#%	United States
Environmental Protection
1=1 #m Agency
EPA/690/R-01/002F
Final
11-30-2001
Provisional Peer Reviewed Toxicity Values for
4-Bromodiphenyl ether
(CASRN 101-55-3)
Derivation of an Oral RfD
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
1

-------
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(.imol
micromoles
voc
volatile organic compound
11

-------
11-30-2001
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
4-BROMODIPHENYL ETHER (CASRN 101-55-3)
Derivation of an Oral RfD
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
1

-------
11-30-2001
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2001) does not contain an RfD for 4-bromodiphenyl ether
(4-bromophenyl phenyl ether). 4-Bromodiphenyl ether is not included in the Drinking Water
Standards and Health Advisory list (U.S. EPA, 2000). The HEAST (U.S. EPA, 1997) reports
that data were inadequate for risk assessment for 4-bromodiphenyl ether, based on a 1986 HEEP
(U.S. EPA, 1986). Besides the 1986 HEEP on 4-bromodiphenyl ether, the CARA list (U.S.
EPA, 1991, 1994) includes a 1983 HEEP on brominated diphenyl ethers as a class (U.S. EPA,
1983). Neither document contains any relevant toxicity information for 4-bromodiphenyl ether.
ATSDR (2000) has not published a toxicological profile for 4-bromodiphenyl ether, nor has this
chemical been the subject of an IARC monograph (IARC, 2000). The World Health
Organization (WHO, 1994) has published an Environmental Health Criteria document for
Brominated Diphenyl Ethers that includes a discussion of 4-bromodiphenyl ether. The NTP
status report (NTP, 2000) was also searched to identify relevant data for the derivation of a
provisional RfD for 4-bromodiphenyl ether. Update literature searches were conducted from
2

-------
11-30-2001
1985 to June 2000 for data relevant to RfD derivation. The databases searched were: TOXLINE,
TSCATS, MEDLINE, GENETOX, HSDB, EMIC/EMICBACK, DART/ETICBACK, and
RTECS.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding oral exposure of humans to 4-bromodiphenyl ether.
Animal Studies
No oral animal studies suitable for use in the derivation of an RfD for
4-bromodiphenyl ether were located. Available data were limited to a single developmental
toxicity study that found no evidence of maternal or developmental effects produced by
4-bromodiphenyl ether at doses up to 1000 mg/kg-day (Francis, 1989). In this study, groups of
20-21 pregnant Swiss mice were treated with 4-bromodiphenyl ether at doses of 100 or 1000
mg/kg-day by gavage in corn oil on days 5-14 of gestation. There was no effect on maternal
weight gain during gestation, production of litters, litter size, pup survival through weaning, pup
body weights through weaning (except for a slight statistically significant increase in the low
dose group on day 21 only), or pup organ weights at post-weaning sacrifice.
FEASIBILITY OF DERIVING A PROVISIONAL RfD FOR
4-BROMODIPHENYL ETHER
A provisional RfD for 4-bromodiphenyl ether cannot be derived due to lack of suitable
human and animal data.
REFERENCES
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
Francis, B.M. 1989. Relative developmental toxicities of nine diphenyl ethers related to
nitrophen. Environ. Toxicol. Chem. 8: 681-688.
IARC (International Agency for Research on Cancer). 2000. Cumulative cross index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs 75: 459-
491.
3

-------
11-30-2001
NTP (National Toxicology Program). 2000. Management Status Report. Examined August,
2000. Online.
http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html)
U.S. EPA. 1983. Health and Environmental Effects Profile for Brominated Diphenyl Ethers.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986. Health and Environmental Effects Profile for 4-Bromophenyl phenyl ether.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July,
1997. EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Office of Water,
Washington, DC. Online, http://www.epa.gov/ost/drinking/standards/
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
August, 2000. Online, http://www.epa.gov/iris/
WHO (World Health Organization). 1994. Environmental Health Criteria Monograph on
Brominated Diphenyl Ethers. Monograph 162. International Programme on Chemical Safety,
Geneva, Switzerland.
4

-------
11-30-2001
Provisional Peer Reviewed Toxicity Values for
4-Bromodiphenyl ether
(CASRN 101-55-3)
Derivation of an Inhalation RfC
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
1

-------
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(.imol
micromoles
voc
volatile organic compound
11

-------
11-30-2001
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
4-BROMODIPHENYL ETHER (CASRN 101-55-3)
Derivation of an Inhalation RfC
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
1

-------
11-30-2001
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2001) does not contain an RfC for 4-bromodiphenyl ether
(4-bromophenyl phenyl ether). The HEAST (U.S. EPA, 1997) reports that data were inadequate
for risk assessment for 4-bromodiphenyl ether, based on a 1986 HEEP (U.S. EPA, 1986).
Besides the 1986 HEEP on 4-bromodiphenyl ether, the CARA list (U.S. EPA, 1991, 1994)
includes a 1983 HEEP on brominated diphenyl ethers as a class (U.S. EPA, 1983). Neither
document contains any relevant toxicity information for 4-bromodiphenyl ether. ATSDR (2000)
has not published a toxicological profile for 4-bromodiphenyl ether, nor has this chemical been
the subject of an IARC monograph (IARC, 2000). Occupational exposure limits for 4-
bromodiphenyl ether have not been established by the ACGIH (2000), OSHA (2000), or NIOSH
(2000). The World Health Organization (WHO, 1994) has published an Environmental Health
Criteria document for Brominated Diphenyl Ethers that includes a discussion of 4-
bromodiphenyl ether. The NTP status report (NTP, 2000) was also searched to identify relevant
data for the derivation of a provisional RfC for 4-bromodiphenyl ether. Update literature
2

-------
11-30-2001
searches were conducted from 1985 to June 2000 for data relevant to RfC derivation. The
databases searched were: TOXLINE, TSCATS, MEDLINE, GENETOX, HSDB,
EMIC/EMICBACK, DART/ETICBACK, and RTECS.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding inhalation exposure of humans to
4-bromodiphenyl ether.
Animal Studies
No studies were located regarding inhalation exposure of animals to
4-bromodiphenyl ether.
FEASIBILITY OF DERIVING A PROVISIONAL RfC FOR
4-BROMODIPHENYL ETHER
A provisional RfC for 4-bromodiphenyl ether cannot be derived due to lack of suitable
human and animal data.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2000. TLVsŪ and
BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
IARC (International Agency for Research on Cancer). 2000. Cumulative cross index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. 75: 459-
491.
NIOSH (National Institute for Occupational Safety and Health). 2000. NIOSH Pocket Guide to
Chemical Hazards. Index by CASRN. Examined August, 2000. Online.
http://www.cdc.gov/niosh/npg/npgdcas.html
3

-------
11-30-2001
NTP (National Toxicology Program). 2000. Management Status Report. Online.
http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
OSHA (Occupational Safety and Health Administration). 2000. OSHA Standard 1915.1000 for
Air Contaminants. Part Z, Toxic and Hazardous Substances. Examined August, 2000. Online.
http://www.osha-slc.gov/OshStd data/1915 1000.html
U.S. EPA. 1983. Health and Environmental Effects Profile for Brominated Diphenyl Ethers.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986. Health and Environmental Effects Profile for 4-Bromophenyl phenyl ether.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July,
1997. EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
http://www.epa. gov/ iris/
WHO (World Health Organization). 1994. Environmental Health Criteria Monograph on
Brominated Diphenyl Ethers. Monograph 162. International Programme on Chemical Safety,
Geneva, Switzerland.
4

-------
11-30-2001
Provisional Peer Reviewed Toxicity Values for
4-Bromodiphenyl ether
(CASRN 101-55-3)
Derivation of an Oral Slope Factor
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
1

-------
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(.imol
micromoles
voc
volatile organic compound
11

-------
11-30-2001
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
4-BROMODIPHENYL ETHER (CASRN 101-55-3)
Derivation of an Oral Slope Factor
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
1

-------
11-30-2001
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2001) reports a cancer classification for 4-bromodiphenyl ether (4-
bromophenyl phenyl ether) of group D - not classifiable as to human carcinogenicity, based on
no human data and inadequate animal data (one short-term injection study). Due to the absence
of appropriate data, an oral slope factor was not derived. This assessment, verified on 06/15/90,
was based on a 1986 HEEP (U.S. EPA, 1986). 4-Bromodiphenyl ether is not listed in the
Drinking Water Standards and Health Advisory list (U.S. EPA, 2000) or the HEAST (U.S. EPA,
1997). Besides the 1986 HEEP on 4-bromodiphenyl ether, the CARA list (U.S. EPA, 1991,
1994) includes a 1983 HEEP on brominated diphenyl ethers as a class (U.S. EPA, 1983).
ATSDR (2000) has not published a toxicological profile for 4-bromodiphenyl ether, nor has 4-
bromodiphenyl ether been discussed in an IARC monograph (IARC, 2000). The World Health
Organization (WHO, 1994) has published an Environmental Health Criteria document for
Brominated Diphenyl Ethers that includes a discussion of 4-bromodiphenyl ether. The NTP
status report (NTP, 2000) was also searched to identify relevant data for the derivation of a slope
2

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11-30-2001
factor for 4-bromodiphenyl ether. Update literature searches were conducted from 1985 to June
2000 for data relevant to derivation of an oral slope factor. The databases searched were:
TOXLINE, TSCATS, MEDLINE, GENETOX, HSDB, EMIC/EMICBACK,
DART/ETICBACK, and RTECS.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding oral exposure of humans to 4-bromodiphenyl ether.
Animal Studies
No oral animal studies suitable for derivation of an oral slope factor for 4-bromodiphenyl
ether were located.
Other Studies
4-Bromodiphenyl ether was negative in a short-term in vivo screening assay for
pulmonary adenoma in strain A/ST mice that received between 17 and 24 injections of doses
ranging from 40 to 200 mg/kg per injection (Theiss et al., 1977) and for sister chromatid
exchange in vivo in CD-I mice treated by gavage at doses up to 579 mg/kg-day for 14 days
(Borzelleca, 1983).
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR
4-BROMODIPHENYL ETHER
A provisional oral slope factor for 4-bromodiphenyl ether cannot be derived due to lack
of suitable human and animal data.
REFERENCES
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
Borzelleca, J.F. 1983. A review of volatile organic contaminant data. Proc. AWWA Water
Qual. Tech. Conf. p. 225-244.
3

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11-30-2001
IARC (International Agency for Research on Cancer). 2000. Cumulative cross index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. 75: 459-
491.
NTP (National Toxicology Program). 2000. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
Thiess, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for carcinogenicity of
organic contaminants of United States drinking waters by pulmonary tumor response in Strain A
mice. Cancer Res. 37:2717-2720.
U.S. EPA. 1983. Health and Environmental Effects Profile for Brominated Diphenyl Ethers.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986. Health and Environmental Effects Profile for 4-Bromophenyl phenyl ether.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July,
1997. EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Office of Water,
Washington, DC. Online, http://www.epa.gov/ost/drinking/standards/
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
August, 2000. Online, http://www.epa.gov/iris/
WHO (World Health Organization). 1994. Environmental Health Criteria Monograph on
Brominated Diphenyl Ethers. Monograph 162. International Programme on Chemical Safety,
Geneva, Switzerland.
4

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11-30-2001
Provisional Peer Reviewed Toxicity Values for
4-Bromodiphenyl ether
(CASRN 101-55-3)
Derivation of an Inhalation Unit Risk
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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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
1

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NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(.imol
micromoles
voc
volatile organic compound
11

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11-30-2001
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
4-BROMODIPHENYL ETHER (CASRN 101-55-3)
Derivation of an Inhalation Unit Risk
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
1

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11-30-2001
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2001) reports a cancer classification for 4-bromodiphenyl ether (4-
bromophenyl phenyl ether) of group D - not classifiable as to human carcinogenicity, based on no
human data and inadequate animal data (one short-term injection study). Due to the absence of
appropriate data, an inhalation unit risk was not derived. This assessment, verified 06/15/90, was
based on a 1986 HEEP (U.S. EPA, 1986). 4-Bromodiphenyl ether is not listed in the HEAST
cancer table (U.S. EPA, 1997). Besides the 1986 HEEP on 4-bromodiphenyl ether, the CARA
list (U.S. EPA, 1991, 1994) includes a 1983 HEEP on brominated diphenyl ethers as a class
(U.S. EPA, 1983). ATSDR (2000) has not published a toxicological profile for 4-bromodiphenyl
ether, nor has 4-bromodiphenyl ether been discussed in an IARC monograph (IARC, 2000). The
World Health Organization (WHO, 1994) has published an Environmental Health Criteria
document for Brominated Diphenyl Ethers that includes a discussion of 4-bromodiphenyl ether.
The NTP status report (NTP, 2000) was also searched to identify relevant data for the derivation
of an inhalation unit risk for 4-bromodiphenyl ether. Update literature searches were conducted
2

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11-30-2001
from 1985 to June 2000 for data relevant to derivation of an inhalation unit risk. The databases
searched were: TOXLINE, TSCATS, MEDLINE, GENETOX, HSDB, EMIC/EMICBACK,
DART/ETICBACK, and RTECS.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding inhalation exposure of humans to
4-bromodiphenyl ether.
Animal Studies
No studies were located regarding inhalation exposure of animals to
4-bromodiphenyl ether.
Other Studies
4-Bromodiphenyl ether was negative in a short-term in vivo screening assay for
pulmonary adenoma in strain A/ST mice that received between 17 and 24 injections of doses
ranging from 40 to 200 mg/kg per injection (Theiss et al., 1977) and for sister chromatid
exchange in vivo in CD-I mice treated by gavage at doses up to 579 mg/kg-day for 14 days
(Borzelleca, 1983).
FEASIBILITY OF DERIVING A PROVISIONAL INHALATION UNIT RISK FOR
4-BROMODIPHENYL ETHER
A provisional inhalation unit risk for 4-bromodiphenyl ether cannot be derived due to
lack of suitable human and animal data.
REFERENCES
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Online, http://www.atsdr.cdc.gov/toxpro2.html
Borzelleca, J.F. 1983. A review of volatile organic contaminant data. Proc. AWWA Water
Qual. Tech. Conf. p. 225-244.
3

-------
11-30-2001
IARC (International Agency for Research on Cancer). 2000. Cumulative cross index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. 75: 459-
491.
NTP (National Toxicology Program). 2000. Management Status Report. Examined August,
2000. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
Thiess, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for carcinogenicity of
organic contaminants of United States drinking waters by pulmonary tumor response in Strain A
mice. Cancer Res. 37:2717-2720.
U.S. EPA. 1983. Health and Environmental Effects Profile for Brominated Diphenyl Ethers.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986. Health and Environmental Effects Profile for 4-Bromophenyl phenyl ether.
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July,
1997. EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
October, 2000. Online, http://www.epa.gov/iris/
WHO (World Health Organization). 1994. Environmental Health Criteria Monograph on
Brominated Diphenyl Ethers. Monograph 162. International Programme on Chemical Safety,
Geneva, Switzerland.
4

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