)j'r
P/EPA
00k
United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-6068
Hay, 1990
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 2-HEXANONE
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
DRAFT: DO NOT CITE OR QUOTE
NOTICE
'This document 1s 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 Agency policy. It 1s being circulated for comments
on Us technical accuracy and policy Implications.
HEADQUARTERS LIBRARY
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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DISCLAIMER
This report Is 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
1s 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 for 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 In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is 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 Is sent to the Program Officer (OSWER).
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 Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. 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 RfOs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, a carcinogenic potency factor, or
Q]* (U.S. EPA, 1980), Is provided. 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. An RfD may also be derived for the noncarclno-
genlc health effects of compounds that are also carcinogenic.
Reportable quantities (RQs) based on both chronic toxldty and carclno-
genldty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of
as specified under the Comprehensive Environmental Response,
and Liability Act (CERCLA). These two RQs (chronic toxldty
genlclty) represent two of six scores developed (the remaining
IgnUabllHy, 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, 1984 and 1986c, respectively.
a release
Compensation
and cardno-
four reflect
111
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EXECUTIVE SUMMARY
2-Hexanone Is known by the synonyms butyl methyl ketone, methyl butyl
ketone and propyl acetone (Hawley, 1981; Wlndholz, 1983). It Is a colorless
liquid that 1s soluble 1n alcohol and ether and slightly soluble In water
(Wlndholz, 1983). Production data for 2-hexanone are limited. In 1977, the
Tennessee Eastman Company manufactured between 1 and 10 million pounds of
2-hexanone .{U.S. EPA, 1977). However, the 1988 Directory of Chemical
Producers (SRI, 1988) and the U.S. International Trade Commission (US1TC,
1988) do not have listings for 2-hexanone, suggesting that 1t Is not
currently manufactured on an Industrial scale In the United States for use
as an end-product. Current Import figures are not available. 2-Hexanone Is
used as a medium-evaporating solvent for nitrocellulose, acrylates, vinyl
and alkyd coatings (Papa and Sherman, 1981).
2-Hexanone appears to be readily degradable 1n air, water and soil; It
Is not likely to be a persistent environmental contaminant. If released to
the atmosphere 2-hexanone Is expected to exist 1n the vapor phase where It
will degrade by reaction with sunlight-formed HO radical. Based upon an
experimentally determined rate constant (WalUngton and Kurylo, 1987), the
half-life for this reaction has been estimated to be -2.4 days for typical
atmospheric conditions. If released to the aquatic environment, 2-hexanone
may degrade by blodegradatlon or be physically removed by volatilization.
2-Hexanone appears to be readily biodegradable based upon results from
limited blodegradatlon screening studies (Babeu and Valshnav, 1987; Valshnav
et al., 1987; Shelton and Tledje, 1984). Volatilization half-lives of -12
hours and 5.7 days can be estimated for a shallow model river and
environmental pond, respectively (Thomas, 1982; U.S. EPA, 1986a). If
Iv
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released to soil, 2-hexanone may be susceptible to significant
blodegradatlon based on analogy to the blodegradatlon screening studies
noted above. Although significant leaching Is possible, concurrent bio-
degradation may decrease the potential Importance of leaching. 2-Hexanone
1s used as a medium-evaporating solvent (Papa and Sherman, 1981) and Is
expected to undergo significant evaporation from dry surfaces.
2-Hexanone can be released to the aquatic environment by wastewater
streams generated at various fossil-fuel processing and chemical manufactur-
ing sites and by leaching from hazardous waste sites and municipal landfills
(HSDB, 1989; Brown and Donnelly, 1988; Myers, 1983). This compound Is
released to the atmosphere by evaporation from Us use as a solvent (Graedel
et al., 1986). 2-Hexanone occurs naturally. It has been detected as a
volatile component of blue- cheese, nectarines, raw chicken breast and
poultry manure (Day and Anderson, 1965; Takeoka et al., 1988; Grey and
Shrlmpton, 1967; Yasuhara, 1987). The general population may be exposed to
2-hexanone through Ingestlon of natural and processed foods (In which H
occurs naturally) and through Inhalation of vapors from commercial coatings
containing 2-hexanone as a solvent (HDSB, 1989). Insufficient monitoring
data are available to estimate average human dally Intakes of 2-hexanone
using food, Inhalation or drinking water.
The 96-hour LC and EC5Q for the fathead minnow, Plmephales
prgmelas. exposed to 2-hexanone under flowthrough conditions was 428 mg/S.
(Gelger et al., 1986). The ED for scud, Gammarus. mea'sured as the loss
of an escape response when organisms experienced a mechanical stimulus
delivered by hand to either lateral surface when exposed to 2-hexanone was
420 mg/a.
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The EC for mixed mlcroblal cultures, measured as the concentration
of 2-hexanone that would reduce the maximum observed blodegradatlon rate by
50%, was 5510 mg/i (0.055 M) (Valshnav, 1986). Tests assessing the
efficacy of 2-hexanone as a repellent for the bee, Apis florea. revealed
that bees exposed to concentrations of 2-hexanone from 62.5 and 4dOO mg/i
resulted In 64.0 and 82.6% repelled, respectively (Gupta and Mohla, 1986;
Gupta, 1987).
2-Hexanone 1s absorbed readily from the GI tract, the respiratory tract,
and through the skin. Respiratory uptake data In humans (DIVIncenzo et al.,
1978) Indicate that -75-92% of Inhaled 2-hexanone was absorbed by the lungs
and respiratory mucosa following exposure to 10-100 ppm for 4-7.5 hours.
Approximately 65-68% of 2-hexanone vapor was absorbed by the lungs of dogs
exposed to 50-100 ppm 2-hexanone for 6 hours. 2-Hexanone can also be
absorbed readily through the skin. A dermal absorption rate of 4.8-8.0
iig/mln'Hnf2 was determined In humans from the analysis of excretion
data (DIVIncenzo et al., 1978).
Although distribution of radioactivity from administered
(l-i«C)-2-hexanone appears to be rapid and widespread, the highest
concentrations of radioactivity following oral administration of 2-hexanone
In rats were detected 1n the liver and blood (DIVIncenzo et al., 1977).
Following absorption, 2-hexanone undergoes extensive metabolism and
elimination. 2-Hexanone 1s metabolized by hepatic cytochrome P-450 oxldases
with the formation of 5-hydroxy-2-hexanone and 2,5-hexanedlone (DIVIncenzo
et al., 1977; Courl et al., 1978). The metabolism of 2-hexanone to
2,5-hexanedlone Is regarded as metabolic activation, since there 1s evidence
that 2,5-hexanedlone mediates the neurotoxlclty and testlcular toxUlty of
2-hexanone. 2,5-Hexaned1ol 1s formed by the oxidation of 2-hexanol or by
the reduction of 5>hydroxy-2-hexanone. Urinary metabolites of 2-hexanone
v1
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Include 2,5-hexanedlone, 2-hexanol, 5-hydroxy-2-hexanone and
2,5-d1methylfuran. 2-Hexanol, -5-hydroxy-2-hexanone, and 2,5-d1methylfuran
are excreted as glucuronldes.
Rats administered 14C-2-hexanone by gavage excreted 44% of the dose 1n
the breath as 14C02 (38%) and 2-hexanone (6%) (DIVIncenzo et al., 1977).
Forty and 1.4% of the dose was excreted 1n the urine and feces, respec-
tively. About 14% remained In the carcass 48 hours after dosing.
Humans Ingesting 0.1 mg/kg of (1-14C)-2-hexanone excreted 40% of the
dose In the breath as 14CO and 26% In urine (DIVIncenzo et al., 1978).
Excretion of 2-hexanone Is less complete 1n humans than In rats.
Acute Inhalation exposure of animals or humans to high concentrations of
2-hexanone vapor causes an almost Immediate Irritation to the eyes and nose
(Schrenk et al., 1936). In guinea pigs, exposure to 6500-20,000 ppm
resulted 1n ataxla, narcosis and death (Schrenk et al., 1936). The cause of
death In guinea pigs was attributed to narcosis. Congestion of the lungs,
kidneys and liver was found during autopsy examination. In humans, exposure
to 1000 ppm for a few minutes resulted In moderate ocular and nasal Irrita-
tion (Schrenk et al.. 1936).
Results of subchronlc Inhalation animal studies Indicate that 2-hexanone
neurotoxlclty 1s characterized by the development of peripheral neuropathy
(Mendell et al.. 1974; Spencer et al., 1975; Salda et al., 1976; Johnson et
al., 1977). Neuropathologlcal features of peripheral nerve damage Include
giant axonal swellings and axonal degeneration. Peripheral nerve damage Is
associated with hlndllmb drag and weakness of the forellmbs and hlndllmbs In
rats, monkeys and cats. Electrodlagnostk studies reveal accompanying
abnormalities In EMG and MNCV (Johnson et al., 1977; Duckett et al., 1979).
Behavioral studies revealed alterations In rats exposed to levels
associated with hlstopathologlcal evidence of peripheral neuropathy (Johnson
vll
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et al., 1977). Intermittent exposure to 50 ppm, the lowest concentration
tested 1n animal Inhalation studies, was associated with decreased MNCV and
extensive nerve demyellnatlon 1n rats (Duckett et al., 1979). Clinical
signs of neuropathy have been documented In humans exposed to 2-hexanone In
the work environment at concentrations as low as 9.2-36.0 ppm (Allen et al.,
1975).
Several oral gavage and drinking water studies Indicate that the effects
of oral exposure to 2-Hexanone are similar to those associated with Inhala-
tion exposure (Krasavage et al., 1979, 1980; Homan and Maronpot, 1978;
Abdel-Rahman et al., 1978). Generally, large doses were administered to
produce the typical neurological syndrome. In one study, testlcular atrophy
was observed In rats treated by gavage at 600 mg/kg/day for 10 weeks
(Krasavage et al., 1980). The oral studies were not performed at dosages
sufficiently low to Identify thresholds for neuropathy.
Data were not located regarding the cardnogenldty of 2-hexanone to
animals or humans exposed by any route. No data were located regarding the
mutagenlclty of 2-hexanone In prokaryotk or eukaryotlc test systems. In a
teratogenldty study using pregnant rats, a decrease In maternal weight gain
was observed at 1000 or 2000 ppm 2-hexanone for 6 hours/day throughout
gestation (Peters et al., 1981). A reduction In the number and weight of
live offspring was detected In rats exposed to 2000 ppm 2-hexanone. Post-
natal behavioral changes were observed In both the 1000 and 2000 ppm groups.
These results were corroborated by Tyl et al. (1987) who found a
decrease In maternal weights in mice and rats only after exposure to 3000
ppm of 2-hexanone during days 6-15 of gestation. Evidence of developmental
toxlclty was only observed In the group exposed to 3000 ppm and was limited
vlll
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to Increased Incidence of dead fetuses (only seen In mice), reduced fetal
body weight per Utter, and reductions In skeletal ossification (mice and
rats). There was no evidence of a dose-dependent Increase In developmental
toxldty, nor any evidence of any type of treatment-related effect, at 300
or 1000 ppm 1n either species.
2-Hexanone was assigned to U.S. EPA Group 0: not classifiable as to
carclnogenldty to humans because of a lack of cancer data In animals or
humans for any route of exposure. Therefore, neither estimates of carcino-
genic potency nor RQ derivation based on cancer were possible.
Subchronlc Inhalation and oral data confirm that peripheral neuropathy
1s the critical effect of exposure to 2-hexanone, and several studies
Identify FELs associated with gross Impairment of neurological function such
as paralysis or hlndllmb footdrag. NOAELs for this effect were not Identi-
fied and studies that may have defined LOAELs were Insufficiently reported
to serve as the basis for RfD derivation. Therefore, RfO values were not
derived for subchronlc or chronic Inhalation or oral exposure.
An RQ of 100 was derived for 2-hexanone based on neuropathy In rats
exposed Intermittently to 100 ppm In the air (Johnson et al.f 1977, 1979).
1x
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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 2
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. M1crob1al Degradation 4
2.2.3. Volatilization 5
2.2.4. Adsorption 5
2.2.5. B1oconcentrat1on 5
2.3. SOIL 5
2.3.1. Mlcrobtal Degradation 5
2.3.2. Adsorption/Leaching 5
2.3.3. Evaporation 6
2.4. SUMMARY 6
3. EXPOSURE 8
3.1. WATER 8
3.2. FOOD 9
3.3. INHALATION 9
3.4. DERMAL 9
3.5. SUMMARY 10
4. ENVIRONMENTAL TOXICOLOGY 11
4.1. AQUATIC TOXICOLOGY 11
4.1.1. Acute Toxic Effects on Fauna 11
4.1.2. Chronic Effects on Fauna 11
4.1.3. Effects on Flora 12
4.1.4. Effects on Bacteria 12
4.2. TERRESTRIAL TOXICOLOGY 12
4.2.1. Effects on Fauna 12
4.2.2. Effects on Flora 12
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TABLE OF CONTENTS (cont.)
Page
4.3. FIELD STUDIES 12
4.4. AQUATIC RISK ASSESSMENT 13
4.5. SUMMARY 13
5. PHARMACOKINETCS 15
5.1. ABSORPTION 15
5.2. DISTRIBUTION 1&
5.3. METABOLISM 17
5.4. EXCRETION 20
5.5. SUMMARY 21
6. EFFECTS 23
6.1. SYSTEMIC TOXICITY 23
6.1.1. Inhalation Exposure 23
6.1.2. Oral Exposure 27
6.1.3. Other Relevant Information 29
6.2. CARCINOGENICITY 31
6.2.1. Inhalation 31
6.2.2. Oral 31
6,2.3. Other Relevant Information 31
6.3. MUTAGENICITY 31
6.4. DEVELOPMENTAL TOXICITY 31
6.5. OTHER REPRODUCTIVE EFFECTS 34
6.6. SUMMARY 34
7. EXISTING GUIDELINES AND STANDARDS 37
7.1. HUMAN 37
7.2. AQUATIC 37
8. RISK ASSESSMENT 38
8.1. CARCINOGENICI1Y 38
8.1.1. Inhalation 38
8.1.2. Oral 38
8.1.3. Other Routes 38
8.1.4. Weight of Evidence 38
8.1.5. Quantitative Risk Estimates 38
8.2. SYSTEMIC TOXICITY 38
8.2.1. Inhalation Exposure 38
8.2.2. Oral Exposure 40
xl
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TABLE OF CONTENTS (cent.).
Page
9. REPORTABLE QUANTITIES 43
9.1. BASED ON SYSTEMIC TOXICITY
9.2. BASED ON CARCINOGENICITY .
10. REFERENCES.
APPENDIX A: LITERATURE SEARCHED
APPENDIX B: SUMMARY TABLE FOR 2-HEXANONE
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
2-HEXANONE .
43
47
49
61
64
65
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No.
6-1
9-1
9-2
9-3
LIST OF TABLES
Title
Page
Acute Lethal Toxldty of 2-Hexanone 30
loxUHy Summary for 2-Hexanone 44
Composite Scores for 2-Hexanone 46
2-Hexanone: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 48
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LIST OF ABBREVIATIONS
BCF
BOD
BTU
CNS
CS
DNA
"50
E050
EEG
EHG
F344
FEL
GI
GMAV
GMCV
ow
LC50
LOAEL
MNCV
ppb
ppm
Bloconcentratlon factor
Biological oxygen demand
British thermal unit
Central nervous system
Composite Score
Deoxyrlbonuclelc add
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Effective dose to 50% of recipients
Electroencephalograms
Electromyography
Fischer 344
Frank effect level
Gastrointestinal
Genus mean acute value
Genus mean chronic value
Soil sorptlon coefficient standardized
with respect to organic carbon
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effec.t level
Motor nerve conduction velocities
Parts per billion
Parts per million
xlv
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RfD
RNA
RQ
RVd
RVe
STEL
TLV
TWA
MS
LIST OF ABBREVIATIONS (cont.)
Reference dose
Rlbonucleic acid
Reportable quantity
Dose-rating value
Effect-rating value
Short-term exposed level
Threshold limit value
Time-weighted average
Water solubility
xv
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1 . INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
2-Hexanone Is also known by the synonyms butyl methyl ketone, methyl
butyl ketone and propyl acetone (Hawley, 1981; Wlndholz, 1983). The struc-
ture, molecular weight, empirical formula and CAS number for 2-hexanone are
as follows:
Molecular weight: 100.16
Empirical formula: C,H,,,0
o i c
CAS Registry number: 591-78-6
1.2. PHYSICAL AND CHEMICAL PROPERTIES
2-Hexanone Is a colorless liquid that Is soluble In alcohol and ether
(Wlndholz, 1983). Selected physical properties are as follows:
Melting point:
Boiling point:
Specific gravity:
Vapor pressure:
at 25°C
Hater solubility:
at 25°C
Log Kow:
Flash point:
Odor threshold (air):
Conversion factors:
(air at 20°C)
-55.8°C
127.5°C
0.8125 (20/20'C)
11.6 mm Hg
16,000 ppm
1.38
28°C (open cup)
0.28-0.35 mg/m3
1 mg/m3=0.24 ppm
1 ppm=4.16 mg/m3
Papa and Sherman, 1981
Papa and Sherman, 1981
Papa and Sherman, 1981
Engineering Sciences
Data Unit, 1975
Erlchsen, 1952
Hansch and Leo, 1985
Papa and Sherman, 1981
Verschueren, 1983
2-Hexanone 1s flammable and considered a moderate fire risk {Hawley, 1981)
0183d
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Ketones such as 2-hexanone undergo addition, redox and condensation reac-
tions forming alcohols, ketals, acids and amines (Papa and Sherman, 1981).
1.3. PRODUCTION DATA
The available production data for 2-hexanone are very limited. The
public portion of the U.S. EPA TSCA Production File for 1977 lists the
following producers of 2-hexanone (U.S. EPA, 1977):
Polak's Frutal Works (Mlddleton, NY)
Manufacturer: production range confidential
Tennessee Eastman Company {Klngsport, TN)
Manufacturer: production range of 1-10 million Ibs,
Roure Bertrand DuPont, Inc. (Teaneck, NJ)
Importer: production range of <1000 Ibs.
The 1988 Directory of Chemical Producers (SRI, 1988) and the U.S. Inter-
national Trade Commission (USITC, 1988) do not have listings for 2-hexanone,
suggesting that It Is not currently manufactured on an Industrial scale for
use as an end-product. This compound may be Imported Into the United States
but current Import figures are not available. The 1987 OPD Chemical Buyers
Directory lists Chemcentral Corp., Chemical Dynamics Corp., Davos Chemical
Corp. and Penta Manufacturing Company as suppliers of 2-hexanone (CMR, 1986).
2-Hexanone can be prepared by reacting 1-hexene with l,4-benzoqu1none
(Flnley, 1982) or by reacting acetyl chloride with butylmagneslum chloride
(Morettl, 1978).
1.4. USE DATA
2-Hexanone is used as a medium-evaporating solvent for nitrocellulose,
acrylates, vinyl and alkyd coatings (Papa and Sherman, 1981).
1.5. SUMMARY
2-Hexanone 1s known by the synonyms butyl methyl ketone, methyl butyl
ketone and propyl acetone (Hawley, 1981; VMndholz, 1983). It Is a colorless
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liquid that 1s soluble In alcohol and ether -and slightly soluble In water
(Wlndholz, 1983). Production data for 2-hexanone are limited. In 1977, the
Tennessee Eastman Company manufactured between 1 and 10 million pounds of
2-hexanone (U.S. EPA, 1977). However, the 1988 Directory of Chemical
Producers (SRI, 1988) and the USITC (1988) do not have listings for
2-hexanone, suggesting that H Is not currently manufactured on an
Industrial scale In the United States for use as an end-product. Current
Import figures are not available. 2-Hexanone Is used as a
medium-evaporating solvent for nitrocellulose, acrylates, vinyl and alkyd
coatings (Papa and Sherman, 1981).
ft
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based upon Us relatively high vapor pressure of 11.6 mm Hg at 25°C (see
Section 1.2.), 2-hexanone 1s expected to exist almost entirely In the vapor
phase In the ambient atmosphere (Elsenrelch et al., 1981). The dominant
degradation process 1n ambient air 1s probably reaction with sunlight-formed
HO radical. Based upon an experimentally determined rate constant of
6.64xlO~lz cma/mol-sec at 23°C (Wellington and Kurylo, 1987) and an
average atmospheric HO radical concentration of 5x10 molecules/cm3,
the half-life for this reaction can be estimated to be -2.4 days.
In terms of environmental contaminants, 2-hexanone has a relatively high
water solubility of 16,000 ppm at 25°C (see Section 1.2.), suggesting that
physical removal from air by wet deposition (washout by rainfall,
dissolution In clouds, etc.) 1s possible.
2.2. WATER
2.2.1. Hydrolysis. Experimental hydrolysis data regarding 2-hexanone
were not located. However, ketones are generally resistant to environmental
hydrolysis (Harris, 1982); therefore, hydrolysis of 2-hexanone In the
aquatic environment Is not expected to be Important.
2.2.2. MUroblal Degradation. 2-Hexanone appears to be readily bio-
degradable based upon results from limited blodegradatlon screening studies
(Babeu and Valshnav, 1987; Valshnav et al., 1987; Shelton and Tledje, 1984).
Using an acclimated mixed culture Inocula and the standard BOD technique,
2-hexanone was found to have a BOO of 5.22 over a 5-day Inoculation period
(Babeu and Valshnav, 1987; Valshnav et al., 1987). 2-Hexanone was also
found to be susceptible to blodegradatlon under anaerobic conditions. In a
study using an anaerobic digester sludge Inocula, conversion to >75% of
0183d -4- 06/12/89
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theoretical methane production was observed during an 8-week Incubation
period (Shelton and Tledje, 1984).
2.2.3. Volatilization. Based upon a water solubility of 16,000 ppm and a
vapor pressure of 11.6 mm Hg at 25°C (see Section 1.2.), the Henry's Law
constant for 2-hexanone can be estimated to be 9.56x10"' atm-m'/mol. A
Henry's Law constant of this magnitude Indicates that volatilization from
environmental waters may have some significance, but 1s probably not rapid
(Thomas, 1982). Using a model river estimation method (Thomas, 1982), the
volatilization half-life of 2-hexanone from a river 1 m deep flowing 1 m/sec
with a wind velocity of 3 m/sec can be estimated to be -12 hours. The
volatilization half-life from a model environmental pond can be estimated to
be -5.7 days (U.S. EPA, 1986a).
2.2.4. Adsorption. The relatively high water solubility (In comparison
with other environmental contaminants) of 2-hexanone suggests that
partitioning from the water column to sediment and suspended material should
not be significant.
2.2.5. Bloconcentratlon. Experimental BCFs for 2-hexanone In fish were
not located. A BCF of 6.6 can be calculated using a log K value of 1.38
(Hansch and Leo, 1985) and the following equation (Bysshe, 1982): log BCF .
0.76 log K - 0.23. This calculated BCF value Indicates that
bloconcentratlon In aquatic organisms 1s probably not Important.
2.3. SOIL
2.3.1. Mlcroblal Degradation. Data specific to the mlcroblal degradation
of 2-hexanone in soil were not located In the literature dted In Appendix
A. However, based upon the limited blodegradatlon screening tests discussed
In Section 2.2.2., 2-hexanone may be readily biodegradable 1n soil.
2.3.2. Adsorption/Leaching. Data specific to the leaching of 2-hexanone
In soil were not located In the literature cited In Appendix A. A K of
0183d
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05/23/90
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21 can be estimated using a WS of 16,000 ppm and the following equation
{Lyman, 1982): log KQ(, = 3.64-0.55 log WS. This estimated KQC value
Indicates very high soil mobility (Swann et al., 1983). Although
significant leaching Is possible, concurrent blodegradatlon may decrease the
potential Importance of leaching.
2.3.3. Evaporation. 2-Hexanone can be expected to evaporate relatively
rapidly from dry surfaces. It 1s used as a medium-evaporating solvent for
nitrocellulose, acrylates, vinyl and alkyd coatings (Papa and Sherman,
1981). In an evaporation rate test pertinent to solvents used for coatings,
2-hexanone was found to have an evaporation half-life of -0.9 hours (Park
and Hofmann, 1932).
2.4. SUMMARY
2-Hexanone appears to be readily degradable In air, water and soil;
therefore, It Is not likely to be a persistent environmental contaminant.
If released to the atmosphere, 2-hexanone is expected to exist In the vapor
phase where 1t will degrade by reaction with sunlight-formed MO radical.
Based upon an experimentally determined rate constant (Walllngton and
Kurylo, 1987), the half-life for this reaction has been estimated to be -2.4
days for typical atmospheric conditions. If released to the aquatic
environment, 2-hexanone may degrade by blodegradatlon or be physically
removed by volatilization. 2-Hexanone appears to be readily biodegradable
based upon results from limited blodegradatlon screening studies (Babeu and
Valshnav, 1987; Valshnav et al., 1987; Shelton and Tledje, 1984). Volatili-
zation half-lives of -12 hours and 5.7 days can be estimated for a shallow
model river and environmental pond, respectively (Thomas, 1982; U.S. EPA,
1986a). If released to soil, 2-hexanone may be susceptible to significant
blodegradatlon based on analogy to the blodegradatlon screening studies
0183d
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noted above. Although significant leaching Is possible, concurrent
blodegradatlon may decrease the potential Importance of leaching.
2-Hexanone 1s used as a medium-evaporating solvent (Papa and Sherman, 1981)
and Is expected to undergo significant evaporation from dry surfaces.
0183d
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3. EXPOSURE
2-Hexanone occurs as a natural product. It has been detected as a
volatile component of blue cheese, nectarines, raw chicken breast and
poultry manure (Day and Anderson, 1965; Takeoka et al., 1988; Grey and
Shrlmpton, 1967; Yasuhara, 1987). Hence, the general population may be
exposed to 2-hexanone through IngesUon of natural and processed foods (1n
which 1t occurs naturally) and through Inhalation of vapors from commercial
coatings containing 2-hexanone as a solvent (HOSB, 1989).
Another possible source of exposure to 2-hexanone Is through Inhalation
during Its manufacture, formulation Into products and use as an evaporatlng-
medlum solvent (HSDB, 1989). The National Occupational Exposure Survey has
estimated that 810 U.S. workers are potentially exposed to 2-hexanone based
upon surveys conducted between 1981 and 1983 (NIOSH, 1988).
3.1. WATER
2-Hexanone Is released to the aquatic environment by various wastewater
emissions. It has been found In process water from jm situ coal gasifica-
tion In Gillette, HY (7 ppm), in the aqueous condensate from low-BTU gasifi-
cation of rosebud coal in Morgantown, WV (202 ppm), and 1n retort water from
Jjl situ oil shale processing at Rock Springs, WY (53 ppm) (HSDB, 1989). It
has also been detected in one of 63 wastewater effluents and 22 Intake
waters from a wide range of chemical manufacturing areas across the United
States (HSDB, 1989).
2-Hexanone can also be released to groundwater by leaching from waste
sites. Leachates collected from municipal landfills have been found to
contain 2-hexanone at levels of 0.148 ppm (Brown and Donnelly, 1988). A
0183d
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concentration ranging from not detected- to 0.38 ppm was Identified 1n a
leachate discharge to a ditch near an abandoned landfill In Tybouts Corner,
OE (HSDB, 1989). 2-Hexanone was detected at a concentration of 87 ppb 1n
the Blscayne Aquifer (groundwater) In Oade County, FL, 1n 1982 In the
vicinity of an inactive waste drum recycling site (Myers, 1983). An average
concentration of 7135 ppb (maximum of 14,000 ppb) was found In two well
water samples at an unauthorized hazardous waste disposal site 1n Lang
township, NJ (HSDB, 1989). In 1984, 2-hexanone was detected In 3 of 11 well
waters at an abandoned landfill 1n Tybouts Corner, DE (HSDB, 1989).
3.2. FOOD
2-Hexanone has been qualitatively detected as a volatile component of
tree-ripened nectarines (Takeoka et al., 1988), raw chicken breast muscle
(Grey and Shrlmpton, 1967), mountain cheese (Dumont and Adda, 1978), blue
cheese (Day and Anderson, 1965) and roasted filberts (Klnlln et al., 1972).
3.3. INHALATION
2-Hexanone Is released to the atmosphere by evaporation from Us use as
a solvent (Graedel et al., 1986). The primary environmental release of
manufactured ketones (such as 2-hexanone) Is reported to be evaporation from
solvent uses (Lande et al., 1976). 2-Hexanone 1s also reported to occur In
tobacco smoke (Graedel et al., 1986).
2-Hexanone has been qualitatively detected In air samples from the
southern Black Forest 1n southwest Germany and in suburban air samples from
Tubingen, West Germany (Juttner, 1986).
3.4. DERMAL
Pertinent monitoring data regarding the dermal exposure of 2-hexanone
were not located In the available literature as cited in Appendix A.
0183d
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J.5. SUMMARY
2-Hexanone can be released to the aquatic environment by wastewater
streams generated at various fossil-fuel processing and chemical manufactur-
ing sites and by leaching from hazardous waste sites and municipal landfills
(HSD8, 1989; Brown and Donnelly, 1988; Myers, 1983). This compound Is
released to the atmosphere by evaporation from Us use as a solvent (Graedel
et a!., 1986). 2-Hexanone occurs naturally. It has been detected as a
volatile component of blue cheese, nectarines, raw chicken breast and
poultry manure (Day and Anderson, 1965; Takeoka et al., 1988; Grey and
Shrlmpton, 1967; Yasuhara, 1987). The general population may be exposed to
2-hexanone through 1ngest1on of natural and processed foods (1n which It
occurs naturally) and through Inhalation of vapors from commercial coatings
containing 2-hexanone as a solvent (HDSB, 1989). Insufficient monitoring
data are available to estimate average human dally Intakes of 2-hexanone
through food, Inhalation or drinking water.
0183d
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Gelger et al. (1986) assessed the
acute toxlclty of 2-hexanone to the fathead minnow, Plmephales promelas,
under flowthrough conditions at 25°C. Minnows used 1n the test were 26-37
days old. Concentrations of 2-hexanone In test solutions were analytically
verified. Investigators reported a 96-hour LC5_ and EC,Q of 428 mg/i.
Confidence limits to this estimate could not be calculated.
Elliott and McElwee (1988) assessed the anaesthetic action of 2-hexanone
In the scud, Gammarus. Test organisms were transferred In groups of six to
400-2000 ml of test solution. Their responses were observed until a
steady state was achieved. The endpolnt used to determine the ED_ was
the loss of an escape response when organisms experienced a mechanical
stimulus delivered by hand to either lateral surface. The Investigators
reported an ED,-0 of 420 mg/i (4.23 mmol/l).
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY -- Pertinent data regarding the effects of chronic
exposure of aquatic fauna to 2-hexanone were not located In the available
literature cited 1n Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION Experimentally generated
BCFs for 2-hexanone in fish were not located In the available literature
cited In appendix A. A BCF of 6.6 was calculated using the log K value
of 1.38 (see Chapter 2) and the following equation (Lyman et al., 1982):
log BCF = 0.76 log KQW - 0.23. This BCF indicates that bloconcentration
in fish Is not significant.
0183d
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4.1.3. Effects on Flora.
4.1.3.1. TOXICITY Pertinent data regarding the toxic effects of
exposure of aquatic flora to 2-hexanone were not located In the available
literature cited 1n Appendix A.
4.1.3.2. BIOCONCENTRATION Pertinent data regarding the bloconcen-
tratlon potential of 2-hexanone In aquatic flora were not located In the
available literature cited In Appendix A.
4.1.4. Effects on Bacteria. Valshnav (1986) manometrlcally assessed the
ability of 2-hexanone to Inhibit the blodegradatlon of 2-hexanone by
acclimated mixed mlcroblal cultures. Assays were conducted on a Warburg
apparatus at 30°C over a 75-mlnute exposure period. The ECrg, the concen-
tration of 2-hexanone that would reduce the maximum observed blodegradatlon
rate by 5054, was 5510 mg/l (0.055 mol/l).
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Gupta and Hohla (1986) assessed the efficacy of
2-hexanone as a bee repellent. The number of bees In the control and test
area of an olfactometer were counted at 1-minute Intervals for 5 minutes
before application of 2-hexanone at 0.0625 and 0.5 g/8.. These levels
repelled 64.1 and 81.854 of the bees In the test area versus control. Subse-
quently, Gupta (1987) assessed the efficacy of 2-hexanone as a repellent for
the bee, Aj)1s f 1 j)rea. Average repellency ranged from 64.0% at 62.5 mg/st
to 82.654 at 4000 mg/l.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to 2-hexanone were not located in the
available literature cited In Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of 2-hexanone on flora and fauna In
the field were not located 1n the available literature cited 1n Appendix A.
0183d
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4.4. AQUATIC RISK ASSESSMENT
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to 2-hexanone precluded the development of a freshwater
criterion (Figure 4-1). Development of a freshwater criterion requires the
results of acute assays with a salmonld fish species, a nonsalmonld fish or
amphibian, planktonlc and benthlc crustaceans, an Insect, a nonarthropod and
nonchordate species and an Insect or species from a phylum not previously
represented. The development of a freshwater criterion also requires data
from chronic toxlclty tests with two species of fauna and one species of
algae or vascular plant and at least one bloconcentratlon study.
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to 2-hexanone precludes the development of a saltwater
criterion. Development of a saltwater criterion will require the generation
of data In all of the required categories.
4.5. SUMMARY
for the fathead minnow, Plmephales
promelas. exposed to 2-hexanone under flowthrough conditions was 428 mg/a
The 96-hour LC5Q and EC
(Gelger et al.t 1986). The ED,-n for scud, Gammarus. measured as the loss
of an escape response when organisms experienced a mechanical stimulus
delivered by hand to either lateral surface when exposed to 2-hexanone was
420 mg/1.
The EC for mixed mlcroblal cultures, measured as the concentration
of 2-hexanone that would reduce the maximum observed blodegradatlon rate by
50%, was 5510 mg/S, (0.055 H) (Valshnav, 1986). Tests assessing the
efficacy of 2-hexanone as a repellent for the bee. Apis florea, revealed
that bees exposed to concentrations of 62.5 and 4000 mg/i of 2-hexanone
resulted In 64.0 and 82.6% repelled, respectively (Gupta and Hohla, 1986;
Gupta, 1987).
0183d
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Fami ly
«l
Chordate (Salmoriid-f ish)
tt£
Chordate (warmwater fish)
#3
Choi-date (fish or amphibian)
«4
Crustacean (planktonic)
#5
Crustacean (bent hie)
#£
Insect an
*7
non-ftrthropod /-Chordate
KG
New Insect an or phylum
represent at ive
#3
al gae
#10
Vascular plant
Nft=Not flva liable, »LCS. and
Pimephales prornelas
BMflV
Nfl
4£Bb
Nft
Nft
Nft
Nft
Nft
Nfl
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
ECi o in mg/L
TEST TYPE
SMCV«
Nft
Nft
Nft
Nft
Nft
Nft
Nft
Nft
NO
Ntt
for the fathead
BCF-
Nft
NA
Nft
Nft
Nft
Nft
Nft
Nft
Nfl
Nft
minnow,
FIGURE 4-1
Organization Chart for Listing GMAVs, GHCVs and BCFs Required to Derive
Numerical Water Quality Criteria to Protect Freshwater Aquatic Life from
Exposure to 2-Hexanone
Source: U.S. EPA/OWRS, 1986
0183d
-14-
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5. PHARMACOKINETICS
5.1. ABSORPTION
2-Hexanone 1s absorbed readily by the lungs, by the SI tract and through
the skin 1n humans and animals. A study In which three healthy male humans
were exposed for 4 hours to 100 ppm 2-hexanone or for 7.5 hours to 10 or 50
ppm 2-hexanone Indicated, by the difference between concentrations 1n
Inhaled and exhaled air, that 75-92% of the Inhaled 2-hexanone is absorbed
by the respiratory mucosa and lungs (DWincenzo et al., 1978). Exposure to
10 and 50 ppm for 7.5 hours resulted In 2-hexanone concentrations of 1.4 and
9.3 ppm 1n expired air, respectively. An average 2-hexanone breath
concentration of 22 ppm was achieved following exposure to 100 ppm for 4
hours.
Steady state appears to have been achieved within the first hour. A
serum concentration of 1.2 iig/mi 2-hexanone was obtained following a
4-hour exposure to 100 ppm. 2-Hexanone was not detectable in the serum
after exposure to 10 or 50 ppm. In similar experiments, D1V1ncenzo et al.
(1978) determined that -65-68% of 2-hexanone vapor was absorbed by the lungs
of four young male beagle dogs that were exposed to 50 or 100 ppm 2-hexanone
for 6 hours. Steady state appears to have been reached within the first 2
hours of exposure.
DIVIncenzo et al. (1977) examined the absorption of 2-hexanone following
a single gavage dose of 20 or 200 mg/kg 14C-labeled 2-hexanone in corn oil
to young adult male CD rats. 2-Hexanone was absorbed rapidly from the GI
tract. Serum 2-hexanone concentration peaked at 38 ng/ma within 2 hours
of treatment at 200 mg/kg. Of the administered dose of radioactivity,
38-42% was excreted as C0?, while 2.2-6% was excreted unchanged in expired
air. Over a 48-hour period, 35-40% was excreted in urine, and 0.8-1.4% was
recovered in feces. From 13.6-17.6% was retained In the body, primarily in
0183d
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the blood and liver. Total recovery ranged from 97-99% of the administered
dose of radioactivity.
Humans also absorb 2-hexanone from the GI tract readily. Two male
humans that were given a single oral dose of 0.1 mg/kg 14C-2-hexanone
eliminated 29.0-50% of the radioactivity In the breath as 14C02.
Expiration of 14CQp reached a peak 4 hours after treatment: Urinary
excretion accounted for 25.0-27.6% of the radio-activity. Overall recovery
of 14C was 65.8% (OlVlncenzo et al., 1978).
The skin 1s also an effective route of absorption for 2-hexanone 1n
humans. On the basis of excretion data, an absorption rate of 4.8-&.0
ug/m1n~lcnf2 has been estimated 1n humans (D1V1ncenzo et al., 1978).
The average amount of 14C-2-hexanone absorbed through the human skin was
21.4 mg. In male beagle dogs exposed dermally to 14C-2-hexanone,
excretion data Indicated that the rate of dermal absorption plateaued at <20
minutes, then rose markedly over the next 40 minutes. The 8-hour cumulative
excretion accounted for 16.8% of a dose of unspecified magnitude (OlVlncenzo
et al., 1978).
5.2. DISTRIBUTION
Forty-eight" hours after rats were orally administered
{l-14C)-2-hexanone (200 mg/kg) the highest concentrations of radioactivity
were found 1n the liver and blood (DIVIncenzo et al., 1977). Without
providing data, the Investigators also stated that distribution of
radioactivity was widespread. DIVIncenzo et al. (1976) determined a serum
half-life of 2-hexanone In guinea pigs to be 78 minutes following
1ntraper1toneal administration of 450 mg/kg 2-hexanone In corn oil. The
clearance time of 2-hexanone 1n the serum was 6 hours. The amount of
2-hexanone equivalents in the blood compartment at 1 hour after dosing was
1.4% of the administered dose, Indicating extensive distribution.
0183d
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Abdel-Rahman et al. (1976) determined a peak blood level of 650
jig/ml, achieved within 30 mlrvutes, In adult male Wlstar rats treated
1ntraper1toneal1y with -460 mg/kg 2-hexanone. The half-life for the rapid
Initial phase of elimination from blood was 10 minutes, followed by a slower
phase of elimination with a 7-hour half-life. A similar serum elimination
time of 6 hours for 2-hexanone was determined In rats after oral administra-
tion of 200 mg/kg (DlVlncenzo et al., 1977), although the peak serum concen-
tration was only 38 vg/ma.
DlVlncenzo et al. (1977) studied the subcellular distribution of radio-
activity In the liver, kidney and brain of rats <24 hours after oral
treatment with 200 mg/kg of (l-14C)-2-hexanone. Tissue fractions examined
Included the acid-soluble fraction, DNA, RNA, crude llpld fraction and
original homogenate. Subcellular distributions of radioactivity In liver,
kidney and brain were similar among the tissues. Radioactive incorporation
into llplds and protein reached a peak at 8 hours and remained unchanged or
decreased at 24 hours.
5.3. METABOLISM
The metabolism of (l-14C)-2-hexanone has been studied following gavage
administration of a 20 or 200 mg/kg dose to rats (DlVlncenzo al. 1977).
Thirty-eight percent of the administered dose was identified as 14CO? in
the breath. Radioactive metabolites of 2-hexanone in the serum included
2-hexanol, 5-hydroxy-2-hexanone and 2,5-hexanedione. Metabolites detected
in the urine included 2-hexanol, 5-hydroxy-2-hexanone, 2,5-hexaned1one,
2,5-d1methylfuran, y-valerolactone, norleuclne and urea.
DlVlncenzo et al. (1978) exposed three male volunteers to 2-hexanone for
4 hours (100 ppm) or 7.5 hours (10 or 50 ppm). Exposure to 100 ppm for 4
hours produced an average 2-hexanone concentration in the expired air of 22
0183d
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ppm; exposures to 10 and 50 ppm for 7.5 hours produced mean breath
concentrations of 1.4 and 9.3 ppm, respectively. 2,5-Hexanedlone, a
neurotoxlc and testlcular toxic metabolite, was still detected 1n the serum
after exposure to 50 and 100 ppm of 2-hexanone up to 3 hours after cessaton
of the exposure.
The metabolism of 2-hexanone In guinea pigs following a single Intra-
perltoneal Injection of 450 mg/kg 2-hexanone was Investigated by DIVIncenzo
et al. (1976). The principal serum metabolite of 2-hexanone was 2,5-hexane-
dlone. 5-Hydroxy-2-hexanone and 2-hexanol were also Identified In the
serum. Courl et al. (1978) detected 2-hexanol and 2,5-hexanedlone In the
blood and urine of guinea pigs treated with 114 mg/kg 2-hexanone by the
Intraperltoneal route. Abdel-Rahman et al. (1976) detected 2-hexanol and
2,5-hexanedlone 1n the blood of rats and guinea pigs following Intraperlto-
neal Injection of 2-hexanone. Rats and guinea pigs were administered ~213
and 356 mg/kg 2-hexanone, respectively. Abdel-Rahman et al. (1976) were
unable to detect 2,5-hexanedlone In the blood of rats exposed continuously
by Inhalation to 400 ppm 2-hexanone for <60 days.
There Is some evidence for the Involvement of hepatic cytochrome P-450
In the u-1 oxidation of 2-hexanone to 5-hydroxy-2-hexanone and 2,5-hexane-
dlone (Courl et al., 1978; DIVIncenzo et al., 1977). DIVIncenzo et al.
(1977) reported that pretreatment of rats with 35 mg/kg SKF 525A. a mixed-
function oxldase Inhibitor, markedly Increased the respiratory excretion of
14CO? and decreased urinary radioactivity (DIVIncenzo et al., 1977).
Figure 5-1 depicts a proposed metabolic scheme for 2-hexanone based upon
the studies of DIVIncenzo et al. (1977, 1978). 2-Hexanone can undergo
metabolism by several pathways, such as reduction, a-ox1dat1on, «-l
oxidation, decarboxylatlon and transamlnatlon. One step of the metabolism
of 2-hexanone Involves the reduction of the carbonyl group to the secondary
0183d
-18-
12/07/89
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-19-
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alcohol 2-hexanol. Another Involves the oxidation of the u-1 carbon atom
to form the hydroxyketone, 5-hydroxy-2-hexanone. The hydroxyketone 1s
further oxidized to 2,5-hexaned1one. Presumably, the expired 14CO? 1s
produced by the a-ox1dat1on of (l-14C)-2-hexanone to a-ketohexanoate,
followed by decarboxylatlon to 14CO~ and 1-Pentanal. Alternatively,
14CO_ could be formed from the decarboxylatlon of 2-keto-5-hydroxy
hexanolc acid that results from the oxidation of 5-hydroxy-2-hexanone.
14C-Norleudne can be formed from the a-ox1dat1on of (l-14C)-2-hexa-
none to a-ketohexanoate, which In turn can undergo transamlnation. As
shown In Figure 5-1, the formation of 2,5-hexaned1one, -y-valerolactone and
the cyclic metabolite, 2,5-d1methylfuran, proceeds from 5-hyroxy-2-hexanone.
2-Hexanol, 5-hydroxy-2-hexanone and 2,5-d1methylfuran are excreted as glucu-
ronldes. Metabolism of 2-hexanone to CO- Is considered a detoxification
pathway, whereas the formation of 2,5-hexanedlone, a neurotoxlc metabolite.
Is regarded as metabolic activation.
5.4. EXCRETION
Two volunteers who Ingested a single oral dose of 0.1 mg/kg
14C-2-hexanone excreted -4054 of the total dose as 14CO_ In the breath
(OlVlncenzo et al.t .1978). Levels of respiratory 14CO- peaked within 4
hours and declined gradually within 3-5 days. Excretion of radioactivity In
the urine within 8 days accounted for 26.3% of the administered dose. The
feces were not assayed for radioactivity. The overall recovery of 14C was
65.8%.
Rats administered 14C-2~hexanone (20 or 200 mg/kg) by gavage excreted
44% of the dose In their breath as 14CO (38%) and as unchanged
2-hexanone (6%) (OlVlncenzo et al., 1977). Urinary excretion of radioactiv-
ity represented 40% of the total dose, while elimination of radioactivity In
0183d -20- 06/12/89
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the feces was 1.4%. After 48 hours, 14% of the dose remained 1n the body,
whereas 8% remained after 6 days. The experiments performed with humans and
rats Indicate that radioactivity derived from (l-14C)-2-hexanone was
excreted more completely by rats (DIVIncenzo et al., 1977, 1978).
5.5. SUMMARY
2-Hexanone 1s absorbed readily from the GI tract, the respiratory tract,
and through the skin. Respiratory uptake data In humans (DIVIncenzo et al.,
1978) Indicate that -75-92% of Inhaled 2-hexanone was absorbed by the lungs
and respiratory mucosa following exposure to 10-100 ppm for 4-7.5 hours.
Approximately 65-68% of 2-hexanone vapor was absorbed by the lungs of dogs
exposed to 50 or 100 ppm 2-hexanone for 6 hours. A dermal absorption rate
of 4.8-8.0 ng/m1n~1cm~2 was determined In humans from the analysis of
excretion data (DIVIncenzo et al., 1978).
Although distribution of radioactivity from administered
(1-14C)-2-hexanone appears to be rapid and widespread, the highest
concentrations of radioactivity following oral administration of 2-hexanone
1n rats were detected In the liver and blood (DIVIncenzo et al., 1977).
Following absorption, 2-hexanone undergoes extensive metabolism and
elimination. 2-Hexanone Is metabolized by hepatic cytochrome P-450 oxldases
with the formation of 5-hydroxy-2-hexanone and 2,5-hexaned1one (DIVIncenzo
et al., 1977; Courl et al., 1978). The metabolism of 2-hexanone to
2,5-hexanedlone Is regarded as metabolic activation, since there Is evidence
that 2,5-hexanone mediates the neurotoxlclty and testlcular toxlclty of
2-hexanone. 2,5-Hexanedlol Is formed by the oxidation of 2-hexanol or by
the reduction of 5-hydroxy-2-hexanone. Urinary metabolites of 2-hexanone
Include 2,5-hexaned1one, 2-hexanol, 5-hydroxy-2-hexanone and 2,5-dlmethyl-
furan. 2-Hexanol, 5-hydroxy-2-hexanone, and 2.5-dlmethylfuran are excreted
as glucuronldes.
0183d
-21-
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Rats administered 1«C-2-hexanone by gavage excreted 44% of the dose In
the breath as l«C02 (38%) and 2-hexanone (6%) (DIVIncenzo et al.. 1977).
Forty and 1.4% of the dose was excreted 1n the urine and feces, respec-
tively. About 14% remained 1n the carcass 48 hours after dosing.
Humans Ingesting 0.1 mg/kg of (l-14C)-2-hexanone excreted 40% of the
dose In the breath as «C02 and 26% 1n urine (DIVIncenzo et al., 1978).
Excretion of 2-hexanone 1s less complete In humans than In rats.
0183d
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC -- Spencer et al. (1975) exposed six rats to 1300
ppm 2-hexanone, 6 hours/day, 5 days/week for 4 months. Three rats served as
controls. During each exposure, the rats exhibited slight narcosis after 4
hours and loss of coordination after 5.5 hours. Exposed rats had a slow
progressive weight loss beginning on the 73rd day of exposure. In addition,
exposed rats developed a pronounced hindUmb foot drop between the third and
fourth months of exposure to 2-hexanone. Some of the exposed rats also
exhibited severe proximal hlndllmb and forellmb weakness. Peripheral and
central nerve fiber damage was prominent. Pathological alterations In
peripheral nerves Included axonal dilatation along with fiber swelling and
paranodal myelln retraction. Axonal degeneration was observed In peripheral
nerves, spinal cord, medulla oblongata and cerebellum.
Mendel 1 et al. (1974) evaluated the neurotoxlc effects of 2-hexanone In
rats and cats. Four Sprague-Dawley rats and four domestic cats were exposed
to 2-hexanone, 24 hours/day, 7 days/week for 12 weeks. The Initial exposure
concentration of 600 ppm was adjusted to 400 ppm at an unspecified time
because of weight loss in the exposed groups. Pair-fed animals were used as
controls. Routine recording of the electrical activity of various muscles
Including suprasplnatus, triceps, extensor carpi, deep digital flexors,
paraspinals, quadriceps, hamstring, gastrocnemius and anterior tiblaUs were
performed by EHG. Signs of clinical weakness, such as dragging of hind
limbs, developed in exposed animals at 5-8 weeks (for cats) and 11-12 weeks
(for rats). Pathological changes in exposed cats, as revealed by EMG
findings, consisted of abnormal Insertlonal activity with positive waves,
0183d
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which developed between 4 and 6 weeks. Fibrillation potentials In muscles
at rest were evident between 9 and 10 weeks. A decrease In the velocity of
ulnar nerve conduction occurred In cats between 7 and 9 weeks. All muscles
examined displayed these EMG changes. H1stopatholog1cal examination of the
sciatic nerves of exposed animals revealed a peripheral neuropathy charac-
terized by focal swelling of the axon along the nerve fiber, accumulation of
neurofllaments and thinning of the myelln sheath In the area of axonal
swelling and denudation of myelln 1n both species.
Signs of neuropathy were reported In groups of 12 rats that were exposed
continuously to 2-hexanone at 225 ppm for <66 days or 400 ppm for <42 days
(Salda et al., 1976). Paralysis developed 1n the rats exposed to 225 ppm at
66 days and 1n the rats exposed to 400 ppm at 42 days. Serial sacrifice of
the rats for hlstopathologlcal examination of the sciatic nerves revealed
that the earliest changes were the accumulation of neurofllaments, followed
by axonal swelling and thinning of the myelln sheath and eventual denudation
of myelln.
Muscular weakness and sciatic nerve axonal hypertrophy and degeneration,
along with myelln breakdown, were observed In nine rats exposed to 200 ppm
2-hexanone, 8 hours/day, 5 days/week for 6 weeks (Duckett et al., 1974).
There were four control rats; sex and strain of the rats and method of
measurement of exposure levels were not specified. Duckett et al. (1979)
reported an effect of 2-hexanone on sciatic nerve conduction velocity In
rats, but at a lower concentration. Forty Wlstar white rats were exposed to
50 ppm 2-hexanone for 6 months, 8 hours/day, 5 days/week. A decrease In
MNCV In the exposed group was observed. Demyellnatlon of the sciatic nerve
was present in 32 of the rats, with 2 of the rats also showing evidence of
axonal hypertrophy. According to the authors, the observed extensive
0183d
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demyell nation and minimal axonal changes differ from the observations In
previous studies of 2-hexanone-1nduced neuropathy, which have described
axonal pathology as the primary lesion with secondary demyellnation.
Johnson et al. (1977) Investigated the behavioral and neurological
effects of 2-hexanone 1n rats and monkeys. Groups of 10 albino male rats
(Sprague-Dawley) and 8 male monkeys (Hacaca fasdcularls) were exposed to
2-hexanone at 0, 100 or 1000 ppm for 6 hours/day, 5 days/week. Exposure to
1000 ppm was terminated after 25 weeks, when rats and monkeys demonstrated a
bilateral neuropathy manifested as a hlndUmb drag. Five of the monkeys
were subjected to hlstopathologlcal examination; three were maintained
without subsequent exposure to evaluate the reversibility of the effects.
Exposure to 100 ppm was terminated after 29 weeks (rats) or 41 weeks
(monkeys), when (presumably) the exposed animals exhibited hlndllmb drag.
The animals were subjected to several neurological tests, Including
recording of maximum MNCV of the sciatic, tibia! and ulnar nerves, absolute
refractory period of these nerves and muscle action potentials. In
addition, EEG and visual evoked potentials were recorded from monkeys, and
exposed rats (number In each group not specified) were trained so that the
Investigators could evaluate the effects of 2-hexanone on operant behavior.
Behavior after exposure was compared with pretreatment performance.
A statistically significant (p<0.05) concentration- and duration-related
depression In MNCV were observed In the sciatic, tibia! and ulnar nerves of
the exposed monkeys and rats. Also, a reduction In evoked muscle action
potentials was reported that reached statistical significance 1n monkeys at
1000 ppm. Rats exposed to 1000 ppm 2-hexanone displayed Impaired operant
behavior after 2 weeks. Exposure to 100 ppm 2-hexanone had no effect on
operant behavior. An Increase In the latency of visual evoked potentials
was observed In monkeys following 4 months of exposure to 1000 ppm. There
0183d
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were no effects on absolute refractory time or EE6. The three monkeys
exposed previously to 1000 ppm and then maintained to evaluate recovery
exhibited no change In sciatic, tibia! HNCV during the first 2 months of the
recovery period. Complete recovery of the HNCV occurred over the next
4-month period. Animals (species not stated) exposed to 100 ppm exhibited
complete recovery of sclatlctlblal HNCV 1n 2 months.
Johnson et al. (1979) reported no effect on gross hlstopathology In
liver, spleen, kidney, adrenal or brain tissues In rats or monkeys exposed
to 100 or 1000 ppm for 29 or 41 weeks, respectively. Neuropathologlcal
examination of the sciatic nerves from rats and monkeys In the 1000 ppm
group showed axonal swelling and myelln thinning. Honkeys exposed to 100
ppm showed an Increase In nonmyellnated fibers and endoneural collagen, and
a decrease In large fibers.
Five male rats exposed by Inhalation to 700 ppm 2-hexanone, 72 hours/
week for 11 weeks showed a reduction In weight gain with depletion of
adipose tissue and marked atrophy of the hlndllmb musculature (Katz et al.,
1980). The rats were exposed for two 20-hour periods and two 16-hour
periods during the work week. A control group of five rats was exposed to
conditioned air. A significant depression In testlcular weight was also
observed. Clinical chemistry and hematologlcal values were similar among
exposed and control rats except for a significant reduction In the total
white blood cell counts of treated rats. Signs of neuropathy were also
evident as early as the second week of exposure.
Allen et al. (1975) reported an outbreak of neuropathy In humans exposed
to 2-hexanone In an occupational setting. Screening procedures (question-
naire, EHG and nerve conduction tests) Identified 86 Individuals affected
with toxic neuropathy among 1157 workers In a fabric-printing plant In which
2-hexanone was used as a solvent. The clinical syndrome was presented as an
0183d
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Insidious distal motor and sensory disorder with minimal reflex loss.
Severely affected Individuals also exhibited moderate weight loss. The time
course of the outbreak correlated with exposure to 2-hexanone, which had
been Introduced as a new solvent ~7 months earlier. Further Investigation
revealed that symptoms developed In one worker after only 5 weeks of
exposure. Levels of 2-hexanone associated with the outbreak were determined
to be 9.2-36.0 ppm. Several other chemicals were present In "trace"
amounts. An Investigation of dally work habits of the employees revealed
that at least some of the workers were subjected to dermal as well as
Inhalation exposure. The condition of the workers Improved upon elimination
of 2-hexanone from the work environment.
6.1.1.2. CHRONIC Pertinent data regarding the toxlclty of 2-hexa-
none following chronic Inhalation exposure In laboratory animals or humans
were not located In the available literature cited In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC -- Krasavage et al. (1980) Investigated the
neurotoxlc effects of 2-hexanone (-96% purity) 1n rats after oral adminis-
tration. Groups of five adult male COBS rats were administered 0 or 600
mg/kg/day neat 2-hexanone by gavage, 5 days/week until pronounced hind-limb
drag was observed. Controls were treated on the same schedule with
distilled water. Exposure to 2-hexanone was terminated at 10 weeks because
of hlndllmb drag. Treated rats had reduced food consumption and reduced
body weights compared with controls. Hlstopathologlcal examination revealed
giant axonal neuropathy and testlcular atrophy.
Homan and Maronpot (1978) reported that 1000 mg/kg/day of 2-hexanone
administered to female Wlstar rats In their drinking water for 120 days
produced muscle weakness and atrophy and peripheral neuropathy. Other
0183d
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effects Included a reduction In both food and water consumption, decreased
rate of body weight gain and Increased relative kidney weight.
Abdel-Rahman et. al. (1978) examined the effects of 2-hexanone, adminis-
tered In drinking water, on water consumption, body weight, puplllomotor
activity and locomotor activity In guinea pigs. H1stopatholog1cal examina-
tion was not performed. Groups of five English short hair guinea pigs (sex
not reported) were administered 2-hexanone In their drinking water at
concentrations of 0.1 or 0.25% for 24 weeks. On the basis of an average
dally water consumption of 60 mi/day and an average body weight of -0.6 kg
after 8 weeks of treatment (body weights were recorded only through the 8th
week of treatment), dosages were -0, 100 and 250 mg/kg/day. Exposed guinea
pigs gained weight more rapidly than controls. Locomotor activity, measured
only In guinea pigs at the 0.25% level at 8 weeks, was marginally (p<0.1)
depressed. Pupillary response was decreased to about the same degree In
both exposed groups (0.57 mm at 0.1% and 0.6 mm at 0.25%) compared with
controls (1.06 mm). Statistical analysis was not performed, lo determine
the time to onset, the experiment was repeated at the 0.25% level. De-
creased pupillary response was observed within the first week of treatment,
compared with controls (p<0.001), and decreased progressively throughout the
5 weeks of exposure.
A significant reduction 1n body weight was observed at all dose levels
In male rats that were administered 2-hexanone at concentrations of 0.25,
0.5 and 1.0% In the drinking water for 10-13 months (Krasavage et al.,
1979). Assuming an average water Intake of 0.14 8,/kg/day (U.S. EPA,
1986b), the estimated doses are 350, 700 and 1400 mg/kg/day. The authors
reported that morphologic changes observed were similar for those of other
reports for this chemical.
0183d
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6.1.2.2. CHRONIC Perlnent data regarding the toxlclty of 2-hexa-
none following chronic oral exposure were not located In the available
literature dted 1n Appendix A.
6.1.3. Other Relevant Information. Table 6-1 summarizes the results of
the acute lethal exposure to 2-hexanone derived from several animal studies.
The oral LD5Q data Indicate that rats and mice are nearly equally
sensitive to the acute toxldty of 2-hexanone. The dermal LD5Q data In
rabbits suggest that absorption occurs readily by this route.
Schrenk et al. (1936) examined the acute toxlclty of 2-hexanone In
guinea pigs following exposure to 2-hexanone vapors at concentrations of 0,
1000, 2300, 6500 or 20000 ppm for <810 minutes. Nasal Irritation occurred
within the first minute at all levels of exposure. Eye Irritation and
lacrlmatlon occurred In all groups within 30 minutes. Incoordlnatlon was
observed at 5-10 minutes at 20,000 ppm, at 20-30 minutes at 6500 ppm and at
90 minutes at 2300 ppm. Narcosis was observed at 20-30 minutes at 2000 ppm
and at 90-120 minutes at 6500 ppm. Dyspnea and gasping were noted at 30-60
minutes at 20,000 ppm and at 240-540 minutes at 6500 ppm. Guinea pigs
exhibited narcosis after a 20- to 30-mlnute exposure to 20,000 ppm vapor.
Lethality occurred at 20,000 ppm at 70 minutes and at 6500 ppm at 540
minutes. Apparently, death was due to narcosis rather than to Irritation of
the lungs. Autopsy examination of animals that died during exposure
revealed slight congestion of the brain, and moderately marked congestion of
the lungs, kidneys and liver. No gross pathology was observed in guinea
pigs exposed to 2200 ppm vapor for 90 and 270 minutes, or to 1000 ppm for
810 minutes. Volunteers exposed for a few minutes to 1000 ppm 2-hexanone
vapor experienced moderate eye and nasal Irritation.
Specht et al. (1940) reported acute toxlclty of 2-hexanone In guinea
pigs. Ten female guinea pigs exposed by Inhalation to 6000 ppm for <525
0183d -29- 12/07/89
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TABLE 6-1
Acute Lethal Toxlclty of 2-Hexanone
Species
Rat
House
Rat
Route
oral
oral
Inhalation
Result
L050 2590
LD50 2430
8000 pptn
mg/kg
mg/kg
lethal to
Reference
NIOSH,
NIQSH,
NIOSH,
1989
1989
1989
6/6 1n 4 hours
Rat Inhalation 4000 ppm lethal to
0/6 In 4 hours
Guinea pig Inhalation 6000 ppm lethal to all
animals by 9 hours
Rabbit dermal 1050 4800 mg/kg
Smyth et al., 1954
Specht et al.. 1940
NIOSH, 1989
0183d
-30-
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minutes displayed symptoms of narcosis, depressed body temperature, reduced
heart and respiratory rate, loss of cornea! reflex and eye and upper
respiratory tract Irritation. Seven guinea pigs died between 100 and 525
minutes. Spencer and Schaumberg (1977) observed clinical, gross and micro-
scopic evidence of neuropathy In 11 young, adult Sprague-Dawley rats exposed
continuously by Inhalation to 600 ppm 2-hexanone for 3.5 days. Sixteen age-
and weight-matched rats served as controls.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenUHy of 2-
hexanone following Inhalation exposure were not located 1n the available
literature cited 1n Appendix A.
6.2.2. Oral. Pertinent data regarding the carclnogenlcHy of 2-hexanone
following oral exposure were not located 1n the available literature cited
In Appendix A.
6.2.3. Other Relevant Information. Other relevant Information regarding
the carclnogenUlty of 2-hexanone were not located 1n the available
literature cited 1n Appendix A.
6.3. HUTAGENICITY
Pertinent data regarding the mutagenUHy of 2-hexanone were not located
In the available literature cited 1n Appendix A.
6.4. DEVELOPMENTAL TOXICITY
There are relatively few data regarding the capacity for 2-hexanone to
produce developmental toxlclty. Peters et al. (1981) examined the effects
of 2-hexanone on postnatal development and behavior In rats following
chronic Inhalation exposure. Groups of 25 pregnant F344 rats were exposed
to 500, 1000 or 2000 ppm 2-hexanone for 6 hours/day throughout the 21 days
of gestation. Control groups were established for each of the exposed
groups. Rats In the 2000 ppm group were pair-fed since exposure at this
0183d -31- 05/23/90
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concentration was associated with a reduction In maternal food consumption.
Behavioral, neurological, liver function, clinical pathological, organ
weight and h1stopatholog1cal evaluations of the offspring were performed at
various times until the offspring were 20 months old. Behavioral tests
Included righting reflex, Inclined screen performance, food maze behavior,
open-field behavior, activity wheel behavior, endurance swim test and
avoidance conditioning.
2-Hexanone exposure reduced maternal weight gain by 10 and 14% at the
1000 and 2000 ppm levels, respectively. Exposure to 2000 ppm resulted In
muscular Incoordlnatlon and weakness by exposure day 20. Reduced number and
weight of live offspring were reported at 2000 ppm. These effects were not
reported 1n the 500 ppm group, which -- because of problems 1n the experi-
ment was terminated before the offspring were 3 weeks of age. There were
no consistent treatment-related alterations 1n survival, organ weights or
hlstopathologlcal appearance of several major organs and tissues. Organs
examined were adrenals, brain, heart, kidney, liver, lung, ovaries,
pituitary, pancreas, prostate, seminal vesicles, spleen, testls, thymus,
thyroid and uterus. PentobarbHal-lnduced sleeping time (evaluated only In
offspring of the 2000 ppm group) was Increased In prenatally exposed males
and decreased In prenatally exposed females.
Alterations 1n several of the behavioral tests (Inclined screen, food
maze behavior, open field, activity wheel) were detected following exposure
to 1000 and 2000 ppm of 2-hexanone. The results of some of the tests
suggest that 2-hexanone exposure Is associated with hyperactlvlty In young
but not In aged rats. Further, the authors noted that exposure of pregnant
rats caused a lifelong dose-dependent reduction In the growth of male and
female offspring.
0183d -32- 12/07/89
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Using Inhalation chambers, Tyl et al. (1987) exposed pregnant F344 rats
and CD-I mice to the 2-hexanone vapors. The exposures occurred on gestation
days 6 through 15 and at concentrations of 0, 300, 1000 or 3000 ppm. Rats
were sacrificed on gestatlonal day 21 and mice on gestatlonal day 18. There
was no evidence of a treatment-related effect at 300 or 1000 ppm In either
mice or rats.
Rats exposed to 3000 ppm, observed through gestation day 15, demon-
strated maternal toxidty (decreased body weight, reduced body weight gain,
and decreased food consumption). These effects were directly related to the
exposure and returned to normal during the postexposure period {gestation
days 15-21). At the time of the scheduled sacrifice, dams exposed to 3000
ppm had a statistically significant Increase In relative kidney weight;
there were no other treatment-related findings.
Alterations In developmental parameters In rat fetuses that demonstrated
statistically significant effects were limited to a reduction In fetal
weight and a reduction 1n skeletal ossification. These effects were only
seen In the group exposed to 3000 ppm. There were no statistically signifi-
cant changes In the external, visceral, skeletal or total malformations In
any of the exposed groups relative to the controls.
Similarly, mice were found to have maternal toxidty after exposure to
3000 ppm, specifically, the death of three pregnant dams on gestation day 6.
At the time of the scheduled sacrifice, observations of maternal toxidty
were limited to dams exposed to 3000 ppm. These animals had statistically
significant Increases In abs.olute and relative liver weight; there were no
other treatment-related findings.
Relative to the controls, developmental toxidty In mice was limited to
groups exposed to 3000 ppm. This Included statistically significant
Increases In the number of dead fetuses, significant reduction In fetal body
0183d -33- 12/07/89
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weight per litter and reductions In skeletal ossification. As with the
exposed rats, there were no statistically significant changes In the
external, visceral, skeletal or total malformations 1n any of the exposed
groups relative to the controls.
6.5. OTHER REPRODUCTIVE EFFECTS
As noted In Sections 6.1.1.1. and 6.1.2.1., respectively, following
Inhalation exposure to the 2-hexanone (700 ppm, 72 hours/week for 11 weeks)
Katz et al. (1980) observed a significant depression In testlcular weight
and Krasavage et al. (1980) found that exposure by gavage (600 mg/kg/day, 5
days/week for up to 11 weeks) produced a testlcular atrophy. Similar to the
neuropathy, the production of the 2,5-hexaned1one metabolite appears to be
an Integral feature of the biochemical mechanism leading to the effect.
The testlcular effects have been evaluated by directly administering the
2,5-hexanedlone to test animals. The mechanism of action for the effect
appears to be an alteration of the biochemistry (principally llpld metabo-
lism) of the testls (Gillies et al., 1981; Boekelhelde, 1987). Another
ramification of exposure appears to be attributable to a direct action on
the Sertol! cells (Chapln et al., 1982) by Inducing a biochemical dysfunc-
tion of the systems associated with mlcrotubule assembly {Boekelhelde,
1987). Further, this effect 1s dependent on the dose rate and 1s Indepen-
dent of the total dose (Boekelhelde and Eveleth, 1988). Curiously, this Is
the direct opposite of the dynamics associated with the 2,5-hexaned1one
Induced Injury of the nervous system (Krasavage et al., 1980).
6.6. SUMMARY
Acute Inhalation exposure of animals or humans to high concentrations of
2-hexanone vapor causes an almost Immediate Irritation to the eyes and nose
(Schrenk et al., 1936). In guinea pigs, exposure to 6500-20,000 ppm
0183d -34- 12/07/89
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resulted In ataxla, narcosis and death {Schrenk et al., 1936). The cause of
death In guinea pigs was attributed to narcosis. Congestion of the lungs,
kidneys and liver was found during autopsy examination. In humans, exposure
to 1000 ppm for a few minutes resulted In moderate ocular and nasal
Irritation (Schrenk et al., 1936).
Results of subchronlc Inhalation animal studies Indicate that 2-hexanone
neurotoxlclty Is characterized by the development of peripheral neuropathy
(Mendell et al., 1974; Spencer et al., 1975; Salda et al., 1976; Johnson et
al., 1977). Neuropathologlcal features of peripheral nerve damage Include
giant axonal swellings and axonal degeneration. Peripheral nerve damage Is
associated with hlndUmb drag and weakness of the forellmbs and hlndllmbs In
rats, monkeys and cats. Electrodlagnostk studies reveal accompanying
abnormalities 1n EHG and MNCV (Johnson et al., 1977; Duckett et al.. 1979).
A marked depression In testlcular weight was noted by one Investigator
(Katz, 1980).
Behavioral studies revealed alterations In rats exposed to levels asso-
ciated with hlstopathologlcal evidence of peripheral neuropathy (Johnson et
al., 1977). Intermittent exposure to 50 ppm, the lowest concentration
tested In animal Inhalation studies, was associated with decreased MNCV and
extensive nerve demyellnatlon In rats (Duckett et al., 1979). Clinical
signs of neuropathy have been documented In humans exposed to 2-hexanone In
the work environment at concentrations as low as 9.2-36.0 ppm (Allen et al.,
1975).
Several oral gavage and drinking water studies Indicate that the effects
of oral exposure to 2-Hexanone are similar to those associated with
Inhalation exposure (Krasavage et al., 1979, 1980; Homan and Haronpot, 1978;
Abdel-Rahman et al., 1978). Generally, large doses were administered to
0183d -35- . 12/07/89
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produce the typical neurological syndrome. In one study, testlcular atrophy
was observed In rats treated by gavage at 600 mg/kg/day for 10 weeks
(Krasavage et al., 1980). The oral studies were not performed at dosages
sufficiently low to Identify thresholds for neuropathy.
Testlcular effects have been studied 1n greater detail by administering
2,5-hexanedlone directly to test animals. Alterations are observed In the
biochemistry of Upld metabolism and mlcrotubule assembly (Gillies et al.,
1981; Boekelhelde, 1987). These effects appear to be dependent on the dose
rate and are Independent of the total dose (Boekelhelde and Eveleth, 1988).
Data were not located regarding the carclnogenlcHy of 2-hexanone to
animals or humans exposed by any route. No data were located regarding the
mutagenldty of 2-hexanone In prokaryotlc or eukaryotlc test systems. In a
teratogenldty study 1n pregnant rats, a decrease In maternal weight gain
was observed at 1000 or 2000 ppm 2-hexanone for 6 hours/day throughout
gestation (Peters et al., 1981). A reduction In the number and weight of
live offspring was detected 1n rats exposed to 2000 ppm 2-hexanone. Post-
natal behavioral changes were observed In both the 1000 and 2000 ppm groups.
These results were corroborated by Tyl et al. (1987) who found a
decrease In maternal weights 1n mice and rats only after exposure to 3000
ppm of 2-hexanone during days 6-15 of gestation. Evidence of developmental
toxlclty was only observed In the group exposed to 3000 ppm and was limited
to Increased Incidence of dead fetuses (only seen In mice), reduced fetal
body weight per litter, and reductions In skeletal ossification (mice and
rats). There was no evidence of a dose-dependent Increase In developmental
toxlclty, at 300 or 1000 ppm In either species.
0183d -36- 12/07/89
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The current ACGIH (1988) recommended TWA-TLV for 2-hexanone 1s 5 ppm (20
mg/m3). ACGIH (1988) does not recommend a STEL for 2-hexanone. These
recommendations are based largely on the Inhalation and oral studies In
animals that associate peripheral neuropathy with exposure to the compound
(ACGIH, 1986). OSHA (1989) lists transitional limits for 2-hexanone of 100
ppm (410 mg/m3) and final rule limits of 5 ppm (20 mg/m3), Identical to
the ACGIH (1988) recommendation.
7.2. AQUATIC
Guidelines and standards to protect aquatic life from exposure to
2-hexanone were not located 1n the available literature cited In Appendix A.
0183d -37- 09/11/89
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
2-hexanone to animals or humans following Inhalation exposure were not
located In the available literature cited In Appendix A.
8.1.2. Oral. Pertinent data regarding the carclnogenlclty of 2-hexanone
to animals or humans following oral exposure were not located 1n the
available literature cited In Appendix A.
8.1.3. Other Routes. Pertinent data regarding the carclnogenlcUy of
2-hexanone following other routes of exposure were not located In the
available literature dted In Appendix A.
8.1.4. Weight of Evidence. The lack of data regarding the carclnogenlc-
lty of 2-hexanone 1n humans or animals Is the basis for assigning 2-hexanone
to U.S. EPA Group D -- not classifiable as to human carclnogenlclty, using
the U.S. EPA (1986c) classification scheme.
8.1.5. Quantitative Risk Estimates. The lack of positive carclnogenlclty
data for 2-hexanone precludes quantitative estimation of carcinogenic risk.
8.2. SYSTEMIC TOXICITY
8-.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) -- Several studies
have demonstrated the development of peripheral neuropathy in rats, cats and
monkeys following Inhalation exposure to 2-hexanone (Mendell et al., 1974;
Spencer et al., 19-75; Salda et al., 1976; Spencer and Schaumberg, 1977;
Johnson et al., 1977, 1979; Ouckett et al., 1974, 1979). CNS effects,
progressive weight loss and a pronounced hlndllmb foot drop were noted In
rats (Rec. #3) exposed to 1300 ppm 2-hexanone, 6 hours/day, 5 days/week for
4 months (Spencer et al., 1975). Mendell et al. (1974) reported altered
0183d -38- 12/07/89
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electrical actlvHy of muscles, hlndllmb drag and hlstopathologlcal evidence
of severe neuropathy In cats (Rec. #5) and rats (Rec. #4) exposed continu-
ously to 400 ppm. Salda et al. (1976) reported paralysis In rats exposed
continuously to 400 ppm for 42 days or to 225 ppm for 66 days (Rec. #15).
Johnson et al. (1977) exposed rats and monkeys 6 hours/day, 5 days/week to
1000 ppm for 25 weeks or to 100 ppm for 29 weeks (rats, Rec. #2) or 41 weeks
(monkeys, Rec. #1), when exposures were terminated because hlndllmb drag was
evident. MNCV 1n the sciatic, tlblal and ulnar nerves were decreased In a
generally concentration- and duration-related manner. Exposure to 1000 ppm
6 hours/day 5 days/week for 25 weeks had no effect on the hlstopathologlcal
morphology of liver, spleen, kidney, adrenal or brain tissues In rats or
monkeys, Indicating that peripheral neuropathy Is the critical effect of
repeated exposure to lower levels of 2-hexanone. Because gross Impairment
of neurological function was observed by Spencer et al. (1975) at 1300 ppm,
by Mendell et al. (1974) at 400 ppm, by Salda et al. (1976) at 2?5 and 400
ppm and by Johnson et al. (1977) at 1000 and 100 ppm, these studies define
FELs but do not define LOAELs for peripheral neuropathy.
Duckett et al. (1979) reported a reduction In MNCV, along with extensive
demyellnatlon of the sciatic nerve. In rats subjected to 50 ppm ?-hexanone 8
hours/day, 5 days/week for 6 months (Rec. #8). The data were available only
In an abstract, however, and were reported In Insufficient detail to
determine whether the observed effects define a PEL or a LOAEL. Therefore,
1t Is Inappropriate to use this study as the basis of an RfO.
Allen et al. (1975) reported an outbreak of neuropathy In humans exposed
to 2-hexanone In an occupational setting. The clinical symptoms correlated
with exposure to 2-hexanone on a time course basis; 2-hexanone was Intro-
duced as a new solvent ~7 months before symptoms were reported. Concentra-
tions of 9.2-36.0 ppm were quantified In the workroom atmosphere. However,
0183d -39- 09/11/89
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U appears that some of the workers also had skin contact with liquid
2-hexanone, so that both dermal and Inhalation exposure may have been In-
volved. Trace amounts of other chemicals were also present In the workroom
air. These data are not appropriate for deriving an RfD for Inhalation
exposure because a threshold for neuropathy 1n humans was not Identified,
the workers were exposed simultaneously to a number of chemicals and mixed
routes of exposure were Involved. The data are sufficient, however, to
suggest that neuropathy In humans may occur at or below levels associated
with neuropathy In laboratory animals.
The available data, therefore, are insufficient for derivation of an RfD
for subchronlc Inhalation exposure to 2-hexanone. It is recommended that a
well-designed Inhalation study be performed with groups of rats exposed
continuously to 2-hexanone at concentrations <50 ppm. Because of the
Insidious and progressive nature of the neurologic syndrome associated with
this chemical, the study duration should be at least 6 months. Several
behavioral and neurological variables should be evaluated.
8.2.1.2. CHRONIC EXPOSURE ~ No data regarding the chronic Inhalation
effects of 2-hexanone are available. In the absence of sufficient sub-
chronic data, an RfD cannot be derived for chronic Inhalation exposure to
2-hexanone.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE In a 90-day gavage study, 5
rats (Rec. #4) were administered 600 mg/kg/day 2-hexanone, 5 days/week
(Krasavage et a!., 1980). Peripheral neuropathy, paralysis, decrease in
weight gain and testicular atrophy were observed. Because paralysis
represents a gross Impairment of neurologic function, the 600 mg/kg/day
dosage 1s considered a PEL rather than a LOAEL. Homan and Haronpot (1978)
0183d -40- 09/11/89
-------
reported that 1000 mg/kg/day of 2-hexanone administered to rats 1n their
drinking water for 120 days produced muscle weakness and atrophy and
peripheral neuropathy (Rec. #2). This study was available only as a brief
abstract.
Abdel-Rahman et al. (1978) treated groups of five guinea pigs with
2-hexanone In their drinking water at doses of 100 (Rec. #3) and 250
mg/kg/day. Decreased locomotor activity was noted at the 250 mg/kg/day
level at 8 weeks. Pupillary response was decreased at both dosage levels.
In addition, a significant Increase 1n body weight was observed at both
dosages. This study was too limited In scope (hlstopathologlcal examination
was not performed), however, to be considered for RfO derivation.
Krasavage et al. (1979) administered 2-hexanone to rats at doses of 350
mg/kg/day (Rec. #1), 700 mg/kg/day and 1400 mg/kg/day in the drinking water
for 10-13 months. A significant reduction In body weight occurred at all
dose levels. Typical cllncal signs of neuropathy were noted in rats exposed
at the two highest doses. All treated groups of rats exhibited morpho-
logical signs typical for the compound. This study was available only in an
abstract, however, and was too briefly reported to evaluate the effects at
the lowest dosage; hence, the study cannot serve as the basis of an RfO.
The available subchronic oral data, while demonstrating that neuro-
logical effects are the critical effects of oral exposure to 2-hexanone, are
insufficient to serve at the basis for quantitative risk assessment. Oral
studies designed to evaluate peripheral neuropathy In rats at dosages <350
mg/kg/day should be initiated. Because of the insidious and progressive
nature of the neurologic syndrome, exposures should continue for at least 6
months.
0183d -41- 09/11/89
-------
8.2.2.2. CHRONIC EXPOSURE Studies of chronic oral exposure to
2-hexanone were not available. In the absence of sufficient subchronk
* data, an RfD cannot be derived for chronic oral exposure to 2-hexanone.
0183d -42- 09/11/89
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxiclty of 2-hexanone was discussed 1n Chapter 6 and dose-response
data considered for CS derivation are summarized In Table 9-1. Since no
chronic toxldty data are available, subchronlc data were considered. A
finding common to both the Inhalation and oral studies [except for the
developmental toxldty study by Peters et al., 1981)] 1s peripheral neuro-
pathy, which was frequently accompanied by muscular weakness, paralysis,
hlndllmb drag and hlstopathologlcal evidence of axonal degeneration. The
occupational study by Allen et al. (1975), 1n which neuropathy was reported
1n workers who experienced both Inhalation and dermal exposure, 1s not
Included In Table 9-1. In the study by Peters et al. (1981), exposure to
1000 and 2000 ppm of 2-hexanone (6 hours/day through gestation) produced a
10 and 14% weight loss, respectively. In addition, at 1000 ppm there was a
decrease In body weights and behavioral effects In male offspring; at 2000
ppm there was a decrease 1n the number of live pups, a decrease In the body
weights of all offspring and behavioral alterations.
Besides typical signs of 2-hexanone-1nduced neuropathy, Krasavage et al.
(1980) found testlcular atrophy and a decrease In weight gain In rats
administered 600 mg/kg/day 2-hexanone by gavage, 5 days/week for 90 days.
In a 24-week drinking water study limited to evaluation of reflexes and
behavior In guinea pigs, 100 mg/kg/day resulted 1n Impaired pupillary reflex
(Abdel-Rahman et al., 1978).
Table 9-2 presents CSs and RQs derived for the lowest human equivalent
dosages associated with each of the effects compiled 1n Table 9-1. Because
of the Insidious and progressive nature of the syndrome, neuropathy was
assigned an RV of 8. The fetotoxlc effects reported by Peters et al.
0183d -43- 09/11/89
-------
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-------
(1981) were also assigned an R\L of 8. The Impaired pupillary reflex
6
reported In guinea pigs (Abdel-Rahman et a!., 1978) was assigned an RVg of
7. The highest CS calculated, 22.4 associated with neuropathy In rats
exposed by Inhalation (Johnson et al.p 1977, 1979), was selected as most
stringently representing the chronic toxldty of 2-hexanone. The CS of 22.4
and Us corresponding RQ of 100 are presented In Table 9-3.
9.2. BASED ON CARCINOGENICITY
No data were located regarding the carclnogenlclty of 2-hexanone In
humans or animals, and the compound was placed 1n EPA Group D. Hazard
ranking based on carclnogenlclty Is not possible for EPA Group D substances;
therefore, an RQ based on carclnogenlclty cannot be assigned.
0183d -47- 09/11/89
-------
TABLE 9-3
2-HEXANONE
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species:
Dose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
Inhalation
rat
23.3
29 weeks
peripheral neuropathy and hlndllmb drag
3.3
8
26.7
100
Johnson et a!., 1977, 1979
'Equivalent human dose
0183d
-48-
09/11/89
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-------
Katz, G.V., 3.L. O'Donoghue, G.D. 01 Vlncenzo and C.3. Terhaar. 1980.
Comparative neurotoxlclty and metabolism of ethyl n-butyl ketone and methyl
n-butyl ketone In rats. Toxlcol. Appl. Pharmacol. 52(1): 153*158.
K1nl1n, T.E., R. Muralldhara, A.O. PHtet, A. Sanderson and 3.P. Halradt.
1972. Volatile components In roasted filberts. 3. Agrlc. Food Chem. 20:
1021-1028.
Krasavage, H.3., J.L. O'Donoghue and C.3. Terhaar. 1979. Oral chronic
toxlclty of methyl-n-propyl ketone, methyl n-butyl ketone and hexane In
rat. Toxlcol. Appl. Pharmacol. (Part 2): A205.
Krasavage, W.J., 3.L. O'Donoghue, G.D. D1 Vlncenzo and C.3. Terhaar. 1980.
The relative neurotoxlclty of methyl-n-butyl ketone, n-hexane and their
metabolites. Toxlcol. Appl. Pharmacol. 52(3): 433-441.
Lande, S.S., P.R. Durkln, D.H. Christopher, P.H. Howard and 3. Saxena.
1976. Investigation of selected potential environmental contaminants:
Ketonlc solvents. U.S. EPA, Office of Toxic Substances, Washington, DC.
EPA 560/2-76-003. p. 292.
Lyman, W.3. 1982. Adsorption coefficients for soil and sediments. In:
Handbook of Chemical Property Estimation Methods, H.3. Lyman, W.F. Reehl and
D.H. Rosenblatt, Ed. McGraw-Hill Book Co., NY. p. 4-1 to 4-11.
Lyman, H.3., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. Environmental Behavior of Organic Compounds.
McGraw-Hill Book Co., New York, NY. p. 5-5.
0183d -55- 09/11/89
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Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer Res. 35: 1379-1386.
Mendell, J.R., K. Salda, M.F. Ganansia et al. 1974. Toxic polyneuropathy
produced by methyl N-butyl ketone. Science. 185(4153): 787-789.
Morettl, T.A. 1978. Acetic acid derivatives (acetyl chloride). In:
Klrk-Othmer Encyclopedia of Chemical Technology, 3rd ed., M. Grayson and D.
Eckroth, Ed. John Wiley and Sons, Inc., NY. 1: 162-163, 166-167.
Myers, V.B. 1983. Remedial activities at the Miami drum site, Florida.
Natl. Conf. Manage. Uncontrolled Hazard. Waste Site. p. 354-357.
NIOSH (National Institute for Occupational Safety and Health). 1988.
National Occupational Exposure Survey (NOES). Computer database printout.
5-10-88. p. 53.
NIOSH (National Institute for Occupational Safety and Health). 1989. RTECS
(Registry of Toxic Effects of Chemical Substances). 2-Hexanone, CAS
Registry No. 591-78-6. Online.
OSHA (Occupational Safety and Health Administration). 1989. 29 CFR Part
1910. A1r Contaminants; Final Rule. p. 2940.
Papa, A.J. and P.O. Sherman, Jr. 1981. Ketones. In,: Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed., M. Grayson and D. Eckroth, Ed. John
Wiley and Sons, Inc., New York. 13: 894-897, 934-935, 940-941.
0183d -56- 09/11/89
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Park, J.G. and H.E. Hofmann. 1932. Aliphatic ketones as solvents. Ind.
Eng. Chem. 24: 132-134.
Peters, M.A., P.M. Hudson and R.L. D1xon. 1981. Effect totlgestatlonal
exposure to methyl N-butyl ketone has on postnatal development and behavior.
Ecotoxlcol. Environ. Saf. 5: 291-306.
Salda, K., J.R. Wendell and H.S. Weiss. 1976. Peripheral nerve changes
Induced by methyl n-butyl ketone and potentlatlon by methyl ethyl ketone.
J. Neuro. Exper. Neurol. 35(3): 207-225.
Schrenk, H.H., H.P. Yant and F.A. Patty. 1936. Acute Response of Guinea
Pigs to Vapors of Some New Commercial Organic Compounds. X. Hexanone
(Methyl Butyl Ketone}. Public Health Report, Vol. 51 p. 624-631.
NIOSH/00129658.
Shelton, D.R. and J.H. Tledje. 1984. General method for determining
anaerobic blodegradatlon potential. Appl. Environ. Mlcroblol. 47: 850-857.
Smyth, H.F., C.P. Carpenter, C. Well and U.C. Pozzanl. 1954. Range Finding
Tox1c1ty Data. List V. AMA Arch. Ind. Hyg. Occup. Med. 10: 61-68.
Specht, H., J.W. Miller, P.3. Valaer and R.R. Sayers. 1940. Acute Response
of Guinea Pigs to the Inhalation of Ketone Vapors. Federal Security Agency,
U.S. Public Health Service, Washington, DC. National Institute of Health
Bull. No. 176.
0183d -57- 09/11/89
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Spencer, P.S. and H.H. Schaumburg. 1977. Ultrastructural studies of the
dying-back process. IV. Differential vulnerability of PNS and CNS fibers In
experimental central-peripheral distal axonopathles. J. Neuropathol Exp.
Neurol. 36(2): 300-320.
Spencer, P.S., H.H. Schaumburg, R.L. Raleigh and C.J. Terhaar. 1975.
Nervous system degeneration produced by the Industrial solvent methyl
n-butyl ketone. Arch. Neurol. 32: 219-222.
SRI (Stanford Research Institute). 1988. 1988 Directory of Chemical
Producers: United States of America. SRI International, Henlo Park, CA.
Swann, R.L., D.A. Laskowskl, P.3. McCall, K. VanderKuy and H.3. Dlshburger.
1983. A rapid method for the estimation of the environment parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Takeoka, G.R., R.A. Flath, H. Guntert and W. Jennings. 1988. Nectarine
volatlles: Vacuum steam distillation versus headspace sampling. J. Agrlc.
Food Chem. 36: 553-560.
Thomas, R.G. 1982. Volatilization from water. Irr. Handbook of Chemical
Property Estimation Methods, W.O. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed.
McGraw-Hill Book Co., NY. p. 15-1 to 15-34.
Tyl, R.H., K.A. France, L.C. Fisher, et al. 1987. Developmental toxlclty
of Inhaled methyl Isobutyl ketone In Fisher 344 rats and CD-I mice. Fund.
Appl. Toxlcol. 8: 310-327.
0183d -58- 09/11/89
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U.S. EPA. 1977. Computer print-out of non-confidential production data
from the TSCA Production File for 1977. U.S. Environmental Protection
Agency, Washington, DC.
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): 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Tox1c1ty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Exams II Computer Simulation. Athens, GA.
U.S. EPA. 1986b. 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. 1986c. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51: 33992-34003.
U.S. EPA/OWRS (Office of Water Regulations and Standards). 1986. Guide-
lines for Deriving Numerical National Water Quality Criteria for the Protec-
tion of Aquatic Organisms and Their Uses. U.S. EPA, Washington, DC. N1IS
PB85-227049/XAB. p. 22-58, 98.
0183d -59- 09/11/89
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USITC (U.S. International Trade Commission). 1988. Synthetic Organic
Chemicals. U.S. Production and Sales. USITC Pub!. 2118, Washington, DC.
Valshnav, D.D. 1986. Chemical structure-blodegradatlon Inhibition and fish
acute toxldty relationships for narcotic Industrial chemicals. Toxic.
Assess. 1(2): 227-240.
Valshnav, D.D., R.S. Boethllng and L. Babeu. 1987. Quantitative structure-
blodegradabUHy relationships for alcohols, ketones and allcycllc com-
pounds. Chemosphere. 16: 695-703.
Verscheuren, K. 1983. Handbook of Environmental Data Organic Chemicals,
2nd ed. Van Nostrand Relnhold Co., New York. p. 320.
Walllngton, T.J. and M.J. Kurylo. 1987. Flash photolysis resonance
fluorescence Investigation of the gas-phase reactions of OH radicals with a
series of aliphatic ketones over the temperature range 240-440 K. J. Phys.
Chem. 91: 5050-5054.
Wlndholz, H., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Rahway,
NJ. p. 866.
Yasuhara, A. 1987. Identification of volatile compounds 1n poultry manure
by gas chromatography-mass spectrometry. 3. Chromatogr. 387: 371-378.
0183d -60- 09/11/89
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In Hay, 1988, and the following secondary
sources were 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).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. 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. 28. John Wiley and
Sons, NY. p. 2879-3816.
0183d -61- 09/11/89
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Clayton, G.O. 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.
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. IARC, WHO, 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 Haste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. 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). 1987. 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 In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M.t Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0183d -62- 09/11/89
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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 H.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
HcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed.
Prepared for the Resources Agency of California, State Water
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-26960S.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, OC. EPA 540/9-79-003. NTIS PB 80-196876.
0183d -63- 09/11/89
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APPENDIX B
Summary Table for 2-Hexanone
Species Exposure Effect RfD or q-j* Reference
Inhalation Exposure
Subchronlc ID
Chronic ID
Cardnogenlclty 10
Oral Exposure
Subchronic 10
Chronic ID
Cardnogenlclty ID
REPORTABLE QUANTITIES
Based on Chronic Toxlclty:
Based on Cardnogenlclty:
ID ID
ID ID
ID ID
ID ID
ID ID
ID ID
100
ID
ND ID
NO ID
ND ID
ND ID
ND ID
ND ID
Johnson
et al.,
1977, 1979
ID
ID - Insufficient data; ND = not derived
0183d
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 2-HEXANONE
C.I. DISCUSSION
Dose/duration-response graphs for Inhalation and oral exposure to
2-hexanone generated by the method of Crockett et al. (1985) using the
computer software by Durkln and Meylan (1988) developed under contract to
ECAO-C1nclnnat1 are presented In Figures C-l, C-2 and C-3. Data used to
generate these graphs are presented 1n Section C.2. In the generation of
these figures, all responses are classified as adverse (FEL, AEL or LOAEL)
or nonadverse (NOEL or NOAEL) for plotting. For Inhalation exposure the
ordlnate expresses concentration 1n either of two ways. In Figure C-l the
experimental concentration expressed as mg/m3 was multiplied by the time
parameters of the exposure protocol (e.g., hours/day and days/week) and Is
presented as expanded experimental concentration [expanded exp cone
(mg/ma)]. In Figure C-2, the expanded experimental concentration was
multiplied by the cube root of the ratio of the animal: human body weight to
adjust for species differences In basal metabolic rate (Mantel and
Schnelderman, 1975) to estimate an equivalent human or scaled concentration
[scaled cone (mg/m3). For oral exposure the ordlnate expresses dosage as
human equivalent dose. The animal dosage In mg/kg/day Is multiplied by the
cube root of the ratio of the animal:human body weight to adjust for species
differences In basal metabolic rate (Mantel and Schnelderman, 1975). The
result Is then multiplied by 70 kg, the reference human body weight, to
express the human equivalent dose as mg/day for a 70 kg human.]
The boundary for adverse effects (solid line) Is drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point an Infinite
0183d -65- 09/11/89
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imeee
imee-
i
6
hi
e.aeei
(Inhalation Exposure)
e.eei 9.01 e.i
HUMAN EQUIU DURATION (fraction lifespan)
ENVELOP HtTMOt
Key:
F . FEl
L « LOAEL
N - NOAEL
Solid line * Adverse Effects Boundary
Dashed line « No Adverse Effects Boundary
FIGURE C-l
Dose/Duration Response Graph for Inhalation Exposure to 2-Hexanone,
Expanded Experimental Concentration
0183d
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18008
E
V
o
w
V
9.8991
on Exposure>
e.eei e.ei e.i
HUMAN EQUIO DURATION (fraction lifespan)
EWELOP rETHOI>
Key:
F » FEL
L « LOAEL
N - NOEL
Solid line - Adverse Effects Boundary
Dashed line « No Adverse Effects Boundary
FIGURE C-2
Dose/Duration Response Graph for Inhalation Exposure to 2-Hexanone,
Scaled Concentration
0183d
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«
»
W
VI
o
e
1
10000~ ~
8.8081
<0i*»l Exposure)
T2
F4
LI
I I 1 I 1
4-
e.eei e.ei 0.1
HUMAN EQUIU DURATION (fraction lifespan)
ENVELOP HFTHOD
Key:
F . FEL
L - LOAEL
Solid line « Adverse Effects Boundary
Dashed line = No Adverse Effects Boundary
FIGURE C-3
Dose/Duration Response Graph for Inhalation Exposure to 2-Hexanone,
Envelope Method
0183d
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line Is extended upward parallel to the dose axis. The starting point Is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process Is continued
to the lowest adverse effect dose or concentration. From this point a line
1s extended to the right parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
Using the envelope method, the boundary for no-adverse effects (dashed
line) Is drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point a line parallel to the duration axis 1s extended
to the dose or concentration axis. The starting point Is then connected to
the next lower or equal no-adverse effect dose or concentration at a longer
duration of exposure. When this process can no longer be continued, a line
1s dropped parallel to the dose or concentration axis to the duration axis.
The no-adverse effects region lies below the no-adverse effects boundary.
At either ends of the graph between the Adverse Effects and no-adverse
effects boundaries are regions of ambiguity. The area (If any) resulting
from Intersection of the adverse effects and no-adverse effects boundaries
Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located In the
region of contradiction are dropped from consideration and the no-adverse
effect boundary 1s redrawn so that It does not Intersect the adverse effects
boundary and no region of contradiction 1s generated. This method results
in the most conservative definition of the no-adverse effects region.
Figures C-l and C-2 present dose/duration-response graphs for Inhalation
exposure drawn by the envelope method. Figure C-l presents results using an
expanded experimental concentration. The adverse effects boundary 1s
0183d -69- 09/11/89
-------
defined by several experimental points (Recs. #1, 5, 8) associated with
peripheral neuropathy (Johnson et al., 1977, 1979; Hendell et al., 1974;
Duckett et al., 1979) In the rat, cat and monkey. The adverse effects
boundary also Includes studies that reported eye and upper respiratory tract
Irritation (Rec. #12) and mortality (Rec. #13) In acutely exposed guinea
pigs (Schrenk et al.,. 1936; Specht et al., 1940). The only nonadverse
effect point {Rec. #16) was a NOEL for lethality 1n rats (Smyth et al.,
1954).
Figure C-2 presents the graph redrawn so that the data are expressed as
scaled concentration. Scaling excluded from the adverse effects boundary a
PEL for peripheral neuropathy In cats (Rec. #5) but Included a PEL (Rec. #6)
for neuropathy In rats (Duckett et al., 1974) and a PEL (Rec. #10) for
mortality In rats (Smyth et al., 1954).
Figure C-3 presents the dose/duration-response graph generated by the
envelope method for oral exposure. The adverse effects boundary Is defined
by lethality data In guinea pigs (Rec. #8) and mice (Rec. #7) and a LOAEL
(Rec. #3) for Impaired pupillary response 1n guinea pigs (NIOSH, 1979;
Abdel-Rahman et al., 1978). There were no nonadverse points to plot; there-
fore, only an adverse effects region and a region of ambiguity are defined.
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Inhalation Exposure
Chemical Name: 2-Hexanone
CAS Number: 591-78-6
Document Title: Health and Environmental Effects Document on 2-Hexanone
Document Number: pending
Document Date: pending
Document Type: HEED
0183d -70- 09/11/89
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RECORD #1
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Monkeys
Male
PEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
73.0
41.0 weeks.
41.0 weeks
Number Exposed: 8
Number Responses: NR
Type of Effect: NEURP
Site of Effect: PNS
Severity Effect: 8
TOO ppm (410 mg/m3), range: 100 or 1000 ppm 6 hours/day,
5 days/week; decreased motor nerve conduction velocity, hind-
limb drag.
Johnson et al., 1977, 1979
RECORD #2: Species: Rats
Sex: Male
Effect: FEL
Dose: 73.0
Duration Exposure: 29.0 weeks
Duration Observation: 29.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10
NR
NEURP
PNS
8
Comment: 100 ppm (410 mg/m3}, range: 100 or 1000 ppm 6 hours/day,
5 days/week; decreased motor nerve conduction velocity, hind-
limb drag. *
Citation: Johnson et al., 1977, 1979
RECORD #3: Species: Rats
Sex: NR
Effect: FEL
Route: Inhalat.1
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
on
6
NR
NEURP
PNS
8
Dose:
Duration
Duration
6
NR
NEURP
CNS
8
Exposure:
Observation:
6
NR
MGTDC
BODY
3
951.0
4.0 months
4.0 months
Comment: 1300 ppm (5325 mg/m3) 6 hours/day, 5 days/week; hlndllmb
drop, PNS and CNS nerve fiber damage, loss of body weight,
Citation: Spencer et al., 1975
0183d
-71-
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RECORD #4:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
FEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
1639.0
12.0 weeks
12.0 weeks
Number Exposed: 4
Number Responses: NR
Type of Effect: NEURP
SHe of Effect: PNS
Severity Effect: 8
400 ppm (1639 mg/m3) continuous; hlndllmb drag and giant
axonal swelling.
Mendell et al., 1974
RECORD #5: Species: Cats
Sex: NR
Effect: FEL
Dose: 1639.0
Duration Exposure: 12.0 weeks
Duration Observation: 12.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
4
NR
NEURP
PNS
8
Comment: 400 ppm (1639 mg/m3); hlndllmb drag, axonal swelling,
altered EMG.
Citation: Wendell et al., 1974
RECORD #6:
Species:
Sex:
Effect:
Route:
Rats
NR
FEL
Inhalation
Dose:
Duration
Duration
Exposure:
Observation:
195.0
6.0 weeks
6.0 weeks
Comment:
Citation;
Number Exposed: 9
Number Responses: NR
Type of Effect: NEURP
Site of Effect: PNS
Severity Effect: 8
200 ppm (819 mg/m3} 8 hours/day, 5 days/week; peripheral
neuropathy (hlndllmb drag), axonal degeneration.
Duckett et al., 1974
0183d
-72-
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RECORD #7;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
LOAEL
Inhalation
Dose: 1639.0
Duration Exposure: 6.0 weeks
Duration Observation: 6.0 weeks
Number Exposed: 12
Number Responses: NR
Type of Effect: NEURP
Site of Effect: PNS
Severity Effect: 7
400 ppm (1639 mg/m3) continuous; paralysis, axonal
degeneration, demyellnatlon.
Salda et al.t 1976
RECORD #8: Species: Rats
Sex: NR
Effect: PEL
Route: Inhalat
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Ion
40
NR
NEURP
PNS
8
Dose: 49.0
Duration Exposure: 6.0 months
Duration Observation: 6.0 months
Comment: 50 ppm (205 mg/m3) 8 hours/day, 5 days/week; decreased motor
nerve conduction velocity, 32/40 rats had demyellnatlon of
sciatic nerve, 2/40 had axonal degeneration.
Citation: Ouckett et a!., 1979
RECORD #9: Species: Rats
Sex: Hale
Effect: PEL
«
Dose:
Duration Exposure:
Duration Observation:
1229.0
11.0 weeks
11.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
15
NR
NEURP
PNS
8
15 15
NR NR
WGTDC WGTDC
TESTE BODY
4 4
Comment:
Citation:
700 ppm (2868 mg/ma) 72 hours/168 hours; decreased body
weight gain, depletion of adipose tissue and atrophy of hind-
limb musculature. A significant depression In testlcular
weight was noted.
Katz et al., 1980
0183d
-73-
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RECORD #10:
Comment:
Citation:
RECORD #11:
Species: Rats Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed: 6
Number Responses: 6
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 10
8000 ppm (32,772 mg/m3) for 4 hours; lethal to 6/6.
Smyth et al . , 1954
Species: Guinea pigs Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
5462.0
1.0 days
1.0 days
24579.0
3.0 days
3.0 days
Comment: 6000 ppm (24579 mg/m3); lethal to all animals by 72 hours
of exposure.
Citation: Specht, 1940
RECORD #12: Species: Guinea
Sex: NR
Effect: LOAEL
pigs
Dose:
Duration Exposure:
Duration Observation:
4097.0
0.6 days
0.6 days
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
NR
NR
IRRIT
EYE
9
NR
NR
IRRIT
NASAL
9
Comment: 1000 ppm (4097 mg/m3) for up to 810 minutes (range 1000,
2300, 6500 or 20,000 ppm); nasal and ocular Irritation;
mortality at 6500 ppm.
Citation: Schrenk et al., 1936
0183d
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RECORD #13:
Comment:
Citation:
RECORD #14:
Comment:
Citation:
RECORD #15:
Species: Guinea pigs Dose: 8909.0
Sex: NR Duration Exposure: 0.4 days
Effect: PEL Duration Observation: 0.4 days
Route: Inhalation
Number Exposed: 10
Number Responses: 7
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
6000 ppm (24,579 mg/m3) up to 525 minutes.
Specht et al., 1940
Species: Rats Dose: 2458.0
Sex: NR Duration Exposure: 9.0 days
Effect: LOAEL Duration Observation: 9.0 days
Route: Inhalation
Number Exposed: 11
Number Responses: NR
Type of Effect: NEURP
SHe of Effect: PNS
Severity Effect: 8
600 ppm (2458 mg/m3) continuous; neuropathologlcal
Spencer and Schaumberg, 1977
Species: Rats Dose: 922.0
Sex: NR Duration Exposure: 66.0 days
Effect: FEL Duration Observation: 66.0 days
Route: Inhalation
Number Exposed: 12
Number Responses: NR
Type of Effect: NEURP
SHe of Effect: PNS
Severity Effect: 8
Comment: 225 ppm (922 mg/m3) continuous; paralysis, axonal
degeneration, demyellnatlon.
Citation: Salda et al., 1976
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RECORD #16:
Species:
Sex:
Effect:
Route:
Rats
NR
NOEL
Inhalation
Dose: 2731.0
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Comment:
Citation:
Number Exposed: 6
Number Responses: 0
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 10
4000 ppm (16386 mg/m3) for 4 hours; no lethality,
Smyth et al., 1954
Oral Exposure
Chemical Name:
CAS Number:
Document Title:
Number:
Document Date:
Document Type:
2-Hexanone
591-78-6
Health and Environmental
pending
pending
HEED
Effects Document on 2-Hexanone
RECORD #1:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Water
Dose:
Duration
Duration
Exposure:
Observation:
350.0
10.0 months
10.0 months
Comment:
Citation:
Number Exposed: NR NR
Number Responses: NR NR
Type of Effect: NEURP WGTDC
Site of Effect: PNS BODY
Severity Effect: 8 3
0.25% (range: 0.25, 0.5, 1.0%); 350, 700 and 1400 mg/kg/day.
Decreased body weight at all doses. Signs of neuropathy at
the two highest dose levels, morphologic changes at all doses
Krasavage et al., 1979
0183d
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RECORD #2:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Water
Dose: 1000.0
Duration Exposure: 120.0-days
Duration Observation: 120.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: NEURP
Site of Effect: PNS
Severity Effect: 8
Comment:
Citation:
RECORD #3:
1000 mg/kg/day; continuous for 120 days; muscle weakness and
atrophy, neuropathology.
Homan and
Species:
Sex:
Effect:
Route:
Maronpot (1978)
Guinea pigs
NR
LOAEL
Water
Dose:
Duration Exposure:
Duration Observation:
100.0
24.0 weeks
24.0 weeks
Number Exposed: 5 5
Number Responses: NR NR
Type of Effect: FUNP WGTIN
Site of Effect: EYE BODY
Severity Effect: 7 3
0.1% (range: 0.1, 0.25%, doses 100, 250 mg/kg/day) estimated
from data provided; Impaired pupillary response, altered
locomotor activity measured only at 0.25%.
Abdel-Rahman et al. (1978)
RECORD #4:
Species:
Sex:
Effect:
Route:
Rats
Male
FEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
429.0
90.0 days
90.0 days
Comment:
Citation;
5
NR
NEURP
PNS
8
5
NR
ATROP
TESTE
4
5
NR
MGTOC
BODY
4
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
600 ppm (2458 mg/m3); 5 days/week; severe hlndleg footdrop,
paralysis, and decrease In weight gain, and testlcular
atrophy were reported.
Krasavage et al., 1980
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RECORD #5:
Comment:
Citation:
RECORD #6:
Comment:
Citation:
RECORD #7:
Comment:
Citation:
Species: Rats Dose: 2590.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SUe of Effect: NR
Severity Effect: 10
1050 value, details not provided.
Smyth et a!., 1954
Species: Mice Dose: 2430.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: MR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 10
LDgo value, details not provided.
NIOSH, 1989
Species: Mice Dose: 1000.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SUe of Effect: NR
Severity Effect: 10
I.DLO value, details not provided.
NIOSH, 1979
0183d
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RECORD #8: Species: Guinea pigs Dose:- 914.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 10
Comment: LQ|_Q value, details not provided.
Citation: NIOSH, 1979
NR = Not reported
0183d -79- 09/11/89
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C 20460
MAYI°
SUBJECT: Health and Environmental Effects Document
for 2-Hexaaon*
OF
AND DEVELOPMENT
FROM: William H. Farland, Ph.D.
Director
Office of Health and Environmental
Assessment (RD-689)
TO: Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Waste (WH-562B)
I am forwarding copies of the Health and Environmental
Effects Document for 2-H«x*non« (ECAO-Cin-G068).
The HEEDs support, listings under RCRA, as well as, provide
health-related limits and goals for emergency and remedial
actions under CERCLA. These documents represent scientific
summaries of the pertinent available data on the environmental
fate and mammalian and aquatic toxicity of each chemical at an
extramural effort of about $10K. The attached document has been
reviewed within OHEA, by staff in OPP and OTS, and by two
external scientists.
Should you wish to see any of the files related to the
development of the HEEDs, please call Chris DeRosa at FTS:
6B4-7531.
Attachment
-------
DATE:
ROUTE SLIP
K. Bruneske (OS-305)
M. Callahan (RD-689)
P. Durkin (SRC)
R. Hardesty (RD-689)
B. Hostage (OS-210)
S. Irene (OS-33-)
E. HcNamara (PM-
J. Moore (RD-689)
M. Pfaff (RD-689)
C. Ris (RD-689)
R. Rubenstein (OS-330)
R. Scarberry (OS-330)
C. Zamuda (OS-240)
.
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