r^~ FINAL
ECAO-CIN-G001
500ECAOCING001
>EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR ACETOPHENONE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Region V, Library
230 South Dearborn Street
Chicago, Illinois 60604
DRAFT: DO NOT CITE OR QUOTE
NOTICE
document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Aqency poUcy. It is being circulated for comments
an Us technical accuracy and policy implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. A
carcinogenic potency factor, or q-\* (U.S. EPA, 1980), 1s provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazar-
dous substance for which notification 1s required 1n the event of a release
as specified under the CERCLA. These two. RQs (chronic toxldty and cardno-
genldty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer-based RQs are defined In U.S.
EPA, 1983 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Acetophenone 1s a colorless liquid with a sweet, pungent odor (Hawley,
1981) that 1s sparingly soluble (0.55 wt X at 20°C) 1n water (Papa and
Sherman, 1981). In 1981, 4.439 million pounds of acetophenone were produced
1n the United States by three manufacturers (USITC, 1982). Currently, five
companies have been cited as operating six U.S. production facilities for
this chemical (SRI, 1986). Acetophenone 1s used as a chemical Intermediate
for resins, Pharmaceuticals, corrosion Inhibitors and dyestuffs; as a
solvent for gums, resin dyestuffs and h1gh-melt1ng aromatic chemicals; as a
polymerization catalyst and photosensltlzer 1n organic synthesis; as a
flavoring agent for tobacco and in perfumery (Papa and Sherman, 1981;
Hindholz, 1983; Dorsky et al., 1963).
If acetophenone Is released to water, mlcroblal degradation and vola-
tilization are expected to be the major environmental fate and transport
processes. A number of blodegradatlon studies have shown that^acetophe-
none 1s significantly biodegradable (Ludzack and Ettlnger, 1963; Mills and
Stack, 1954; KharUonova and Sklovskaya, 1967; Urano and Kato, 1986; Dore et
al., 1975; Sasaki, 1978). The volatilization half-life from a river 1 m
deep flowing at 1 m/sec with a wind velocity of 3 m/sec was estimated to be
3.7 days. Hydrolysis, oxidation, adsorption to sediments and bloconcentra-
tlon are not expected to be significant. When acetophenone Is released to
the ambient atmosphere, reaction with photochemlcally-produced hydroxyl
radicals Is expected to be the dominant removal mechanism; the half-life for
this reaction has been estimated to be -2 days (U.S. EPA, 1987). In the
atmosphere, acetophenone will exist almost entirely 1n the vapor phase.
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If acetophenone 1s released to soil, m1crob1al degradation Is likely to be
the major degradation process. Based on various adsorption studies (Hassett
et al., 1980; Brlggs, 1981; Gerstl and Mlngelgrln, 1984; Southworth and
Keller, 1986), acetophenone 1s expected to be mobile In soil and susceptible
to significant leaching. Acetophenone 1s also expected to evaporate from
dry soil surfaces,
Acetophenone occurs naturally 1n various plant oils, In the buds of
balsam poplar and 1n Concord grapes (Dorsky et al., 1963; Nicholas, 1973).
It has been detected 1n drinking waters, surface waters, groundwaters and
waste effluent waters (see Table 3-1). The presence of acetophenone 1n
environmental waters Is most likely the result of discharges from Industrial
sources. Based on various U.S. ambient air monitoring data of urban/
suburban areas, an average dally Inhalation Intake of 4.6 jig has been
estimated (Brodzlnsky and Singh, 1982). Acetophenone 1s emitted to the
atmosphere In automobile and dlesel exhausts (Graedel, 1978; Hampton et al.,
1982), 1n stack effluents from waste Incineration (3ames et al., 1984) and
by vaporization from perfumes (Abrams et al., 1975). Data were Insufficient
to estimate the dally human exposure to this compound from 1ngest1on of
foods and drinking water.
The only available data concerning toxlclty of acetophenone to aquatic
organisms were 96-hour IC™ values of 155 and 162 mg/i for fathead
minnows, Plmephales promelas (Brooke et al., 1984; Hattson et al., 1976).
Although quantitative data concerning absorption were not available,
metabolism and toxlclty data Indicate that acetophenone Is absorbed by both
the gastrointestinal and respiratory tracts. Studies using rabbits Indicate
that acetophenone Is metabolized to (-)l-phenylethanol, which 1s excreted In
the urine as glucuronlde and sulfate conjugates (Smith et al., 1954; K1ese
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and Lenk, 1974). Other metabolUes of acetophenone excreted In the urine
are p-, m- and «-hydroxyacetophenone, mandellc add and MppuMc acid
(K1ese and Lenk, 1974).
The tox1c1ty of acetophenone has not been well studied. No studies
concerning the chronic toxlclty or carc1nogen1c1ty of acetophenone were
available. The subchronlc toxldty studies Indicate that acetophenone may
be more toxic following Inhalation exposure than oral, exposure. Pinching
and Dovlng (1974) found degeneration of olfactory bulbs 1n young rats
exposed continuously to 8.89 mg/ma for up to 3 months. This corresponds
to an uptake from air of 8.6 mg/kg/day (see Table 9-1). Imasheva (1965)
found changes In the ratio of chronaxles of antagonist muscle, a decrease In
the albumin/globulin ratio, congestion of cardiac vessels and dystrophy of
the Hver In rats exposed to acetophenone continuously at 0.07 mg/m* for
70 days. This corresponds to Intake from air of 0.045 mg/kg/day. No
effects were found at 0.007 mg/ma. In contrast, no effects were noted 1n
rats fed acetophenone In the diet at levels up to 8450 ppm for 17 weeks
(Hagan et al., 1967) or 1n rats treated at dietary levels that provided up
to 102 mg/kg/day for 30 days (Smyth, 1946).
Reported oral ID™ values of acetophenone 1n rats range from 0.9-3.2
g/kg (see Table 6-1), while the median lethal concentration of acetophenone
1n air for mice 1n a 4-hour exposure was 1.2 mg/l (Ovchagov, 1964). This
corresponds to the Intake from air of 127 mg/kg.
The only reproductive study available was a skin application study In
which no effects on reproduction or development were noted 1n rats treated
with acetophenone at 0.48 g/kg on gestation days 10-15 (Lagno and
BakhH1z1na, 1969).
v1
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Acetophenone tested negative In a reverse mutation assay (ElUger et
al., 1984), but did cause DNA chain breaks after photosensHlzatlon (Rahn et
al., 1974). The toxlcologlcal significance of the photosensHlzatlon study
Is uncertain.
A subchronlc Inhalation RfD of 0.0002 mg/m3 or 0.003 nig/day, and a
chronic Inhalation RfD of 0.00002 mg/m3 or 0.0003 mg/day were derived from
a continuous exposure of 0.007 mg/m3 for 70 days In rats, using
uncertainty factors of 100 and 1000. At 0.07 mg/m3, rats had congestion
of cardiac vessels and liver dystrophy (Imasheva, 1966). Low confidence was
placed 1n the RfDs because of Inadequate reporting and lack of supporting
data.
A subchronlc oral RfD of 5 mg/kg/day or 300 mg/day and a chronic oral
RfD of 0.5 mg/kg/day or 35 mg/day were derived from a dietary NOEL of 10,000
ppm (500 mg/kg/day) In rats for 17 weeks. This was the highest dose tested
1n the study by Hagan et al. (1967). Therefore, there was no LOAEL.
Uncertainty factors of 100 for the subchronlc RfD and 1000 for the chronic
RfD were used. Low confidence was placed 1n these RfDs because the study
did not define an effect level, the NOEL was -50% of the oral LD,. for
rats and supporting data were lacking.
An RQ of 100 based on chronic toxlclty was derived from the subchronlc
Inhalation study by Imasheva (1966).
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. Photolysis 5
2.2.4. M1crob1al Degradation 6
2.2.5. Volatilization .- 6
2.2.6. Adsorption 7
2.2.7. Bloconcentratlon 7
2.3. SOIL 7
2.3.1. M1crob1al Degradation 7
2.3.2. Chemical Degradation 7
2.3.3. Adsorption/Leaching 8
2.3.4. Volatilization 8
2.4. SUMMARY 8
3. EXPOSURE 10
3.1. WATER 10
3.2. FOOD 10
3.3. INHALATION 13
3.4. DERMAL 13
3.5. SUMMARY '. 13
4. AQUATIC TOXICITY 15
4.1. ACUTE TOXICITY 15
4.2. CHRONIC EFFECTS 15
4.3. PLANT EFFECTS 15
4.4. SUMMARY 15
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TABLE OF CONTENTS (cont.)
Page
5. PHARHACOKINETCS 16
5.1. ABSORPTION 16
5.2. DISTRIBUTION 16
5.3. METABOLISM 16
5.4. EXCRETION 18
5.5. SUMMARY 19
6. EFFECTS 20
6.1. SYSTEMIC TOXICITY 20
6.1.1. Inhalation Exposures 20
6.1.2. Oral Exposures 21
6.1.3. Other Relevant Information 22
6.2. CARCINOGENICITY 23
6.3. MUTAGENICITY 23
6.4. TERATOGENICITY 23
6.5. OTHER REPRODUCTIVE EFFECTS 25
6.6. SUMMARY 25
7. EXISTING GUIDELINES AND STANDARDS 27
7.1. HUMAN 27
7.2. AQUATIC 27
8. RISK ASSESSMENT 28
8.1. CARCINOGENICITY 28
8.1.1. All Routes 28
8.1.2. Weight of Evidence 28
8.1.3. Quantitative Risk Assessment 28
8.2. SYSTEMIC TOXICITY 28
8.2.1. Inhalation Exposure 28
8.2.2. Oral Exposure 29
9. REPORTABLE QUANTITIES 31
9.1. BASED ON SYSTEMIC TOXICITY 31
9.2. BASED ON CARCINOGENICITY 31
10. REFERENCES 35
APPENDIX A: LITERATURE SEARCHED 49
APPENDIX B: SUMMARY TABLE 52
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LIST OF TABLES
No. Title Page
1-1 Current U.S. Manufacturers of Acetophenone 3
3-1 Water Monitoring Data for Acetophenone 11
6-1 Acute Oral Toxldty of Acetophenone 24
9-1 Toxldty Summary for Acetophenone 32
9-2 Inhalation Composite Scores for Acetophenone
Using the Rat 33
9-3 Acetophenone: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 34
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
BOD Biochemical oxygen demand
BOOT Biochemical oxygen demand, theoretical
CAS Chemical Abstract Service
CS Composite score
DNA Deoxyr1bonucle1c add
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kom Sorptlon coefficient standardized
with respect to soil organic matter
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppb Parts per billion
ppm Parts per million
ppt Parts per thousand
RfD Reference dose
RQ Reportable quantity
RV0- Dose-rating value
RVe Effect-rating value
UV Ultraviolet
US Water solubility
x1
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Acetophenone 1s the common chemical name, but this compound 1s also
known as 1-phenylethanone, phenyl methyl ketone, acetylbenzene and hypnone
(Wlndholz, 1983). The structure, molecular weight, empirical formula and
CAS Registry number for acetophenone are as follows:
0 = C - CH3
o
Molecular weight: 120.15
Empirical formula: CgHgO
CAS Registry number: 98-86-2
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Acetophenone 1s a colorless liquid with a sweet, pungent odor and taste
(Hawley, 1981). It 1s freely soluble In alcohol, chloroform, ether, fatty
oils and glycerol (Hlndholz, 1983). Selected physical properties are listed
below:
Melting point:
Boiling point:
Specific gravity:
Refractive Index (20°C):
Water solubility:
at 20°C
Vapor pressure:
at 25°C
at 37.1°C
Log Kow:
Flash point:
A1r conversion factor:
(20eC)
20.5°C
201.7*C
1.0296 (20/20°C)
1.5342
0.55 wt %
(5500 mg/l)
0.372 mm Hg
1.0 mm Hg
1.58
82°C (closed cup)
93°C (open cup)
1 mg/m3 =0.20 ppm
Wlndholz, 1983
Papa and Sherman, 1981
Papa and Sherman, 1981
Papa and Sherman, 1981
Papa and Sherman, 1981
H1ne and Mookerjee, 1975
Perry and Green, 1984
Hansch and Leo, 1985
Papa and Sherman, 1981
Papa and Sherman, 1981
Verschueren, 1983
0001 d
03/23/87
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The chemical reactions of acetophenone are typical of alkyl aryl ketones
(Dorsky et al., 1963). These reactions Include addition and condensation at
the carbonyl group, nuclear substitution and side-chain substitution.
Acetophenone Is combustible {Hawley, 1981).
1.3. PRODUCTION DATA
In 1981, 4.439 million pounds of acetophenone were produced 1n the
United States by three manufacturers (USITC, 1982); this Is the most recent
production figure available. In 1983, 0.733 million pounds of acetophenone
were Imported Into the United States through principal customs districts
(USITC, 1982).
Table 1-1 lists current U.S. manufacturers of acetophenone. Acetophe-
none can be manufactured by the oxidation of ethylbenzene or obtained as a
by-product from the production of phenol using cumene oxidation (Hawley,
1981; Dorsky et al., 1963). In addition, acetophenone 1s produced as an
Intermediate by-product during the production of propylene oxide using the
hydroperoxlde process; however, this acetophenone Is recycled and not
Isolated as an end-product (K1rk and Dempsey, 1982).
1.4. USE DATA
Acetophenone Is used as a chemical Intermediate for resins, pharmaceutl-
cals, corrosion Inhibitors and dyestuffs; as a perfume base for bath soaps;
and as a solvent for gums, resin dyestuffs and high-melting aromatic chemi-
cals (Papa and Sherman, 1981). It 1s also used 1n perfumery, 1n organic
synthesis as a photosens1t1zer, as a polymerization catalyst and as a
flavoring agent for tobacco (Wlndholz, 1983; Dorsky et al., 1963). A
percentage breakdown for each Individual use was not available.
0001d -2- - 04/23/87
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TABLE 1-1
Current U.S. Manufacturers of Acetophenone*
Manufacturer
Location
Allied-Signal, Inc. (Allied Corp)
Atlantic Richfield Co.
ARCO Specialty Chem.
Lyondell Petrochem.
Georgia Gulf Corp.
G1vaud1an Corp.
Texaco Inc.
Frankford, PA
West Chester, PA
Channelview, TX
Bound Brook, NJ
Clifton, N3
El Dorado, KS
*Source: SRI, 1986
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1.5. SUMMARY
Acetophenone 1s a colorless liquid with a sweet, pungent odor (Hawley,
1981) that 1s sparingly soluble (0.55 wt X at 20°C) 1n water (Papa and
Sherman, 1981). In 1981, 4.439 million pounds of acetophenone were produced
1n the United States by three manufacturers (USITC, 1982). Currently, five
companies have been cited as operating six U.S. production facilities for
this chemical (SRI, 1986). Acetophenone 1s used as a chemical Intermediate
for resins, Pharmaceuticals, corrosion Inhibitors and dyestuffs; as a
solvent for gums, resin dyestuffs and high-melting aromatic chemicals; as a
polymerization catalyst and photosensltlzer 1n organic synthesis; as a
flavoring agent for tobacco and 1n perfumery (Papa and Sherman, 1981;
Wlndholz, 1983; Dorsky et al., 1963).
OOOld - -4- - 03/23/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Reaction with photochemlcally-produced hydroxyl radicals 1s expected to
be the dominant removal mechanism for acetophenone 1n the ambient atmo-
sphere. The half-life for this reaction 1s estimated to be ~2 days and Is
based on an average atmospheric hydroxyl radical concentration of 8x10*
molecules/cm3 and an estimated rate constant at 25°C of 5xlO~12
cmVmolecule-sec (U.S. EPA, 1987).
Based on Us relatively high vapor pressure (E1senre1ch et al., 1981),
acetophenone 1s expected to exist almost entirely In the vapor phase In the
atmosphere.
2.2. HATER
2.2.1. Hydrolysis. Since ketones, 1n general, are resistant to hydroly-
sis, this process Is not expected to be Important for acetophenone degrada-
tion 1n aquatic environment (Lyman et al., 1982; Lande et al., 1976).
2.2.2. Oxidation. The rate constant for the reaction of acetophenone
with hydroxyl radicals In water at room temperature was ~2.9-5.4xl09
M"1- sec"1 (Anbar and Neta, 1967; Dorfman and Adams, 1973). Given the
assumption that natural waters have an average hydroxyl radical
concentration of 10"17 M (Mill et al., 1980), a minimum half-life of 149
days can be estimated from the rate constant data. Therefore, the oxidation
reaction will not be Important 1n water.
2.2.3. Photolysis. Acetophenone absorbs UV light significantly 1n the
environmentally Important range of >290 nm (Draper and Crosby, 1983), which
Indicates a potential for direct photolysis In the environment. Irradiation
of an aqueous solution of acetophenone with UV light >285 nm was shown to
OOOId -5- 05/21/87
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produce superoxlde species, while no superoxlde was formed In dark controls
(Draper and Crosby, 1983); however, kinetics of the potential photoaltera-
tlons of aqueous acetophenone were not provided. Acetophenone can act as a
photosensltlzer whereby H transfers Us excited state energy (obtained from
UV light absorption) to a receptor molecule, and the receptor molecule
undergoes alteration. The end result for the excited acetophenone Is Us
return to the ground state without any photochemical alterations (Lande et
a!., .1976).
2.2.4. M1crob1al Degradation. Ludzack and Ettlnger (1963) studied the
blodegradatlon of acetophenone In Ohio River water. B1o-ox1dat1on had a lag
time of -3 days and was followed by rapid carbon dioxide production. About
half of the theoretical yield of carbon dioxide was recovered 1n 6 days
following the first dose and 3 days following the second dose.
Several BOD studies found acetophenone to be significantly biodegrad-
able. Mills and Stack (1954) measured a 10-day BOOT of 56%, using a sewage
seed, while Kharltonova and Sklovskaya (1967) measured a 5-day BOOT of
46.1%. Urano and Kato (1986) determined a 10-day BOOT of -90% with
activated sludge, using an electrolytic resplrometer method and noted that
ketones, 1n general, are changed Into carboxyllc adds by b1o-ox1dat1on.
Dore et al. (1975) reported a 5-day BOOT of 32% using three polluted surface
waters as Inoculum. The Japanese blodegradabllUy tests show acetophenone
to be significantly biodegradable (Sasaki, 1978).
These data Indicate that blodegradatlon 1s likely to be an Important,
and potentially dominant, removal process for acetophenone In water.
2.2.5. Volatilization. The Henry's Law constant for acetophenone was
determined to be -0.000011 atm-mVmol at 25°C (Hackay et al., 1982; Hlne
0001d -6- 05/21/87
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and Mookerjee, 1975). Using Henry's Law constant, the volatilization
half-life from a river 1 m deep flowing at 1 m/sec with a wind velocity of 3
ra/sec 1s estimated to be "3.7 days, using the method outlined 1n Lyman et
al. (1982). Volatilization from rivers or other bodies of water deeper than
1 m and flowing at a speed <1 m/sec will be slower.
2.2.6. Adsorption. Based on the adsorption to soils and sediments data
(Section 2.3.3.), acetophenone Is not expected to partition significantly
from the water column to aquatic sediment; however, acetophenone has been
detected 1n river bed sediment In a region of heavy Industrial discharge
(Stelnhelmer et al., 1981).
2.2.7. B1oconcentrat1on. The BCF of an organic compound can be estimated
from the following two recommended regression equations (Lyman et al., 1982):
log BCF * 0.76 log KQW - 0.23 (2-1)
log BCF = 2.791 - 0.564 log WS (ppm) (2-2)
Based on a log^K of 1.58 and a WS of 5500 ppm for acetophenone (see
Section 1.2.), the BCF values estimated from Equations 2-1 and 2-2 are 9 and
5, respectively. These BCF values Indicate that bloconcentratlon 1n aquatic
organisms 1s not expected to be significant.
2.3. SOIL
2.3.1. Mlcroblal Degradation. Experimental soil studies were not found;
however, mlcroblal degradation data (see Section 2.2.4.) suggest that
significant blodegradatlon of acetophenone 1s likely to occur In soil.
2.3.2. Chemical Degradation. Pertinent data regarding the chemical
degradation of acetophenone 1n soil could not be located 1n the reviewed
literature and data bases as cited 1n Appendix A. Based on water-related
data, hydrolysis and oxidation are not expected to be significant.
Therefore, mlcroblal degradation 1s likely to be the major degradation
process 1n soil.
OOOld -7- . , 05/21/87
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2.3.3. Adsorption/Leaching. The adsorption of acetophenone by soils has
been studied by several Investigators. Hassett et al. (1980) determined
K values of 22-95 In 14 soils and sediments collected from Ohio,
oc
Missouri, Mississippi and Illinois rivers and their watersheds with organic
carbon contents ranging from 0.11-2.38%. BMggs (1981) measured a Freund-
Hch adsorption coefficient of 0.42 for an Australian soil of 1.09% organic
matter content, which corresponds to a K value of 66. Gerstl and
Mlngelgrln (1984) determined- an average K value of 21.9 (corresponds to
On)
a K of 37.8) for 12 soils and sediments with organic matter content
ranging from 0.11-7.85%. Southworth and Keller (1986) determined KQC
values of 105-270 for three soils from West Virginia and Tennessee.
K values <150 Indicate high soil mobility, while values between 150
and 500 Indicate medium soil mobility (Swann et al., 1983). Therefore,
acetophenone Is expected to be mobile 1n soil and susceptible to significant
leaching.
2.3.4. Volatilization. The vapor pressure of acetophenone (0.372 mm Hg
at 25°C) suggests that evaporation from dry surfaces may occur; however, the
relative significance of volatilization from moist soils Is not clear.
2.4. SUMMARY
If acetophenone 1s released to water, mlcroblal degradation and
volatilization are expected to be the major environmental fate and transport
*
processes. A number of blodegradatlon studies have shown that acetophenone
c
1s significantly biodegradable (Ludzack and Ettlnger, 1963; Mills and Stack,
1954; Kharltonova and Sklovskaya, 1967; Urano and Kato, 1986; Oore et al.,
1975; Sasaki, 1978). The volatilization half-life from a river 1 m deep
flowing at 1 m/sec with a wind velocity of 3 m/sec was estimated to be
QQOld . -8- - - 05/21/87
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3.7 days. Hydrolysis, oxidation, adsorption to sediments and bloconcentra-
tlon are not expected to be significant. If acetophenone Is released to the
ambient atmosphere, reaction with photochemically-produced hydroxyl radicals
Is expected to be the dominant removal mechanism; the half-life for this
reaction has been estimated to be -2 days (U.S. EPA, 1987). In the atmo-
sphere, acetophenone will exist almost entirely 1n the vapor phase. If
acetophenone 1s released to soil, mlcroblal degradation Is likely to be the
major degradation process. Based on various adsorption studies (Hassett et
al., 1980; Brlggs, 1981; Gerstl and Mlngelgrln, 1984; Southworth and Keller,
1986), acetophenone Is expected to be mobile 1n soil and susceptible to
*
significant leaching. Acetophenone Is expected to evaporate from dry soil
surfaces.
0001d -9- . . 04/23/87
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3. EXPOSURE
Acetophenone occurs naturally In oil of castoreum, oil of labdanum resin
and oil of St1rl1nq1a Iat1fo11a. In the buds of balsam poplar (Dorsky et
a!., 1963), and 1n Concord grape essence (Nicholas, 1973). The heavy-oil
fraction of coal tar contains small amounts of acetophenone (Dorsky et al.,
1963).
3.1. HATER
Table 3-1 lists various water monitoring data for acetophenone. Aceto-
phenone has been detected 1n drinking water, surface and groundwaters, and
waste effluent waters. The data for drinking water are Insufficient to
accurately estimate an average dally Intake for humans. The U.S. EPA STORET
Data Base contains 13 reported observations for acetophenone, with maximum
and minimum concentrations of 72 and 1 ppb, respectively, and a mean concen-
tration of 11.3 ppb (U.S. EPA, 1986b).
The presence »f acetophenone 1n the various environmental waters report-
ed 1n Table 3-1 1s most likely the result of discharges from Industrial
sources. Abrams et al. (1975) suggested that acetophenone could also be
formed 1n groundwaters or drinking waters by the decomposition of phenyl
methyl carblnol.
3.2. FOOD
Limited food monitoring data regarding acetophenone were located.
Acetophenone was 1 of 187 organic compounds detected 1n roasted filbert nut
volatHes (Klnlln et al., 1972). Pell1zzar1 et al. (1982) detected aceto-
phenone 1n 8/8 mother's milk samples collected from volunteers In Bridge-
vine, PA, Bayonne and Jersey City, NJ, and Baton Rouge, LA.
OOOld - -10- ' ' 04/23/87
-------
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3.3. INHALATION
Brodzlnsky and Singh (1982) compiled various U.S. ambient air monitoring
data pertaining to acetophenone. Seven air samples from rural/remote areas
contained no acetophenone, three samples from urban/suburban areas contained
a mean concentration of 46 ppt and 66 samples from source dominated areas
contained a mean concentration 750 ppt. Smeyers-Verbeke et al. (1984)
detected acetophenone 1n the ambient air of Delft, Netherlands.
Assuming an average acetophenone concentration of 46 ppt (0.230
yg/m3) 1n a typical urban/suburban atmosphere, an average dally Intake
of 4.6 vg can be calculated assuming a dally Intake of 20 m* of air.
Acetophenone 1s released to the atmosphere 1n automobile and dlesel
exhausts, and 1n plant volatile* (Hampton et al., 1982; Graedel, 1978). In
addition, 1t has been detected as a combustion product of waste Incineration
(Games' et al., 1984) and may therefore be present 1n Incineration stack
effluents. Abrams et al. (1975) cited vaporization from perfumes as an
emission source.
3.4. DERMAL
Pertinent data regarding the monitoring of dermal exposure to acetophe-
none could not be located 1n the available literature as cited In Appendix A.
3.5. SUMMARY
Acetophenone occurs naturally In various plant oils. 1n the buds of
balsam poplar and 1n Concord grapes (Dorsky et al., 1963; Nicholas, 1973).
It has been detected 1n drinking waters, surface waters, groundwaters and
waste effluent waters (see Table 3-1). The presence of acetophenone 1n
environmental waters Is most likely the result of discharges from Industrial
0001d * -13- ' - 04/23/87
-------
sources. Based on various U.S. ambient air monitoring data of urban/
suburban areas (Brodzlnsky and Singh, 1982), an average dally Inhalation
Intake of 4.6 yg has been estimated. Acetophenone Is emitted to the
atmosphere In automobile and dlesel exhausts (Graedel, 1978; Hampton et al.,
1982), 1n stack effluents from waste Incineration (James et al., 1984) and
by vaporization from perfumes (Abrams et al., 1975). Data were Insufficient
to estimate the dally human exposure to this compound from 1ngest1on of
foods and drinking water.
0001d ' -14- " 04/23/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The only available data concerning the toxlclty of acetophenone to
aquatic organisms were 96-hour LC50 values of 155 and 162 mg/i for
fathead minnows, Plmephales promelas (Brooke et al., 1984; Mattson et al.,
1976).
4.2. CHRONIC EFFECTS
Pertinent data regarding the toxldty of acetophenone to aquatic organ-
Isms could not be located In the available literature as dted 1n Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding the toxlclty of acetophenone to aquatic plants
could not be located In the available literature as dted 1n Appendix A.
4.4. SUMMARY
The only available data concerning the toxlclty of acetophenone to
.aquatic organisms were 96-hour LC,.Q values of 155 and 162 mg/s. for
fathead minnows, Plmephales promelas {Brooke et al., 1984; Mattson et al.,
1976).
OOOld • -15- " " 05/21/87
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5. PHARMACOKINETICS
5.1. ABSORPTION
Quantitative data regarding the absorption of acetophenone could not be
located 1n the available literature as cited 1n Appendix A. An oral study
(Sections 5.3. and 5.4.) and an Inhalation study (Section 6.1.1.) resulting
1n systemic toxldty Indicate that acetophenone Is absorbed by the gastro-
intestinal and respiratory tracts.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of acetophenone could not be
located 1n the available literature as cited 1n Appendix A.
5.3. METABOLISM
Smith et al. (1954) examined the urinary metabolites of acetophenone 1n
chinchilla rabbits treated by gavage with acetophenone 1n water, and found
that acetophenone was metabolized to (-)l-phenylethanol glucuronlde and the
sulfate.
K1ese and Lenk (1974) also examined the metabolism of acetophenone In
rabbits. Male rabbits were Injected 1ntraper1toneally with a total of
5.36 g of acetophenone, and the urine was collected for 48 hours and
examined for metabolites both before and after Incubation with glu-
curonldase. The urinary metabolites Identified were (-)l-phenylethanol and
w-hydroxyacetophenone. About half of the 1-phenylethanol was excreted
unconjugated, while the remaining was Identified following Incubation with
glucuronldase. p-Hydroxyacetophenone, m-hydroxyacetophenone and phenols
were also Identified 1n the urine. Using these data and the data of
Thlerfelder and Dalber (1923) and Thlerfelder and Klenk (1924), who found
hlppurlc add and mandellc add 1n the urine of rabbits treated with
acetophenone, K1ese and Lenk (1974) proposed the pathway presented In
Figure 5-1.
OOOld * -16- " 05/21/87
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COOH
CHOH
CH,
H-C-OH
on«9«-
o>id«tion
conjugation
n«ndtl1C
•Cid i-Z
R * Slucuronic or
sulfuric acid
FIGURE 5-1
Proposed Metabolic Pathway 1n the Rabbit
Souice: Klese and Lenk, 1974
0001 d
--17-
03/23/87
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Lelbman (1971) studied the metabolism of acetophenone 1n preparations of
rat and rabbit liver cytosol and mlcrosomes. He found that In the presence
of NAOPH, acetophenone was reduced to 1-phenylethanol. When NAOPH was
removed from the system, the amount of 1-phenylethanol was greatly decreased.
Studies using preparations from rabbit livers revealed that most of the
reducing activity was In the cytosol fraction rather than the mlcrosomes.
Acetophenone reducing activity, although not as great as 1n the liver, was
also found In cytosol preparations of rabbit kidney, heart and lung, but not
1n the brain. Lelbman (1971) also found that pretreatment of rats with
phenobarbltal did not affect the rate of acetophenone reduction by homo-
genates of the liver.
The enzymes Involved 1n the reduction of acetophenone are alcohol
dehydrogenase and aromatic aldehyde-ketone reductase (Lande et al., 1976).
An additional enzyme, <*,B-unsaturated ketone reductase, which 1s Involved
1n the reduction of other ketones, .was shown to be Inactive 1n the reduction
of acetophenone In vitro 1n a study using enzyme Isolated from dog erythro-
cytes and human liver (Fraser et al., 1967).
5.4. EXCRETION
Smith et al. (1954) found that -47X of an oral dose of acetophenone (450
mg/kg) administered to rabbits was excreted In the urine as (-)l-phenyl-
ethanol glucuronlde, while 3% was excreted as the sulfate. The excretion of
the glucuronlde was nearly complete 1 day after dosing.
Analysis of rabbit urine 48 hours after an 1ntraper1toneal Injection of
acetophenone revealed that -3.6% of the dose was excreted as 1-phenylethanol
(both free and conjugated), and -0.95% was excreted as w-hydroxyacetophe-
none (Kelse and Lenk, 1974). About 0.012* of the dose was recovered from
0001d * -18- " 03/23/87
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the urine as unmetabollzed acetophenone. Other urinary metabolites which
comprised <1% of the administered dose were p-hydroxyacetophenone,
m-hydroxyacetophenone and phenols, and -22-41% 1s hlppurlc add.
5.5. SUMMARY
Although quantitative data concerning absorption were not available,
metabolism and toxlclty data Indicate that acetophenone 1s absorbed by both
the gastrointestinal and respiratory tracts. Studies 1n rabbits Indicate
that acetophenone Is metabolized to (-)l-phenylethanol, which 1s excreted 1n
the urine as glucuronlde and sulfate conjugates (Smith et al., 1954; Klese
and Lenk, 1974). Other metabolites of acetophenone excreted 1n the urine
are p-, ra- and u-hydroxyacetophenone, mandellc add and hlppurlc add
(Klese and Lenk, 1974).
OOOld -19- 05/21/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC — Pinching and Dewing (1974) exposed groups of
four Hlstar rats (2 weeks of age at start of experiment) to acetophenone
vapor at 7.4xlO~8 M (8.89 mg/m3) continuously for periods varying from 1
week to 3 months. Similar groups of rats, exposed to filtered air, were
maintained as controls. The rats were sacrificed at -1, 2 or 3 months of
age and examined for degeneration of olfactory bulb cells. The results
showed that acetophenone exposure caused a specific pattern of degeneration
of olfactory bulb cells. The degeneration noted was principally a darkening
and shrinkage of cell bodies and did not Involve cell death. The patterns
of degeneration did not change with Increasing exposure period, but changes
were better defined and more marked after 2 months than at earlier periods.
No other parameters were examined.
In a Russian study (Imasheva, 1966), groups of 15 white male rats were
exposed continuously to acetophenone vapor at 0, 0.007 or 0.07 mg/m3 for
70 days. The behavior, body weights and chronaxy of antagonist muscles of
all rats were examined. In addition, chollnesterase activity and protein
fractions of the blood serum of five rats/group were examined. After the
exposure period, some of the rats (number unspecified) from each group were
sacrificed and hlstologlcal examinations of unspecified organs were made.
The results of the study revealed no changes In the parameters examined 1n
rats exposed to 0.007 mg/m3. Rats exposed to 0.07 mg/m* showed changes
1n the ratio of chronaxles of antagonist muscles and a decrease In the
albumin/globulin ratio of the blood, with no change 1n the amount of total
protein. Changes 1n chollnesterase activity were also observed In the high-
QOOld . -20- - - 05/21/87
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dose group but were Inconsistent; several rats showed a depression of
activity, while an Increase 1n activity was observed 1n one rat. H1sto-
pathologlcal examination of the high-dose rats revealed congestion of the
cardiac vessels and pronounced dystrophy of the "liver.
6.1.1.2. CHRONIC — Pertinent data regarding the chronic Inhalation
toxldty of acetophenone could not be located In the available literature as
cited 1n Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. ACUTE — Reported oral LD5Q values of acetophenone In rats
range from 0.9-3.2 g/kg (Table 6-1), while the median lethal concentration
of acetophenone 1n air for mice 1n a 4-hour exposure was 1.2 mg/i
(Ovchagov, 1964).
6.1.2.2. SUBCHRONIC — In a 30-day study, Smyth (1946) fed groups of
five male and five female albino rats acetophenone 1n the diet at levels of
0, 0.003, 0.0125, 0.05 or 0.2%. As determined by the author, these dietary
levels provided the rats with doses of 0, 1, 6, 25 or 102 mg/kg/day. The
acetophenone was added to the diet 1n lard. No dose-related changes were
noted 1n the amount of food eaten, growth, fatness, liver or kidney weights,
blood urea or mlcropathology of unspecified organs.
Hagan et al. (1967) fed groups of 10 male and 10 female weanling
Osborne-Mendel rats commercially-available acetophenone 1n the diet at 0,
1000, 2500 or 10,000 ppm (0, 50, 125, 500 mg/kg bw) for 17 weeks. During a
7-day period, -31% of the acetophenone was lost from the diet by
volatilization, so that the mean loss was -15.5%. Adjusting for the loss of
acetophenone, the mean weekly levels of acetophenone 1n the food, were 0,
845, 2113 or 8450 ppm. The results of the study revealed no
treatment-related effects. The parameters examined were body weight, organ
weights, hematology and macroscopic examinations at sacrifice.
OOOld -21- _ 05/21/87
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TABLE 6-1
Acute Oral Tox1c1ty of Acetophenone
Species
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Rabbit
Dose
(g/kg)
3.0
0.9
2.2
1.07
3.2
2.55
1.03
1.76
Dilution/Vehicle
NS
20% 1n 1%
Terg1tol*t
undiluted
propylene glycol
undiluted
undiluted
NS
NS
Mortality Data
H-day LDso
14-day LDso
14-day LQ$Q
14-day LDso
14-day LDso
14-day LDso
LD50
14-day LDso
Reference
Smyth and
Carpenter, 1944
Smyth, 1946
Hell on
Institute, 1956
Mellon
Institute, 1956
Jenner et a!.,
1964
Smyth et al.,
1969
E.I. Dupont
DeNemours and
Co., 1983
Mellon
Institute, 1956
tAn aqueous solution of 25% sodium 3,9-d1ethyl-6-tr1deconal sulfate used
as a dispersing agent.
NS = Not specified
0001 d
-22-
05/21/87
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Comprehensive microscopic examinations of 6-8 males and 6-8 females of the
high-dose and control groups also revealed no changes.
6.1.2.3. CHRONIC — Pertinent data regarding the chronic oral
toxlclty of acetophenone could not be located In the available literature as
cited 1n Appendix A.
6.1.3. Other Relevant Information. Smyth et al. (1969) studied the joint
toxic action of equal volumes of a number of chemicals by gavage 1n female
albino rats. When acetophenone was mixed with an equal volume of tetra-
chloroethylene or acetonltrlle the effect was more than additive, as deter-
mined by the ratios of the predicted to the observed LD5Q.
Abstracts of Russian studies describe Investigations of the toxldty of
acetophenone vapor 1n combination with benzene (Tsulaya, 1967), phenol
(Korneev, 1967) or acetone (Tkach, 1967). Rats exposed to benzene vapor at
0.9 mg/ma and acetophenone at 0.003 mg/m3 for 84 days showed no changes
1n muscular chronaxy, concentrations of nucleic adds 1n the blood, 17-keto-
sterolds In the urine or changes 1n leukocyte and erythrocyte counts
(Tsulaya, 1967). Korneev (1967) stated that a mixture of 0.00747 mg/m3
phenol and 0.00517 mg/m8 acetophenone affected visual acuity 1n humans,
while 0.00759 mg/m3 phenol and 0.00357 mg/m3 acetophenone had an effect
on cerebral potential. Animals (species unspecified) exposed to phenol at
0.0637 mg/m3 and acetophenone at 0.01732 mg/m3 showed changes In cholln-
esterase activity, motor muscle-antagonist chronaxy, pronounced eoslnopenla,
porphyMn metabolism and urine !7-ketostero1d content. Chronic continuous
exposure of rats to acetophenone and acetone at fractions of their olfactory
thresholds (thresholds * 1.096 mg/m3 acetone, 0.01 mg/m3 acetophenone)
resulted 1n "subordination of brain function to motor chronaxy of the muscle
antagonists, depressed blood chollnesterase activity. Increased urinary
OOOld . -23- - - 05/21/87
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coproporphyrln and !7-ketostero1ds and reduction of blood eoslnophlls"
(Tkach, 1967).
Imasheva (1966) exposed three human subjects to acetophenone to
determine the effect of exposure on light sensitivity of the eye. At 0.02
mg/m3, acetophenone caused a decrease 1n light sensitivity In all three
subjects, while acetophenone at 0.007 mg/m3 was Inactive.
Rats exposed to a mist of acetophenone at 21-24 mg/i (21,000-24,000
mg/m3) for 2 hours survived, but 6/6 rats died after 4 hours of exposure.
The deaths of these rats were attributed to anesthesia; the lungs, kidneys
and liver of these animals were congested (Smyth, 1946).
E.I. Dupont DeNemours and Co. (1983) and Smyth (1946) reported that six
rats exposed to acetophenone at 210 ppm (1032 mg/m3) for 8 hours survived
the exposure. Ovchagov (1964) stated that the median lethal concentration
of acetophenone for mice 1n a 4-hour exposure was 1.2 mg/l.
The acute oral toxlclty of acetophenone has been studied by a number of
Investigators. The toxldty values found are presented 1n Table 6-1.
6.2. CARCINOGENICITY
Pertinent data regarding the cardnogenlcHy of acetophenone could not
be located In the available literature as cited 1n Appendix A.
6.3. HUTAGENICITY
Acetophenone tested negative for reverse mutations In Salmonella
typh1mur1um strains TA100, TA98 and TA1537 both with and without rat S-9
metabolic activation 1n a plate Incorporation assay at levels up to 3000
nmol/plate (ElUger et a!., 1984).
Rahn et al. (1974) found that acetophenone caused ONA chain breaks 1n
DNA Isolated from EscheMchla coll strain B(3)T" after photosens1t1zat1on.
OOOld ' -24- • 05/21/87
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6.4. TERATOGENICITY
In a study by Lagno and Bakht1z1na (1969), summarized by Krasavage et
al. (1982), acetophenone applied to the skin of pregnant rats at 0.48 mg/kg
on gestation days 10-15 did not result 1.n any changes 1n the gestation
period, size of Utters, weight of offspring, or time of appearance of hair
or teeth, opening of eyes, or the appearance of reflexes.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of acetophenone
could not be located In the available literature as cited In Appendix A.
6.6. SUMMARY
The toxlclty of acetophenone has not been well studied. No studies
concerning the chronic toxlclty or carclnogenlclty of acetophenone were
available. The subchronlc toxldty studies Indicate that acetophenone may
be more toxic following Inhalation exposure than oral exposure. Pinching
and Oovlng (1974) found degeneration of olfactory bulbs 1n young rats
exposed continuously to 8.89 mg/ma for up to 3 months. Imasheva (1966)
found changes 1n the ratio of chronaxles of antagonist muscle, a decrease 1n
the albumin/globulin ratio, congestion of cardiac vessels and dystrophy of
the liver 1n rats exposed to acetophenone continuously at 0.07 mg/m3 for
70 days. No effects were found at 0.007 mg/ma. In contrast, no effects
were noted In rats fed acetophenone In the diet at levels up to 8450 ppm for
17 weeks (Hagan et al., 1967), or In rats treated at dietary levels that
provided up to 102 mg/kg/day for 30 days (Smyth, 1946).
The only reproductive study available was a skin application study In
which no effects on reproduction or development were noted 1n rats treated
with acetophenone at 0.48 g/kg on gestation days 10-15 (Lagno and
Bakh1t1z1na, 1969).
QQOld * -25- " " 05/21/87
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Acetophenone tested negative 1n a reverse mutation assay (ElUger et
al., 1984), but did cause DMA chain breaks after photosensltlzatlon (Rahn et
al., 1974). The lexicological significance of the photosensltlzatlon study
Is uncertain.
QQOld * -26- " " Q5/2V87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Acetophenone 1s regarded as a safe food additive (U.S. FDA, 1975).
Other guidelines and standards, Including EPA ambient water and air quality
criteria, drinking water standards, FAQ/WHO ADIs, EPA or FDA tolerances for
raw agricultural commodities or food, and ACGIH, NIOSH or OSHA occupational
exposure limits could not be located 1n the available literature as cited In
Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of acetophenone could not be located In the available literature
as cited 1n Appendix A.
OOOld * -27- " - 05/21/87
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. All Routes. Pertinent data regarding the cardnogenldty of
acetophenone following Inhalation, oral or other routes of exposure could
not be located 1n the available literature as cited 1n Appendix A.
8.1.2. Height of Evidence. Acetophenone has not been examined 1n any
carclnogenlclty studies; therefore, acetophenone can be placed 1n EPA Group
D, no data for carclnogenlclty available (U.S. EPA, 1986c).
8.1.3. Quantitative Risk Assessment. Pertinent data regarding the
carclnogenlclty of acetophenone could not be located 1n the available
literature; therefore, quantitative risk assessment based on carclnogenlclty
cannot be conducted.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS-THAN-LIFETIME EXPOSURES (SUBCHRONIC) — Pinching and
Dovlng (1974) examined the effect of acetophenone exposure on the olfactory
bulb. A specific pattern of degeneration of cells of the olfactory bulb was
noted 1n rats exposed to acetophenone at 8.89 mg/ma for up to 3 months.
Because this study did not define a NOAEL and because olfactory bulb degen-
eration was the only parameter examined, this study 1s Inadequate for risk
assessment.
The only other inhalation study of acetophenone available was reported
by Imasheva (1966). In this study, groups of 15 male rats were exposed to
acetophenone continuously at 0, 0.007 or 0.07 mg/m3 for 70 days. No
effects were observed 1n rats exposed to 0.007 mg/m3. At 0.07 mg/m3,
congestion of cardiac vessels and Hver dystrophy were noted. Rats also
showed changes 1n the ratio of chronaxles of antagonist muscles and a
OOOld ' -28- " 05/21/87
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decrease In the albumin/globulin ratio of the blood, with no change 1n the
amount of total protein. The corresponding NOAEL In rats Is 0.0045 mg/kg/
day. Using an uncertainty factor of 100 (10 for Interspedes extrapolation
and 10 for 1ntraspec1es variability), a tentative subchronlc Inhalation RfD
of 0.00004 mg/kg/day can be obtained. For a 70 kg human that corresponds to
0.003 mg/day. This corresponds to an air concentration of 0.0002 mg/m».
The level of confidence 1n the subchronlc Inhalation RfO 1s low because
there are no studies that support the findings of the Imasheva (1966) study.
In addition, the Imasheva (1966) study used only male rats, and although 15
rats were used per dose group, only 5/group were used to study chollnester-
ase activity and serum protein levels, while hlstopathologlcal examinations
were conducted on an unspecified number of rats.
8.2.1.2. CHRONIC EXPOSURES — Pertinent data regarding the chronic
exposure of acetophenone could not be located In the available literature as
cited 1n Appendix A. A chronic Inhalation RfD can be estimated from the
subchronlc Inhalation study using an additional uncertainty factor of 10.
Applying the additional uncertainty factor, the chronic Inhalation RfD for
acetophenone 1s 0.000005 mg/kg/day or 0.0003 mg/day, corresponding to an air
concentration of 0.00002 mg/m3.
8.2.2. Oral Exposure.
8.2.2.1. LESS-THAN-LIFETIME EXPOSURES (SUBCHRONIC) — In the 30-day
study by Smyth (1946), no effects were noted In rats fed acetophenone 1n the
diet at levels of 0, 1, 6, 25 or 102 mg/kg/day. The only other subchronlc
study available was the 17-week study by Hagan et al. (1967) 1n which no
effects were noted 1n rats fed diets containing acetophenone at 0, 50, 125
or 500 mg/kg/day. Neither study defines an effect level, but because the
Hagan et al. (1967) study was longer and because higher dose levels were
used, It Is more appropriate for the derivation of the RfD.
OOOld ' -29- ' " 05/21/87
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Assuming a rat consumes a dally amount of food equivalent to 5% of Its
body weight (U.S. EPA, 1986d), the high-dose rats consumed acetophenone at
-500 mg/kg/day. Applying an uncertainty factor of 100 (10 for species-to-
species extrapolation and 10 to protect sensitive humans), a subchronlc RfD
of 5 mg/kg/day or 350 mg/day for a 70 kg human Is derived.
The level of confidence 1n the subchronlc RfD 1s low. The Hagan et al.
(1967) study used only 10 male and 10 female rats/dose group, and only 6-8
rats of each sex of just the high-dose group were examined microscopically.
The Hagan et al. (1967) study did not define an effect level, and the NOEL
was near the oral LD5Q for rats, which ranges from 0.9-3.2 g/kg. In addi-
tion, other data to support this RfD were not located 1n the available
literature. Since acetophenone has not been tested for carclnogenlcHy,
teratogenldty or other reproductive effects, 1t 1s uncertain whether the
RfD will be protective.
8.2.2.2. CHRONIC EXPOSURES — Pertinent data regarding the oral
chronic exposure of acetophenone could not be located 1n the available
literature as dted 1n Appendix A. However, a chronic RfD can be derived by
dividing the subchronlc RfD by an additional uncertainty factor of 10 to
extrapolate from subchronlc to chronic exposure. Dividing the subchronlc
RfD derived from the Hagan et al. (1967) study by 10, a chronic RfD of 0.5
mg/kg/day or 35 mg/day for a 70 kg human Is derived. The level of confi-
dence In this RfD 1s low for reasons stated previously (see Section 8.2.2.1.)
and because the study was subchronlc.
OOOld -30- 05/21/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty of acetophenone was discussed In Chapter 6. The only
toxldty studies 1n which toxic effects were observed were the Inhalation
studies, which are summarized 1n Table 9-1.
Pinching and Dovlng (1974) observed olfactory bulb degeneration 1n rats
exposed continuously to 8.89 mg/m3 for up to 3 months. Since this was the
only exposure level Investigated, 1t 1s not known 1f olfactory bulb degener-
ation would occur at a lower exposure level; therefore, the NED for this
effect 1s not known. Furthermore, olfactory bulb degeneration was the only
endpolnt examined. Since Imasheva (1966) observed liver dystrophy and
cardiac vessel congestion at a continuous exposure level of 0.07 mg/m3, 1t
1s possible that the rats 1n the Pinching and Dovlng (1974) study also had
systemic effects. Imasheva (1966) did not observe effects at 0.007 mg/ma.
Thus, an RQ can be derived from the Imasheva (1966) study. The effects at
0.07 mg/m3 warrant an RV of 5. The exposure level Is equivalent to a
human dose of 0.008 mg/kg/day (see table 9-1), which when multiplied by 70
kg and divided by an uncertainty factor of 10 to approximate chronic
exposure equals the MED of 0.056 mg/day (Table 9-2). The MED corresponds to
an RVrf of 7.4. Multiplying the RVrf by the RVg yields the CS of 37,
which corresponds to an RQ of 100 (Tables 9-2 and 9-3).
9.2. BASED ON CARCINOGENICITY
Pertinent data regarding the carc1nogen1dty of acetophenone were not
available; therefore, an RQ based on carclnogenlclty Is not warranted.
OOOld * -31- " " 05/21/87
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TABLE 9-2
Inhalation Composite Scores for Acetophenone Using Rat Tox1c1ty Data3
Animal Dose
(mg/kg/day)
0.045
Chronic
Human MED° RVd
(mg/day)
0.056 7.4
Effects
•
Dystrophy of the
liver, decrease 1n
albumin/globulin
ratio, congestion
of cardiac vessels
RVe CS RQ
5 37 100
aSource: Imasheva, 1966
bThe dose was divided by an uncertainty factor of 10 to approximate chronic
exposure.
OOOld . -33- - - 05/21/87
-------
TABLE 9-3
Acetophenone
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
Inhalation
0.056 rag/day
dystrophy of the "liver, decrease 1n albumin/globulin ratio
Imasheva, 1966
7.4
5
37
100
'Equivalent human dose
000 Id
-34-
05/21/87
-------
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Tkach, N.Z. 1967. Combined effect of low atmospheric concentrations of
acetone and acetophenone on man and animals. B1ol. De1stv1e G1g. Znachenle
Atmos. Zagryaznenll. 19: 170-186. (CA 69:29934t)
Tsulaya, T.P. 1967. Sanltary-toxlcologlc features of the combined action
of a mixture of benzene and acetophenone vapors 1n the atmosphere. G1g.
Sanlt. 32(4): 6-10. (CA 67:14646k)
Urano, K. and Z. Kato. 1986. Evaluation ranks of priority organic com-
pounds. J. Hazardous Materials. 13: 147-159.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
0001d • -46- " " 05/21/87
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U.S. EPA. 1986a. Methodology for Evaluating Carclnogenldty 1n Support of
Reportable Quantity Adjustments Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1986b. STORET Water Quality Data Base. Online: December, 1986.
U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986d. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1987. Graphical Exposure Modeling System (GEMS). Octanol-Water
Partition Coefficient (CLOGP) and/or Fate of Atmospheric Pollutants (FAP)
computer data systems. U.S. EPA, Research Triangle Park, NC.
U.S. FDA (Food and Drug Administration). 1975. Food Additive Regulations
No 56. 21 CFR 121.1164. (Cited 1n Lande et al., 1976)
USITC (U.S. International Trade Commission). 1982. Synthetic Organic
Chemicals. United States Production and Sales, 1981. USITC Publ. 1292,
Washington, DC. p. 25-27.
0001d * -47- " " 05/21/87
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Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. Van Nostrand Relnhold Co., NJ. p. 152-153.
yindholz, M., Ed. 1983. The Merck Index. 10th ed. Merck and Co.. Inc.,
Rahway, NJ. p. 11.
Zoeteman, 8.C.J., E. Degreef and F.J.J. Brlnkman. 1981. Persistence of
organic contaminants 1n groundwater, lessons from soil pollution Incidents
1n the Netherlands. Sc1. Total Environ. 21: 187-202.
0001d * -48- " " 05/21/87
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n December, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, 6.0. and F.E. Clayton. Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
OOOld. - -49- - - 05/21/87
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
OOOld - * -50- " 05/21/87
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington. DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Hater
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0001d * -51- ' - - 05/21/87
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U.S. Environmental Protection Agency
ftegion V, Library ^
230 South Dearborn Street x'
Chicago, Illinois 60604
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