18,000 mg/m3 (95% CI: 15,000-21,000 mg/m3). Exposure to
>14,000 mg/m3 resulted in loss of righting reflex, diminished startle response, lethargy, tremors,
spasms, labored or rapid breathing, red nasal discharge, and darkened eyes. A slight-to-moderate
body-weight loss (up to 8%) was observed in rats exposed to 7,100 mg/m3, and a slight-to-severe
weight loss (4.1—17.5%) was observed in the rats exposed to >14,000 mg/m3. No other
endpoints (including gross and histopathology) were examined.
The second study (Huntingdon Research Center. 1987) was conducted at a lower
concentration. Groups of 10 albino Wistar rats (five/sex/group) were exposed (whole-body as
opposed to nose only) to 0 (clear air control), or 5.95 mg/L (or 5,950 mg/m3) of
l-bromo-4-fluorobenzene for 4 hours. No rats died during the study. Clinical signs during
exposure were consistent with a mildly irritant vapor and included abnormal respiratory pattern
and body posture. During the postexposure observation period, signs included abnormal
respiratory pattern and fascicular tremors. Four of five female rats developed hair loss from the
back during the observation period; a single control female exhibited hair loss from the head.
Food and water consumption, body weight, and relative lung weight were unaffected. There
were no macroscopic or microscopic findings in the lungs, liver, and kidneys (the only tissues
examined) attributable to exposure to l-bromo-4-fluorobenzene.
Genotoxicity Studies
In a compilation of genotoxicity results for a large number of chemicals, Seifried et al.
(2006)	reported that 1 -bromo-4-fluorobenzene gave inconclusive results in the L5 1787 TK
mouse lymphoma mutagenicity assay when tested with and without metabolic activation at doses
up to 0.1 |ig/mL, No additional genotoxicity information was located.
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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-4-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.
Table 4. Summary of Noncancer Reference Values for
l-Bromo-4-fluorobenzene (CASRN 460-00-4)
Toxicity
Type (units)
Species/
Sex
Critical Effect
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
land iff
(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
land iff
(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)
Screening
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-4-fluorobenzene (CASRN 460-00-4)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3) 1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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DERIVATION OF ORAL REFERENCE DOSES
There are no relevant data on the effects of l-bromo-4-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-4-fluorobenzene in humans or
animals exposed by inhalation. However, a screening subchronic p-RfC is derived based on data
for structurally similar compounds (see Appendix A).
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-4-fluorobenzene following both oral and inhalation exposure as shown in
Table 6.
Table 6. Cancer WOE Descriptor for l-Bromo-4-fluorobenzene (CASRN 460-00-4)
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-4-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-4-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-4-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-4-fluorobenzene (CASRN 460-00-4) and Candidate Analogs1
l-Bromo-4-fluorobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Fluorobenzene
Bromobenzene
Structure
CASRN
460-00-4
462-06-6
108-86-1
106-37-6
615-54-3
Molecular weight
175
157
236
315
DSSTox similarity score (%)'
100
NV
NV
NV
NV
ChemlDplus similarity score (%)'
100
<50
<50
<50
OECD toolbox similarity score (%)'
100
Melting point (°C)
-17.4
-42.2
-30.6
87.3
44.5
Boiling point (°C)
151.5
84.7
156
218.5
275
10 3 (estimated)
Vapor pressure (mm Hg at 25°C)
3.7 (estimated)'
4.18
Henry's law constant (atm-m3/mole at 25°C)
6.3 x 10 3 (estimated)'
3.9 x 10 4 (estimated)
Water solubility (mg/L)
270 (estimated)'
1,540 (at 30°C)
446 (at 30°C)
4.9
4.66 (estimated)
Log K,
3.08
2.27
2.99
3.79
NA
NA
NA
NA
NA
pKa
'Data was gathered from PHYSPROP for each respective compound unless otherwise specified (U.S. EPA. 2012b).
''DSSTox (2016).
°ChemIDplus Advanced, similarity scores (ChemlDplus. 2017).
dOECD (2016).
NA = not applicable; NV = not available; OECD = Organization for Economic Co-operation and Development.
12
1 -Bromo-4-fluorobenzene

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Physicochemical properties indicate that l-bromo-4-fluorobenzene and all candidate
surrogates are likely to be bioavailable by oral and inhalation routes (based on water solubility).
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 (whereas fluorobenzene and
bromobenzene are liquids), 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
1,4-dibromobenzene (84%). Low similarity scores (29-44%) 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-4-fluorobenzene and the candidate
surrogates (see Table A-2). There were no data on inhalation toxicokinetics of
l-bromo-4-fluorobenzene or the candidate surrogate compounds.
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Table A-2. Comparison of Available ADME Data for l-Bromo-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates
l-Bromo-4-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
CASRN 460-00-4
CASRN 462-06-6
CASRN 108-86-1
CASRN 106-37-6
CASRN 615-54-3
Xf
LL
b
a"
Xf
lY
Absorption
67% in rats exposed orally
(based on elimination via
urine)
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
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1 -Bromo-4-fluorobenzene

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Table A-2. Comparison of Available ADME Data for l-Bromo-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates
l-Bromo-4-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Metabolites
Rats exposed orally
Urinary (as sulfate and
glucuronide conjugates):
•	Phenol, 2-bromo-5-fluoro-
•	Phenol, 5-bromo-2-fluoro-
•	1,2-Benzenediol,
6-bromo-3-fluoro- or
1,4-benzenediol,
5-bromo-2-fluoro-
Unidentified metabolites;
study authors suggested that
they may be mercapturic acids
or other sulfur-containing
metabolites
Rats exposed orally
Urinary (as sulfate and
glucuronide conjugates):
•	Phenol, 4-fluoro-
•	Phenol, 2-fluoro-
•	Phenol, 3-fluoro-
•	1,2-Benzenediol, 4-fluoro-
•	1,2-Benzenediol, 3-fluoro-
Unidentified metabolites;
study authors suggested that
they may be mercapturic
acids or other
sulfur-containing metabolites
Rabbits exposed orally
Urinary (% dose):
•	Sulfate conjugate (21%)
•	Glucuronide conjugate
(10%)
•	Mercapturic acid (1.6%)
12% of the sulfate and
glucuronide conjugates
consisted of catechol
derivatives
Rats, mice, and rabbits exposed orally
Urinary (% dose):
•	4-bromophenyl mercapturic acid
(35-38%)
•	Phenol, 3-bromo- (9-23%)
•	Phenol, 4-bromo- (3-13%)
•	Phenol, 2-bromo- (3-12%)
•	Bromobenzene (1.2%)
Similar in rabbits; higher 2-bromophenol
(12.1%) and lower 3- and 4-bromophenol
(8.8 and 3.1 %, respectively) in mice
Rabbits exposed orally
Urinary (% dose):
•	Sulfate conjugate (37%)
•	Glucuronide conjugate (40%)
•	Mercapturic acid (21%)
28% of the sulfate and glucuronide
conjugates consisted of catechol
derivatives
Rats exposed i.v. or i.p.
Urinary (% urinary radioactivity):
•	Bromophenyl mercapturic acid
(48-70%)
•	Phenol, 4-bromo- (18-37%)
•	1,2-Benzenediol, bromo- (4-6%)
•	Bromophenyldihydrodiol (4%)
•	Phenol, 2-bromo- (3-4%)
Rats and mice exposed orally
Urinary (% dose):
•	Phenol,
2,5-dibromo- (23-39%)
•	Phenol, 3-bromo- (0.6-1.0%)
•	Phenol, 2-bromo- (0.2-0.3%)
Rabbits exposed i.p.
Urinary (ether extractable
metabolites):
•	Phenol, 2,4-dibromo-
•	Phenol, 2,5-dibromo-
Rats exposed i.p.
Urinary (% urinary
radioactivity):
•	Phenol, 2,5-dibromo- (84%)
•	1,4-dibromobenzene (5.3%)
•	Benzenethiol,
2,5-dibromo- (4.6%)
•	Bromophenol (isomer not
identified; 1.9%)
•	Methylated benzenethiol,
2,5-dibromo- (0.8%)
Two additional metabolites
containing ethylmercapto groups
and free mercapto groups in
addition to methyl mercapto
group already on ring (2.6 and
0.5%)
Rats exposed orally
ND
Rabbits exposed i.p.
Urinary (ether extractable
metabolites):
•	Phenol, 2,4,5-tribromo-
•	Phenol, 2,4,6-tribromo-
Third tribromophenol not
identified
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Table A-2. Comparison of Available ADME Data for l-Bromo-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates
l-Bromo-4-fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Continued:
Continued:
Continued:
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%)
Continued:
Continued:
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1 -Bromo-4-fluorobenzene

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Table A-2. Comparison of Available ADME Data for l-Bromo-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates
l-Bromo-4-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: 67%
•	Feces: ND
(% dose in 24 hr):
•	Urine: 83%
•	Feces: ND
(% dose):
•	Urine: a 60-71%
•	Feces: ND
(% dose):
•	Urine: 24-40%
•	Feces: ND
Rats exoosed i.o.
(% dose in 72 hr)
•	Urine: 30%
•	Feces: 3.6%
Sources
koerts et al. (1997)
Koerts et al. (1997); Azouz et
al. (1953. 1952)
Miller et al. (1990); Oeino (1984); Ruzo
et al. (1976); Zamraelione et al. (1973);
Azouz et al. (1953. 1952)
Szvmanska et al. (2002); Oeino
(1984): Ruzo etal. (1976)
Ruzo et al. (1976)
ADME = absorption, distribution, metabolism, and excretion; i.p. = intraperitoneal; i.v. = intravenous; ND = no data; PB = phenobarbital.
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After oral exposure, 67% of l-bromo-4-fluorobenzene, 60-70% of bromobenzene, and
24-40% of 1,4-dibromobenzene is absorbed (Koerts et al.. 1997; 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-4-fluorobenzene or the other candidate surrogates was located; however,
given that l-bromo-4-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-4-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-4-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 (see Figure A-l). Available data suggest that, for the
l-bromo-4-fluorobenzene target chemical and 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.au and Monks (1997)1. 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 suggest a small role for GSH conjugation.
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1 -Bromo-4-fluorobenzene

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B-

l-Bromo-4-fliiorobenzeive
2-8romo-S-ftuorophenoi 5-Bromo-2-iuorophen®l
8-Bronier-3 fluoro-1,2-benzenediol
or
F
5-Brarmo-2 fluoro-1.4-benzenediol
Figure A-l. Putative Metabolism of l-Bromo-4-fluorobenzene
[based on Koerts et al. (1997)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 contrast to the results
with bromobenzene, mercapturic or premercapturic acids, when they were reported, occurred in
smaller quantities (<10% of administered dose) in the urine of animals exposed to
l-bromo-4-fluorobenzene, fluorobenzene, 1,4-dibromobenzene, and 1,2,4-tribromobenzene. In a
comparative metabolism study (Quino. 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 Qui no (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
19
1 -Bromo-4-fluorobenzene

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al. (1997) hypothesized that unidentified metabolites detected in small quantities in the urine of
rats exposed to l-bromo-4-fluorobenzene and fluorobenzene might be mercapturic acids or other
sulfur-containing metabolites, but these metabolites cannot be definitively identified.
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 or rabbits exposed to l-bromo-2-fluorobenzene,
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 (S/vmanska
et al.. 2002; Ogino. 1984; Ru/.o 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-4-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 (Ru/.o 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-3,5dibromothiophenyl-1 -methyl (14-19%), 2-hydroxy-3,5-dibromothiophenyl-
1-methyloxide (7—9%), and 3,5-dibromophenylmercapturic 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; Ru/.o et al.. 1976; Zampaglione et al.. 1973) or
1 -bromo-4-fluorobenzene (Koerts et al.. 1997).
In summary, the metabolism of l-bromo-4-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 contrast, available data on the l-bromo-4-fluorobenzene target chemical and the
remaining candidate surrogates 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 metabolic pathways, fluorobenzene, 1,4-dibromobenzene, and
1,2,4-tribromobenzene appear to be the most reasonable metabolic surrogates, with
bromobenzene possibly to a lesser extent.
Toxicity-Like Surrogates
There are no repeated-dose oral toxicity data for l-bromo-4-fluorobenzene or
fluorobenzene. Table A-3 summarizes available subchronic and chronic oral toxicity values for
bromobenzene, 1,4-dibromobenzene, and 1,2,4-tribromobenzene. As the table shows, the liver is
20
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the target organ for all of the brominated candidate surrogates; 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). The rat
oral median lethal dose (LD50) for l-bromo-4-fluorobenzene (2,700 mg/kg) is of comparable
magnitude to the available values for fluorobenzene and bromobenzene (4,399 and 2,383 mg/kg,
respectively; see Table A-3).
There are no repeated-exposure inhalation toxicity data for l-bromo-4-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
4-hour inhalation median lethal concentration (LC50) for l-bromo-4-fluorobenzene in the rat
(18,000 mg/m3) is similar to available LC50 values for fluorobenzene and bromobenzene (26,908
and 20,411 mg/m3, respectively; see Table A-4); however, the durations associated with the LC50
values for the candidate surrogates were not reported.
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-bromo-/>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 MOAs for fluorobenzene, 1,4-dibromobenzene, and
1,2,4-tribromobenzene was not available.
As shown in Table A-4, 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 in rats and mice; 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-4-fluorobenzene is hepatotoxic too. However, in the absence of repeated-exposure
toxicity data for l-bromo-4-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-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates

l-Bromo-4-
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
,JO"
a'
a"
,iT
lYr
POD (mg/kg-d)
NA
NA
24.1
10
5
POD (HED)
mg/kg-da
NA
NA
3.5 lb
2°
lc
POD type
NA
NA
BMDLio
NOAEL
NO A F.I.
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-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates

l-Bromo-4-
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
1 -Bromo-4-fluorobenzene

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Table A-3. Comparison of Available Subchronic and Chronic Oral Toxicity Data for
l-Bromo-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates

l-Bromo-4-
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]) [NTP (1985b) as
In a 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 weieht
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).
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Table A-3. Comparison of Available Subchronic and Chronic Oral Toxicity Data for
l-Bromo-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates

l-Bromo-4-
fluorobenzene
Fluorobenzene
Bromobenzene
1,4-Dibromobenzene
1,2,4-Tribromobenzene
Source
NA
NA
NTP (1985b) as cited in U.S. EPA
(2009)
Carlson and Tardiff (1977)
Carlson and Tardiff (1977)
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;
chro modac rvo rrhea (CliemlDolus.
2016a)
ND
ND
'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 = (BW„14 BWh1/4), where B\V„ = 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-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates

l-Bromo-4-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

0"
a"
J?
IY
POD (mg/m3)
NA
8.9
63
NA
NA
POD type
NA
BMCLio (HEC)
BMCLio (HEC)
NA
NA
Subchronic UFC
NA
300 (UFa x UFh x UFd)
300 (UFa x UFh x UFd)
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-4-fluorobenzene (CASRN 460-00-4) and Candidate Surrogates

l-Bromo-4-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 (2011b)
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 (1985a)
GiemlDplus (2016b)
GiemlDplus (2016a)
NA
NA
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-4-fluorobenzene target and
fluorobenzene, 1,4-dibromobenzene, and 1,2,4-tribromobenzene, and to a lesser extent,
bromobenzene. Among those compounds with toxicokinetic data, all are absorbed after oral
exposure and primarily excreted in the urine. Available in vivo data on metabolism of
l-bromo-4-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 the l-bromo-4-fluorobenzene precludes identifying one or more
candidates as better "toxicity-like" surrogates (i.e., a surrogate that exhibits similar target organ
toxicity as l-bromo-4-fluorobenzene).
Given the absence of data on the toxicity of l-bromo-4-fluorobenzene, as well as
remaining questions regarding the specific metabolite(s) that are 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 derivation of
screening subchronic and chronic provisional reference doses (p-RfDs) for
l-bromo-4-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; thus, it is the most health-protective choice for a surrogate. 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-4-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 was selected as the surrogate for deriving a subchronic p-RfC for
l-bromo-4-fluorobenzene because the subchronic POD (10% benchmark concentration lower
confidence limit human equivalent concentration [BMCLio (HEC)] of 8.9 mg/m3) is lower than
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the POD and p-RfC for bromobenzene (see Table A-4). The choice of fluorobenzene as the
surrogate for deriving a screening subchronic p-RfC precludes deriving a screening chronic
p-RfC for l-bromo-4-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-4-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 was 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
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derivation of the l-bromo-4-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
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 was converted to an HED according to current U.S. EPA
(201 lc) guidance. In Recommended Use of Body Weight* 4 as the Default Method in Derivation
of the Oral Reference Dose (U.S. EPA, 201 lc), 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 or developmental endpoints.
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, which is not a portal-of-entry or
developmental 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-4-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,
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reflecting lack of any repeated-exposure toxicity information for l-bromo-4-fluorobenzene).
The screening subchronic p-RfD for l-bromo-4-fluorobenzene is derived as follows:
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
1 -bromo-4-fluorobenzene.
Table A-5. Uncertainty Factors for the Screening Subchronic p-RfD for
l-Bromo-4-fluorobenzene (CASRN 460-00-4)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following l-bromo-4-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 l-bromo-4-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-4-fluorobenzene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is an 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 was also selected as the surrogate for l-bromo-4-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-4-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 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-4-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
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Table A-6 summarizes the uncertainty factors for the screening chronic p-RfD for
1 -bromo-4-fluorobenzene.
Table A-6. Uncertainty Factors for the Screening Chronic p-RfD for
l-Bromo-4-fluorobenzene (CASRN 460-00-4)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following l-bromo-4-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 WeightB/4 as the Default Method in
Derivation of the Oral Reference Dose (TJ.S. EPA. 201 lc).
UFd
10
A UFd of 10 is applied to account for the absence of toxicity data for l-bromo-4-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-4-fluorobenzene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is an 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 a Screening Subchronic Provisional Reference Concentration
Based on the overall WOE approach presented in this PPRTV assessment, fluorobenzene
was selected as the surrogate for l-bromo-4-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-4-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
20°C. 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
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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
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 adjustedfor continuous exposure in Spr ague-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.
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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
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 LOAELADJof375 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
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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.
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-4-fluorobenzene
provisional toxicity value because the molecular-weight difference between the two compounds
is less than twofold (Wang et ai, 2012).
In deriving a screening subchronic p-RfC for l-bromo-4-fluorobenzene, a 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-4-fluorobenzene). The screening subchronic p-RfC for
l-bromo-4-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
1 -bromo-4-fluorobenzene.
Table A-7. Uncertainty Factors for the Screening Subchronic p-RfC for
l-Bromo-4-fluorobenzene (CASRN 460-00-4)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following l-bromo-4-fluorobenzene exposure.
The toxicokinetic uncertainty has been accounted for by calculating an HEC.
UFd
10
A UFd of 10 is applied to account for the absence of toxicity data for l-bromo-4-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-4-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-day 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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