Jffl;	United States
iPilfEnvironmental Protectioi
if % Agency
EPA/690/R-11/002F
Final
06-15-2011
Provisional Peer-Reviewed Toxicity Values for
Acetophenone
(CASRN 98-86-2)
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
Ambuja Bale, PhD, DABT
National Center for Environmental Assessment, Washington, DC
Martin W. Gehlhaus, III, MHS
National Center for Environmental Assessment, Washington, DC
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	iii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	 1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	3
HUMAN STUDIES	8
Oral Exposure	8
Inhalation Exposure	8
ANIMAL STUDIES	8
Oral Exposure	8
Sub chronic-duration Studies	8
Chronic-duration Studies	10
Developmental and Reproduction Studies	10
Inhalation Exposure	11
Sub chronic-duration Studies	12
Chronic-duration Studies	13
Developmental and Reproduction Studies	13
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	13
DERIVATION 01 PROVISIONAL VALUES	16
DERIVATION OF ORAL REFERENCE DOSE	16
Derivation of Subchronic p-RfD	16
Derivation of Chronic RfD	18
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	18
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	18
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	18
APPENDIX A: PROVISIONAL SCREENING VALUES	19
APPENDIX B: DATA TABLES	21
APPENDIX C: BMD MODELING OUTPUTS FOR ACETOPHENONE	22
APPENDIX D: REFERENCES	23
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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
NOAELhec
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
ACETOPHENONE (CASRN 98-86-2)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris), the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Acetophenone is made from benzene and acetylchoride in the presence of aluminum
chloride or catalytically from acetic and benzoic acids (ACGIH, 2001). It is used in perfume to
yield an orange blossom-like odor (ACGIH, 2001) and as a food flavoring agent (WHO, 2001).
The empirical formula for acetophenone is CsHgO (see Figure 1). A table of physicochemical
properties is provided below (see Table 1). In this document, "statistically significant" denotes a
p-value of <0.05.
o
Figure 1. Acetophenone Structure
Table 1. Physicochemical Properties Table for
Acetophenone (CASRN 98-86-2)a
Property (unit)
Value
Boiling point (°C)
201.7
Melting point (°C)
20.5
Density (g/cm3)
1.0296
Vapor pressure (mm Hg at 25°C)
0.372
pH (unitless)
Not available
Solubility in water (g/L at 25°C)
5.5
Relative vapor density (air =1)
4.1
Molecular weight (g/mol)
120.15
Flash point (°C)
82 (closed cup); 93 (open cup)
Octanol/water partition coefficient (unitless)
1.58
"Values from ACGIH (2001) and EPA (1987).
No reference dose (RfD), reference concentration (RfC), or cancer assessment for
acetophenone is included on the Drinking Water Standards and Health Advisories List
(U.S. EPA, 2006). IRIS (U.S. EPA, 1989) reports an RfD for acetophenone of 0.1 mg/kg-day
based on general toxicity from a sub chronic-duration rat toxicity study but does not report an
RfC. No RfC is reported in the Health Effects Assessment Summary Tables (HEAST)
(U.S. EPA, 2010), but a subchronic RfD of 1 mg/kg-day, based on the same subchronic-duration
rat study used in the IRIS assessment, is reported. The Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1994) does not include a Health and Environmental Effects
Profile (HEEP) for acetophenone (U.S. EPA, 2009). The toxicity of acetophenone has not been
reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR, 2011). The World
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Health Organization (WHO) evaluated the toxicity of acetophenone and determined that there
was no safety concern (WHO, 2001), estimating a daily intake of 170 |ig/day or 3 |ig/kg-day.
CalEPA (2008) has not derived toxicity values for exposure to acetophenone. An occupational
exposure limit (TLV-TWA) of 10 ppm for acetophenone was derived by the American
Conference of Governmental Industrial Hygienists (ACGIH, 2001), but no occupational
exposure limit has been developed by the National Institute of Occupational Safety and Health
(NIOSH, 2009) or the Occupational Safety and Health Administration (OSHA, 2009).
IRIS (U.S. EPA, 1989) reported an EPA (1986) cancer weight-of-evidence classification
of Group D (Not Classifiable as to Human Carcinogenicity) for acetophenone based on the lack
of carcinogenicity studies in humans or animals. The International Agency for Research on
Cancer (IARC, 2009) has not reviewed the carcinogenic potential of acetophenone nor was
acetophenone included in the National Toxicology Program's 11th Report on Carcinogens (NTP,
2005). CalEPA (2008) has not prepared a quantitative estimate for the carcinogenic potential of
acetophenone.
Literature searches were conducted on sources published from 1900 through
February 3, 2011. for studies relevant to the derivation of provisional toxicity values for
acetophenone, CAS No. 98-86-2. Searches were conducted using EPA's Health and
Environmental Research Online (HERO) 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 (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multidatabase Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for risk
assessment values: ACGIH, AT SDR, 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 information for all of the potentially relevant acute, subchronic, and
chronic toxicity 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. Entries for the principal studies
are bolded and identified by the marking "PS." Following the table, important aspects of all the
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studies in the table are provided in the same order as the table. The phrase "statistical
significance", used throughout the document, indicates ap-value of <0.05.
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Table 2. Summary of Potentially Relevant Data for Acetophenone (CASRN 98-86-2)
Notes3
Category
Number of Male/Female,
Species, Study Type, and
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference
(Comments)
Human
1. Oral (mg/kg-d)b

Subchronic
Not reported
1.4-8.6
Weaker and slower pulse rate,
increased frequency of
urination, and a slight, transient
decrease in hemoglobin levels
4.3
NA
6.4
BIBRA (1991)

Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
2. Inhalation (mg/m3)b

Acute
Number and sex were not
reported, acute, single
exposure
Not reported
Malaise, headache, stomach
pain, dizziness, and sleepiness
None
NA
None
BIBRA (1991)
3 odor-sensitive volunteers,
no other details provided
0.007-0.02
Decreased eye-sensitivity to
light
0.007
NA
0.01
Imasheva (1966)
5 normal volunteers, sex not
reported, inhalation, 40-50
min
0.003 or 0.007
Decreased energy assimilation
in the brain as measured by
electrical brain activity
0.003
NA
0.007
Imasheva (1966)

Subchronic
None

Chronic
None

Developmental
None

Reproductive
None

Carcinogenic
None
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Table 2. Summary of Potentially Relevant Data for Acetophenone (CASRN 98-86-2)
Notes3
Category
Number of Male/Female,
Species, Study Type, and
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference
(Comments)
Animal
1. Oral (mg/kg-d)b
IRIS
(1989)
Subchronic
10/10, Osborne-Mendel rat,
diet, 7 d/wk, 17 wks
0, 42,106, or 423
(adjusted)"1
No critical effect
423
NA
None
Hagan et al. (1967)
PS, NPR
10/5, Sprague-Dawley rat,
gavage, 7 d/wk, 33 d in
males and 34 d in females
0, 75,225, or 750
(adjusted)
Neurological: decreased mean
forelimb grip strength and
motor activity
Systemic: pre and
postsalivation; increased liver
and kidney weight in females
225
75
NA
750
225
ATF (2003)

Chronic
None
PS, NPR
Developmental
10/10, Sprague-Dawley rat,
gavage, 7 d/wk, Gestational
Day (GD) 0 to Lactation
Day (LD) 4 (dams and
offspring)
0, 75,225, or 750
(adjusted)
Decreased pup survival and
pup body weight during
lactation
225
NA
750
ATF (2003)
PS, NPR
Reproductive
10/10, Sprague-Dawley rat,
gavage, 7 d/wk, 28-42 d
beginning 14 d prior to
mating
0, 75,225, or 750
(adjusted)
Decreased live birth index
225
NA
750
ATF (2003)

Carcinogenic
None
2. Inhalation (mg/m3)b

Subchronic
15 males, white rat,
inhalation, continuous, 70 d
0.007 or0.076e
Changes in muscle antagonist,
decreased cholinesterase
activity, increased incidence of
cardiovascular plethora, and
acute liver dystrophy
0.007
NA
0.076
Imasheva (1966)

4 (sex not specified), Wistar
rat, inhalation, continuous, 1
or 5 wk or 2 mo
1.2f
Degeneration of mitral cells in
the olfactory bulb
None
NA
1.2
Pinching and
Doving (1974)
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Table 2. Summary of Potentially Relevant Data for Acetophenone (CASRN 98-86-2)
Notes3
Category
Number of Male/Female,
Species, Study Type, and
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference
(Comments)


6-12 males, Wistar rat,
inhalation, continuous,
33-230 d
0.04 or 2.2s
Histopathological changes of
the olfactory bulb
None
NA
0.04
Dalland and Doving
(1981)

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 dose (HED in mg/kg-day) or human equivalent concentration (HEC
in mg/m3) units. All exposure values of long-term exposure (4 weeks and longer) are converted from a discontinuous to a continuous (weekly) exposure. Values for
inhalation (cancer and noncancer) and oral (cancer only) are further converted to an HEC/D. Values from animal developmental studies are not adjusted to a continuous
exposure.
°Not reported by the study author but determined from data.
dThe adjusted daily doses were calculated by EPA (1989) as follows: 10,000 ppm x 0.845, based on 15.5% volatilization = 8450 ppm; assuming a rat consumed 5% of its
body weight, 8450 ppm (mg/kg food) x 0.05 kg food/kg body weight/day = 423 mg/kg-day.
"HECexresp was calculated as follows: dose x hours treated ^ 24 hours x days treated ^ 7 days x ratio of blood/gas partition coefficient = 0.007 mg/m3 / 24 ^ 24 / 7 ^ 7 x
1 = 0.007 mg/m3.
rHECR,si- was calculated as follows: 7.4 x 10~8moles/L x 120.15 g/mole x 1000 mg/g x 1000 L/m3 = 8.9 mg/m3 x24^24x7^7x Regional Gas Deposition Ratio
(RGDR) of 0.136 = 1.2 mg/m3.
8HECREsp was calculated as follows: 2.0 x 10~9moles/L x 120.15 g/mole x 1000 mg/g x 1000 L/m3 = 0.24 mg/m3 x24^24x7^7x RGDR of 0.154 = 0.04 mg/m3.
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HUMAN STUDIES
Oral Exposure
No studies investigating the effects of subchronic or chronic-duration oral exposure to
acetophenone in humans were identified. BIBRA (1991) provides details on a study by Mairet
and Combemale (1886), which was published in a foreign language and reported no clinical
effects with oral doses of 100-300 mg/day (stated to be equivalent to 1.4-4.3 mg/kg-day) for an
unspecified amount of time in healthy subjects. Healthy subjects exposed to doses of 450 to
600 mg/day (equivalent to 6.4-8.6 mg/kg-day) had weaker and slower pulse rates, increased
frequency of urination, and slight, transient decreases in hemoglobin levels. The compound,
reportedly used as an anticonvulsant and hypnotic, was apparently being tested for therapeutic
use. The authors reported that the doses of acetophenone in mentally abnormal or epileptic
patients did not cause muscular excitement, although there was some evidence of a tranquilizing
effect, and some patients complained of a burning sensation in the stomach.
Inhalation Exposure
Little information is available regarding inhalation exposure to acetophenone in humans.
Malaise, headache, stomach pain, dizziness, and sleepiness have been reported after a single
exposure to an unspecified amount of vapor (BIBRA, 1991). The original source of this
information (Laborde, 1885) was unavailable for review. Imasheva (1966), translation provided
by Levine (BIBRA, 1991), reported an odor perception threshold of 0.01 mg/m3 in
18 "odor-sensitive" volunteers. Acetophenone-induced "eye sensitivity" (not further defined or
explained) to light was tested in 3 of the 18 volunteers. All three volunteers reported a decrease
"3
in eye sensitivity to light when exposed to 0.015-mg/m acetophenone—but to a lesser degree
than when exposed to 0.02 mg/m3. At 0.01-mg/m3 acetophenone, one of the three volunteers
-3
reported a decreased sensitivity to light; no changes were observed at 0.007 mg/m . Imasheva
(1966) also tested the electrical brain activity of five presumably normal volunteers (18-35 years
old) during a 40-50-minute test. A lowering (35-40%) in the total amount of energy assimilated
by the brain (stated as statistically reliable by the study authors) was noted in all volunteers
"3
between Minutes 2 and 6 of exposure to 0.007-mg/m acetophenone, but there were no
recordable changes at 0.003 mg/m3.
ANIMAL STUDIES
Oral Exposure
The effects of oral exposure of animals to acetophenone have been evaluated in two
subchronic-duration (Hagan et al., 1967) studies and a reproductive/developmental screening
(ATF, 2003) toxicity study. There are currently no chronic-duration oral studies with
acetophenone in animals. The subchronic-duration study and reproductive/developmental
screening study was a single study performed concurrently but conducted in two parts and
reported as proprietary data (ATF, 2003). Because the reproductive/developmental screening
study is a single study and is not written up as separate components, it will only be referenced as
a single study (i.e., ATF, 2003).
Subchronic-duration Studies
Male and female (10/sex/dose) Osborne-Mendel rats (husbandry not reported) were
administered 0-, 1000-, 2500-, or 10,000-ppm acetophenone (purity not reported) daily via the
diet for 17 weeks (Hagan et al., 1967). These doses correspond to adjusted daily doses (ADDs)
of 0, 42, 106, or 423 mg/kg-day (as calculated by U.S. EPA, 1989). The study does not provide
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details on the controls (i.e., untreated or concurrent vehicle). Diets were prepared weekly, but it
was determined that 31% of the test compound was lost from the diet during the 7 days. This
loss could be attributed to volatility (15.5%) and stability of the compound at room temperature
(U.S. EPA, 1989). Body weight, food consumption, and general condition were evaluated
weekly. Hematology (including white blood cells [WBCs], erythrocyte counts, hematocrit, and
hemoglobin) was measured at study termination. At termination, animals were sacrificed,
grossly examined, and organs were weighed (including liver, kidneys, spleen, heart, and testes).
These same organs, as well as abdominal and thoracic viscera and one hind leg (to provide bone,
bone marrow, and muscle), were preserved for histopathological examination from three or four
rats per sex from the control and high-dose groups. No treatment-related effects were observed.
There is no GLP (Good Laboratory Practice) statement provided. The authors did not provide a
NOAEL. However, IRIS provides aNOAEL of 423 mg/kg-day (U.S. EPA, 1989). This
NOAEL is the highest dose tested in the study at which no effects were observed (Hagan et al.,
1967).
The study by ATF (2003) is selected as the principal study for deriving the screening
subchronic p-RfD. The ATF (2003) study was provided as a proprietary study with only the
text available for review (no data summary tables were available). The study was stated to be a
repeated dose toxicity test combined with a reproductive/developmental screening test conducted
according to the Organization for Economic Co-operation and Development (OECD) Guideline
No. 422 and was GLP compliant. Acetophenone (98.8% pure) was administered daily via
gavage at adjusted doses of 0, 75, 225, or 750 mg/kg-day in corn oil to male and female
Sprague-Dawley rats from Charles River Laboratories, Inc. in Raleigh, North Carolina (10 male
and 5 female rats/treatment group for the repeated dose toxicity portion of the test). Dose
formulations were tested for homogeneity, stability, and analytical concentration. All were
found to be within acceptable ranges, and the dose formulation was determined to be stable for at
least 10 days at room temperature. All rats were treated for a minimum of 28 days during the
toxicity phase. Males from the toxicity phase were mated with females in the reproduction
phase. Animals were checked twice per day for mortality and general health. Cage-side
observations for clinical signs of toxicity were conducted daily within 2 hours of dosing.
Detailed clinical observations were conducted weekly. An abbreviated functional observational
battery (FOB) test (including home cage observation, removal from home cage observation, open
field observation, manipulative tests, and motor activity assessments) was conducted weekly.
Body weight and food consumption were measured every 3-5 days. Blood was collected from
five animals/sex/treatment and hematology (including erythrocyte count, hematocrit,
hemoglobin, mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration
[MCHC], mean corpuscular volume [MCV], platelet count, total and differential WBC count,
prothrombin time, and activated partial prothrombin time) and clinical chemistry (including
alanine aminotransferase [ALT], albumin, globulin, albumin/globulin ratio, alkaline phosphatase,
aspartate aminotransferase [AST], calcium, cholesterol, creatinine, glucose, sodium, potassium,
chloride, phosphorus, total bilirubin, total serum protein, triglycerides, and urea nitrogen) tests
were performed. All animals were necropsied at sacrifice. The adrenals, epididymides, brain,
heart, kidneys, liver, spleen, testes, and thymus were weighed. All OECD
guideline-recommended tissues/organs were processed for histopathology in
five animal s/sex/treatment group. The study authors used appropriate statistical analyses
including one-way analysis of variance (ANOVA), Tukey-Kramer test, Fisher's exact test,
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Levene's test for homogeneity of variance, Kruskal Wallis nonparametric ANOVA followed by
Dunn's test, and Chi-square test followed by Fischer's exact test.
No mortality occurred in this study (ATF, 2003). Clinical signs included pre and
postdose salivation in the mid- and high-dose groups and postdose wobbly gait and urine staining
(low incidence) in the high-dose group. Some high-dose females also exhibited hair loss.
High-dose animals had a statistically significant mean lower body weight and food consumption
compared with the controls early in the study, but it appeared to rebound in the second half of the
study. However, the mean body weights of the high-dose males were 5-10% lower than the
controls from Treatment Days 3-30. High-dose males had a statistically significant decrease in
mean forelimb grip strength and motor activity on Day 29. There were no treatment-related
effects on hematology. Clinical chemistry data indicated a statistically significant increase in the
cholesterol levels of high-dose males and females (750 mg/kg-day) and increased total protein
and calcium levels in high-dose males. Although the biological significance of this is not clear,
the study authors stated that these numbers were outside the historical control range observed in
the test laboratory. Values in the 225-mg/kg-day group were within the historical control range
even if they were statistically different from the controls; however, there appeared to be a
dose-related increase in total protein, albumin, and globulin that appeared to be related to
increased liver weights. There were no abnormal findings at necropsy. There was a statistically
significant increase in the relative liver weight in high-dose males compared with the control. In
females, there was a statistically significant increase in absolute and relative liver weight and
relative kidney weight in the mid- and high-dose groups. Mild-to-moderate hyaline droplet
nephropathy was observed in all of the male treatment groups. The results were not dose related
and were not considered toxicologically relevant to humans. There were no other
histopathological changes related to treatment. The systemic NOAEL was stated to be
75 mg/kg-day, with a neurological NOAEL of 225 mg/kg-day. The study authors did not report
a LOAEL, but a LOAEL of 225 mg/kg-day can be derived for systemic effects, based on pre and
postdose salivation, and increases in liver and kidney weight in females. The neurological
LOAEL is 750 mg/kg-day, based on decreased mean forelimb grip strength and motor activity in
male rats.
Chronic-duration Studies
No chronic-duration oral studies with acetophenone are available.
Developmental and Reproduction Studies
For the reproductive/developmental phase of the ATF (2003) study, male and female rats
were treated for a minimum of 14 days before mating, and female rats were treated through
Lactation Day (LD) 3. Males from the toxicity phase were mated with females in the
reproduction phase. The F0 generation was checked twice per day for mortality and general
health. Cage-side observations were conducted once per day within 2 hours of dosing. Detailed
clinical observations were conducted at least weekly until evidence of mating, and then females
were checked daily through gestation and lactation. Males were processed as part of the repeated
dose toxicity study detailed above. Body weights of the F0 females were measured on Days 0, 3,
7, and 12 prior to mating. After evidence of mating was detected, females were weighed on
Gestational Days (GDs) 0, 7, 14, and 20 and on LDs 1 and 4. Food consumption was measured
on the same days as the body weight. After at least 14 days of treatment, a single male was
cohabitated with a single female for a maximum of 14 days. Mating was considered to have
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occurred if the presence of a sperm-positive vaginal smear or copulary plug was detected. The
day copulation was detected was designated as GD 0, and the female was returned to its cage.
Females were observed for abnormal nesting, parturition, and nursing behaviors. Females with
no evidence of mating were sacrificed 19 days after mating began, females that failed to deliver
were sacrificed on GD 25, and F0 females and their offspring were sacrificed on LD 4. All
females were sacrificed and necropsied. Uterine contents were examined, and the number of
implants and the number of corpora lutea were recorded. Although all OECD guideline-
specified tissues were collected from F0 females, routine histopathology was not conducted. In
F1 pups, viability, sex, external examinations, and body weights were evaluated. Stillborn or
dead pups were examined for abnormalities. On LD 4, all live pups were sacrificed and
examined for external abnormalities. The study authors used appropriate methods of statistical
analysis, which included ANOVA, Tukey-Kramer test, Fisher's exact test, Levene's test for
homogeneity of variance, Kruskal Wallis nonparametric ANOVA followed by Dunn's test, and
Chi-square test followed by Fisher's exact test.
No parental mortality occurred in this study (ATF, 2003). The details of the
repeated-dose portion of the study are provided above. Clinical signs in the dams primarily
occurred in the mid- and high-dose groups and included a low incidence of urine staining, pre-
and postdose salivation, and postdose feces small in size. Decreased activity, pale skin, unkempt
appearance, rough coat, and a postdose wobbly gait were observed in the high-dose group,
though at a low incidence. There was a slight (6%), but statistically nonsignificant, lower body
weight in high-dose dams that was related to a statistically significant lower body-weight gain
during GDs 0-7 due to decreased food consumption. There were no treatment-related effects on
the mating index, fertility index, mean gestation length, or ability to deliver. However, there was
an increase in the number of litters with stillborn pups in the treated groups (2/7, 4/9, 3/10, and
7/9 females delivered stillborn pups in the control, 75-, 225-, and 750-mg/kg-day groups,
respectively). This translated into a statistically significant decrease in the live birth index
(number of liveborn pups/number of pups delivered) in the high-dose group. In addition, six of
the high-dose litters with liveborn pups had no pups surviving to LD 4. The number of pups
surviving to sacrifice on LD 4 were 99 in the control, 131 in the 75-mg/kg-day group, 137 in the
225-mg/kg-day group, and only 25 in the 750-mg/kg-day group. These translated into viability
indexes of 94.3%, 96.3%, 94.5%, and 22.9%, respectively, which were statistically significant in
the high-dose group compared with the control. The study report did not report any
abnormalities in the stillborn or dying pups. The mean pup body weight was statistically lower
in the high-dose group compared with the control group on LDs 1 and 4 and was outside of the
historical control range. The reproductive/developmental NOAEL was stated to be
225 mg/kg-day. The reproductive/developmental LOAEL is considered to be 750 mg/kg-day,
based on the decreased live birth index, pup survival, and body weight of pups during lactation.
Inhalation Exposure
The only available inhalation toxicity studies with acetophenone are subchronic.
However, the endpoints are questionable, and the study details are lacking. Imasheva (1966)
examined the most endpoints, but the reporting of the study details is inadequate. Pinching and
D0ving (1974) and Dalland and D0ving (1981) examined only the olfactory bulb histopathology
and/or avoidance reactions in acetophenone-exposed rats.
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Subchronic-duration Studies
Imasheva (1966) exposed 15 white male rats (60-70 g) to continuous acetophenone
"3
(97% pure) at concentrations of 0.007 or 0.076 mg/m or clean air for 70 days
(15 animals/treatment group). Clinical signs, body weight (measured every 10 days), dynamics,
muscle antagonist "chronaxie ratio" (measured every 10 days), whole blood cholinesterase
(five animals/group), blood serum protein fractions (five animals/group), and gross necropsy and
histopathology were evaluated. The study author described in detail measured differences in the
motor chronaxie ratios, cholinesterase levels, and serum protein fractions.
Every 10 days, Imasheva (1966) used an electronic impulse stimulator to measure the
motor chronaxie of the extensor and flexor muscles.1 The flexor and extensor muscle chronaxie
-3
ratio was similar between the controls and the 0.007-mg/m group. However, in rats
"3
administered 0.076 mg/m , there was a change in the ratio (stated as a reverse character) at the
end of the second month. Whole blood cholinesterase was determined using the Pokrovskii
colorimetric assay. Again, at the end of the second month, shifts in cholinesterase activity
occurred in the 0.076-mg/m3 group. In three of the rats, there was a decrease (average of 22%)
in activity, while in one rat, there was a 45% increase in activity. Fractions of albumin and
globulins, as well as total protein levels, were also examined every 20 days. While there was no
change in the total protein levels, transient changes were noted in all fractions. Albumin
decreased by 38.7-48.9%) of initial levels by the end of the first month, while globulin levels
demonstrated a corresponding increase. The study author stated that original levels were
obtained after 20 days of recuperation. At the end of treatment, some animals (exact number not
provided) were sacrificed for gross and histopathological examinations. The effects that were
reported were conditions referred to, but not defined, as cardiovascular plethora3 and acute liver
dystrophy in rats administered 0.076 mg/m . The study authors did not report a NOAEL.
However, a NOAEL of 0.007 mg/m3 can be determined from the data. The LOAEL is
"3
0.076 mg/m , based on changes in chronaxie ratios, shifts in cholinesterase activity, transient
changes in protein fractions, and histopathology; however, the toxicological significance of any
of the endpoints is not clear.
Pinching and D0ving (1974) tested the effects of inhalation exposure of several odorous
compounds including acetophenone on the olfactory tissues of four weanling Wistar rats (sex
ratios not reported). Animals (28-39 g, approximately 2 weeks old) were continuously exposed
o
to 7.4 x 10" -M (molar) acetophenone (purity not reported) for varying durations of exposure
ranging from 1 week to 3 months. According to tabulated data, rats were exposed to
acetophenone for 1-week or 5-week exposure periods. Data were also presented for animals
exposed for 2 months, but the study report did not discuss 3-month exposures to acetophenone.
Controls received filtered room air only. The focus of the study was limited to histopathological
examination of the mitral cells in the olfactory bulb. There was moderate degeneration of these
cells observed in rats exposed to acetophenone; results were similar between paired animals in
the 1-month and 2-month exposure groups. It is assumed that this effect is respiratory (i.e.,
According to the author, changes in muscle chronaxie ratios could be used as an indicator of central nervous system
damage. Chronaxie, along with rheobase, are points along the strength duration curve for electrical stimulus of an
excitable tissue such as nerve or muscle.
2This assay measures changes in cholinesterase activity as color changes in a pH indicator resulting from
hydrolyzation of acetylcholine.
3This term was not defined or clarified and is not elsewhere in the existing medical literature.
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including the olfactory epithelium) because the study lacks any data to indicate that there was
systemic toxicity and the HEC was calculated as a respiratory effect. The study authors did not
report a NOAEL. No NOAEL can be established from the data as presented. The LOAEL,
however, is 1.2 mg/m3, based on moderate degeneration in the mitral cells of the olfactory bulb
observed at a single concentration.
Dalland and D0ving (1981) exposed 14-day-old male Wistar rats to control air or
continuous exposure to acetophenone (purity not reported) for 33, 50, or 230 days in a study
focused on alterations in tissues and cell types of the olfactory bulb in the brain (this is assumed
to be a respiratory effect including the respiratory epithelium lacking any indication of systemic
toxicity in the study). The study report stated that the concentrations in the two cages of
acetophenone were 2.0 x 10"9 and 1.2 x 10"7 M (HEC of 0.04 and 2.2 mg/m3, respectively, based
on the assumption that this is a respiratory effect including the olfactory epithelium). There were
three exposure groups in this study. In Group 1, rats were exposed for 50 days (6 rats per
treatment group), then sacrificed for histological examination. In Group 2, rats were exposed for
33 days (12 rats per treatment group), then transferred to laboratory cages. Forty days later, the
animals were tested for avoidance reaction. These 12 animals were separated into three groups
for conditioned stimulus testing (control air, acetophenone, or 4-methylvaleric acid). Three
weeks after avoidance-reaction tests, they were sacrificed for histological examination. In
Group 3, rats were exposed for 230 days (9 rats per treatment group). One rat each from the
control and acetophenone groups was tested for avoidance reaction 200 days later, and the rest
were sacrificed 150 days after testing. Response to a conditioned stimulus was tested with a
20-second presentation of acetophenone at concentrations of 3.6 or 7.2 x 10"9M when rats were
drinking. The unconditioned stimulus was a 1-second scrambled electrical shock of 0.4 mA
(milliampere) given through the grid floor of the box immediately after the conditioned stimulus.
Rats sacrificed immediately after 50 days of exposure exhibited shrinkage and
cytoplasmic darkening of the mitral cells in distinct patterns (Dalland and D0ving, 1981). The
histopathology of the olfactory bulb was still altered following removal from acetophenone, but
the patterns were different in the three groups. All rats developed an avoidance reaction to the
strongest conditioned stimulus within 3 days with no differences between the groups. Results
indicate that rats still respond to the odor even after having been exposed to it for long periods of
time; morphological changes in the olfactory bulb did not alter the behavior. The study authors
did not provide a NOAEL. No NOAEL can be established from the data. Based on the
"3
histopathology of the olfactory bulb, the LOAEL is 0.04 mg/m .
Chronic-duration Studies
There are no chronic-duration inhalation studies available for acetophenone.
Developmental and Reproduction Studies
No studies could be located regarding the effects of inhaled acetophenone on
reproduction or fetal development.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Acetophenone is rapidly absorbed from the gut, metabolized efficiently by the liver to
benzoic acid or mandelic acid, and excreted primarily in the urine and, to a very small extent, in
the feces (WHO, 2001).
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The genotoxicity of acetophenone has been tested in numerous studies using various in
vitro test systems (see Table 3). These tests indicate that acetophenone is not mutagenic but may
be clastogenic. Studies investigating the genotoxic potential of acetophenone in vivo were not
identified.
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Table 3. Other Studies for Acetophenone (CASRN 98-86-2)
Tests
Materials and Methods
Results
Conclusions
References
Genotoxicity
Tested for reverse mutation in
Salmonella typhimurium (Ames
assay, strains TA100, TA98, and
TA1537), with and without metabolic
activation at concentrations up to
3000 nmoles/plate.
No increase in mutagenic activity.
Acetophenone was not
mutagenic in Salmonella
typhimurium.
Elliger et al.
(1984)
Genotoxicity
Tested for reverse mutation in
Salmonella typhimurium (Ames
assay, strains TA100, TA2637,
TA98), with and without metabolic
activation at concentrations ranging
from 0.05 to 5.0 mg/plate.
No increase in mutagenic activity.
Acetophenone was not
mutagenic in Salmonella
typhimurium.
Nohmi et al.
(1985)
Genotoxicity
Tested for reverse mutation in
Salmonella typhimurium (Ames
assay, strains TA100, TA98), with
and without metabolic activation
(concentrations not reported).
No increase in mutagenic activity
was observed with any of the
cigarette smoke condensate
including the one containing
acetophenone.
Acetophenone was not
mutagenic in Salmonella
typhimurium.
Curvall et al.
(1985)
Genotoxicity
Tested for the induction of sister
chromatid exchanges (SCEs) in a
fraction of cigarette smoke
condensate (<100 |ig/ml) known to
contain acetophenones, benzonitriles,
indoles, methyl alkylketones, and
esters of fatty acids.
There was a statistically
significant increase in SCE
(p < 0.01) with the cigarette
smoke condensate fraction
containing acetophenone.
There can be no definitive
conclusion on the effect of
acetophenone on SCE
induction because it was
only one constituent in the
mixture that was tested.
Curvall et al.
(1985)
Genotoxicity
Chromosomal aberrations in hamster
lung cells. Concentrations of
0.8-1.2 mg/plate in the absence of S9
and 0.6-1.0 mg/mL in the presence
of S9.
Acetophenone caused
chromosomal aberrations in
hamster lung cells in the presence
of metabolic activation but not in
the absence.
Metabolic activation is
needed to cause
chromosomal aberrations.
Sofuni et al.
(1985)
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DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present a summary of noncancer and cancer reference values,
respectively. IRIS data are indicated in the table, if available.
DERIVATION OF ORAL REFERENCE DOSE
Derivation of Subchronic p-RfD
No subchronic p-RfD values can be derived because no adequate, well-described studies
are available.
There are two studies available that examine the subchronic effects of acetophenone by
the oral route of exposure in animals. The Hagan et al. (1967) study was used by IRIS to
develop a chronic RfD; however, the study report is lacking in its presentation of the data, and no
effects were found, even at the highest dose tested. The study did not examine neurological or
reproductive/developmental effects. ATF (2003) conducted a combined repeated dose toxicity,
screening reproductive/developmental study. In this study, neurological tests and
reproductive/developmental screening were conducted, and effects were observed. However, the
ATF (2003) study was a proprietary study that was not peer reviewed, and only the text without
summary or individual data tables was available for review. The ATF (2003) study provides a
lower POD for endpoints not tested in the Hagan et al. (1967) study. At the highest dose tested
(423 mg/kg-day), no effects were observed (Hagan et al., 1967). However, because the ATF
(2003) study was not peer reviewed and the data were not available for review, the subchronic
p-RfD derived from the study is relegated to a screening value and is provided in Appendix A.
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Table 4. Summary of Noncancer Reference Values for Acetophenone (CASRN 98-86-2)
Toxicity Type (Units)a
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Screening subchronic
p-RfD (mg/kg-day)
Rat/M+F
Neurotoxicity,
reproductive and
developmental toxicity
8 x 10"1
NOAEL
225
300
ATF (2003)
Chronic RfD
(mg/kg-day)
(IRIS, 1989)
Rat/M+F
Absence of general
toxicity
1 x 10"1
NOAEL
423
3000
Hagan et al. (1967)
Subchronic p-RfC
(mg/m3)
None
None
None
None
None
None
None
Chronic p-RfC (mg/m3)
None
None
None
None
None
None
None
aAll the reference values obtained from IRIS are indicated with latest review date.
Table 5. Summary of Cancer Values for Acetophenone (CASRN 98-86-2)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
None
None
None
p-IUR
None
None
None
None
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Derivation of Chronic RfD
IRIS (U.S. EPA, 1989) reported an RfD of 0.1 mg/kg-day, based on the lack of effects on
growth, hematology, or macroscopic tissue changes in male and female Osborne-Mendel rats
exposed to 0-, 1000-, 2500-, or 10,000-ppm acetophenone (equivalent to 0, 42, 106, and
423 mg/kg-day, respectively) in the diet for 17 weeks (Hagan et al., 1967) and an uncertainty
factor of 3000. Subsequent to the IRIS posting, additional relevant studies have been reported.
These studies are summarized in this PPRTV document.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No subchronic or chronic p-RfC values can be derived because no adequate,
well-described studies are available.
Limited information is available regarding the effects of acetophenone by the inhalation
route of exposure in humans or animals. The only human studies available were acute exposure
study and were not adequately described. Limited information such as histopathology of the
olfactory bulb and avoidance reactions in rats is reported in the Dalland and D0ving (1981).
Similarly, the Pinching and D0ving (1974) study includes only the histopathology of the
olfactory bulb. While the study by Imasheva (1966) measured more endpoints, including clinical
signs and body weight, no data were provided for these endpoints. The lack of experimental
details, specifics of the protocol used, and description of instrumentation of the study by
Imasheva (1966) precludes the use of this study for the derivation of inhalation toxicity values.
Although chronaxie, the principal endpoint reported in this study, was used to estimate the
relative excitability of muscles in the clinical setting, results from the method are acknowledged
to be difficult to reproduce for technical reasons (Oka and Miyajima, 2002; Geddes, 2004). The
strength-duration curves of the muscle response used to estimate chronaxie and the chronaxie
ratio are difficult to generate primarily due to the individual characteristics of the test subjects
and, historically, to the subjective visual detection of the start of muscle vibration. Other
deficiencies within the study are the lack of any descriptions of the standardization of response
judging, as well as no indication that the measurements were made in an unbiased manner.
These may be substantial confounding factors for any dose-response relationship and are
considered sufficient to preclude the use of this study for the purposes of deriving a provisional
value. In addition, the findings of altered levels of cholinesterase activity are limited in their
interpretation only as a biomarker of exposure (criteria stated in Guidelines for Neurotoxicity
Risk Assessment, U.S. EPA, 1998). Although an oral study (ATF, 2003) did report alterations in
salivation, which may be an autonomic effect mediated by cholinesterase activity, it was
transient in nature and occurred at a low incidence at doses much higher than the concentration
used by Imasheva (1966).
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
IRIS provides a cancer WOE descriptor of Classification D (i.e., "Inadequate Information
to Assess Carcinogenic Potential') (U.S. EPA, 1989).
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The available data do not support derivation of quantitative estimates for either oral
(p-OSF) or inhalation (p-IUR) exposure.
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APPENDIX A: PROVISIONAL SCREENING VALUES
For the reasons noted in the main document, it is inappropriate to derive a provisional
subchronic p-RfD for acetophenone. However, information is available which, although
insufficient to support derivation of a provisional toxicity value under current guidelines, may be
of limited use to risk assessors. In such cases, the Superfund Health Risk Technical Support
Center summarizes available information in 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 document. Users
of screening toxicity values in a supplement to a PPRTV assessment should understand that there
is considerably more uncertainty associated with the derivation of a supplement 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 Heath Risk
Technical Support Center.
DERIVATION OF SCREENING PROVISIONAL ORAL REFERENCE DOSES
The study by ATF (2003) is selected as the principal study for derivation of the screening
subchronic p-RfD. The critical endpoints are decreased mean forelimb grip strength and motor
activity in male rats, decreased live birth index (i.e., increase in the number of stillborn pups),
decreased number of F1 pups surviving to LD 4, and decreased pup body weight. All these
effects occurred at the same dose (i.e., 750 mg/kg-day), but because the individual data were not
available, BMD modeling could not be conducted; as such the critical effects are grouped
together with a POD of 750 mg/kg-day. This study is a proprietary study (ATF, 2003) and has
not been peer reviewed, but appears to follow OECD Guideline No. 422, meets the standards of
study design and performance, and was GLP compliant. Details are provided in the "Review of
Potentially Relevant Data" section. Benchmark dose (BMD) analysis is not possible because no
summary or individual data are available for review. Among the available, acceptable studies,
this study represents the lowest POD for developing a subchronic p-RfD.
The POD in this study is a NOAEL of 225 mg/kg-day.
No dosimetric adjustments are made because the doses in the principal study were
administered via gavage in mg/kg-day, 7 days a week, for the study duration, and no animal-to-
human body-weight adjustment is used for oral noncancer assessments.
The screening subchronic p-RfD for acetophenone, based on a POD of 225 mg/kg-day in
male and female rats, is derived as follows:
Screening Subchronic p-RfD = NOAELadj UF
= 225 mg/kg-day -^300
= 8 x 10"1 mg/kg-day
Table A. 1 summarizes the uncertainty factors for the screening subchronic p-RfD for
acetophenone.
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Table A.l. Uncertainty Factors for Screening Subchronic p-RfD of Acetophenone"
UF
Value
Justification
UFa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential
toxicokinetic and toxicodynamic differences between rats and humans. There
are no data to determine whether humans are more or less sensitive than rats to
the general toxicity of acetophenone.
UFd
3
A UFd of 3 is selected because the database includes one acceptable
developmental study in rats (ATF, 2003) but no acceptable two-generation
reproduction studies.
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 has been developed using a NOAEL.
UFS
1
A UFS of 1 is applied because a sub chronic-duration study (ATF, 2003) was
utilized as the principal study.
UFC
<3000
300

aATF (2003).
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APPENDIX B: DATA TABLES
There are no data available from the principal studies to present in tables.
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APPENDIX C: BMD MODELING OUTPUTS FOR ACETOPHENONE
There are no BMD modeling outputs for acetophenone.
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APPENDIX D: REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). (2011) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service.
Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed February 3, 2011.
BIBRA (BIBRA Working Group). (1991) Toxicity profile: acetophenone. BIBRA Toxicology
Advise and Consulting, England. HERO ID 201679.
CalEPA (California Environmental Protection Agency). (2008) All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as on December 18, 2008. Air Toxicology and
Epidemiology, Office of Environmental Health Hazard Assessment, Sacramento, CA. Available
online at http://www.oehha.ca.gov/air/chronic_rels/AllChrels.html. Accessed December 14,
2009.
Curvall, M; Jansson, T; Pettersson, B; et al. (1985) In-vitro studies of biological effects of
cigarette smoke condensate 1. Genotoxic and cytotoxic effects of neutral semivolatile
constituents. Mutat Res 157(2-3): 169-180. HERO ID 201681.
Dalland, T; D0ving, KB. (1981) Reaction to olfactory stimuli in odor-exposed rats. Behav
Neural Biol 32:79-88. HERO ID 201682.
Elliger, CA; Henika, PR; Macgregor, JT. (1984) Mutagenicity of flavones, chromones and
acetophenones in Salmonella typhimurium: New structure-activity relationships. Mutat Res
135(2):77- 86. HERO ID 201686.
Geddes, LA. (2004) Accuracy limitations of chronaxie values. IEEE Trans BiomedEng 51:
176-181. HERO ID 644164.
Hagan, EC; Hansen, WH; Fitzhugh, OG; et al. (1967) Food flavourings and compounds of
related structure. II. Subacute and chronic toxicity. FoodCosmet Toxicol 5(2): 141-157.
HERO ID 399321.
IARC (International Agency for Research on Cancer). (2009) IARC Monographs on the
evaluation of carcinogenic risks to humans. Available online at
http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed December 14, 2009.
HERO ID 201837.
Imasheva, NB. (1966). Threshold acetophenone concentrations determined by acute and
chronic experimental inhalation. In: USSR Literature on Air Pollution and Related Occupational
Diseases, A Survey by B.S. Levine. Washington, DC, U.S. Dept. of Commerce. Volume 16,
Book 29, pp. 58-68. Original publication in Meditisina. (Russian). Translation was provided
by Levine, BS as part of the survey. HERO ID 201694.
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NIOSH (National Institute for Occupational Safety and Health). (2009) NIOSH (National
Institute for Occupational Safety and Health). (2005) NIOSH pocket guide to chemical hazards.
Index of Chemical Abstracts Service Registry Numbers (CAS No.). Atlanta, GA: Center for
Disease Control and Prevention, U.S. Department of Health, Education and Welfare. Available
online at http://www.cdc.gov/niosh/npg/npgdcas.html. Accessed on December 14, 2009. HERO
ID 081445.
Nohmi, T; Miyata, R; Yoshikawa, K; et al. (1985) Mutagenicity tests on organic chemical
contaminants in city water and related compounds I. Bacterial mutagenicity tests (Japanese).
Bull Natl Inst Hyg Sci (Tokyo) 103:60-64. HERO ID 201730.
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at
http://ntp-server.ni ehs. nih.gov/index. cfm?objectid=3 2BA9724-F1F6-975E-
7FCE50709CB4C932. Accessed December 14, 2009. HERO ID 093207.
Oka, H; Miyajima, T. (2002) Development of chronaxie measurement system based on muscle
vibration. Biomechanisms (Japan Baiomekanizumu) 16:37-46. HERO ID 644162.
OSHA (Occupational Safety and Health Administration). (2009) Air contaminants:
occupational safety and health standards for shipyard employment, subpart Z, toxic and
hazardous substances. U.S. Department of Labor, Washington, DC. OSHA Standard
1915.1000. Available online at
http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=102
86. Accessed on December 14, 2009. HERO ID 625691.
Pinching, AJ; D0ving, KB. (1974) Selective degeneration in the rat olfactory bulb following
exposure to different odours. Brain Research 82(2): 195-204. HERO ID 377971.
Sofuni, T; Hayashi, M; Matsuoka, A; et al. (1985) Mutagenicity tests on organic chemical
contaminants in city water and related compounds. II. Chromosome aberration tests in cultured
mammalian cells. Bull Natl Inst Hyg Sci (Tokyo) 0(103):64-75. HERO ID 201741.
U.S. EPA (Environmental Protection Agency). (1986) Guidelines for carcinogen risk
assessment. Risk Assessment Forum, Washington, DC; EPA/630/R-00/004. September 1986.
Available online at http://epa.gov/raf/publications/pdfs/CA%20GUIDELINES_1986.PDF
HERO ID 199530.
U.S. EPA (Environmental Protection Agency). (1987) Health and environmental effects
document for acetophenone. U.S. Environmental Protection Agency, Cincinnati, OH;
PB91-216358. HERO ID 597098.
U.S. EPA (Environmental Protection Agency). (1989) Integrated Risk Information System
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