United States
Environmental Protection
1=1 m m Agency
EPA/690/R-11/029F
Final
3-24-2011
Provisional Peer-Reviewed Toxicity Values for
Fluorobenzene
(CASRN 462-06-6)
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
Harlal Choudhury, DVM, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
Geniece M. Lehmann, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	ii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	6
Oral Exposures	6
Inhalation Exposures	6
Other Exposures	6
ANIMAL STUDIES	6
Oral Exposures	6
Inhalation Exposures	6
Subacute Studies	6
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	10
DERIVATION 01 PROVISIONAL VALUES	10
DERIVATION 01 ORAL REFERENCE DOSES	11
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)	11
Derivation of Chronic Provisional RfD (Chronic p-RfD)	11
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	12
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)	12
Derivation of Chronic Provisional RfC (Chronic p-RfC)	12
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	13
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	13
Derivation of Provisional Oral Slope Factor (p-OSF)	13
Derivation of Provisional Inhalation Unit Risk (p-IUR)	13
APPENDIX A. PROVISIONAL SCREENING VALUES	14
APPENDIX B. DATA TABLES	18
APPENDIX C. BMD OUTPUTS	22
APPENDIX D. REFERENCES	26
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELrec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
FLUOROBENZENE (CASRN 462-06-6)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) 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 (PPRTVs) 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 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 a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
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 5-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 documents conclude that
a PPRTV cannot be derived based on inadequate data.
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 Resource Conservation and Recovery Act (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.
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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 document 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.
Fluorobenzene is an intermediate in the production of pharmaceuticals, pesticides, and
other organic compounds. The empirical formula for fluorobenzene is CeHsF (see Figure 1). A
table of chemicophysical properties is provided below (see Table 1). In this document,
"statistically significant" denotes a Rvalue of <0.05.
INTRODUCTION
F
Figure 1. Fluorobenzene Structure
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Table 1. Chemico-physical Properties Table (Fluorobenzene)3
Property (unit)
Value
Boiling point (°C at 760 mm Hg)
84.73
Melting point (°C)
-40
Density (g/cm3)
1.024
Vapor pressure (Pa at 20°C)
8000
pH (unitless)
Not available
Solubility in water (g/100 mL at 20°C)
0.15
Relative vapor density (air = 1)
Not available
Molecular weight (g/mol)
96.10
Flash point (°C)
-15
Octanol/water partition coefficient (unitless)
2.27
aValues from DuPont Co. (2003).
No reference dose (RfD), reference concentration (RfC), or cancer assessment for
fluorobenzene is included in the EPA IRIS database (U.S. EPA, 2010b) or on the Drinking Water
Standards and Health Advisories List (U.S. EPA, 2006). No RfD or RfC values are reported in
HEAST (U.S. EPA, 2010a). The CARA list (U.S. EPA, 1994) does not include a Health and
Environmental Effects Profile (HEEP) for fluorobenzene. The toxicity of fluorobenzene has not
been reviewed by ATSDR (2008) or the World Health Organization (WHO, 2010). CalEPA
(2008, 2009a) has not derived toxicity values for exposure to fluorobenzene. The American
Conference of Governmental Industrial Hygienists (ACGIH, 2010), the National Institute of
Occupational Safety and Health (NIOSH, 2005), and the Occupational Safety and Health
Administration (OSHA, 2010) have not derived exposure limits.
The HEAST (U.S. EPA, 2010a) has not reported an EPA (1986) cancer
weight-of-evidence (WOE) classification for fluorobenzene. Fluorobenzene has not been
evaluated under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005). The
International Agency for Research on Cancer (IARC, 2010) has not reviewed the carcinogenic
potential of fluorobenzene. Fluorobenzene is not included in the 11th Report on Carcinogens
(NTP, 2005). CalEPA (2008, 2009a,b,c) has not prepared a quantitative estimate of carcinogenic
potential for fluorobenzene.
Literature searches were conducted on sources published from 1900 through
March 1, 2010, for studies relevant to the derivation of provisional toxicity values for
fluorobenzene, CAS No. 462-06-6. Searches were conducted using EPA's Health and
Environmental Research Online (HERO) evergreen database of scientific literature. HERO
searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane
Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations
Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing
Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR:
Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through
the National Service Center for Environmental Publications [NSCEP] and National
Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and
CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET
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(Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC,
EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER,
LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); WHO; and Worldwide Science. The following databases outside of HERO were
searched for risk assessment values: ACGIH, ATSDR, CalEPA, EPA IRIS, EPA HEAST, EPA
HEEP, EPA OW, EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for fluorobenzene and includes all
potentially relevant repeated short-term, subchronic-duration, and chronic-duration studies.
NOAELs, LOAELs, and BMDL/BMCLs are provided in HED/HEC units for comparison except
that oral noncancer values are not converted to HEDs and are identified in parentheses as
(Adjusted) rather than HED/HECs. Principal studies (PS) are identified in bold.
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Table 2. Summary of Potentially Relevant Data for Fluorobenzene (CASRN 462-06-6)
Notes3
Category
Number of Male/Female,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb'c
BMDL/
BMCLb
LOAELbc
Reference
(Comments)
Human
None
Animal
1. Oral (mg/kg-day)b

Subchronic
None

Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
2. Inhalation (mg/m3)b
PS,
NPR
Subacute
5/5 Sprague-Dawley rat,
inhalation (nose only),
6 hours/day, 7 days a
week, 28 days
92.5,375,
and 1560
Clinical signs: hunched posture and
piloerection in medium- and high-dose groups
that increased over time. Medium- and
high-dose group males showed increased
relative liver weight, which was also seen in
the high-dose females; relative kidney weights
were increased in high-dose males;
histopathological effects were observed in the
liver and kidneys of high dose males.
92.5
8.9
375
Safepharm
Labs, Ltd.
(1993)

Subchronic
None

Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
aNotes: IRIS = Utilized by IRIS, date of last update; PS = principal study; NPR = not peer reviewed.
bDosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to human equivalent doses (HEDs in mg/kg-day) or human equivalent concentrations (HECs in
mg/m3) units. Noncancer oral data are only adjusted for continuous exposure.
following EPA guidance for Category 3 gases (U.S. EPA, 2009), concentrations were converted to adjust for continuous exposure by using the following equation:
ConcADj = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days). Concentrations were calculated for an extrarespiratory effect for a
Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio.
ConcHEc = ConcADj x Blood Air Partition Coefficient of 1.
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HUMAN STUDIES
Oral Exposures
No studies investigating the effects of subchronic- or chronic-duration oral exposure to
fluorobenzene in humans were identified.
Inhalation Exposures
No quantitative data were located regarding the toxicity of fluorobenzene to humans
following subchronic- or chronic-duration inhalation exposure.
Other Exposures
No subchronic or long-term studies investigating the effects of occupational exposure to
fluorobenzene in humans were identified.
ANIMAL STUDIES
Oral Exposures
No subchronic-duration, chronic-duration, reproduction, or developmental studies
regarding the effects of oral exposure to fluorobenzene could be located.
Inhalation Exposures
The effects of inhalation exposure of animals to fluorobenzene have been evaluated in a
subacute (Safepharm Labs, Ltd., 1993) toxicity study. No subchronic-duration, chronic-duration,
reproductive, or developmental inhalation studies could be identified.
Subacute Studies
The study by Safepharm Labs, Ltd. (1993) is selected as the principal study for
deriving the screening subchronic p-RfC. In an unpublished, Good Laboratory Practice
(GLP)-certified, subacute inhalation toxicity study, Safepharm Labs, Ltd. (1993) exposed groups
of 10 Sprague-Dawley 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 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
adjusted for continuous exposure in Sprague-Dawley 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 period for 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
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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 calculated for
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 prepared for microscopic
examinations. Lungs, gross lesions, liver, and kidneys from the other dose groups were
examined as well. Samples of the sternum bone and the teeth were taken from each rat and
pooled to analyze for fluoride.
Data were analyzed to yield group means and standard deviations, where necessary.
Absolute and relative organ weights and hematological and blood chemistry parameters were
analyzed using one-way analysis of variance incorporating the F-max test for homogeneity
variance. Data with heterogeneous variance were tested using the Kruskal-Wallis analysis of
variance and Mann-Whitney I /-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 and piloerection 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. 1 and B.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
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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 0.37-mg/L (NOAELadj of 92.5-mg/m3) fluorobenzene,
based on the lack of treatment-related adverse effects at this dose level. A LOAELadj of
375 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 of peer review and the shortness in exposure duration, the quality of the study
supports its use in the derivation of a screening subchronic p-RfC.
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Table 3. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Genotoxicity
Conducted Ames test on Salmonella
typhimurium strains TA98, TA1538,
TA1537, TA100, and TA1535 with and
without rat liver metabolic activation.
Authors reported no positive results in any strain
with or without metabolic activation.
Negative for
mutagenicity.
Shimizu et al.
(1983)
Genotoxicity
Conducted preincubationally modified Ames
test using S. typhimurium strains TA97,
TA98, TA100, and TA1535 with and without
rat and hamster liver metabolic activation.
Test results indicated a positive response.
Activation and strain unknown.
Positive for
mutagenicity.
Zeiger and
Margolin (2000)
Genotoxicity
Performed in vivo micronucleus assay in
mice. Procedure was based on the
recommendations for OECD Guideline 474
(OECD, 1997), but precise study methods
were unavailable.
Results were negative. OECD Guideline 474
(OECD, 1997) defines negative as meaning there
was no significant increase in the ratio of
normochromatic to polychromatic erythrocytes.
These results suggest
no genotoxicity of
fluorobenzene.
DuPont Co.
(2003)
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 3 presents summary of short-term studies. The genotoxicity of fluorobenzene has
been tested in multiple studies. In a published study, Shimizu et al. (1983) investigated the
mutagenic effects of fluorobenzene on Salmonella typhimurium. The study authors conducted an
Ames test using S9 rat liver fraction in strains TA98, TA1538, and TA1537 to evaluate potential
frameshift mutations, and in strains TA100 and TA1535 to evaluate potential mutation by
base-pair substitution and incubation for 3 days. The authors observed no change in the number
of revertant colonies and concluded that fluorobenzene is not genotoxic with or without
metabolic activation.
In a National Toxicology Program-sponsored, published study, Zeiger and Margolin
(2000) performed an in vitro bacterial reverse mutation assay investigating the genetic toxicity of
fluorobenzene on S. typhimurium strains. The authors conducted a modified Ames test, using a
preincubation procedure with and without rat and hamster liver metabolic activation in strains
TA97 and TA98 to evaluate potential frameshift mutations and in strains TA100 and TA1535 to
evaluate potential mutation by base-pair substitution and incubation for 3 days. The authors
reported that fluorobenzene was mutagenic; however, the strains and activation resulting in the
positive response were not specified.
Cytotest Cell Research Gmbh & Co. (1991) conducted a micronucleus assay
investigating the genotoxicity of fluorobenzene in mice. Though the original report and data of
Cytotest Cell Research Gmbh & Co. (1991) is reported in German, an acceptable review of the
study has been conducted by DuPont Co. (2003), and information from DuPont Co. (2003) is
presented for the purposes of this review. The authors conducted an OECD (1997) 474 mouse
micronucleus assay by dosing NMRI male and female mice with fluorobenzene (99.7% pure) in
corn oil (unreported dose and method of administration) and measuring the ratio of
normochromatic to polychromatic erythrocytes (NCEs and PCEs, respectively). The results
were reported to be negative, indicating no significant increase in the number of micronucleated
PCEs was found in test subjects as compared to controls.
The genotoxicity of fluorobenzene has been tested using in vitro test systems (Cytotest
Cell Research Gmbh & Co., 1991; Zeiger and Margolin, 2000; Shimizu et al., 1983). With these
few reported studies, the literature on the mutagenicity of fluorobenzene is equivocal. Further
investigations are needed before a conclusive understanding of the mutagenic potential of
fluorobenzene can be reached.
DERIVATION OF PROVISIONAL VALUES
Table 4 below presents a summary of noncancer reference values. Table 5 presents a
summary of cancer values. The toxicity values are converted to HEC/HED units, with the
exception of noncancer oral values, which are converted to adjusted daily doses (ADJ). The
conversion process is described in the footnotes. IRIS data are indicated in the tables, if
applicable.
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Table 4. Summary of Reference Values for Fluorobenzene (CASRN 462-06-6)a
Toxicity Type (Units)
Species/Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
UF
Principal
Study
Subchronic p-RfD
(mg/kg-day)
None
None
None
None
None
None
None
Chronic p-RfD
(mg/kg-day)
None
None
None
None
None
None
None
Screening Subchronic
p-RfC (mg/m3)
Sprague-Dawley
rat/male
Centrilobular
hepatocyte
enlargement
3.0 x 10"2
BMC
8.9
300
Safepharm
Labs, Ltd.
(1993)
Screening Chronic
p-RfC (mg/m3)
Sprague-Dawley
rat/male
None
None
None
None
None
None
following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations
were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADi= Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days);
ConcnEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory
effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default
value of 1.0 is used for this ratio.
Table 5. Summary of Cancer Values for Fluorobenzene (CASRN 462-06-6)a
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
None
None
None
p-IUR
None
None
None
None
""Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations
were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADj= Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days);
ConcHEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory
effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default
value of 1.0 is used for this ratio.
DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
No appropriate human or animal studies examining the effects of oral
sub chronic-duration exposure could be located. Therefore, derivation of a subchronic p-RfD is
precluded.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
No human or animal studies examining the effects of oral chronic-duration exposure
could be located. Therefore, derivation of a chronic p-RfD is precluded.
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DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Table 6 presents a summary of inhalation studies identified.
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
No subchronic p-RfC can be derived for the following reason: A nonpeer-reviewed study
is selected as the principal study. However, a screening value is provided in Appendix A.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
No human or animal inhalation studies examining the effects of chronic exposure could
be located. Because the study used to derive the subchronic p-RfC is a subacute study, it cannot
be used to derive a chronic provisional value. Therefore, derivation of a chronic p-RfC is
precluded.
Table 6. Summary of Relevant Inhalation Toxicity Studies for Fluorobenzene
Reference
Number of
Male/Female,
Species
Exposure
(mg/m3)
Frequency/
Duration
NOAELW
(mg/m3)
loaelAI)I
(mg/m3)
Critical
Endpoint
Safepharm
Labs, Ltd.
(1993)
5/5
Sprague-Dawley
rats
92.5, 375,
and 1560
6 hours/day, 7
days a week,
28 days (nose
only)
92.5a
375a
Centrilobular
hepatocyte
enlargement
""Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations
were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADi= Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed/Total Days);
ConcnEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory
effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default
value of 1.0 is used for this ratio.
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CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 7 identifies the cancer WOE descriptor for fluorobenzene.
Table 7. Cancer WOE Descriptor for Fluorobenzene
Possible WOE
Descriptor
Designation
Route of Entry
(Oral, Inhalation,
or Both)
Comments
"Carcinogenic to humans "
N/A
N/A
No human cancer studies are available.
"Likely to be carcinogenic
to humans "
N/A
N/A
No strong animal cancer data are
available.
"Suggestive evidence of
carcinogenic potential"
N/A
N/A
The evidence from human and animal
studies is not sufficient to be suggestive
of carcinogenicity.
"Inadequate information
to assess carcinogenic
potential"
X
Both
Inadequate information is available
to assess carcinogenic potential. The
mutagenicity studies are equivocal,
and in vivo studies have not been of
sufficient duration to evaluate
carcinogenicity.
"Not likely to be
carcinogenic to humans "
N/A
N/A
No strong evidence of
noncarcinogenicity in humans is
available.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
No human or animal studies examining the carcinogenicity of fluorobenzene following
oral exposure have been located. Therefore, derivation of a p-OSF is precluded.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No human or animal studies examining the carcinogenicity of fluorobenzene following
inhalation exposure have been located. Therefore, derivation of a p-IUR is precluded.
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APPENDIX A. PROVISIONAL SCREENING VALUES
DERIVATION OF SCREENING PROVISIONAL INHALATION REFERENCE
CONCENTRATIONS
Derivation of Screening Subchronic Provisional RfC (Subchronic p-RfC)
For the reasons noted in the main document, it is inappropriate to derive a provisional
subchronic p-RfC for fluorobenzene. However, information is available that, 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 a supplement and develops a screening value.
Appendices receive the same level of internal and external scientific peer review as the main
document to ensure their appropriateness within the limitations detailed in the main document.
Users of the screening toxicity values in a supplement to a PPRTV assessment should understand
that there is considerably more uncertainty associated with the derivation of a supplemental
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.
The study by Safepharm Labs, Ltd. (1993) is selected as the principal study for the
derivation of a screening subchronic p-RfC. The study is unpublished but is reviewed in
DuPont's (2003) Robust Summary for Fluorobenzene, which is publicly available as part of
EPA's Chemical Right-to-Know Program. The study is GLP compliant, but does not reach the
exposure duration that current EPA and OECD guidelines recommend for an inhalation study.
The critical endpoint, resulting in the benchmark concentration lower bound 95%
confidence interval (BMCL), is centrilobular hepatocyte enlargement in male Sprague-Dawley
rats. Other endpoints considered for modeling include an increase in kidney weight, eosinophilic
droplets in the tubular epithelium of the kidney, and by the enlargement in the liver of male rats
exposed to 375 mg/m3 or more of fluorobenzene, and is specifically mentioned by the study
authors as being an "observed effect of concern." There are no other studies of an appropriate
duration to support the findings of the Safepharm Labs, Ltd. (1993) study. Chlorobenzene, a
similar but more studied chemical than fluorobenzene, has been shown in subchronic- and
chronic-duration inhalation rodent studies to cause an increase in liver and kidney weights
(ASTDR, 1990). Available data from chlorobenzene support identifying the liver and kidneys as
target organs for toxicity in rodents. The significant liver and kidney changes observed in the
study by Safepharm Labs, Ltd. (1993) (centrilobular hepatocyte enlargement, relative liver
weight, eosinophilic droplets in the kidney, and relative kidney weight) were considered as
candidates for determination of a point of departure (POD) and were modeled using EPA's
BMDS (version 2.1) (2008). The summary of the modeling results for all endpoints considered
is presented in Table C. 1. The results from the modeling of the centrilobular hepatocyte
enlargement data represent the lowest and most appropriate BMCL, and, thus, POD for
developing a screening p-RfC.
The characteristics of fluorobenzene indicate that it is a Category 3 gas and, thus, has
effects peripheral to the respiratory system (U.S. EPA, 2009). Because Category 3 gases cause
extrarespiratory effects, the concentrations in the study were converted to adjusted doses (to
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account for continuous exposure) and then to HEC concentrations utilizing a default blood:air
partition coefficient of 1 because the actual value is unknown.
To determine the POD for derivation of the screening subchronic p-RfC, benchmark dose
(BMD) modeling of the centrilobular hepatocyte enlargement data has been conducted using
EPA's BMDS (version 2.1) (2008). As recommended by EPA (2008), a 10% risk above the
control mean has been used as the benchmark response (BMR) level.
The following dosimetric adjustments were made for inhalation exposure in adjusting for
continuous exposure and then human equivalent concentrations:
Continuous exposure conversion:
Coiicadj = Concentration x (Hours per Day x Days Dosed + Total Days)
= 0.37 mg/L x 1000 L/m3 x (6 h 24 h in a day) x
(28 Days Dosed ^ 28 Total Days)
= 370 mg/m3 x 0.25
= 92.5 mg/m3
HEC conversion:
ConcHEc
ConcADj x Blood Air Partition Coefficient
= 92.5 mg/m x 1
= 92.5 mg/m3
Table A.l presents the model input data for the incidence of hepatocyte enlargement in
male rats exposed to fluorobenzene by inhalation for 28 days.
Table A.l. Concentration-Response Data for Fluorobenzene-Induced Hepatocyte
Enlargement in Male Rats Exposed by Inhalation for 28 Days3
Cone (mg/L)
Coiicadj (mg/m3)b
Coiichec (mg/m3)b
Subjects in
Dose Group
Incidence
0
0
0
5
0
0.37
92.5
92.5
5
2
1.50
375
375
5
3
6.25
1560
1560
5
4
aSafepharm Labs, Ltd. (1993).
bFollowing the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009)
concentrations were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADj = Concentrations in mg/L x 1000 L/m3 x (Hours per Day ^ 24 hours) x (Days Dosed ^ Total Days);
ConcHEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an
extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans
is unknown, a default value of 1.0 is used for this ratio.
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Table A.2 shows the modeling results. Adequate model fit is obtained for hepatocyte
enlargement incidence data using the Log-Logistic model. The modeling results for hepatocyte
enlargement yield a BMCio of 24.6 mg/m3 and a BMCLio of 8.9 mg/m3.
Table A.2. Model Predictions for Hepatocyte Enlargement in Male Rats Exposed
by Inhalation for 28 Days"
Model
Goodness-of-Fit
/?-Valueb
AICb for
Fitted
Model
BMC10
(mg/m3)
BMCL10
(mg/m3)
Conclusions
Gamma
0.29
25.229
74.177
33.904
Hit bound (power =1)
Weibull
0.29
25.229
74.173
33.904
Hit bound (power =1)
Log-Probit
0.21
25.855
117.737
40.369
Hit bound (slope = 1)
Log-Logistic
0.91
20.962
24.563
8.871
Lowest AIC
Lowest BMCL
Hit bound (slope = 1)
Multistage
0.29
25.229
74.173
33.904
Maximum order beta = 0
P2 = 0
03 = 0
Logistic
0.23
26.580
198.917
100.387

Probit
0.23
26.588
201.270
113.902

Quantal Linear
0.29
25.229
74.173
33.904

"Safepharm Labs Ltd., 1993.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL = lower confidence limit
(95%) on the benchmark concentration.
-3
The screening subchronic p-RfC is based on the BMCLio of 8.9 mg/m (lowest BMCLio
for a range of 9-114) derived from male rats exposed to fluorobenzene for 28 days (Safepharm
Labs Ltd., 1993). The screening subchronic p-RfC for fluorobenzene, based on the BMCLio, is
derived as follows:
Screening Subchronic p-RfC = BMCLisd + UFC
= 8.9 mg/m3 ^ 300
= 0.03 mg/m3 or 3 x 10~2 mg/m3
Table A.3 summarizes the uncertainty factors (UFs) for the screening subchronic p-RfC
for fluorobenzene.
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Table A.3. Uncertainty Factors for Screening Subchronic p-RfC for Fluorobenzene
UF
Value
Justification
Notes
UFa
3
A UFa of 3 is applied for animal-to-human extrapolation to
account for the toxicodynamic portion of a UFA, because the
toxicokinetic portion (10°5) has been addressed in dosimetric
conversions.

ufd
10
A UFd of 10 is selected because there are no acceptable
two-generation reproduction studies or developmental studies,
and there are no indications of any other studies that may be
relevant for the database UF.

UFh
10
A UFh of 10 is applied for intraspecies differences to account
for potentially susceptible individuals in the absence of
information on the variability of response in humans.

ufl
1
A UFl of 1 is applied because the POD was developed using a
BMCL.

UFS
1
A UFS of 1 is applied because a subchronic-duration study was
utilized as the critical study.
A UFS greater than 1
is not necessary
when using
subacute study to
support a
subchronic value.
UFC
300


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APPENDIX B. DATA TABLES
Table B.l. Body and Organ Weights in Sprague-Dawley Rats Exposed to Inhaled

Fluorobenzene for 28 Days3

Exposure Group (Human Equivalent Concentration, mg/m3)

0 mg/L
0.37 mg/L
1.50 mg/L
6.25 mg/L
Parameter
(0)b
(92.5)b
(375)b
(1560)b
Male
Sample size
5
5
5
5
Final body weight0
312± 17
333 ±26
339 ±32
320 ±36
Adrenal gland0
0.0334 ±0.0080
0.0404 ±0.0128
0.0419 ±0.0073
0.0403 ±0.0114
Brain0
1.9417 ±0.0698
1.9462 ±0.0771
1.9964 ±0.0517
1.8847 ±0.1086
Heart0
1.2317 ±0.1486
1.3466 ±0.1667
1.3366 ±0.1477
1.2651 ±0.1712
Kidneys0
2.1192 ±0.1284
2.3213 ±0.2689
2.4787 ±0.2937
2.4747 ± 0.3402
Liver0
11.2929 ± 1.1165
12.5349 ± 1.3711
14.263 ± 1.8717d
14.5066 ± 1.3553d
Lungs0
1.5063 ±0.0570
1.5511 ±0.0848
1.5056 ±0.1607
1.4079 ±0.1811
Pituitary0
0.0090 ±0.0015
0.0133 ±0.0015d
0.0137 ±0.0026d
0.0092 ±0.0017
Spleen0
0.6470 ± 0.0766
0.6445 ±0.1095
0.7208 ± 0.0796
0.6687 ±0.1256
Gonads0
4.0022 ±0.2316
4.1775 ±0.2197
4.1332 ±0.2833
4.1712 ±0.2978
Female
Sample size
5
5
5
5
Final body weight0
226 ± 16
237 ±28
225 ± 23
229 ±9
Adrenal gland0
0.0444 ±0.0041
0.0609 ±0.0053°
0.0495 ±0.0123
0.0500 ±0.0115
Brain0
1.7808 ±0.0678
1.9142 ±0.0760°
1.8002 ±0.1076
1.8139 ±00.413
Heart0
0.9744 ±0.0939
0.9638 ±0.1150
0.8672 ±0.1020
0.9125 ±0.0684
Kidneys0
1.6653 ±0.0930
1.7663 ±0.1963
1.7167 ±0.1970
1.7858 ±0.2181
Liver0
8.5148 ±0.6904
8.7789 ± 1.0033
8.5537 ±0.9723
9.3969 ±0.3052
Lungs0
1.3077 ±0.1136
1.2636 ±0.1375
1.2444 ±0.1017
1.2238 ±0.0702
Pituitary0
0.0144 ±0.0040
0.0122 ±0.0034
0.0118 ±0.0032
0.0123 ±0.0029
Gonads0
0.3413 ±0.0798
0.3618 ± 0.1134
0.5902 ±0.0399
0.5237 ±0.0494
aSafepharm Labs, Ltd. (1993).
bFollowing the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009)
concentrations were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days);
ConcnEc = ConcADi x Blood Air Partition Coefficient of 1; concentrations were calculated for an
extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is
unknown, a default value of 1.0 is used for this ratio.
°Mean ± SD.
Significantly different from control group at the p < 0,01 level by one-way analysis of variance performed by
the researchers.
"Significantly different from control group at the p < 0.05 level by one-way analysis of variance performed by
the researchers.
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Table B.2. Relative Organ Weights (Percentage of Body Weight) in Sprague-Dawley
Rats Exposed to Inhaled Fluorobenzene for 28 Days3
Exposure Group (Human Equivalent Concentration, mg/m3)
Parameter
0 mg/L
(0)b
0.37 mg/L
(92.5)b
1.50 mg/L
(375)b
6.25 mg/L
(1560)b
Male
Sample size
5
5
5
5
Adrenal gland0
0.0109 ±0.0027
0.0121 ±0.0031
0.0127 ±0.0027
0.0127 ±0.0029
Brain0
0.6374 ±0.0534
0.5984 ±0.0282
0.6035 ± 0.0466
0.6021 ±0.0556
Heart0
0.4058 ±0.0712
0.4113 ±0.0656
0.4133 ±0.0789
0.4026 ± 0.0454
Kidneys0
0.6994 ± 0.0493
0.7032 ±0.0306
0.7446 ± 0.0458
0.7842 ± 0.0494d
Liver0
3.6883 ±0.1919
3.7994 ±0.1782
4.2361 ±0.1889°
4.6111 ±0.1877°
Lungs0
0.4934 ±0.0235
0.4721 ±0.0295
0.4532 ±0.0373f
0.4462 ± 0.023 lf
Pituitary0
0.0029 ± 0.0005
0.0040 ± 0.0004d
0.0041 ±0.0004°
0.0029 ± 0.0005
Spleen0
0.2112 ±0.0175
0.1955 ±0.0287
0.2169 ±0.0170
0.2109 ±0.0196
Gonads0
1.3114 ±0.0932
1.2719 ±0.0852
1.2469 ±0.0737
1.3447 ±0.2584
Female
Sample size
5
5
5
5
Adrenal gland0
0.0206 ±0.0016
0.0257 ± 0.0026f
0.0218 ±0.0031
0.0220 ± 0.0043
Brain0
0.7899 ±0.0374
0.8299 ±0.0868
0.8073 ± 0.0769
0.8061 ±0.0392
Heart0
0.4308 ± 0.0222
0.4153 ±0.0394
0.3867 ±0.0281f
0.4048 ±0.0312
Kidneys0
0.7385 ±0.0425
0.7603 ± 0.0446
0.7663 ± 0.0669
0.7932 ±0.1066
Liver0
3.7672 ±0.1119
3.7745 ±0.1368
3.8111 ±0.2072
4.2625 ±0.3416d
Lungs0
0.5784 ±0.0213
0.5473 ± 0.0473
0.5576 ± 0.0420
0.5434 ±0.0464
Pituitary0
0.0066 ± 0.0020
0.0053 ±0.0013
0.0054 ±0.0018
0.0054 ±0.0012
Spleen0
0.2398 ±0.0324
0.2401 ±0.0329
0.2643 ± 0.0243
0.2318 ±0.0149
Gonads0
0.0322 ±0.0054
0.0469 ± 0.0058
0.0565 ±0.0052
0.0567 ± 0.0080
aSafepharm Labs, Ltd. (1993).
bFollowing the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009)
concentrations were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days);
ConcnEc = ConcADi x Blood Air Partition Coefficient of 1; Concentrations were calculated for an
extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is
unknown, a default value of 1.0 is used for this ratio.
°Mean ± SD.
Significantly different from control group at the p < 0.01 level by one-way analysis of variance performed by
the researchers.
"Significantly different from control group at the p < 0.001 level by one-way analysis of variance performed by
the researchers.
Significantly different from control group at the p < 0.05 level by one-way analysis of variance performed by
the researchers.
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Table B.3. Incidences of Histopathological Findings in Kidneys and Livers of
Sprague-Dawley Rats Exposed to Inhaled Fluorobenzene for 28 Days3
Exposure Group (Human Equivalent Concentration, mg/m3)
Parameter
0 mg/L
(0)b
0.37 mg/L
(92.5)b
1.50 mg/L
(375)b
6.25 mg/L
(1560)b
Male Rats
Kidney
Groups of basophilic/dilated
tubules0
0/5
0/5
2/5
2/5
Eosinophilic droplets proximal
tubular epithelium0
0/5
0/5
3/5
4/5 d
Liver
Scattered mononuclear cell foci0
5/5
5/5
5/5
5/5
Focal hepatocyte necrosis0
0/5
0/5
0/5
1/5
Centrilobular hepatocyte
enlargement0
0/5
2/5
3/5
4/5 d
Female Rats
Kidney
Groups of basophilic/dilated
tubules0
2/5
0/5
0/5
0/5
Liver
Scattered mononuclear cell foci0
5/5
4/5
5/5
5/5
Focal hepatocyte necrosis0
0/5
0/5
1/5
0/5
aSafepharm Labs, Ltd. (1993).
''Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009)
concentrations were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days);
ConcnEc = ConcADi x Blood Air Partition Coefficient of 1; concentrations were calculated for an
extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans
is unknown, a default value of 1.0 is used for this ratio.
°Number of animals with endpoint/number of animals examined.
Significantly different from control (p < 0.05) by Fisher's exact test (two-tailed) performed for this review.
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Table B.4. Fluoride Concentration in Sternum and Teeth3
Exposure Group (Human Equivalent Concentration,
mg/m3)

0 mg/L
0.37 mg/L
1.50 mg/L

6.25 mg/L
Parameter
(0)b
(92.5)b
(375)b

(1560)b
Fluoride concentration (ppm)
Male
Sample size
5
5
5
5
Sternum0
100
339 [+239]
344 [+244]
556 [+456]
Teeth0
138
92 [-33]
273 [+98]
396 [186]
Female
Sample size
5
5
5
5
Sternum0
149
277 [+86]
427 [+187]
534 [+258]
Teeth0
60
213 [+255]
292 [+387]
436 [+627]
aSafepharm Labs, Ltd. (1993).
''Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009)
concentrations were converted to adjust for continuous exposure and HEC by using the following equations:
ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed + Total Days);
ConcnEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an
extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is
unknown, a default value of 1.0 is used for this ratio.
°Mean [change compared to control].
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APPENDIX C. BMD OUTPUTS
Table C.l. Summary of BMDS Results for Fluorobenzene3
Endpoint
Gender Species
Model Type
£
s
OS
u
S
as
-J
U
S
as
BMC/BMCL
%
H
2
13
>
i
a.
H
2
cS
>
i
%
0
H
,2
sS
>
1
a.
/j-Valuc Test 4
U
—
<
Scaled Residual
of Interest
Model Selection
Notes
Bound Flags?
Parameter Notes
Liver
Centrilobular
hepatocyte
enlargement13
Male
Rat
Dichotomous
-Log-Logistic
0.1
2.5 x lo1
8.9 x 10°
2.8
N/A
N/A
N/A
0.908
20.9618
0
Lowest AIC
Lowest BMCL
hit bound
(slope =1)
Flag
Hit bound
(slope = 1)
Relative Liver
Weight0
Male
Rat
Continuous-
Hill
1
1.2 x 102
4.7 x 101
2.6
<0001
0.999
0.985
NA
-39.5839
0.00037
Lowest BMCL
p-score p < 0.1
Wrong variance
model
No
Flag

Kidney
Eosinophilic
droplets
proximal
tubular
epithelium
Male
Rat
Dichotomous
-Log-Probit
0.1
1.3 x 102
6.6 x 101
1.9
N/A
N/A
N/A
0.715
15.2874
-0.538
Lowest AIC
hit bound
(slope =1)
Flag
Hit bound
(slope = 1)
Relative
Kidney Weight
Male
Rat
Continuous-
Linear
1
2.4 x 102
1.4 x 102
1.7
<0001
<0001
0.332
0.332
-74.9061
-0.0961
Lowest AIC
Lowest BMCL
No
Flag

Relative Liver
Weight
Female
Rat
Continuous-
Linear
1
4.0 x 102
2.4 x 102
1.7
1 X 10"3
0.06
0.521
0.922
-43.2711
-0.677
Lowest AIC
Lowest BMCL
No
Flag

Relative Lung
Weight
Male
Rat
Continuous-
Linear
1
1.2 x 103
7.0 x 102
1.8
0.135
0.655
0.655
0.164
-116.618
0.322
Lowest AIC
Lowest BMCL
No
Flag

aSafepharm Labs, Ltd. (1993).
bEndpoint used for POD.
°No models for this endpoint passed the selection criteria for an appropriate fit.
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SafePharml993_Liver_ CentrilMLogLogisticl
Log-Logistic Model with 0.95 Confidence Level
Log-Logistic
1
0.8
0.6
0.4
0.2
0
B
BMD
0
200
400
600
800
1000
1200
1400
1600
dose
15:20 04/28 2010
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File:
C:\l\SafePharm 1993 Liver Centril M LogLogistic 1. (d)
Gnuplot Plotting File:
C:\l\SafePharm 1993 Liver Centril M LogLogistic l.plt
Wed Apr 28 15:20:01 2010
[add notes here]
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-
slope*Log(dose) ) ]
Dependent variable = DichEff
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Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial
background =
intercept =
slope =
Parameter Values
0
-5.73806
1
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope
have been estimated at a boundary point, or have been
specified by the user,
and do not appear in the correlation matrix )
intercept
intercept	1
Parameter Estimates
Confidence Interval
Variable	Estimate
Upper Conf. Limit
background	0
~k
intercept	-5.39846
~k
slope	1
Std. Err.
95.0% Wald
Lower Conf. Limit
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model	Log(likelihood) # Param's Deviance Test d.f. P-value
Full model	-9.23213	4
Fitted model	-9.48092	1 0.497573	3
0.9194
Reduced model	-13.7628	1 9.06129	3
0.02849
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AIC:	20.9618
Goodness of Fit
Scaled
Dose Est. Prob. Expected Observed	Size	Residual
0.0000 0.0000 0.000 0.000	5	0.000
92.5000 0.2950 1.475 2.000	5	0.515
375.0000 0.6291 3.146 3.000	5	-0.135
1560.0000 0.8759 4.379 4.000	5	-0.515
ChiA2 = 0.55	d.f. = 3	P-value = 0.9082
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMC =	2 4.5628
BMCL =	8 . 8712 8
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APPENDIX D. REFERENCES
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U.S. EPA (Environmental Protection Agency). (2009) Risk assessment guidance for superfund
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