TOXICOLOGICAL PROFILE FOR
 

2-HEXANONE
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

September 1992
 
ii
 

DISCLAIMER
 

The use of company or product name(s) is for identification only and does
 

not imply endorsement by the Agency for Toxic Substances and Disease Registry.
 










1
 

1. PUBLIC HEALTH STATEMENT
 

This Statement was prepared to give you information about 2-hexanone and
 

to emphasize the human health effects that may result from exposure to it.
 

The Environmental Protection Agency (EPA) has identified 1,177 sites on its
 

National Priorities List (NPL). 2-Hexanone has been found in at least 15 of
 

these sites. However, we do not know how many of the 1,177 NPL sites have been
 

evaluated for 2-hexanone. As EPA evaluates more sites, the number of sites at
 

which 2-hexanone is found may change. This information is important for you to
 

know because 2-hexanone may cause harmful health effects and because these
 

sites are potential or actual sources of human exposure to 2-hexanone.
 

When a chemical is released from a large area, such as an industrial
 

plant, or from a container, such as a drum or bottle, it enters the
 

environment as a chemical emission. This emission, which is also called a
 

release, does not always lead to exposure. You can be exposed to a chemical
 

only when you come into contact with the chemical. You may be exposed to it in
 

the environment by breathing, eating, or drinking substances containing the
 

chemical or from skin contact with it.
 

If you are exposed to a hazardous chemical such as 2-hexanone, several
 

factors will determine whether harmful health effects will occur and what the
 

type and severity of those health effects will be. These factors include the
 

dose (how much), the duration (how long), the route or pathway by which you
 

are exposed (breathing, eating, drinking, or skin contact), the other
 

chemicals to which you are exposed, and your individual characteristics such
 

as age, sex, nutritional status, family traits, life style, and state of
 

health.
 

1.1 WHAT IS 2-HEXANONE?
 

2-Hexanone, also known as methyl n-butyl ketone or MBK, is a clear,
 

colorless liquid with a somewhat sharp odor. The liquid form can easily
 

evaporate into the air as a vapor. It is a waste product of wood pulping, coal
 

gasification, and oil shale operations. 2-Hexanone was formerly used in paint
 

and paint thinner and in various chemical substances. However, since it
 

was found to have harmful health effects, it is no longer made in the United
 

States, and its uses have been restricted. There are no known major natural
 

sources of 2-hexanone in the environment. When 2-hexanone is released to
 

rivers or lakes, it dissolves very easily, and it may evaporate into the air
 

in a few days. We do not know if 2-hexanone binds to soil. When 2-hexanone is
 

released to the water, air, or soil, it is probably broken down into smaller
 

products, possibly within a few days.
 

More information on the physical and chemical properties, uses, and
 

releases of 2-hexanone and how it behaves in the environment can be found in
 

Chapters 3, 4, and 5.
 
2
 

1. PUBLIC HEALTH STATEMENT
 

1.2 HOW MIGHT I BE EXPOSED TO 2-HEXANONE?
 

You can be exposed to 2-hexanone if you live near an industry or
 

hazardous waste site that releases the liquid into wastewater or the gas form
 

into the surrounding air. These industries include coal gasification plants,
 

oil shale operations, and wood pulping mills. We have no information on
 

background levels of 2-hexanone in the environment.
 

2-Hexanone has been found as a natural substance in foods such as cheese,
 

nectarines, nuts, bread, and chicken muscle. We do not know the levels of 2­

hexanone in these foods. 2-Hexanone has been found in milk and cream at levels
 

up to 0.018 ppm (0.018 parts of 2-hexanone in one million parts of liquid).
 

These levels are far below the levels that have caused harmful effects in
 

animals. It has also been found in drinking water and soil near hazardous
 

waste sites. Exposures at these sites may take place if you drink the
 

contaminated water or bathe in it, if you get contaminated soil on your skin,
 

or if you breathe the contaminated air.
 

More information on how you might be exposed to 2-hexanone is given in
 

Chapter 5.
 

1.3 HOW CAN 2-HEXANONE ENTER AND LEAVE MY BODY?
 

2-Hexanone can enter your body when you breathe its vapors, eat food or
 

drink water that contains it, or when you come in contact with it through your
 

skin. When 2-hexanone is breathed in, about 75% of it is taken up and remains
 

in the body unchanged or as a breakdown product for an unknown length of time.
 

If it enters the body by mouth, about 65% of the chemical leaves the body
 

slowly (in about a week), either unchanged or as breakdown products, in the
 

breath and urine. The rest may either stay in the body or may leave the body
 

slowly through the breath or urine. One of the breakdown products, called 2,5­

hexanedione, may be responsible for the harmful effects on the nervous system
 

(see Section 1.4). When 2-hexanone gets in through the skin, some leaves the
 

body through the lungs and urine within a few hours. We have no information on
 

how much stays in the body or for how long. If you live or work near a
 

hazardous waste site, you may be exposed to 2-hexanone in the air that you
 

breathe or in the water you drink or bathe in, if it contains small amounts of
 

this chemical.
 

More information on how 2-hexanone enters and leaves the body is given in
 

Chapter 2.
 

1.4 HOW CAN 2-HEXANONE AFFECT MY HEALTH?
 

The most important health concern for humans from exposure to 2-hexanone
 

is its harmful effects on the nervous system. These effects were seen in
 

workers who were exposed to 2-hexanone for almost a year. The major effects
 

were weakness, numbness, and tingling in the skin of the hands and feet.
 
3
 

1. PUBLIC HEALTH STATEMENT
 

Similar effects were seen in animals that ate or breathed high levels of 2­

hexanone; these effects included weakness, clumsiness, and paralysis.
 

We do not know whether 2-hexanone can cause cancer or birth defects. In
 

one study, when pregnant rats were exposed to 2-hexanone in the air, fewer
 

offspring lived after birth, and those that did survive had low birth weights.
 

Many of the studies in which the health effects of 2-hexanone in humans
 

or animals were reported did not use pure 2-hexanone. Therefore, we do not
 

know whether the results were caused by 2-hexanone itself or by the other
 

chemicals in the mixture.
 

More information on health effects of 2-hexanone can be found in
 

Chapter 2.
 

1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
 

EXPOSED TO 2-HEXANONE?
 

Tests can be used to find out whether you have recently been exposed to
 

2-hexanone. The tests measure levels of 2-hexanone or its breakdown products
 

in blood or urine. These tests require special equipment and are done in a
 

special laboratory, so they are usually not available in a doctor's office.
 

However, these tests cannot be used to predict whether harmful effects will
 

occur.
 

More information on how 2-hexanone can be measured in exposed humans is
 

given in Chapters 2 and 6.
 

1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
 

PROTECT HUMAN HEALTH?
 

The federal government has set certain regulations and guidelines to help
 

protect people from the possible health effects of 2-hexanone in the
 

workplace. The Occupational Safety and Health Administration (OSHA) has set a
 

limit of 5 ppm (5 parts of 2-hexanone in 1 million parts of air) as an average
 

exposure level to this chemical over a 40-hour work week. The American
 

Conference of Governmental Industrial Hygienists (ACGIH) has made the same
 

recommendation. The National Institute for Occupational Safety and Health
 

(NIOSH) recommends an even lower limit, 1 ppm, as an average exposure during a
 

10-hour period.
 

More information on governmental regulations regarding 2-hexanone can be
 

found in Chapter 7.
 
4
 

1. PUBLIC HEALTH STATEMENT
 

1.7 WHERE CAN I GET MORE INFORMATION?
 

If you have any more questions or concerns not covered here, please
 

contact your state health or environmental department or:
 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology
 

1600 Clifton Road, E-29
 

Atlanta, Georgia 30333
 

This agency can also provide you with information on the location of the
 

nearest occupational and environmental health clinic. Such clinics specialize
 

in recognizing, evaluating, and treating illnesses that result from exposure
 

to hazardous substances.
 
5
 

2. HEALTH EFFECTS
 

2.1 INTRODUCTION
 

The primary purpose of this chapter is to provide public health
 

officials, physicians, toxicologists, and other interested individuals and
 

groups with an overall perspective of the toxicology of 2-hexanone and a
 

depiction of significant exposure levels associated with various adverse
 

health effects. It contains descriptions and evaluations of studies and
 

presents levels of significant exposure for 2-hexanone based on toxicological
 

studies and epidemiological investigations.
 

In the evaluation of studies described in this chapter, the purity of the
 

test compound was considered. As shown in the text, tables, and figures, three
 

general categories of 2-hexanone purity were indicated in the studies:
 

• Purity of 96% or more 

• 70% purity (technical grade) 

• Purity was not stated in the cited publication 

In technical grade 2-hexanone, the 30% impurity was identified as methyl
 

isobutyl ketone, and the possible implications of its presence in the test
 

substance were discussed.
 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
 

To help public health professionals address the needs of persons living
 

or working near hazardous waste sites, the information in this section is
 

organized first by route of exposure--inhalation, oral, and dermal--and then
 

by health effect--death, systemic, immunological, neurological, developmental,
 

reproductive, genotoxic, and carcinogenic effects. These data are discussed in
 

terms of three exposure periods --acute (less than 15 days), intermediate (15­

364 days), and chronic (365 days or more).
 

Levels of significant exposure for each route and duration are presented
 

in tables and illustrated in figures. The points in the figures showing
 

noobserved- adverse-effect levels (NOAELS) or lowest-observed-adverse-effect
 

levels (LOAELS) reflect the actual doses (levels of exposure) used in the
 

studies. LOAELs have been classified into "less serious" or "serious" effects.
 

These distinctions are intended to help the users of the document identify the
 

levels of exposure at which adverse health effects start to appear. They
 

should also help to determine whether or not the effects vary with dose and/or
 

duration, and place into perspective the possible significance of these
 

effects to human health.
 

The significance of the exposure levels shown in the tables and figures
 

may differ depending on the user's perspective. For example, physicians
 

concerned with the interpretation of clinical findings in exposed persons may
 

be interested in levels of exposure associated with "serious" effects. Public
 

health officials and project managers concerned with appropriate actions to
 
6
 

2. HEALTH EFFECTS
 

take at hazardous waste sites may want information on levels of exposure
 

associated with more subtle effects in humans or animals (LOAEL) or exposure
 

levels below which no adverse effects (NOAEL) have been observed. Estimates of
 

levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of
 

interest to health professionals and citizens alike.
 

Estimates of exposure levels posing minimal risk to humans (MRLs) have
 

been made, where data were believed reliable, for the most sensitive noncancer
 

effect for each exposure duration. MRLs include adjustments to reflect human
 

variability from laboratory animal data to humans.
 

Although methods have been established to derive these levels (Barnes et
 

al. 1988; EPA 1989), uncertainties are associated with these techniques.
 

Furthermore, ATSDR acknowledges additional uncertainties inherent in the
 

application of the procedures to derive less than lifetime MRLs. As an
 

example, acute inhalation MRLs may not be protective for health effects that
 

are delayed in development or are acquired following repeated acute insults,
 

such as hypersensitivity reactions, asthma, or chronic bronchitis. As these
 

kinds of health effects data become available and methods to assess levels of
 

significant human exposure improve, these MRLs will be revised.
 

2.2.1 Inhalation Exposure
 

Numerous studies have been conducted in which animals were exposed to 2­

hexanone via inhalation. However, the purpose of many of these studies was to
 

assess the potential effects of combined exposure to 2-hexanone and another
 

substance (usually chloroform or methyl ethyl ketone [MEK]). Study design has
 

consequently involved exposure to only one concentration of 2-hexanone as a
 

control exposure. A single high dose of 2-hexanone was used in several other
 

studies in order to elicit and study histopathological changes in the affected
 

nervous tissue, In addition, the grade or purity of the 2-hexanone
 

administered was not stated in many studies, or in some cases, hexanone with
 

purity as low as 70% was used. As a result of these various complications, the
 

usefulness of the available data is limited.
 

2.2.1.1 Death
 

The only lethality data available for inhalation exposure to 2-hexanone
 

are from a study by Abdo et al. (1982) in which 1 of 5 hens exposed
 

continuously to 200 ppm 2-hexanone (70% purity) died on day 72 of a 90-day
 

study. At 400 ppm, 2 of 5 hens died by day 27. The cause of death was not
 

stated. No deaths were observed in the groups exposed to 100 ppm and below.
 

The highest NOAEL value and a reliable LOAEL value for death in this
 

species and duration category are recorded in Table 2-l and plotted in Figure
 

2-l.
 




11
 

2. HEALTH EFFECTS
 

2.2.1.2 Systemic Effects
 

The systemic effects observed after inhalation exposure to 2-hexanone are
 

discussed below. The NOAEL values and all reliable LOAEL values for systemic
 

effects in each species and duration category are recorded in Table 2-l and
 

plotted in Figure 2-1.
 

No studies were located regarding respiratory, cardiovascular,
 

gastrointestinal, or dermal/ocular effects in humans or animals after
 

inhalation exposure to 2-hexanone.
 

Hematological Effects. No studies were located regarding hematological
 

effects in humans after inhalation exposure to 2-hexanone.
 

A reduction in total leukocyte counts to about 60% of control
 

values(p<0.05) was observed in rats intermittently exposed to 700 ppm 2­

hexanone (96.1% purity) after 8 weeks of an ll-week study (Katz et al. 1980).
 

Hemoglobin concentration, hematocrit, and differential white cell counts were
 

similar to control values. Although the decrease in total white blood cell
 

counts suggested an effect on bone marrow, the authors found no microscopic
 

evidence of such damage. Therefore, the clinical significance of their
 

findings was uncertain. In addition, only a single dosage level was used in
 

the study.
 

Musculoskeletal Effects. No studies were located regarding
 

musculoskeletal effects in humans or animals after inhalation exposure to 2­

hexanone. Weakness and lack of coordination have been observed in several
 

studies; however, these effects have been attributed to nerve damage (see
 

Section 2.2.1.4).
 

Hepatic Effects. No studies were located regarding hepatic effects in
 

humans after inhalation exposure to 2-hexanone.
 

There was no effect on hexobarbital-induced sleep times in rats exposed
 

continuously to 225 ppm 2-hexanone (purity not stated) for 7 days (Couri et
 

al. 1977). Thus, 2-hexanone exposure under these conditions does not seem to
 

affect the hepatic microsomal enzyme activities associated with this response.
 

No histopathological effects were seen in the livers of rats exposed to 50 ppm
 

2-hexanone (purity not stated) for 6 months (Duckett et al. 1979). However, no
 

additional data on potential hepatic effects were found.
 

Renal Effects. No studies were located regarding renal effects in humans
 

after inhalation exposure to 2-hexanone. No histopathological effects were
 

seen in the kidneys of rats exposed to 50 ppm 2-hexanone (purity not stated)
 

for 6 months (Duckett et al. 1979).
 
12
 

2. HEALTH EFFECTS
 

Other Systemic Effects. The most common systemic effect observed
 

following inhalation exposure to 2-hexanone is weight loss or a decreased rate
 

of weight gain in developing animals.
 

A 1973 outbreak of distal polyneuropathy involving 86 of 1,157 employees
 

was reported in a plant that had been using 2-hexanone for about 10 months in
 

the production of plastic-coated and color-printed fabrics (Allen et al. 1975;
 

Billmaier et al. 1974). (Neurological effects associated with this exposure
 

are discussed in Section 2.2.1.4.) Clinical evaluations indicated that of 10
 

workers whose body weight was recorded, weight loss ranging from 3 to 60
 

pounds was observed in the eight workers found to have moderate to severe
 

neurological impairment (Allen et al. 1975). Of the milder cases, no
 

significant weight change could be correlated with the presence of the
 

disorder. Atmospheric sampling conducted after this incident indicated that 2­

hexanone levels averaged 9.2 ppm in front of the printing machines and 36 ppm
 

behind the machines. After the use of 2-hexanone was discontinued, weight gain
 

was uniformly noted in those who had lost weight.
 

In animal studies involving 3-6 months of inhalation exposure to 2­

hexanone, both weight loss and decreased rates of weight gain in developing
 

animals were noted.
 

A progressive but not statistically significant loss of body weight was
 

reported in monkeys, beginning 4 months after exposure to 1,000 ppm 2-hexanone
 

(purity not stated) (Johnson et al. 1977). These effects were not seen at 100
 

ppm. Exposure of rats to 1,000 ppm 2-hexanone (purity not stated) resulted in
 

statistically significant weight loss at weeks 2-10 and 20-24 (Johnson et al.
 

1977). No effects were seen at 100 ppm in that study or in a similar 6-month
 

study in rats (Egan et al. 1980). Other available single-dose level studies in
 

rats generally support these observations. A marked reduction in weight gain
 

was observed in rats exposed to 700 ppm 2-hexanone (96.1% purity) within 3
 

days of exposure during an ll-week study (Katz et al.1980). Slow progressive
 

weight loss (no details provided) in rats after 10 weeks of exposure to 1,300
 

ppm 2-hexanone (purity not stated) has also been reported (Spencer et al.
 

1975).
 

In hens, a clear dose-response relationship for effects on body weight
 

resulting from inhalation of 2-hexanone was observed during a 13-week study by
 

Abdo et al. (1982). No effects were seen at 10 or 50 ppm. Hens exposed to 100
 

ppm weighed about 92% of their initial weight at the end of 13 weeks of
 

exposure. Hens exposed to 200 ppm weighed 58% of their initial weight after 10
 

weeks of exposure, and hens exposed to 400 ppm weighed 48% of their initial
 

weight after 4 weeks of exposure. Hens exposed to 100 ppm 2-hexanone (70%
 

purity) for 13 weeks had a nonsignificant increase in body weight (Abou-Donia
 

et al. 1985a).
 
13
 

2. HEALTH EFFECTS
 

It is noteworthy that in three species (monkeys, rats, and hens), 3-6
 

months of exposure to 2-hexanone at 100 ppm resulted in little or no effect on
 

body weight parameters. Levels measured in the epidemiological study of
 

exposed workers, however, were only 9.2-36 ppm (Allen et al. 1975). However,
 

these levels were measured after the incident. If these low levels of 2­

hexanone are a reasonably accurate indication of the conditions of human
 

exposure that resulted in the observed weight loss, humans may be a very
 

sensitive species with regard to this parameter. It is not clear whether the
 

affected individuals had decreased appetites and/or food consumption levels in
 

conjunction with their weight loss.
 

2.2.1.3 Immunological Effects
 

No studies were located regarding immunological effects in humans after
 

inhalation exposure to 2-hexanone.
 

A reduction in total white blood cell counts to 60% of control values
 

(p<0.05), but no changes in differential white cell counts or evidence of bone
 

marrow damage, was found in rats intermittently exposed to 700 ppm 2-hexanone
 

after 8 weeks during an ll-week study (Katz et al. 1980). These findings,
 

although inconclusive, suggest that immunological effects may warrant some
 

consideration in future assessments of the potential toxicity of inhalation
 

exposure to 2-hexanone.
 

2.2.1.4 Neurological Effects
 

In humans, the most important effect associated with inhalation exposure
 

to 2-hexanone is neurological dysfunction, most commonly observed as
 

peripheral neuropathy. Widespread attention was brought to this phenomenon
 

after a 1973 outbreak of distal neuropathy in an Ohio fabric finishing plant
 

that had introduced the use of 2-hexanone into its processing operations
 

approximately 10 months before the first cases of neuropathy were reported.
 

The screening of 1,157 employees resulted in the detection of 86 verified
 

cases of neuropathy (Allen et al. 1975). Eleven of these cases were moderate
 

to severe with both motor and sensory involvement; 38 were mild with sensory
 

signs prevailing; and 37 were considered minimal, without clinical
 

manifestations but with characteristic electrodiagnostic abnormalities.
 

General characteristics of the neuropathy included muscle weakness, sensory
 

loss (inability to discriminate pain, touch, temperature, or vibration) in the
 

hands and feet, and diminution or loss of reflexes. Electromyographic (EMG)
 

testing generally indicated that nerve conduction velocities (NCVs) were
 

slower, especially in the ulnar, peroneal, tibial, and sural nerves, and the
 

distal latencies (times to response) were prolonged in parallel to the
 

reduction of the NCV. Other abnormalities included waves and fibrillations,
 

especially in the more severe cases, and a decrease in the number and an
 

increase in the size of motor unit potentials. No histological evidence of
 

nerve damage was obtained in any of these patients. Atmospheric sampling
 

conducted after this incident indicated that 2-hexanone levels in the
 
14
 

2. HEALTH EFFECTS
 

processing plant averaged 9.2 ppm in front of the printing machines and 36 ppm
 

behind them. After the use of 2-hexanone was discontinued, marked improvement
 

was seen in the affected employees during the next few months, including all
 

of the moderate-to-severe cases and most of the mild and minimal cases.
 

However, the authors stated that it was not possible to rule out a possible
 

synergistic effect with methyl ethyl ketone or with other chemicals used at
 

the plant.
 

This industrial incident apparently prompted most of the ensuing animal
 

research on the effects of inhalation exposure to 2-hexanone. Several studies
 

were conducted in rats in an attempt to describe the histopathological basis
 

of the observed neuropathy, and several other studies were concerned with the
 

ability of 2-hexanone exposure to potentiate the adverse effects of exposure
 

to other agents. As described above, most of the animal neurotoxicity studies
 

involved the use of only a single dose of 2-hexanone, usually as a control
 

group for comparison with the effects of combined exposure to 2-hexanone and
 

another compound, and several other studies used a single high dose of 2­

hexanone in order to elicit neurotoxicity and assess the accompanying
 

histopathological changes.
 

In all animals studied, including monkeys, cats, rats, and chickens, the
 

clinical observations generally indicated a progression from weakness and
 

ataxia to complete paralysis of the limbs. These clinical observations were
 

accompanied or preceded by morphological changes in the peripheral nerves,
 

including an increase in the number of neurofilaments in the nerve fibers,
 

axonal swelling, and inpouchings and thinning of the myelin sheath. It is also
 

important to note that 2,5-hexanedione, a metabolite of 2-hexanone in rats,
 

guinea pigs, and humans (DiVincenzo et al. 1976, 1978; Eben et al. 1979) has
 

been observed to elicit severe neuropathy following oral administration to
 

rats (Krasavage et al. 1980) and following oral, dermal, or intraperitoneal
 

administration to hens (Abou-Donia et al. 1982, 1985b). Comparative studies of
 

the relative neurotoxicities of 2-hexanone, 2,5-hexanedione, and other
 

compounds have concluded that 2,5-hexanedione is a more potent neurotoxicant
 

than 2-hexanone (Abou-Donia et al. 1982; Krasavage et al. 1980).
 

Severe neurotoxicity was reported in rats as a result of 7 days of
 

continuous inhalation exposure to 225 ppm 2-hexanone (Couri et al. 1977).
 

However, no data for this toxic effect were given in the study. Paralysis was
 

observed in rats exposed to 225 ppm 2-hexanone (purity not stated) for 9.5
 

weeks or to 400 ppm for 6 weeks (Saida et al. 1976). Inpouchings of the myelin
 

sheath of the peripheral nerves occurred as early as 16 days at both dose
 

levels. Other histopathological findings included denuded fibers and swollen
 

axons. Continuous inhalation exposure of rats to 2-hexanone (purity not
 

stated), initially at 600 ppm but lowered to 400 ppm to prevent weakness and
 

weight loss, resulted in hind limb dragging at 11-12 weeks (Mendell et al.
 

1974b). Histopathological observations were axonal swelling and demyelination
 

of nerve fibers. In rats exposed to 100 ppm 2-hexanone for 25-29 weeks, there
 

was a progressive, statistically significant decrease in the maximum motor
 
15
 

2. HEALTH EFFECTS
 

conduction velocity (MCV) of the sciatic-tibial nerve at 29 weeks and of the
 

ulnar nerve at 17 weeks. An effect on operant behavior, manifest as a reduced
 

response rate in bar-pressing studies, was also reported. At 1,000 ppm
 

exposure, these effects were seen earlier (Johnson et al. 1977). Rats exposed
 

to 700 ppm 2-hexanone (96.1% purity) during an ll-week study developed
 

clinical signs of neurotoxicity as early as the second week of exposure (Katz
 

et al. 1980). Observations included reduced body muscle tone and weakened
 

hind- and forelimb grasping of a wire mesh.
 

In a 6-month study, rats exposed to 100 ppm 2-hexanone (96.7% purity) did
 

not demonstrate clinical signs of neuropathy. However, after 4 months of
 

exposure, giant axonal swellings and demyelination were seen in fibers of the
 

tibia1 nerves; by 6 months degeneration had ascended to the sciatic notch. In
 

the central nervous system, 4-month observations included giant axonal
 

swellings in the medulla oblongata and cerebellum. By 6 months the spinal cord
 

had scattered fiber degeneration in the gracile tract and the lumbar region
 

(Egan et al. 1980). In a 6-month study in rats, inhalation exposure to 50 ppm
 

2-hexanone (purity not stated) resulted in histopathological effects including
 

demyelination of the sciatic nerve, and axonal hypertrophy and beading
 

(Duckett et al. 1979). Rats exposed to 1,300 ppm during a 40-week study
 

developed a pronounced symmetrical hindlimb footdrop, hindlimb and forelimb
 

weakness, and nerve fiber swelling and degeneration (Spencer et al. 1975).
 

In a 10-month study, monkeys exposed to 1,000 ppm 2-hexanone had abnormal
 

results in electrodiagnostic tests (Johnson et al. 1977). There was a
 

progressive and statistically significant decrease in the maximum motor
 

conduction velocity of the sciatic-tibia1 nerves starting at 4 months of
 

exposure and a decrease in the maximum conduction velocity of the ulnar nerves
 

starting at 1 month. Decreased amplitude of evoked muscle action potential was
 

also seen at 1,000 ppm. Results of 100 ppm exposure were similar to those of
 

controls except for a statistically significant decreased response in the
 

ulnar nerve at the 1 and 3 month measurements and in the sciatic-tibia1 nerve
 

only at 9 and 10 months. Recovery to pre-exposure values for motor conduction
 

velocities took 2 months for the 100 ppm group and 6 months for the 1,000 ppm
 

group.
 

Clinical signs of neuropathy were evident in cats after continuous
 

inhalation exposure to 400-600 ppm 2-hexanone (purity not stated) for 5 weeks
 

or more (Mendell et al. 1974b). (Initial exposure to 600 ppm was lowered to
 

400 ppm in order to prevent weakness and weight loss.) Hindlimb dragging was
 

followed by forelimb weakness and eventual paralysis. The EMG studies showed a
 

dramatic decrease (56%) in the ulnar nerve conduction velocity. Axonal
 

swelling and demyelination of the nerve fibers were also observed. One of
 

these cats was observed by Saida et al. (1976) for 4.5 months after exposure
 

in order to assess recovery. The animal eventually regained the ability to
 

walk, swollen axons were greatly reduced in number, and nerve fibers showed
 

signs of remyelination.
 
16
 

2. HEALTH EFFECTS
 

Continuous inhalation exposure of hens to 2-hexanone (purity not stated)
 

initially at 200 ppm, then lowered to 100 ppm to prevent weakness and weight
 

loss, resulted in overt clinical signs of neuropathy at 4-5 weeks when the
 

animals could no longer stand (Mendell et al. 1974b). Histopathological
 

observations included axonal swelling and demyelination of nerve fibers. In a
 

go-day inhalation study in hens followed by a 30-day recovery period,
 

neurological effects were not apparent in the group exposed to 10 ppm 2­

hexanone (70% purity) (Abdo et al. 1982). Mild ataxia (diminished leg
 

movements and reluctance to walk) was seen with 4 weeks of exposure to 50 ppm;
 

this progressed to near paralysis by 13 weeks. At higher levels, these effects
 

were seen earlier. Exposure to 200 ppm resulted in mild ataxia after 2 weeks
 

and paralysis after 10 weeks. Demyelination and axonal swelling were seen in
 

the spinal cord at 50 ppm and in both the spinal cord and peripheral nerves at
 

100 ppm and above. During the 30-day recovery period, slight clinical
 

improvement was seen in the 50 ppm group. In another go-day study, hens
 

exposed to 100 ppm 2-hexanone (70% purity) had mild ataxia after 39 days of
 

exposure but no evidence of histopathological changes in nerve tissue (Abou-


Donia et al. 1985a).
 

As noted above, the test compound used in two of the studies in hens,
 

Abdo et al. (1982) and Abou-Donia et al. (1985a), was technical grade 2­

hexanone with a purity level of 70%. The other 30% component of this
 

formulation was methyl isobutyl ketone. In a 90-day study in which hens were
 

exposed to pure methyl isobutyl ketone at 1,000 ppm via inhalation, this
 

compound failed to induce neurotoxicity (Abou-Donia et al. 1985c). However, in
 

hens simultaneously exposed to 1,000 ppm n-hexane (which by itself was mildly
 

neurotoxic), with increasing concentrations of methyl isobutyl ketone (l00­

1,000 ppm) there was a dose-related response of increasingly severe ataxia
 

progressing to paralysis. In addition, histopathological changes of the
 

nervous system progressed to degeneration of the spinal cord and lesions in
 

the peripheral nerves. These results are important to note because they serve
 

to illustrate that a potential for synergistic interaction or potentiation
 

exists with combined exposure to methyl isobutyl ketone and at least one other
 

compound, n-hexane. It is, therefore, possible that combined exposure to 2­

hexanone and methyl isobutyl ketone, as in the Abdo et al. (1982) and Abou-


Donia et al. (1985a) studies can result in synergistic interaction or a
 

potentiation effect (see Section 2.6).
 

In addition to the neurological effects in the studies described above,
 

behavioral alterations were reported in the offspring of pregnant rats exposed
 

to 1,000 ppm 2-hexanone (purity not stated) during and after gestation (Peters
 

et al. 1981) (see Section 2.2.1.5).
 

The highest NOAEL value in hens and all reliable LOAEL values for
 

neurological effects in each species in the intermediate-duration category are
 

recorded in Table 2-l and plotted in Figure 2-l.
 
17
 

2. HEALTH EFFECTS
 

2.2.1.5 Developmental Effects
 

No studies were located regarding developmental effects in humans after
 

inhalation exposure to 2-hexanone.
 

Behavioral alterations were reported in the offspring of pregnant rats
 

exposed to 1,000 ppm or 2,000 ppm 2-hexanone (purity not stated) during 21
 

days of gestation (Peters et al. 1981). These effects consisted of reduced
 

activity in the open field, increased activity in the running wheel, and
 

deficits in avoidance conditioning. Offspring of treated dams (both dose
 

levels) clung to an inclined screen longer than offspring of controls at all
 

ages (newborn, weanling, puberty, and adult) except geriatric in which results
 

were similar to those of controls. For offspring in the puberty and adult
 

categories, pronounced sex differences were noted, with females in all
 

exposure categories (including controls) clinging from 24% to 100% longer than
 

males. However, the biological significance of this observation is unknown.
 

There was a decreased rate of avoidance learning in puberty-aged females of
 

treated dams and increased random movement in both puberty-aged and adult
 

offspring of treated dams. Behavioral tests in most cases indicated that
 

maternal exposure to 2-hexanone was associated with hyperactivity in the young
 

and decreased activity in the geriatric stage, which the authors speculated to
 

be due to premature aging resulting from the earlier hyperactivity. It is not
 

clear whether these effects are the result of transplacental exposure to 2­

hexanone or of postnatal exposure to 2-hexanone and/or its metabolites via the
 

milk of the exposed dams.
 

In addition, decrements were observed in the weight gain of pregnant rats
 

exposed to 1,000 ppm or 2,000 ppm 2-hexanone during 21 days of gestation
 

(Peters et al. 1981). These decreases were 10% and 14%, respectively;
 

statistical significance was not addressed. Rats in the 2,000 ppm exposure
 

group were observed to eat less than did the controls. There was also a
 

significant decrease in the number and weight of live offspring of dams in the
 

2,000 ppm exposure group.
 

The LOAEL values for developmental effects in rats in the
 

intermediateduration category are recorded in Table 2-l and plotted in Figure
 

2-l.
 

2.2.1.6 Reproductive Effects
 

No studies were located regarding reproductive effects in humans after
 

inhalation exposure to 2-hexanone.
 

Marked and significant reductions in absolute and relative testes weight
 

and atrophy of testicular germinal epithelium were observed in male rats
 

exposed to 700 ppm 2-hexanone for 11 weeks (Katz et al. 1980).
 

The LOAEL value for reproductive effects in rats for the intermediate-


duration category is recorded in Table 2-l and plotted in Figure 2-l.
 
18
 

2. HEALTH EFFECTS
 

2.2.1.7 Genotoxic Effects
 

No studies were located regarding genotoxic effects in humans or animals
 

after inhalation exposure to 2-hexanone.
 

2.2.1.8 Cancer
 

No studies were located regarding cancer effects in humans or animals
 

after inhalation exposure to 2-hexanone.
 

2.2.2 Oral Exposure
 

Several studies were conducted in which only a single high dose of 2­

hexanone was orally administered to rats in an attempt to induce and
 

consequently study the resulting neurotoxic effects. In addition, only a few
 

of the studies were conducted using 2-hexanone of a stated purity of 96% or
 

better. Other studies used a formulation containing 70% 2-hexanone or the
 

purity of the test substance was not stated. As a result, the usefulness of
 

the existing data base using the oral route is limited.
 

2.2.2.1 Death
 

An LD50 of 2,590 mg/kg was calculated for a gavage administration of 2­

hexanone (purity not stated) to rats (Smyth et al. 1954). One of 4 hens
 

administered 2-hexanone (70% purity) at 2,000 mg/kg by gavage died (Abou-Donia
 

et al. 1982). No lethality occurred in 24 hours in 6 male rats that received
 

2-hexanone (>99% purity) at 1,500 mg/kg by gavage (Hewitt et al. 1980a).
 

The highest NOAEL value, a reliable LOAEL value for death and an LD50 value for
 

these species in the acute-duration category are recorded in Table 2-2 and
 

plotted in Figure 2-2.
 

2.2.2.2 Systemic Effects
 

The systemic effects observed after oral exposure to 2-hexanone are
 

discussed below. The highest NOAEL values and all reliable LOAEL values for
 

systemic effects in each species and duration category are recorded in Table
 

2-2 and plotted in Figure 2-2.
 

No studies were located regarding respiratory, cardiovascular,
 

gastrointestinal, hematological, musculoskeletal, or dermal/ocular effects in
 

humans or animals after oral exposure to 2-hexanone.
 

Hepatic Effects. No studies were located regarding hepatic effects in
 

humans after oral exposure to 2-hexanone.
 



22
 

2. HEALTH EFFECTS
 

Various studies were conducted in rats in which the potential hepatic
 

effects of oral administration of 2-hexanone combined with exposure to another
 

agent were assessed. In rats given single doses of 2-hexanone up to 1,500
 

mg/kg by gavage, no effects were observed on liver histology, plasma glutamicpyruvic transaminase levels (as a measure of centrilobular necrosis),
 

measurements of the permeability of the biliary tree, malondialdehyde
 

production (as a measure of lipid peroxidation), or total bilirubin levels in
 

plasma (Cowlen et al. 1984b [2-hexanone purity not stated]; Hewitt et al.
 

1980a [2-hexanone purity >99%]; Hewitt et al. 1986 ]2-hexanone purity not
 

stated]). Rapid depletion of hepatic glutathione (GSH) levels was observed in
 

rats given a-single gavage dose of 2-hexanone (purity not stated) at 1,000
 

mg/kg (Cowlen et al. 1984a) and at 1,500 mg/kg (purity not stated)
 

(Branchflower and Pohl 1981). The effect at 1,000 mg/kg was reported to be
 

transient. Branchflower and Pohl (1981) postulated that this depletion might
 

be associated with the potentiation of toxic effects from chloroform (CHCl2)
 

when coadministered with 2-hexanone, since depletion of hepatic GSH could
 

allow more phosgene (COCl3) (the toxic oxidation product of chloroform) to
 

react with sensitive tissue components.
 

In a 40-week study in which rats were administered 2-hexanone at 400
 

mg/k/day, the levels of liver enzymes (alanine aminotransaminase and aspartate
 

transaminase activities) measured at 4-week intervals were normal (Eben et al.
 

1979).
 

Renal Effects. No studies were located regarding renal effects in humans
 

after oral exposure to 2-hexanone.
 

In studies in which rats were given a single gavage dose of 2-hexanone up
 

to 1,500 mg/kg, no alterations were observed in renal morphology, renal
 

cortical p-aminohippurate accumulation, plasma creatinine concentration (Brown
 

and Hewitt 1984), blood urea nitrogen (BUN), renal GSH levels (Branchflower
 

and Pohl 1981), ornithine carbamyl transferase (OCT) activities, or
 

accumulation of p-aminohippurate (PAH) or tetraethylammonium (TEA) (Hewitt et
 

al. 1980a). In male rats given 2-hexanone at 1,500 mg/kg, however, 9.6% of the
 

renal tubules examined were degenerated (as compared with 1% of controls)
 

(Hewitt et al. 1980a). The statistical significance of this finding was not
 

addressed. Plasma urea concentrations were normal in rats that received daily
 

gavage administrations of 2-hexanone at 400 mg/kg/day for 40 weeks (Eben et
 

al. 1979). Other Systemic Effects. No studies were located regarding effects
 

on body weight in humans after oral exposure to 2-hexanone.
 

Decreased weight gain was (specific data and statistical significance not
 

provided) reported in rats given daily doses of 400 mg/kg/day for 40 weeks
 

(Eben et al. 1979). Rats given 2-hexanone (undiluted) by gavage at
 
23
 

2. HEALTH EFFECTS
 

660 mg/kg/day in a 90-day study, weighed about 65% of control weights by 10
 

weeks of exposure (Krasavage et al. 1980). However, it is not clear from the
 

data provided whether these rats were too weak or ataxic to eat.
 

2.2.2.3 Immunological Effects
 

No studies were located regarding immunological effects in humans or
 

animals after oral exposure to 2-hexanone.
 

2.2.2.4 Neurological Effects
 

No studies were located regarding neurological effects in humans after
 

oral exposure to 2-hexanone.
 

Neurological effects resulting from oral administration of 2-hexanone
 

have been reported in three species of animals. In hens that received a single
 

gavage dose of 2-hexanone at 2,000 mg/kg, mild weakness was observed on the
 

day of administration, followed by apparent recovery in 4-5 days. Hens that
 

received 100 mg/kg showed no signs of neurotoxicity (Abou-Donia et al. 1982).
 

In a subchronic (90-day) phase of the same study, hens administered 2-hexanone
 

at 100 mg/kg/day or higher developed severe ataxia or near paralysis. There
 

was also evidence of histopathological changes including swelling or
 

degeneration of thoracic and lumbar regions of the spinal cord. Some of the
 

observations were described by the authors as equivocal.
 

Severe hindlimb dragging or paralysis was observed in all rats that
 

received 2-hexanone (undiluted) by gavage at 660 mg/kg/day at about day 56 (8
 

weeks) of a go-day study (Krasavage et al. 1980). Morphologic changes
 

indicative of "giant axonal" neuropathy included multifocal axonal swellings
 

and myelin infolding and paranodal retraction. In rats that received 400
 

mg/kg/day in a 40 week study, there was a temporary weakness of the hindlimbs
 

from 17 to 28 weeks of exposure (Eben et al. 1979). Improvement was observed
 

after that period.
 

Abnormal pupillary responses to light (measured by changes in pupillary
 

diameter) were observed in guinea pigs given 2-hexanone in drinking water at
 

dosage levels of approximately 600 mg/kg/day during a 24-week study (Abdel-


Rahman et al. 1978). Effects were seen from the first week of treatment.
 

It is important to note that 2,5-hexanedione, a metabolite in the blood
 

and urine of rats and in the urine of guinea pigs orally administered 2­

hexanone (DiVincenzo et al. 1976; Eben et al. 1979), has been demonstrated to
 

elicit severe neurotoxicity following oral, dermal, or intraperitoneal
 

administration to hens (Abou-Donia et al. 1982; 1985b) and following oral
 

administration to rats (Krasavage et al. 1980).
 
24
 

2. HEALTH EFFECTS
 

Reliable LOAEL values for neurological effects in each species in the
 

intermediate-duration category are recorded in Table 2-2 and plotted in Figure
 

2-2.
 

2.2.2.5 Developmental Effects
 

No studies were located regarding developmental effects in humans or
 

animals after oral exposure to 2-hexanone.
 

2.2.2.6 Reproductive Effects
 

No studies were located regarding reproductive effects in humans after
 

oral exposure to 2-hexanone.
 

Male rats that were given 2-hexanone at 660 mg/kg/day (undiluted) by
 

gavage in a 90-day study were observed to develop atrophy of the germinal
 

epithelium of the testes (Krasavage et al. 1980). However, the statistical
 

significance of this observation was not addressed.
 

2.2.2.7 Genotoxic Effects
 

No studies were located regarding genotoxic effects in humans or animals
 

after oral exposure to 2-hexanone.
 

2.2.2.8 Cancer
 

No studies were located regarding cancer effects in humans or animals
 

after oral exposure to 2-hexanone.
 

2.2.3 Dermal Exposure
 

Very little information was located regarding health effects in humansor
 

animals after dermal exposure to 2-hexanone.
 

2.2.3.1 Death
 

No studies were located regarding death in humans or animals afterdermal
 

exposure to 2-hexanone.
 

2.2.3.2 Systemic Effects
 

No studies were located regarding respiratory, cardiovascular,
 

gastrointestinal, hematological, musculoskeletal, hepatic, or renal effects in
 

humans or animals after dermal exposure to 2-hexanone.
 

Dermal/Ocular Effects. No studies were located regarding dermaI/ocular
 

effects in humans after dermal exposure to 2-hexanone.
 
25
 

2. HEALTH EFFECTS
 

Application of undiluted 2-hexanone to the skin of rabbits for 24 hours
 

resulted in Grade 1 (least severe) irritation (Smyth et al. 1954). Ocular
 

instillation resulted in Grade 3 (moderate) cornea1 necrosis.
 

2.2.3.3 Immunological Effects
 

No studies were located regarding immunological effects in humans or
 

animals after dermal exposure to 2-hexanone.
 

2.2.3.4 Neurological Effects
 

No studies were located regarding neurological effects in humans after
 

dermal exposure to 2-hexanone.
 

2-Hexanone (99% purity) applied to the backs of hens' necks at 100
 

mg/kg/day for 90 days resulted in gross ataxia (Abou-Donia et al. 1985b).
 

Histological changes observed were swollen axons without obvious fragmentation
 

of the axon or myelin sheath. No precautions against licking were mentioned in
 

the study.
 

The LOAEL for neurological effects in hens in the intermediate-duration
 

category is recorded in Table 2-3.
 

No studies were located regarding the following health effects in humans
 

or animals after inhalation exposure to 2-hexanone:
 

2.2.3.5 Developmental Effects
 

2.2.3.6 Reproductive Effects
 

2.2.3.7 Genotoxic Effects
 

2.2.3.8 Cancer
 

2.3 TOXICOKINETICS
 

Data on the toxicokinetics of 2-hexanone, as described in this section,
 

were derived from studies using 2-hexanone with purity of 97% or more. As
 

discussed below, absorption of this compound has been demonstrated in humans,
 

dogs, and rats after administration via inhalation, oral, or dermal exposure.
 

Very little information is available on distribution. A metabolic pathway has
 

been proposed based on the metabolites of 2-hexanone identified in the blood
 

of guinea pigs and rats after intraperitoneal and oral administration,
 

respectively. Expired breath and urine appear to be the main routes of
 

excretion for 2-hexanone and its metabolites.
 

27
 

2. HEALTH EFFECTS
 

2.3.1 Absorption
 

2.3.1.1 Inhalation Exposure
 

The available data indicate that 2-hexanone is well absorbed after
 

administration via the inhalation route. An analysis of the expired breath of
 

humans who inhaled 2-hexanone at 10 or 50 ppm for 7.5 hours or 100 ppm for 4
 

hours indicated that 75%-92% of the inhaled 2-hexanone vapor was absorbed by
 

the lungs and respiratory tract (DiVincenzo et al. 1978).
 

Similarly, beagles that inhaled 2-hexanone at 50 or 100 ppm for 6 hours
 

absorbed 65%-68% of the inhaled vapor (DiVincenzo et al. 1978).
 

2.3.1.2 Oral Exposure
 

2-Hexanone also appears to be well absorbed after oral administration.
 

Humans who ingested a single capsule containing 14C-2-hexanone at 0.1 mg/kg
 

excreted about 40% of the 14C in breath and 26% in urine during the next 8 days
 

(DiVincenzo et al. 1978). This indicates that the absorbed amount averaged at
 

least 66% of the administered dose.
 

Administration of 1-14C-2-hexanone at 20 or 200 mg/kg by gavage to rats
 

resulted in excretion of about 1.2% of the administered radioactivity in the
 

feces, about 44% in the breath, 38% in urine, and 16% remaining in the carcass
 

(DiVincenzo et al. 1977). The results were similar at either dosage level.
 

These findings suggest that about 98% of the administered dose was absorbed.
 

2.3.1.3 Dermal Exposure
 

2-Hexanone is also absorbed after dermal application. The excretion of 14C
 

in the breath and urine of two human volunteers was measured after a 60-minute
 

occlusive application of 14C-2-hexanone to their shaved forearms (DiVincenzo et
 

al. 1978). Calculated skin absorption rates were 4.8 and 8.0 pg/min/cm2

;
 

however, the fraction of 2-hexanone that was absorbed was not calculated. 14CHexanone was also applied to the clipped thorax of beagle dogs, and absorption
 

was observed to be slow at first but increased dramatically after 20 minutes.
 

At 60 minutes, 77 mg of 2-hexanone had penetrated the skin (DiVincenzo et al.
 

1978). The fraction of applied 2 hexanone that was absorbed was not
 

calculated.
 

2.3.2 Distribution
 

2.3.2.1 Inhalation Exposure
 

No studies were located regarding distribution in humans or animals
 

after inhalation exposure to 2-hexanone.
 
28
 

2. HEALTH EFFECTS
 

2.3.2.2 Oral Exposure
 

No studies were located regarding distribution in humans after oral
 

exposure to 2-hexanone.
 

In rats administered a single dose of l4C-2-hexanone at 200 mg/kg by
 

gavage , tissue distribution was reported to be widespread with highest counts
 

in the liver and blood. No quantitative data were given on tissue distribution
 

(DiVincenzo et al. 1977). An analysis of subcellular distribution of the 14C
 

label in liver, brain, and kidney tissue indicated highest counts were
 

associated with the crude lipid fraction and protein, with some recovery in
 

DNA, and little or none in RNA.
 

2.3.2.3 Dermal Exposure
 

No studies were located regarding distribution in humans or animals after
 

dermal exposure to 2-hexanone.
 

2.3.3 Metabolism
 

The proposed metabolic pathway for 2-hexanone, based on 2-hexanone
 

metabolites identified in blood during intraperitoneal studies in guinea pigs
 

(DiVincenzo et al. 1976) and oral studies in rats (DiVincenzo et al. 1977) is
 

presented in Figure 2-3. Because inhalation exposure of humans to 2-hexanone
 

has resulted in the appearance of carbon dioxide in expired air and 2,5­

hexanedione in serum, DiVincenzo et al. (1978) have hypothesized that the
 

metabolic pathway for 2-hexanone is similar in humans and experimental
 

animals. The metabolism of aliphatic ketones has generally been found to
 

proceed via reduction to the corresponding secondary alcohol, which accounts
 

for the formation of 2-hexanol. An alternate pathway is oxidation of the 5­

methylene group to the corresponding alcohol, 5-hydroxy-2-hexanone, which may
 

be followed by further oxidation to the diketone 2,5-hexanedione. Another
 

possibility in the metabolism of 2-hexanone is the cyclization of 5-hydroxy2-hexanone to the corresponding dihydrofuran and oxidation to 2,5­

dimethylfuran (DiVincenzo et al. 1977). However, the formation of these furan
 

moieties may be the result of thermal dehydration and cyclization during gas
 

chromatography (DiVincenzo et al. 1977). In addition, the gamma-valerolactone
 

found in the urine (not shown in figure) is hypothesized to result from
 

alphaoxidation of 5-hydroxy-2-hexanone to 2-keto-5-hydroxyhexanoic acid,
 

decarboxylation and oxidation to 4-hydroxypentanoic acid, and lactonization to
 

gamma-valerolactone (DiVincenzo et al. 1977).


 A strong relationship has been noted between the concentration of 2,5­

hexanedione in the urine and the onset of neuropathic symptoms (Eben et al.
 

1979). Similarly, 2,5-hexanedione was described as eliciting severe neurotoxic
 

symptoms following oral, dermal, or intraperitoneal administration to hens
 

(Abou-Donia et al. 1982, 1985b) and following oral administration to rats
 

(Krasavage et al. 1980).
 

30
 

2. HEALTH EFFECTS
 

There are two major hypotheses related to the mechanism of neurotoxicity
 

of 2,5-hexanedione: covalent binding with axonal components of nerve tissue
 

and inhibition of enzymes associated with the production of energy in this
 

tissue. In vitro studies in which 2,5-hexanedione was incubated with proteins
 

demonstrated that this compound binds to the lysine ∈-amino group resulting in 

the formation of the substituted pyrrole adduct ∈-N-(2,5-dimethylpyrrolyl) 

norleucine (DeCaprio et al. 1982). Covalent binding of 2,5-hexanedione with 

axonal components leading to pyrrole formation and protein cross-linking was 

hypothesized as a possible initiation step leading to axonal degeneration and 

thus may account for the neurotoxic effects observed with exposure to 

gammadiketones in general (DeCaprio et al. 1982, 1988). In vivo confirmation 

of pyrrole formation was reported based on the presence of ∈-N-(2,5­

dimethylpyrrolyl)norleucine in the hydrolyzed serum of a hen that had received
 

2,5-hexanedione at 200 mg/kg/day by gavage for two weeks (DeCaprio et al.
 

1982).
 

Other studies have demonstrated that both 2-hexanone and 2,5-hexanedione
 

can inhibit sulfhydryl-dependent enzymes such as fructose-6-phosphate kinase
 

(an enzyme in the pentose phosphate pathway) and glyceraldehyde-3-phosphate
 

dehydrogenase (an enzyme in the glycolytic pathway) (Sabri et al. 1979b; Sabri
 

1984). Both of these neurotoxicants inhibited fructose-6-phosphate kinase
 

crystallized from rabbit muscle or in rat brain homogenates; in each case,
 

2,5-hexanedione was the far more potent inhibitor (Sabri et al. 1979b).
 

Preincubation with dithiothreitol protected this enzyme from inhibition, which
 

suggests that these compounds interfere with the sulfhydryl groups required
 

for fructose-6-phosphate kinase activity. However, dithiothreitol could not
 

restore enzyme activity after these compounds had been added. In addition,
 

fructose-6-phosphate kinase activity was also reduced in the brain homogenates
 

of rats that had received 2,5-hexanedione at 0.5% of their drinking water for
 

10-12 weeks (Sabri et al. 1979b). Crystalline glyceraldehyde-3-phosphate
 

dehydrogenase from rabbit muscle was also inhibited by both compounds; in this
 

case, 2-hexanone was the more potent inhibitor (Sabri 1984). Levels of ATP
 

were reduced in cat sciatic nerves treated with 2,5-hexanedione (Sabri 1984).
 

2-Hexanone was found to irreversibly inhibit rat brain and rabbit muscle
 

creatine kinase and mouse brain adenylate kinase (Lapin et al. 1982).
 

In addition, oral administration of l-14C-2-hexanone to humans or rats
 

results in the appearance of 14CO2 in the expired breath (DiVincenzo et al.
 

1977, 1978), indicating oxidation/cleavage of the alpha carbon.
 

Administration of SKF525A (a mixed function oxidase inhibitor) to rats before
 

oral administration of 2-hexanone resulted in a marked decrease in the
 

excretion of respiratory 14CO2 for the first 4 hours after administration,
 

followed by a marked increase at 4-8 and 12-24 hours. This suggests that this
 

oxidative step is mediated by a microsomal mixed function oxidase system
 

(DiVincenzo et al. 1977).
 
31
 

2. HEALTH EFFECTS
 

2.3.4 Excretion
 

2.3.4.1 Inhalation Exposure
 

In humans exposed to 2-hexanone via inhalation at 10 or 50 ppm for 7.5
 

hours or to 100 ppm for 4 hours, unchanged 2-hexanone (but none of its
 

metabolites) was found in expired air, and neither 2-hexanone nor any of its
 

metabolites was found in urine during or after exposure (DiVincenzo et al.
 

1978). 2-Hexanone was not detected in the expired air 3 hours after exposure
 

to 50 or 100 ppm. These results suggest slow clearance and possible
 

accumulation of 2-hexanone in humans exposed by this route.
 

In beagle dogs exposed to 2-hexanone via inhalation at 50 or 100 ppm for
 

6 hours, 32% and 35%, respectively, of the inhaled vapor was excreted in the
 

expired breath (DiVincenzo et al. 1978). By 3-5 hours after exposure, 2­

hexanone was no longer detected in expired air. Excretion via other routes was
 

not addressed.
 

2.3.4.2 Oral Exposure
 

In two humans who received a single oral dose of 1-14C-2-hexanone, breath
 

excretion of 14CO2 CO, reached a peak within 4 hours, then decreased slowly over
 

the next 3-5 days. Average overall recovery of the 14C-label in 8 days was 40%
 

in breath and 26% in urine. Feces were not analyzed (DiVincenzo et al. 1978).
 

In rats administered a single oral dose of 1-14C-2-hexanone, DiVincenzo et
 

al. (1977) observed similar results. Radioactivity in breath accounted for
 

about 45% of the administered dose (5% was in unchanged 2-hexanone; 40% was in


14C02,); 35% was found in the urine; 1.5% was recovered in the feces; and about
 

15% remained in the carcass. In male rats that received daily gavage doses of
 

2-hexanone at 400 mg/kg/day for 40 weeks, very low concentrations of free 2­

hexanone were detected in the urine from the third week. A maximum
 

concentration of approximately 20 ug was reached in the 17th week (Eben et al.
 

1979). Similarly, free 2,5-hexanediol was found in the urine after 3 weeks and
 

peaked in the 17th week. Free and conjugated 2,5-hexanedione were present in
 

the urine from the 1st week of the study. The conjugated form peaked in the
 

7th week; whereas excretion levels of the free form were fairly consistent
 

throughout the study. A strong correlation was observed in this study between
 

the onset of neuropathy and the urinary concentration of 2,5-hexanedione when
 

2-hexanone, 2,5-hexanedione or 2,5-hexanediol was administered orally to rats
 

at 400 mg/kg/day.
 

2.3.4.3 Dermal Exposure
 

14C from l-14C-2-hexanone applied to the forearms of two human volunteers
 

was found in the breath and urine (DiVincenzo et al. 1978). In one subject,
 
32
 

2. HEALTH EFFECTS
 

excretion was similar by both routes; in the other subject, the levels were
 

much higher (about 3:l) in the breath. Levels of radioactivity in feces were
 

not measured.
 

2.4 RELEVANCE TO PUBLIC HEALTH
 

As discussed in Section 2.2, estimates of levels of exposure to 2­

hexanone posing minimal risk to humans (MRLs) were to have been made, where
 

data were believed reliable, for the most sensitive noncancer effect for each
 

route and exposure duration. However, no MRLs could be derived for 2-hexanone.
 

No data were located on effects of acute-duration or chronicduration
 

inhalation exposure to 2-hexanone in humans or animals. Available information
 

concerning effects of intermediate-duration inhalation exposure in humans and
 

animals identifies neurological effects as the most sensitive indicator of
 

toxicity, but this information does not reliably identify the threshold for
 

this effect. Therefore, no inhalation MRLs were derived. Available information
 

on acute-duration oral exposure in animals does not identify the most
 

sensitive effect, and while available information on intermediate-duration
 

oral exposure to 2-hexanone in animals suggests that neurotoxicity may be the
 

most sensitive effect, data do not reliably identify the threshold for
 

neurotoxicity. No information was located on effects of chronic-duration
 

exposure to 2-hexanone in humans or animals. Therefore, no oral MRLs were
 

derived. Acute-duration, intermediate-duration, and chronicduration dermal
 

MRLs were not derived for 2-hexanone due to the lack of an appropriate
 

methodology for the development of dermal MRLs.
 

As demonstrated in humans as well as in laboratory animals, the most
 

important concern associated with exposure to 2-hexanone is neuropathy. In all
 

species observed, this neurological effect is generally accompanied by effects
 

on body weight. Based on the results of animal studies, other potential
 

concerns are adverse hematological effects and effects on reproduction and
 

fetal development.
 

Death. There are no data to suggest that lethality is a concern for
 

humans exposed to 2-hexanone via any route. Lethality data in animals include
 

an inhalation study by Abdo et al. (1982) in which 1 of 5 hens died after 72
 

days of continuous exposure to 200 ppm and 2 of 5 hens died by day 27 of
 

exposure to 400 ppm. No deaths were recorded in hens exposed to 100 ppm for 90
 

days. An oral LD50 of 2,590 mg/kg has been reported for rats (Smyth et al.
 

1954). No lethality studies using the dermal route have been located. These
 

findings suggest that lethality is possible with very high concentrations of
 

2-hexanone. However, it is unlikely that humans in any setting would be
 

exposed to levels high enough to result in death.
 

Systemic Effects.
 

Hematological Effects. There is no evidence that adverse hematological
 

effects occurred in workers exposed to 2-hexanone (Allen et al. 1975). The
 
33
 

2. HEALTH EFFECTS
 

potential hematological effects of exposure to 2-hexanone were investigated in
 

an inhalation study by Katz et al. (1980) in which rats were exposed to 700
 

ppm 2-hexanone intermittently for 11 weeks. No effects were observed on
 

hemoglobin concentration, hematocrit, or differential white blood cell counts.
 

However, at about 8 weeks, total white cell counts were reduced to about 60%
 

of control values. Since there was no evidence of a corresponding effect on
 

bone marrow, the authors stated that the clinical significance of this finding
 

was uncertain. However, it is possible that hematological effects may occur in
 

humans exposed to 2-hexanone by inhalation.
 

Hepatic Effects. There are no data on hepatic effects occurring in humans
 

exposed to 2-hexanone; however, these effects have been investigated in
 

several studies in animals using inhalation or oral administration. No effect
 

was found on hexobarbital-induced sleep times in rats continuously exposed to
 

2-hexanone via inhalation at 225 ppm for 7 days (Couri et al. 1977); no
 

histopathological effects were found in the livers of rats exposed to 50 ppm
 

for 6 months (Duckett et al. 1979). In studies conducted via the oral route,
 

single-dose administration of 2-hexanone at levels up to 1,500 mg/kg did not
 

result in effects on liver histology, plasma glutamic-pyruvic transaminase
 

levels (as a measure of centrilobular necrosis), permeability of the biliary
 

tree, malondialdehyde production (as a measure of lipoperoxidation), or total
 

bilirubin levels in plasma (Cowlen et al. 1984b; Hewitt et al. 1980a, 1983,
 

1986). The results of liver enzyme measurements (alanine aminotransferase,
 

aspartate aminotransferase) given at 4-week intervals were normal in rats
 

receiving 2-hexanone at 400 mg/kg/day for 40 weeks (Eben et al. 1979).
 

Hepatic effects were reported in two studies. The rapid depletion of
 

glutathione (GSH) levels was observed in the livers of rats given a single
 

dose of 2-hexanone at 1,500 mg/kg (Branchflower and Pohl 1981), and in another
 

study, an increased liver to body weight ratio was found in rats given 2­

hexanone at the same dose (Hewitt et al. 1983).
 

Based on the available data in animals, 2-hexanone does not appear to be
 

hepatotoxic. However, there is evidence to indicate that it can greatly
 

enhance the hepatotoxicity of other chemicals such as chloroform (see Section
 

2.6).
 

Renal Effects. There are no available data to suggest that renal effects
 

are a potential risk associated with human exposure to 2-hexanone. No
 

histopathological effects were seen in the kidneys of rats exposed to 50 ppm
 

2-hexanone via inhalation for 6 months (Duckett et al. 1979). Renal effects
 

were also investigated in a study in which rats were administered a single
 

gavage dose of 2-hexanone at 1,500 mg/kg. Degenerative changes were reported
 

in 9.6% of the renal tubules in treated animals, as compared with a 1%
 

incidence in controls (Hewitt et al. 1980a). The statistical significance of
 

this finding was not addressed. However, these data do not support a concern
 

for potential renal effects in humans exposed to 2-hexanone.
 
34
 

2. HEALTH EFFECTS
 

Dermal/Ocular Effects. 2-Hexanone applied to the skin of rabbits was
 

minimally irritating; ocular instillation resulted in moderate cornea1
 

necrosis (Smyth et al. 1954). Human ocular contact with this chemical would,
 

therefore, be of concern.
 

Other Effects. In both animals and humans, the most common systemic
 

effect observed following inhalation or ingestion of 2-hexanone was weight
 

loss or decreased weight gain in developing animals. Weight loss and decreased
 

weight gain may be secondary to loss of appetite or inability to feed. Weight
 

loss, ranging from 3 to 60 pounds was reported by Allen et al. (1975) in
 

workers exposed to 2-hexanone for several months in a fabric-finishing plant.
 

These losses were generally seen in the workers with more severe neurological
 

impairment (peripheral neuropathy). Weight loss and decreased rates of weight
 

gain in developing animals were reported in several species exposed via
 

inhalation including rats (Johnson et al. 1977; Katz et al. 1980; Spencer et
 

al. 1975), and hens (Abdo et al. 1982). In most of these studies, little or no
 

effect on body weight was observed with exposure to 100 ppm or less. In oral
 

studies, effects on body weight were also reported in rats (Krasavage et al.
 

1980). These observations indicate that weight loss in adults and decreased
 

weight gains in children would be an area of concern associated with exposure
 

to 2-hexanone.
 

Immunological Effects. There is no information on the immunological
 

effects of human exposure to 2-hexanone. Reductions in total white blood cell
 

count to 60% of control values were reported in rats intermittently exposed to
 

700 ppm 2-hexanone via inhalation for about 8 weeks (Katz et al. 1980).
 

Because there were no effects on differential counts or evidence of bone
 

marrow damage, the full implications of their findings to potential
 

immunological effects in humans are not clear. It is interesting to note that
 

in male mice given either single or 7 daily oral doses of 2,5-hexanedione, a
 

metabolite of 2-hexanone, at a dose that was too low to elicit neurotoxicity
 

(20% of the LD50), there were reductions in the cellularity of the spleen,
 

thymus, and mesenteric lymph nodes. Abnormal results in immune function tests
 

such as delayed hypersensitivity reaction tests, plaque-forming cell assay,
 

phagocytosis by adherent peritoneal exudate cells, and resistance to endotoxin
 

shock were also reported (Upreti and Shanker 1987). In female rats given
 

single or 7 daily oral doses of 2,5-hexanedione at l0%-50% of the LD50
 

decreased cellularity of various lymphoid organs was also observed (Upreti et
 

al. 1986). These studies suggest that immunological effects may be an area of
 

potential concern for humans exposed to 2-hexanone.
 

Neurological Effects. Neurological effects are the most likely public
 

health concern associated with exposure to 2-hexanone. Peripheral neuropathy
 

was reported in workers using 2-hexanone in fabric finishing operations (Allen
 

et al. 1975). In animal studies, neuropathy progressing from mild ataxia to
 

paralysis was reported in inhalation studies using cats (Mendell et al. 1974b;
 

Saida et al. 1976), monkeys (Johnson et al. 1977), rats (Johnson et al. 1977;
 

Saida et al. 1976), and hens (Abdo et al. 1982), and in oral studies using
 
35
 

2. HEALTH EFFECTS
 

rats (Eben et al. 1979; Krasavage et al. 1980), guinea pigs (Abdel-Rahman et
 

al. 1978), and hens (Abou-Donia et al. 1982). Pathological alterations in
 

hens, cats, and rats have been reported to be similar and the clinical
 

manifestations in the experimental animals and the exposed workers were
 

comparable (Mendell et al. 1974b).
 

Examination of the affected nerves in these test species indicated that
 

demyelination and axonal swelling were generally associated with the observed
 

clinical effects. A significant finding was that in rats that became paralyzed
 

as a result of 2-hexanone exposure at 225 ppm for 9.5 weeks or to 400 ppm for
 

6 weeks, histopathological changes of the peripheral nerves occurred as early
 

as 16 days at both exposure levels (Saida et al. 1976). In another study, no
 

clinical signs of neuropathy were observed in rats exposed to 100 ppm 2­

hexanone for 6 months, whereas histopathological changes of both peripheral
 

nerves and tracts of the spinal cord were seen after 4 months of exposure
 

(Egan et al. 1980). These findings suggest that nerve degeneration may also
 

occur in exposed humans well before the characteristic symptoms of peripheral
 

neuropathy (muscle weakness and sensory loss in the hands and feet) become
 

apparent. Electromyographic testing, as used in some of the studies discussed
 

in Sections 2.2.1.4 and 2.2.2.4, appears to be sensitive enough to detect
 

abnormalities in the conduction characteristics of nerves before clinical
 

manifestations occur.
 

Ultrastructural studies of nerve fibers in the peripheral and central
 

nervous systems of exposed animals from several of their studies have led
 

Spencer and Schaumberg (1977b) to the use of the term "dying-back" to describe
 

the nature of the pathology. The most distal extremities of the longest and
 

largest axons appear to be affected first; axonal degeneration seems to,
 

Progress proximally to fibers in the central nervous system.
 

Developmental Effects. There are no available data on the developmental
 

effects of human exposure to 2-hexanone. Concern that the offspring of women
 

exposed to 2-hexanone during pregnancy may be at risk for developmental
 

effects comes from an inhalation study in which behavioral alterations were
 

seen in the offspring of pregnant rats exposed to 1,000 ppm 2-hexanone during
 

gestation (Peters et al. 1981). These effects consisted of reduced activity in
 

the open field, increased activity in the running wheel, and deficits in
 

avoidance conditioning. There was also a decrease in the number and birth
 

weight of live offspring of these rats. These findings suggest that neonate
 

survival may be a concern for human exposure.
 

Reproductive Effects. There are no available data on the reproductive
 

effects of human exposure to 2-hexanone. Reproductive effects may be a
 

concern for women exposed to 2-hexanone based on the findings of an inhalation
 

study in which there were decrements in the weight gain of pregnant rats
 

exposed to 2,000 ppm 2-hexanone during gestation (Peters et al. 1981).
 
36
 

2. HEALTH EFFECTS
 

In addition, marked and significant reductions in absolute and relative
 

testes weight and atrophy of testicular germinal epithelium were reported in
 

male rats exposed to 700 ppm 2-hexanone via inhalation for 11 weeks (Katz et
 

al. 1980), and atrophy of the testicular germinal epithelial was also observed
 

in male rats that received 2-hexanone at 660 mg/kg/day by gavage during a 90­

day study (Krasavage et al. 1980). Histological changes and reduced testicular
 

weight have also been observed in rats that received 2,5-hexanedione for 4
 

weeks at 1% of their drinking water (about 1,400 mg/kg/day) (Boekelheide
 

1987). These observations suggest that effects on semen production and male
 

fertility may be a concern for men exposed to 2-hexanone.
 

Genotoxic Effects. No studies were located regarding the potential
 

genotoxic effects in humans or animals following any route of exposure to 2­

hexanone. No in vitro studies have been located for 2-hexanone.
 

Cancer. No studies were located regarding the potential carcinogenic
 

effects in humans or animals following any route of exposure to 2-hexanone.
 

2.5 BIOMARKERS OF EXPOSURE AND EFFECT
 

Biomarkers are broadly defined as indicators signaling events in biologic
 

systems or samples. They have been classified as markers of exposure, markers
 

of effect, and markers of susceptibility (NAS/NRC 1989).
 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or
 

the product of an interaction between a xenobiotic agent and some target
 

molecule(s) or cell(s) that is measured within a compartment of an organism
 

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the
 

substance itself or substance-specific metabolites in readily obtainable body
 

fluid or excreta. However, several factors can confound the use and
 

interpretation of biomarkers of exposure. The body burden of a substance may
 

be the result of exposures from more than one source. The substance being
 

measured may be a metabolite of another xenobiotic substance (e.g., high
 

urinary levels of phenol can result from exposure to several different
 

aromatic compounds). Depending on the properties of the substance (e.g.,
 

biologic half-life) and environmental conditions (e.g., duration and route of
 

exposure), the substance and all of its metabolites may have left the body by
 

the time biologic samples can be taken. It may be difficult to identify
 

individuals exposed to hazardous substances that are commonly found in body
 

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc,
 

and selenium). Biomarkers of exposure to 2-hexanone are discussed in
 

Section 2.5.1.
 

Biomarkers of effect are defined as any measurable biochemical,
 

physiologic, or other alteration within an organism that, depending an
 

magnitude, can be recognized as an established or potential health impairment
 

or disease (NAS/NRC 1989). This definition encompasses biochemical or
 
37
 

2. HEALTH EFFECTS
 

cellular signals of tissue dysfunction (e.g., increased liver enzyme activity
 

or pathologic changes in female genital epithelial cells), as well physiologic
 

signs of dysfunction such as increased blood pressure or decreased lung
 

capacity. Note that these markers are often not substance specific. They also
 

may not be directly adverse, but can indicate potential health impairment
 

(e.g., DNA adducts). Biomarkers of effects caused by 2-hexanone are discussed
 

in Section 2.5.2.
 

A biomarker of susceptibility is an indicator of an inherent or acquired
 

limitation of an organism's ability to respond to the challenge of exposure to
 

a specific xenobiotic substance. It can be an intrinsic genetic or other
 

characteristic or a preexisting disease that results in an increase in
 

absorbed dose, biologically effective dose, or target tissue response. If
 

biomarkers of susceptibility exist, they are discussed in Section 2.7,
 

"POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."
 

2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to 2-Hexanone
 

2-Hexanone and its various metabolic products (2-hexanol, 2,5­

hexanedione, 5-hydroxy-2-hexanone, 2,5-dimethylfuran) can be measured in
 

biological tissue, fluid, and excreta (Fedtke and Bolt 1986; Nomeir and Abou-


Donia 1985; White et al. 1979). The currently available information, however,
 

does not indicate whether the levels of these substances can be used to
 

calculate or estimate corresponding levels of exposure to 2-hexanone. An
 

additional complication is that because the same metabolites have been
 

identified in the urine of rats orally exposed to n-hexane (Fedtke and Bolt
 

1986), the selection of a specific biomarker for exposure to 2-hexanone is
 

thus unlikely.
 

2.5.2 Biomarkers Used to Characterize Effects Caused by 2-Hexanone
 

There are currently no subtle or sensitive biomarkers of effects
 

associated with exposure to 2-hexanone. Electromyographic testing, however,
 

may prove to be useful in the detection of nerve conduction abnormalities in
 

their early stages, even before they are accompanied by clinical
 

manifestations. Specific electrodiagnostic patterns associated with exposure
 

to 2-hexanone have not been clearly delineated.
 

2.6 INTERACTIONS WITH OTHER CHEMICALS
 

Based on the results of several animal studies, exposure to 2-hexanone
 

can result in the potentiation and exacerbation of adverse effects associated
 

with the administration of other toxic compounds. Oral administration of 2­

hexanone followed by intraperitoneal administration of chloroform to rats has
 

resulted in a variety of hepatic and renal effects including decreased hepatic
 

glutathione levels, increased plasma levels of glutamic pyruvic transaminase
 

and blood urea nitrogen, and degeneration and necrosis of hepatic and renal
 

tissue (Branchflower and Pohl 1981; Brown and Hewitt 1984; Cowlen et al.
 

1984a, 1984b; Hewitt et al. 1980a,b, 1983). Similarly, oral
 
38
 

2. HEALTH EFFECTS
 

administration of both 2-hexanone and chloroform to rats resulted in altered
 

permeability of the biliary tree (Hewitt et al. 1986). In these studies, some
 

or no effect on the end points of interest was observed after administration
 

of 2-hexanone or chloroform alone; administration of both substances resulted
 

in statistically significant and dramatic changes in these effects.
 

These authors have speculated that 2-hexanone potentiates the hepatic
 

toxicity of chloroform by decreasing glutathione levels (Branchflower and Pohl
 

1981; Hewitt et al. 1980a) and by increasing the metabolism of chloroform to
 

the potent hepatotoxicant, phosgene (Branchflower and Pohl 1981; Cowlen et al.
 

1984a, 1984b). Branchflower and Pohl (1981) have speculated that the
 

metabolism of chloroform to phosgene may also be involved in the renal
 

toxicity seen in these studies.
 

2-Hexanone has also been shown to potentiate the neurotoxic effects of
 

some compounds.. In hens, dermal or inhalation exposure to 2-hexanone in
 

combination with dermal application of the pesticide 0-ethyl-0-4-nitrophenyl
 

phenylphosphonothioate (EPN) has resulted in earlier onset and far more severe
 

clinical and histological manifestations of neurotoxic effects than with
 

either chemical exposure alone (Abou-Donia et al. 1985a, 1985b). The authors
 

speculated that this potentiation effect may have been due to induction of
 

hepatic microsomal cytochrome P-450 by EPN, leading to increased metabolism of
 

2-hexanone to its neurotoxic metabolite, 2,5-hexanedione. An alternate
 

explanation is that local trauma to the nervous tissue produced by 2-hexanone
 

and EPN might increase vascular permeability and thus increase the entry of
 

these compounds and their metabolites from circulation.
 

A study in which rats were exposed via inhalation to a combination of 2­

hexanone and methyl ethyl ketone resulted in the potentiation of severe
 

neurotoxic effects including paralysis and histopathological changes. These
 

effects were either not observed or they occurred at much lower frequencies
 

when either of the two compounds was administered separately (Saida et al.
 

1976).
 

These results suggest that persons living or working in the vicinity of
 

hazardous waste sites or workers who are exposed to 2-hexanone in combination
 

with any of the potentially toxic substances discussed above may be at special
 

risk for the effects of exposure to the combination of chemicals.
 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

No population has been identified which is unusually susceptible to toxic
 

effects resulting from 2-hexanone exposure.
 

2.8 MITIGATION OF EFFECTS
 

This section will describe clinical practice and research concerning methods
 

for reducing toxic effects of exposure to 2-hexanone. However, because some
 
39
 

2. HEALTH EFFECTS
 

of the treatments discussed may be experimental and unproven, this section
 

should not be used as a guide for treatment of exposures to 2-hexanone. When
 

specific exposures have occurred, poison control centers and medical
 

toxicologists should be consulted for medical advice.
 

Human exposure to 2-hexanone may occur by inhalation, ingestion, or dermal
 

absorption (see Chapter 5). Dermal exposure to 2-hexanone may cause ocular and
 

skin irritation. Exposure by any route may cause peripheral neuropathy, with
 

nerve degeneration and paralysis (see Section 2.2).
 

Procedures for reducing toxic effects following acute, high level exposure to
 

2-hexanone include measures to reduce or eliminate further absorption.
 

Following dermal or ocular exposure, these procedures include removing
 

contaminated clothing and thoroughly washing the skin and eyes (Bronstein and
 

Currance 1988; Stutz and Janusz 1988). Following acute, high level oral
 

exposure, these procedures include emptying the stomach, using care to avoid
 

aspiration of the gastric contents, followed by administration of activated
 

charcoal and a cathartic to stimulate fecal excretion (Stutz and Janusz 1988).
 

The half-life of 2-hexanone and its metabolites in blood plasma has not been
 

established; however, elimination from the body does appear to occur in less
 

than 24 hours following both inhalation and ingestion exposures (DiVincenzo et
 

al. 1977, 1978). 2-Hexanone is not known to accumulate over time in any
 

tissues in the body (see section 2.3.4). While elimination enhancement
 

through stimulation of metabolism of 2-hexanone may reduce some forms of
 

toxicity, if used within the short time that 2-hexanone is retained in the
 

body, there is the risk that these same metabolic reactions may form reactive
 

metabolites such as 2,5-hexanedione. Furthermore, concurrent exposures to
 

other substances may also occur for which stimulation of these same metabolic
 

pathways is contraindicated. Therefore, the benefit of stimulating specific
 

metabolic pathways to enhance 2-hexanone elimination is unclear and should be
 

studied further.
 

The major toxic effect of exposure to 2-hexanone is neuropathy. Neuropathy can
 

be caused by both 2-hexanone and its metabolite 2,5-hexanedione. A reduction
 

of the neuropathy caused by exposure to 2-hexanone could theoretically be
 

achieved through shunting of metabolism to less toxic metabolites. However, as
 

discussed above, the toxicity of those other metabolites, and the effect of
 

the treatment on metabolism of other potential toxicants, would have to be
 

clearly assessed.
 

Two major hypotheses concerning the mechanism of action of either 2-hexanone
 

or 2,5-hexanedione have been suggested (see section 2.3.3 Metabolism). These
 

mechanisms are 1) inhibition of sulfhydryl dependent enzymes (Lapin et al.
 

1982; Sabri et al. 1979b; Sabri 1984), and 2) covalent binding to axonal
 

components leading to pyrrole formation, protein crosslinking, and axonal
 

degeneration (DeCaprio et al. 1982, 1988). Dithiothreitol has been shown to
 

reduce the inhibition in one of the inhibited enzymes in vitro, suggesting
 
40
 

2. HEALTH EFFECTS
 

that blocking accessibility of the sulfhydryl groups may be an effective
 

method of blocking toxic effects (Sabri et al. 1979b).
 

Interaction of 2-hexanone with EPN (Abou-Donia 1985a) and methyl ethyl ketone
 

(Saida et al. 1976) may occur through the potentiation of the production of
 

2,5-hexanedione. An effective method of reducing the neurotoxic effects of
 

combined exposures to these compounds would be to pharmacologically block the
 

metabolic pathways that lead to the production of 2,5-hexanedione, given the
 

same caveats presented for interference with metabolic pathways presented
 

above. Increasing the breakdown or clearance of 2,5-hexanedione might also be
 

effective.
 

2-Hexanone has been found to enhance the hepatotoxicity of chloroform in
 

animals (Branchflower and Pohl 1981). This may occur in part through
 

depletion of glutathione levels by 2-hexanone, and in part by a 2 hexanonemediated increase in the production of phosgene from chloroform (Branchflower
 

and Pohl 1981; Cowlen et al. 1984a). It is possible that ensuring sufficient
 

glutathione stores in the body may reduce the chances of toxic effects
 

following combined acute exposure to 2-hexanone and chloroform. Specific
 

blockage of the production of phosgene, through the inhibition of liver
 

cytochrome P450, might be an effective method of reducing liver damage.
 

However, an analysis of the net effect of this inhibition on the toxicity of
 

the combined exposure would need to be made prior to recommending this method
 

as a mitigation treatment.
 

2.9 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of
 

ATSDR (in consultation with the Administrator of EPA and agencies and programs
 

of the Public Health Service) to assess whether adequate information on the
 

health effects of 2-hexanone is available. Where adequate information is not
 

available, ATSDR, in conjunction with the National Toxicology Program (NTP),
 

is required to assure the initiation of a program of research designed to
 

determine the health effects (and techniques for developing methods to
 

determine such health effects) of 2-hexanone.
 

The following categories of possible data needs have been identified by a
 

joint team of scientists from ATSDR, NTP, and EPA. They are defined as
 

substance-specific informational needs that, if met, would reduce or eliminate
 

the uncertainties of human health assessment. In the future, the identified
 

data needs will be evaluated and prioritized, and a substance-specific
 

research agenda will be proposed.
 

2.9.1 Existing Information on Health Effects of 2-Hexanone
 

The existing data on health effects of inhalation, oral, and dermal
 

exposure of humans and animals to 2-hexanone are summarized in Figure 2-4.
 

42
 

2. HEALTH EFFECTS
 

The purpose of this figure is to illustrate the existing information
 

concerning the health effects of 2-hexanone. Each dot in the figure indicates
 

that one or more studies provide information associated with that particular
 

effect. The dot does not imply anything about the quality of the study or
 

studies. Gaps in this figure should not be interpreted as "data needs"
 

information (i.e., data gaps that must necessarily be filled).
 

Figure 2-4 graphically depicts the information that currently exists on
 

the health effects that have been observed or studied in humans or animals
 

following exposure to 2-hexanone. Data on intermediate-duration systemic and
 

neurologic effects in humans were derived from a single study of workers
 

exposed to 2-hexanone for about 10 months. Although there is more information
 

on animals, as discussed below, certain factors, such as the use of 2-hexanone
 

of low or unknown purity or the use of a single dosage level in the test
 

protocol, complicate the interpretation of these studies and limit their
 

usefulness.
 

Some information is available from animal studies conducted via the
 

inhalation route in several categories of toxicity including lethality,
 

systemic effects resulting from intermediate-duration exposure, neurologic,
 

reproductive, and developmental effects. In studies conducted via the oral
 

route, some information is available on lethality, systemic effects resulting
 

from acute- or intermediate-duration exposure, reproductive effects, and
 

neurologic effects. Only two studies using the dermal route were available.
 

These provided information on acute and neurologic effects.
 

2.9.2 Data Needs
 

As discussed in previous sections, many of the currently available
 

studies on 2-hexanone used a single dose level of the test compound, the
 

purity of the test compound was not stated in some studies or in some cases,
 

the purity was stated to be as low as 70%. Therefore little or no dose-


response information is available in the existing database. In addition,
 

studies using 2-hexanone of low purity introduce the complications associated
 

with exposures to multiple substances and the potential for chemical
 

interactions. As a result, the available data are limited in their usefulness
 

and must be interpreted with caution.
 

Acute-Duration Exposure. Currently, no data are available on humans for
 

this exposure duration for any route of exposure. In addition, there is no
 

information on acute toxicity in animals following inhalation exposure.
 

Lethality data are available for the rat and hen via the oral route (Abou-


Donia et al. 1982; Hewitt et al. 1980a; Smyth et al. 1954). Existing data are
 

insufficient to derive an MRL for any route of exposure. Acute-duration
 

studies for all routes of exposure using a range of exposure concentrations
 

would be useful in determining potential target organs, especially the nervous
 

system, to identify any dosage thresholds, and to establish dose-response
 

relationships for these effects. Brief human exposure to 2-hexanone may occur
 
43
 

2. HEALTH EFFECTS
 

at hazardous waste sites, at the site of accidental spills, or in the
 

workplace.
 

Intermediate-Duration Exposure. The currently available data on humans
 

exposed to 2-hexanone for this duration period is based on a study of workers
 

exposed to 2-hexanone for about 10 months (Allen et al. 1975). Peripheral
 

neuropathy and weight loss were the major observations. Repeated-dose studies
 

in rats, cats, monkeys, hens, and guinea pigs indicate that the nervous system
 

is the primary target of 2-hexanone exposure via inhalation (Abdo et al. 1982;
 

Abou-Donia et al. 1985a; Duckett et al. 1979; Egan et al. 1980; Johnson et al.
 

1977; Katz et al. 1980; Saida et al. 1976; Spencer et al. 1975), oral (Abdel-


Rahman et al. 1978; Krasavage et al. 1980), or dermal (Abou-Donia et al.
 

1985b) exposure for this duration. In addition, decreased weight gain has been
 

reported in rats and hens exposed via inhalation, decreased white blood cell
 

counts in rats exposed via inhalation (Abdo et al. 1982; Johnson et al. 1977;
 

Katz et al. 1980), and decreased weight gain in rats exposed via gavage
 

(Krasavage et al. 1980). However, the data were not sufficient to derive an
 

MRL for any route. Intermediate-duration (90-day) studies in animals via the
 

inhalation and dermal routes would be useful in developing dose-response
 

relationships, especially in relation to neurological effects. Such
 

information would be valuable for predicting human health effects, because the
 

potential exists for such exposure among populations in the vicinity of
 

hazardous waste sites and in the workplace. In addition, because 2-hexanone
 

has been found in surface water, groundwater, and drinking water in the
 

vicinity of hazardous waste sites, a 90-day study using the oral route would
 

also be useful. These studies should also include investigation of a number of
 

endpoints including the potential hematological, immunological, developmental,
 

and reproductive effects of exposure to 2-hexanone, because the available data
 

indicate that these are areas of potential concern in humans.
 

Chronic-Duration Exposure and Cancer. There is currently no available
 

information on humans or animals exposed to 2-hexanone for this duration
 

period via any route of exposure. Chronic exposure studies using the
 

inhalation, oral, and dermal routes would be useful, because chronic low level
 

exposure via each of these routes is likely to occur in the vicinity of
 

hazardous waste sites or in occupational settings. Data derived from 90-day
 

studies would be useful in determining the dose levels to be used for the
 

chronic-duration studies.
 

There is currently no information on the carcinogenic potential of 2­

hexanone. Chronic-duration studies conducted via any route of exposure should
 

assess this potential effect, since persons living in the vicinity of
 

hazardous waste sites or in occupational settings may be chronically exposed
 

to low levels of 2-hexanone via the oral, inhalation, and dermal routes.
 

Genotoxicity. There are currently no in vivo or in vitro studies that
 

address the genotoxic potential of 2-hexanone. A battery of in vitro
 

genotoxicity tests with 2-hexanone would be useful as a preliminary step in
 
44
 

2. HEALTH EFFECTS
 

assessing its mutagenic potential and determining if further genotoxicity
 

tests would appear to be warranted.
 

Reproductive Toxicity. There is no information on the effects of 2­

hexanone on reproductive parameters in exposed humans via any route of
 

exposure. Available data in animals indicate that inhalation exposure of
 

pregnant rats to 2-hexanone resulted in reduced maternal weight gain (Peters
 

et al. 1981). In male rats, reduced testicular weights and atrophy of the
 

testicular germinal epithelium were reported to result from inhalation
 

exposure (Katz et al. 1980) and atrophy of the testicular germinal epithelium
 

from oral exposure (Krasavage et al. 1980). Because of the limited data base
 

for all routes of exposure, it would be useful to have 90-day studies for all
 

three routes in order to investigate the potential dose-response relationship
 

of exposure to this compound on a number of end points including sperm count
 

and reproductive organ pathology. Because effects on reproduction have been
 

observed, a multi-generation study would be helpful in assessing the potential
 

impact of 2-hexanone exposure on the reproductive capacity of persons living
 

in the vicinity of hazardous waste sites and exposed workers.
 

Developmental Toxicity. There is no information on the effects of
 

exposure to 2-hexanone via any route on human development. There are no animal
 

studies using the oral or dermal routes. The currently available data for
 

animals is based on a single inhalation study in pregnant rats indicating that
 

2-hexanone exposure resulted in decreased litter size and pup weight (Peters
 

et al. 1981). Additional studies investigating a number of developmental end
 

points, and a dose-response relationship via inhalation, oral and dermal
 

exposure would be useful in assessing the potential risks to persons exposed
 

to 2-hexanone in the vicinity of hazardous waste sites or in the workplace.
 

Immunotoxicity. There are currently no data on the effects of 2-hexanone
 

on the human immune system via any route of exposure. Animal data included an
 

inhalation study in which there was a 40% decrease in peripheral white blood
 

cells in rats exposed to 2-hexanone (Katz et al. 1980). In addition, 2,5­

hexanedione, a metabolite of 2-hexanone, was shown to adversely affect
 

lymphoid organs of the immune system in rats and to cause impairment of
 

immunity in mice (Upreti and Shanker 1987). Immunological assessments,
 

including analysis of peripheral blood components and effects on lymphoid
 

tissue, conducted as part of intermediate- or chronic-duration studies and
 

skin sensitization tests would be useful in developing a dose-response
 

relationship and assessing the potential risk to chronically exposed persons
 

in the vicinity of hazardous waste sites or to exposed workers.
 

Neurotoxicity. The nervous system has been clearly established as the
 

major target for 2-hexanone in humans exposed via inhalation (Allen et al.
 

1975) and in animals exposed via any route of exposure (Abdel-Rahman et al.
 

1978; Abdo et al. 1982; Abou-Donia et al. 1982, 1985a,b; Duckett et al. 1979;
 

Egan et al. 1980; Johnson et al. 1977; Katz et al. 1980; Krasavage et al.
 
45
 

2. HEALTH EFFECTS
 

1980; Saida et al. 1976; Spencer et al. 1975) and in the offspring of pregnant
 

rats exposed via inhalation (Peters et al. 1981). However, most of the
 

available information is derived from studies using 2-hexanone of low or
 

unknown purity or using it at a single dosage level, its usefulness is
 

limited. Animal data that would clearly establish dose-response relationships
 

for neurological effects, including histopathological damage as well as
 

clinical manifestations, as a result of exposure to pure 2-hexanone via all
 

routes of exposure and using a range of exposure durations would be useful.
 

This information would be valuable in assessing the potential risks of
 

neurotoxicity in persons exposed to 2-hexanone in the vicinity of hazardous
 

waste sites or at the workplace.
 

Epidemiological and Human Dosimetry Studies. The only epidemiological
 

information that is currently available is the study of workers exposed to 2­

hexanone for about a year (Allen et al. 1975). Humans may be exposed to 2­

hexanone -through contaminated air in the workplace and in the vicinity of
 

hazardous waste sites and consumption of and dermal contact with contaminated
 

water, especially in the vicinity of hazardous waste sites. Epidemiological
 

studies that followed populations exposed to 2-hexanone, either in the
 

vicinity of hazardous waste sites or in the workplace, would be useful in
 

assessing adverse health effects in humans. In any such studies, emphasis
 

should be placed on neurological, hematological, immunological, reproductive,
 

and developmental effects. Similarly, human dosimetry studies of these
 

populations would be useful in associating 2-hexanone levels with the reported
 

effects.
 

Biomarkers of Exposure and Effect. Measurement of 2-hexanone and its
 

metabolites in blood or urine may not provide an adequate indication of
 

exposure to this substance, since these metabolites may also result from
 

exposure to n-hexane (Fedtke and Bolt 1986; Nomeir and Abou-Donia 1985; White
 

et al. 1979). Further work in developing unequivocal evidence of exposure to
 

2-hexanone would be useful.
 

The major target organ of 2-hexanone in humans is the nervous system
 

(Allen et al. 1975), and morphological effects may occur before clinical
 

manifestations of toxicity (Egan et al. 1980). Therefore, the identification
 

of sensitive nonmorphological effects of 2-hexanone exposure (such,as a
 

certain pattern of responses in electromyographics testing) would be useful.
 

Absorption, Distribution, Metabolism, and Excretion. Although some
 

information is available on each of these topics from studies conducted in
 

several species, more information in each of these areas would be useful. In
 

addition, because most of these studies were conducted by the same group of
 

researchers, further studies in other laboratories in each of these areas
 

would be useful in confirming the available data.
 

Available data indicate that 2-hexanone is readily absorbed by humans and
 

various animal species after inhalation, oral, or dermal administration
 
46
 

2 HEALTH EFFECTS
 

(Di Vencenzo et al. 1977, 1978). However, information on the rates of
 

absorption via the inhalation and oral routes, as well as estimates of the
 

fraction of the applied dermal dose that is absorbed, would be useful in
 

assessing potential absorption by exposed humans. In addition, information on
 

potential determinants of absorption such as dose level and nutritional status
 

would also be helpful.
 

Distribution data are limited to a single study in rats using the oral
 

route (DiVincenzo et al. .1977); no quantitative information was provided. The
 

use of multiple species and a comparison of tissue levels of 2-hexanone
 

associated with multiple doses via each route of exposure would be useful in
 

assessing the likelihood that 2-hexanone will reach various potential target
 

organs in exposed humans.
 

The proposed metabolic pathway for 2-hexanone is based on blood
 

metabolites identified during intraperitoneal studies in guinea pigs
 

(DiVincenzo et al. 1976) and oral studies in rats (DiVincenzo et al. 1977).
 

The metabolite 2,5-hexanedione has also been found in human serum after
 

inhalation exposure (DiVincenzo et al. 1978). Because studies in rats exposed
 

to 2-hexanone have indicated a strong relationship between the concentration
 

of 2,5-hexanedione in the urine and the onset of neuropathic symptoms (Eben et
 

al. 1979), it would be useful to also have this information for humans.
 

Limited excretion data are available in humans receiving 2-hexanone via
 

inhalation, oral, and dermal.exposure, in dogs via inhalation exposure, and in
 

rats via oral exposure (DiVincenzo et al. 1977, 1978). However, human data on
 

excretion of 2-hexanone via feces are not available, and the available
 

information in dogs concerns excretion via exhaled breath only. In these and
 

any other studies, information on all routes of excretion would help to
 

evaluate the potential for 2-hexanone clearance in the exposed species.
 

Excretion data in rats receiving 2-hexanone via inhalation and dermal
 

application and in other species receiving 2-hexanone via all three routes
 

would be useful for comparison with the human data and to assess the
 

comparative risks of exposure by each route. In addition, information on
 

excretion rates in each species via each route would be helpful in
 

understanding how long 2-hexanone and its metabolites may persist in the body.
 

Comparative Toxicokinetics. The toxicokinetic studies available in both
 

humans and animals (dogs, rats, and guinea pigs) suggest that there may not be
 

any major differences in the kinetics of this compound across certain species.
 

Metabolites of 2-hexanone in the expired breath (carbon dioxide) of humans and
 

rats exposed via the oral route and the presence of 2,5-hexanedione in the
 

serum of humans exposed via inhalation, as well as in the blood and urine of
 

orally exposed rats and the intraperitoneally exposed guinea pigs, suggest
 

that there is a similar metabolic pathway in humans and experimental animals
 

(DiVincenzo et al. 1976, 1977, 1978). Confirmation of this assumption would be
 

useful. Similar toxic effects, neuropathy and weight loss, have been noted in
 

several species (humans, monkeys, rats, cats, hens, and guinea pigs)
 
47
 

2. HEALTH EFFECTS
 

(Abdel-Rahman et al. 1978; Abdo et al. 1982; Abou-Donia et al 1982, 1985a,b;
 

Allen et al. 1975; Duckett et al. 1979; Egan et al. 1980; Johnson et al. 1977;
 

Katz et al. 1980; Krasavage et al. 1980; Saida et al. 1976; Spencer et al.
 

1975). Therefore, it would also be useful to investigate patterns of
 

distribution, to identify target organs, and to measure rates of excretion in
 

several species and to identify blood metabolites in humans in order to
 

investigate interspecies similarities and differences. Studies in this area
 

would be valuable for predicting toxic effects in humans and for studying the
 

mechanisms of action of this chemical.
 

Mitigation of effects. Recommended methods for the mitigation of acute
 

effects of 2-hexanone poisoning include prevention of absorption of 2-hexanone
 

from the gastrointestinal tract by administration of emetics, binding agents
 

and cathartics or administration of oxygen if exposure is by inhalation
 

(Bronstein and Currance 1988; Stutz and Janusz 1988). No information was
 

located concerning mitigation of effects of lower-level or longer-term
 

exposure to 2-hexanone. Further information on techniques to mitigate such
 

effects would be useful in determining the safety and effectiveness of
 

possible methods for treating 2-hexanone-exposed populations surrounding
 

hazardous waste sites.
 

2.9.3 On-going Studies
 

No research on the toxicity or toxicokinetics of 2-hexanone is known to
 

be in progress.
 

There are, however, some studies currently in progress that are
 

investigating the mechanism of neurotoxicity of the 2-hexanone metabolite,
 

2,5-hexanedione. A study is being conducted at the Oregon Health Sciences
 

University, under the direction of Dr. Bruce Gordon Gold, to correlate the
 

time course of any abnormal expression of phosphorylated neurofilament
 

epitopes (a pathological alteration which occurs in several human
 

neurofibrillary disorders including amyotrophic lateral sclerosis) and distal
 

swellings and axonal degeneration in chronic 2,5-hexanedione neuropathy (in
 

addition to other chemically-induced neuropathies). It is the intention of
 

this study to establish a more universal marker for the presence of secondary
 

changes in neuronal perikarya and to clarify the significance of these
 

alterations in several human disorders such as amyotrophic lateral sclerosis.
 

In a study being conducted at Case Western Reserve University under the
 

direction of Dr. Lawrence Sayre, trifluoromethyl-substituted analogs of 2,5­

hexanedione will be synthesized, compared with the parent compound in chemical
 

model studies, and evaluated for neurotoxicity in rats. This is part of an
 

effort to address how gamma-diketone-induced pyrrole formation at
 

neurofilament-based lysine epsilon-amino groups leads to neurofilament
 

accumulations. Nuclear magnetic resonance (NMR) studies will provide direct
 

visualization of the nature of chemical modification.
 
48
 

2. HEALTH EFFECTS
 

Other research being conducted at Case Western Reserve University under
 

the direction of Dr. Lawrence Sayre is a study in which analogs of 2,5­

hexanedione will be synthesized, studied chemically, and biologically
 

evaluated in an effort to clarify the structural basis of toxicity,
 

particularly in respect to the direct chemical modification of neurofilament
 

proteins by these analogs or any of their metabolites.
 

A study to investigate the possible selective vulnerability of specific
 

neuron types or neuronal components to 2,5-hexanedione, as well as to
 

acrylamide, is being conducted at the Medical College of Georgia under the
 

direction of Dr. Barry Goldstein. The aim of this project is to study the
 

functional changes caused by these compounds in sensory and motor systems
 

which either have different diameter axons or differing levels of adaptation.
 

Electrophysiological studies will determine the time course and severity of
 

involvement of various nociceptors, muscle spindles, and motor unit types to
 

these chemicals. Axoplasmic transport changes will be examined in axons of
 

varied diameter and in different motor unit types (and adaptation levels).
 

The goal is to determine whether there is selective vulnerability of neurons
 

to these toxicants, and if so, whether it is based on axonal diameter or on
 

the functional ability to maintain discharge.
 

A project at Duke University, under the direction of Dr. Doyle Graham, is
 

investigating the molecular pathogenesis of the neuropathy associated with
 

2,5-hexanedione. The goal is to synthesize novel analogs of 2,5-hexanedione
 

and the putative crosslinking metabolites of other toxicants in order to test
 

specific steps in the pathogenetic schemes and to define the identities of the
 

crosslinking adducts. This project includes the synthesis of a series of
 

gamma-diketones which, through the presence of electron-withdrawing or
 

electron-donating groups, will enhance or impair the rate of pyrrole formation
 

and retard or facilitate oxidation of the resulting pyrrole ring.
 
49
 

3. CHEMICAL AND PHYSICAL INFORMATION
 

3.1 CHEMICAL IDENTITY
 

Table 3-1 lists common synonyms, trade names, and other pertinent
 

identification information for 2-hexanone.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

Table 3-2 lists important physical and chemical properties of
 

2-hexanone.
 



53
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.1 PRODUCTION
 

In 1977, the combined U.S. production and import of 2-hexanone was
 

between 453 metric tons and 4,500 metric tons (EPA 1987b, 1981); no breakdown
 

of these figures was provided. The only U.S. producer of 2-hexanone, the
 

Tennessee Eastman Company division of Eastman Kodak, discontinued its
 

production of 2-hexanone in 1979 and sold its remaining reserves by 1981 (EPA
 

1981, 1987b; HSDB 1989; Lande et al. 1976). 2-Hexanone was commercially
 

produced by the catalyzed reaction of acetic acid and ethylene under pressure
 

(EPA 1987b).
 

4.2 IMPORT/EXPORT
 

Currently, 2-hexanone is not produced or used in the United States, and
 

consequently, there is no information on exports or imports (EPA 1987b; HSDB
 

1989).
 

4.3 USE
 

2-Hexanone is not currently manufactured, processed, or used for
 

commercial purposes in the United States (EPA 1987b). 2-Hexanone had been used
 

as a solvent for many materials, primarily in the lacquer industry as a
 

solvent for lacquers and varnish removers. It had also been used as a solvent
 

for ink thinners, resins, oils, fats, and waxes. 2-Hexanone had also been used
 

as an intermediate in the synthesis of organic chemicals (ACGIH 1986; HSDB
 

1989).
 

4.4 DISPOSAL
 

No data were located regarding the disposal of 2-hexanone or on
 

regulations and guidelines regarding its disposal. The favored method for
 

disposal of ketones is incineration (Lande et al. 1976). No quantitative data
 

were located regarding either the generation or disposal of 2-hexanone which
 

may be produced as a degradation product of coal gasification, wood pulping,
 

or oil shale processing.
 

55
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW
 

2-Hexanone is a volatile organic liquid that is very soluble in water.
 

It is expected to be quite mobile in water and soils. Its rate of
 

volatilization is likely to be moderately fast, but equilibration with
 

sediments will be low. Biodegradation of 2-hexanone may occur slowly in water
 

and soil, but bioconcentration is not expected.
 

Exposure of the general population to 2-hexanone is not likely to be
 

high. However, persons living near hazardous waste sites or wood pulping,
 

coal-gasification, or oil-shale processing plants may be exposed to 2 hexanone
 

in contaminated environmental media. In the past, occupational exposures to 2­

hexanone resulted from its manufacture and use. However, since 2-hexanone is
 

not currently manufactured or used commercially in the United States,
 

occupational exposures related to these activities are no longer of special
 

concern.
 

The EPA has identified 1,177 NPL sites. 2-Hexanone has been found at 15
 

of the sites evaluated for the presence of this chemical. However, we do not
 

know how many of the 1,177 NPL sites have been evaluated for the presence of
 

2-hexanone. As more sites are evaluated by the EPA, the number may change
 

(View 1989). The frequency of these sites can be seen in Figure 5-1. Of these
 

sites, 14 are located within the United States and 1 is located in the
 

Commonwealth of Puerto Rico (not shown).
 

5.2 RELEASES TO THE ENVIRONMENT
 

Because 2-hexanone is not currently manufactured, imported, processed, or
 

used for commercial purposes in the United States (EPA 1987b), releases to the
 

environment are not likely to be high. Although it is reported to be released
 

from wood pulping, coal-gasification, and oil-shale processing plants, levels
 

resulting from these operations have been reported as being low. This compound
 

is not listed in the Toxics Release Inventory (TRI).
 

5.2.1 Air
 

No studies were located regarding the amount of 2-hexanone released to
 

the atmosphere. However, since 2-hexanone is no longer produced in the United
 

States (EPA 1987b) or used commercially (EPA 1987b; Lande et al. 1976;
 

O'Donoghue 1985), atmospheric emissions from industrial sources are likely to
 

be small.
 

5.2.2 Water
 

2-Hexanone is released to water by industrial facilities and at
 

hazardous waste sites. 2-Hexanone was detected in 2 of 3 effluents from coal
 

gasification plants and in 1 of 2 effluents from oil shale processing plants
 

57
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

at mean concentrations ranging from 7 to 202 ppb (μg/L) (Pellizzarri et al.
 

1979). The compound has also been tentatively identified in 1 of 63 industrial
 

effluents (Perry et al., 1979), the effluent from a chemical plant
 

(Shackelford and Keith 1976), and in one municipal landfill leachate at 0.148
 

ppm (mg/L) in a study of leachates from 58 municipal and industrial landfills
 

(Brown and Donnelly 1988).
 

2-Hexanone has also been detected in both groundwater and surface water
 

at hazardous waste sites (CLPSD 1989) (see Section 5.4.2), indicating that
 

this is a source of 2-hexanone release to the environment.
 

5.2.3 Soil
 

Soils or sediments may become contaminated with 2-hexanone by landfilling
 

with 2-hexanone-containing solid wastes or by the discharge of contaminated
 

water. 2-Hexanone has been detected in soil samples from hazardous waste sites
 

(CLPSD 1989) (see Section 5.4.3).
 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

2-Hexanone exists in the atmosphere as a vapor. Liquid 2-hexanone is
 

volatile; its vapor pressure has been measured as 1.53x10-2 atm (11.6 mmHg) at
 

25°C (Ambrose et al. 1975). Because 2-hexanone is very soluble in water, a
 

large fraction of 2-hexanone released to the atmosphere, may dissolve in water
 

vapor (such as clouds and rain drops). A Henry's law constant (H) estimates
 

the tendency of a chemical to partition between its vapor phase and water. A
 

value for H may be calculated by dividing the vapor pressure of 2-hexanone by
 

its solubility in water at the same temperature (Mabey et al. 1982). In this
 

case, an estimated value for H is 4.4-7.7x10--5 atm-m3

/mole at about 25°C. The
 

magnitude of this value suggests that a large fraction of vapor-phase 2­

hexanone will dissolve in water, and that precipitation may be an important
 

physical removal mechanism. An analogous air-water partition coefficient
 

measured for 2-hexanone at 37°C was approximately 2.3x10-4 atm-m3

/mole (Sato and
 

Nakajima 1979), which indicates that precipitation will also be an important
 

removal mechanism at this higher temperature.
 

2-Hexanone is very soluble in water, approximately 20-35 g/L (Morrison
 

and Boyd 1974; Verschueren 1983). The magnitude of the estimated Henry's law
 

constant (4.4-7.7x10-5 atm-m3

/mole) indicates that 2-hexanone will volatilize
 

from water, with a half-life in river water of about 10-15 days (Mabey et al.
 

1982). Volatilization will be slower from lakes or ponds (Mabey et al. 1982).
 

There is no information on whether 2-hexanone in water is expected to
 

partition to soils and sediments.
 
58
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

2-Hexanone will probably not be bioconcentrated by organisms in water.
 

An octanol/water partition coefficient (Kow) estimates the partitioning of a
 

chemical between octanol and water. Octanol is believed to best imitate the
 

fatty structures in plants and animal tissues. The Kow of 2-hexanone is
 

approximately 20-40, based on its solubility in water (Hassett et al. 1983).
 

These low values suggest that 2-hexanone will not partition to fatty tissues.
 

A bioconcentration factor (BCF) relates the concentration of a chemical
 

in plants or animals to the concentration of that chemical in the medium in
 

which they live. A BCF of about 7 was calculated for 2-hexanone (Lande et al.
 

1976) using the empirical regression of Neely et al. (1974). This low BCF
 

indicates that bioconcentration is probably not an important fate mechanism
 

for 2-hexanone released into the environment. Biomagnification of 2-hexanone
 

is also not expected to occur to any great extent (Lande et al. 1976).
 

However, no experimental data on the biomagnification potential of 2-hexanone
 

were located to corroborate these assumptions.
 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

The major fate mechanism of atmospheric 2-hexanone is photooxidation.
 

This ketone is also degraded by direct photolysis (Calvert and Pitts 1966),
 

but the reaction is estimated to be slow relative to reaction with hydroxyl
 

radicals (Laity et al. 1973). The rate constant for the photochemicallyinduced
 

transformation of 2-hexanone by hydroxyl radicals in the troposphere has been
 

measured at 8.97x10-12 cm3

/ molecule-set (Atkinson et al. 1985). Using an
 

average concentration of tropospheric hydroxyl radicals of 6x105 molecules/cm3
 

(Atkinson et al. 1985), the calculated atmospheric halflife of 2-hexanone is
 

about 36 hours. However, the half-life may be shorter in polluted atmospheres
 

with higher OH radical concentrations (MacLeod et al. 1984). Consequently, it
 

appears that vapor-phase 2-hexanone is labile in the atmosphere.
 

5.3.2.2 Water
 

2-Hexanone is a ketone, and ketones are generally not degraded by
 

hydrolysis (Lande et al. 1976; Morrison and Boyd 1974). Based on its reactions
 

in air, it seems likely that 2-hexanone will undergo photolysis in water,
 

however no information was located. Based on studies with microorganisms (see
 

Section 5.3.2.3), it is probable that 2-hexanone will be biodegraded in water.
 

5.3.2.3 Soil
 

2-Hexanone may be biodegraded in soil. 2-Hexanone has been shown to be
 

degraded by hydrocarbon-utilizing mycobacteria (Lukins and Foster 1963; Perry
 

-1968). Similarly, certain yeasts have been isolated that can use 2-hexanone
 
59
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

as a carbon source (Lowery et al. 1968). In a study using acclimated microbial
 

cultures, 2-hexanone was significantly biodegraded (Babeu and Vaishnav 1987).
 

An experimental 5-day biological oxygen demand (BOD) determination was about
 

61% of the theoretical BOD value. Although these studies have demonstrated
 

that 2-hexanone may be biodegraded under ideal conditions, no information was
 

located on its biological half-life in soils.
 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
 

5.4.1 Air
 

No studies were located which measured or estimated the concentration of
 

2-hexanone in ambient air.
 

In the past, workplace air concentrations in facilities where 2-hexanone
 

was manufactured or used as a solvent ranged from 1 to 156 ppm (4.1 to 640
 

mg/m3

) (ACGIH 1986), and air concentrations up to 1,636 mg/m3 were measured in
 

the operations areas of some facilities (Bierbaum and Marceleno 1973;
 

Marceleno et al. 1974). However, because 2-hexanone is no longer produced or
 

used commercially in the United States, and because OSHA has reduced the
 

Permissible Exposure Limit (PEL) to 5 ppm (20 mg/m3

) (OSHA 1989), it is
 

unlikely that current workplace air concentrations are as high as they were in
 

the past.
 

5.4.2 Water
 

Data estimating 2-hexanone concentrations in water are sparse. 2­

Hexanone was identified in one of three groundwater samples at a concentration
 

of 87 μg/L (ppb) near a hazardous waste site in Florida (Myers 1983). This
 

compound was also identified in a study of drinking water concentrates and
 

advanced waste treatment concentrates (Lucas 1984).
 

2-Hexanone has been detected in both surface water and groundwater at
 

hazardous waste sites. Data from the Contract Laboratory Program (CLP)
 

Statistical Database indicate that 2-hexanone was found at 2% of the sites at
 

a geometric mean concentration of 7.5 μg/L (ppb) in positive surface water
 

samples and 12 μg/L (ppb) in positive groundwater samples (CLPSD 1989). This
 

database provides data from both NPL and non-NPL waste sites.
 

5.4.3 Soil
 

2-Hexanone was detected in soil samples at 3% of hazardous waste sites
 

(both NPL and non-NPL) at a geometric mean concentration of 40 μg/kg (ppb) in
 

positive samples (CLPSD 1989). No other data were located regarding estimation
 

of 2-hexanone in soils or sediments.
 
60
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.4.4 Other Environmental Media
 

2-Hexanone has been identified among the natural volatile components of
 

several foods including blue and Beaufort cheeses, nectarines, roasted
 

filberts, and chicken muscle (Day and Anderson 1965; Dumont and Adda 1978;
 

Grey and Shrimpton 1967; Kinlin et al. 1972; Takeoka et al. 1988); levels were
 

not stated in these reports. It has also been detected in milk and cream at
 

concentrations ranging from 0.007 to 0.018 ppm (7-18 ppb) and in bread (Lande
 

et al. 1976). Because few quantitative data are available, it is not known if
 

food is an important source of human exposure to 2-hexanone.
 

No studies were located regarding the occurrence of 2-hexanone in any
 

other media.
 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

Human exposure to 2-hexanone may occur by inhalation, ingestion, or
 

dermal exposure. Exposure to small amounts of 2-hexanone may occur by
 

ingestion of foods in which it has been detected. However, since this compound
 

is no longer manufactured or used commercially in the United States,
 

widespread or high-level exposure of the general population to 2-hexanone is
 

not likely.
 

According to surveys conducted by NIOSH, the number of employees
 

potentially exposed to 2-hexanone dropped from 41,600 in the early 1970s (NOHS
 

1989) to 1,100 in the early 1980s (NIOSH 1989). Neither the NOHS nor the NOES
 

databases contain information on the frequency, concentration, or duration of
 

exposures of workers to any of the chemicals listed therein. These surveys
 

provide only estimates of the number of workers potentially exposed to
 

chemicals in the workplace. This dramatic reduction in the extent of
 

occupational exposure parallels the halt of production and the reduction in
 

use of this chemical (EPA 1987b). It is unlikely that many persons are
 

currently occupationally exposed to 2-hexanone, other than as a degradation
 

product resulting from wood pulping, oil shale processing, or coal
 

gasification operations. The NIOSH does not list 2-hexanone among the
 

chemicals considered in an occupational exposure evaluation of coal
 

gasification plants (NIOSH 1978b).
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
 

Populations with potentially high exposure to 2-hexanone include people
 

living near or working in coal gasification, oil shale processing or wood
 

pulping operations, or living near the hazardous waste sites at which 2­

hexanone is likely to occur. The most likely exposure routes are ingestion
 

of or dermal contact with water contaminated from these sources or inhalation
 

of 2-hexanone which has volatilized from contaminated water or soil.
 
61
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Individuals may still be exposed by inhalation or skin absorption from
 

consumer products manufactured prior to 1982 such as lacquers, primers,
 

sealers, and thinners that contain 2-hexanone.
 

5.7 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of
 

ATSDR (in consultation with the Administrator of EPA and agencies and programs
 

of the Public Health Service) to assess whether adequate information on the
 

health effects of 2-hexanone is available. Where adequate information is not
 

available, ATSDR, in conjunction with the NTP, is required to assure the
 

initiation of a program of research designed to determine the health effects
 

(and techniques for developing methods to determine such health effects) of
 

2-hexanone.
 

The following categories of possible data needs have been identified by a
 

joint team of scientists from ATSDR, NTP, and EPA. They are defined as
 

substance-specific informational needs that, if met, would reduce or eliminate
 

the uncertainties of human health assessment. In the future, the identified
 

data needs will be evaluated and prioritized, and a substance-specific
 

research agenda will be proposed.
 

5.7.1 Data Needs
 

Physical and Chemical Properties. The physical and chemical property data
 

available for 2-hexanone are sufficient to allow a limited estimation of the
 

potential environmental fate of this chemical. The estimated Henry's law
 

constant (Mabey et al, 1982) and Koc (Hassett et al. 1983) need to be verified
 

experimentally to help confirm the estimates of partitioning in environmental
 

media. Since there does not seem to be a consensus on the solubility of 2­

hexanone in water (reported values range from about 20-35 g/L) (Morrison and
 

Boyd 1974; Verschueren 1983), additional measurements would be useful to more
 

accurately predict the environmental fate of this compound.
 

Production, Import/Export, Use, and Disposal. 2-Hexanone is no longer
 

produced, imported, or used commercially in the United States (EPA 1987b).
 

Any future manufacture or use is required to be reported to EPA (EPA 1987b).
 

Data from these reports would be helpful in estimating the potential for human
 

exposure to this compound. No data on disposal of 2-hexanone were located.
 

Information on disposal practices for wastes containing 2-hexanone is
 

necessary for estimations of human exposure from this source. No regulations
 

govern the disposal of 2-hexanone.
 

Environmental Fate. The probable transport and partitioning of
 

2-hexanone in environmental media have been predicted based on estimated
 

partition coefficients. Experimental confirmation of these values would help
 

to increase the accuracy of transport and partitioning assessments. The loss
 

mechanisms of 2-hexanone transformations in the atmosphere are fairly-well
 
62
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

understood (Atkinson et al. 1985; Calvert and Pitts 1966; Laity et al. 1973;
 

MacLeod et al. 1984), but the reaction pathways and environmental fates of the
 

transformation products are not known. Very little is known about the fate of
 

2-hexanone in water or soil (Babeu and Vaishnav 1987; Lande et al. 1976;
 

Lowery et al. 1968; Lukins and Foster 1963; Perry 1968). Data on
 

photodegradation and biodegradation of 2-hexanone in surface water and
 

biodegradation of 2-hexanone in groundwater and soil may be helpful in
 

assessing the persistence of 2-hexanone in these media.
 

Bioavailability from Environmental Media. Information on absorption by
 

humans and other animal species indicates that it is well absorbed via the
 

oral and dermal routes (DiVincenzo et al. 1977, 1978). 2-Hexanone has also
 

been demonstrated to be well absorbed by humans and animals following
 

inhalation exposure (DiVincenzo et al. 1978). Information on its
 

bioavailability from contaminated soils would be useful in assessing the risk
 

from exposure to this medium by populations in the vicinity of hazardous waste
 

sites.
 

Food Chain Bioaccumulation. There are no data on the bioaccumulation of
 

2-hexanone in food chains. This lack of data may not be a major limitation in
 

the database because it is unlikely that 2-hexanone is bioconcentrated by
 

plants, aquatic organisms, or animals at lower trophic levels based on its
 

high water solubility (Lande et al. 1976). However, data confirming that
 

bioconcentration does not occur would help to more accurately assess the
 

probability of bioaccumulation of 2-hexanone.
 

Exposure Levels in Environmental Media. Very few data are available
 

regarding the presence of 2-hexanone in any environmental media (CLPSD 1989;
 

Lucas 1984; Myers 1983). Although high levels of this compound are not
 

expected to occur in ambient air, water, or soil, concentrations of 2-hexanone
 

in these media near effluent sources or hazardous waste sites would be helpful
 

in assessing the potential extent and magnitude of human exposures. Exposure
 

Levels in Humans. No information has been located on exposure levels of humans
 

to 2-hexanone in the workplace or in the vicinity of hazardous waste sites. It
 

would be useful to collect information on levels of exposure to 2-hexanone in
 

the environment and associated blood, urine or tissue levels of 2-hexanone
 

and/or its metabolites in the exposed populations. Additional information
 

relating those levels to the subsequent development of health effects would
 

also be extremely useful.
 

Exposure Registries. No exposure registries for 2-hexanone were
 

located. This compound is not currently one of the compounds for which a
 

subregistry has been established in the National Exposure Registry. The
 

compound will be considered in the future when chemical selection is made for
 

subregistries to be established. The information that is amassed in the
 
63
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

National Exposure Registry facilitates the epidemiological research needed to
 

assess adverse health outcomes that may be related to the exposure to this
 

compound.
 

5.7.2 On-going Studies
 

Remedial investigations and feasibility studies conducted at the 15 NPL
 

sites known to be contaminated with 2-hexanone will add to the available
 

database in the categories of exposure levels in humans, exposure levels in
 

the environmental media, and exposure registries.
 

No other on-going studies were located on the fate, transport, or
 

potential for human exposure for 2-hexanone.
 

65
 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that
 

are available for detecting and/or measuring and monitoring 2-hexanone in
 

environmental media and in biological samples. The intent is not to provide an
 

exhaustive list of analytical methods that could be used to detect and
 

quantify 2-hexanone. Rather, the intention is to identify well-established
 

methods that are used as the standard methods of analysis. Many of the
 

analytical methods used to detect 2-hexanone in environmental samples are the
 

methods approved by federal agencies such as EPA and the National Institute
 

for Occupational Safety and Health (NIOSH). Other methods presented in this
 

chapter are those that are approved by groups such as the Association of
 

Official Analytical Chemists (AOAC) and the American Public Health Association
 

(APHA). Additionally, analytical methods are included that refine previously
 

used methods to obtain lower detection limits, and/or to improve accuracy and
 

precision.
 

6.1 BIOLOGICAL MATERIALS
 

In biological systems in which 2-hexanone may have been metabolized, or
 

may itself be a metabolite, consideration must be given to possible binding of
 

the analyte as a conjugate. In such cases, 2-hexanone may be released by
 

hydrolysis with acid (Fedtke and Bolt 1986). Following pre-treatment, which
 

varies with the sample and may include homogenization, centrifugation, and
 

acidification, 2-hexanone can be released from biological samples by purging
 

or perfusion and trapped on a sorbent, extracted with a solvent such as
 

acetone, or extracted directly onto sorbent solids.
 

Sensitive and selective methods are available for the qualitative and
 

quantitative measurement of 2-hexanone, after it is separated from its sample
 

matrix. Gas chromatography using sensitive and highly specific mass
 

spectrometry (MS) or highly sensitive flame ionization detection (FID) is the
 

analytical method most commonly used. Capillary gas chromatography, also known
 

broadly as high resolution gas chromatography (HRGC), has greatly facilitated
 

the analysis of compounds such as 2-hexanone that can be measured by gas
 

chromatography and has resulted in vast improvements in resolution and
 

sensitivity. It has made the choice of a stationary phase much less crucial
 

than is the case with the older method using packed columns. The instrumental
 

capability to separate volatile analytes by HRGC is, for the most part, no
 

longer the limiting factor in their analysis. High performance liquid
 

chromatography (HPLC) may also be used and has the advantage of compatibility
 

with the liquid matrix of biological samples.
 

Methods for detection of 2-hexanone in biological materials are
 

summarized in Table 6-1.
 

67
 

6. ANALYTICAL METHODS
 

6.2 ENVIRONMENTAL SAMPLES
 

For the determination of 2-hexanone in air, the analyte is usually
 

trapped and concentrated from a large volume of air on a solid sorbent such as 

Tenax or activated carbon from which it can be released thermally or eluted 

with a solvent such as carbon disulfide for subsequent measurement. For 

aqueous samples, 2-hexanone is purged with an inert gas and collected on a 

solid such as Tenax, followed by thermal desorption and measurement. 

Cryogenic trapping has also been used for removal of 2-hexanone from water 

samples (Badings et al. 1985). Gas chromatography using sensitive and highly 

specific MS or highly sensitive FID is the analytical method of choice for the 

determination of 2-hexanone in environmental samples. 

Methods for the determination of 2-hexanone in environmental samples are
 

summarized in Table 6-2.
 

6.3 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of
 

ATSDR (in consultation with the Administrator of EPA and agencies and programs
 

of the Public Health Service) to assess whether adequate information on the
 

health effects of 2-hexanone is available. Where adequate information is not
 

available, ATSDR, in conjunction with the NTP, is required to assure the
 

initiation of a program of research designed to determine the health effects
 

(and techniques for developing methods to determine such health effects) of 2­

hexanone.
 

The following categories of possible data needs have been identified by a
 

joint team of scientists from ATSDR, NTP, and EPA. They are defined as
 

substance-specific informational needs that, if met, would reduce or eliminate
 

the uncertainties of human health assessment. In the future, the identified
 

data needs will be evaluated and prioritized, and a substance-specific
 

research agenda will be proposed.
 

6.3.1 Data Needs
 

Methods for Determining Biomarkers of Exposure and Effect. As noted in
 

Section 6.1, methods are available for the qualitative and quantitative
 

measurement of 2-hexanone after it is separated from its sample matrix
 

(Anderson and Harland 1980; Fedtke and Bolt 1986; Nomeir and Abdou-Donia 1985;
 

White et al. 1979). High-resolution gas chromatography for 2-hexanone
 

analysis has been developed to the point that the instrumental capability
 

to separate volatile analytes by HRGC is, for the most part, no longer the
 

limiting factor in their analysis. Flame ionization detection has enabled
 

detection at very low levels and MS has assured specificity in measurement.
 

69
 

6. ANALYTICAL METHODS
 

More specific methods to determine biomarkers of exposure to 2-hexanone
 

would be helpful in detecting exposure to this compound before adverse
 

morphological or clinical effects occur. Finding biological markers of
 

exposure to 2-hexanone is complicated by the fact that this compound is itself
 

a biological indicator of exposure to n-hexane (Fedtke and Bolt 1986). In
 

addition, the presence of the metabolite, 2,5-hexanedione, may indicate
 

exposure to 2-hexanone, but it is also a biological indicator of exposure to
 

n-hexane (Fedtke and Bolt 1986). There is insufficient information in the
 

literature to determine if methods for determining biomarkers of exposure and
 

effect of 2-hexanone are sensitive enough to measure background levels in the
 

population and levels at which biological effects occur. The precision,
 

accuracy, reliability, and specificity of these methods are not sufficiently
 

documented. This information would be valuable for interpreting monitoring
 

data.
 

Refinement of existing purge-and-trap extraction techniques and
 

investigation of alternative concentration methods such as cryotrapping
 

(Pankow and Rosen 1988) and supercritical fluid extraction (King 1989) would
 

be useful. In addition, several major challenges remain. One of these is to
 

transfer analytes that have been isolated from a biological or environmental
 

matrix quantitatively and in a narrow band to the HRGC. Another major
 

challenge is to identify and accurately measure the quantity of compounds in
 

the HRGC peaks. Mass spectrometric detection has been outstanding for
 

identification, but other techniques, particularly Fourier transform infrared
 

spectroscopy (FTIR), may offer some advantages (Wieboldt et al. 1988).
 

Metabolites of 2-hexanone in biological materials are difficult to
 

determine in routine practice because of the lack of standardized methods for
 

their measurement. As shown in Table 6-1, there are very few well
 

characterized methods for the determination of metabolites of 2-hexanone in
 

biological materials (Nomeir and Abou-Donia 1985; White et al. 1979). The
 

precision, accuracy, reliability, and specificity of existing methods need to
 

be evaluated, and the methods refined and adapted to routine practice.
 

Methods for Determining Parent Compounds and Degradation Products in
 

Environmental Media. The media of most concern for human exposure to 2­

hexanone are drinking water (primarily from groundwater sources) and air.
 

From the data presented in Table 6-2 (Badings et al. 1985; EPA 1986; Hawthorne
 

et al. 1985; NIOSH 1984), it may be concluded that the methods available for
 

the determination of 2-hexanone in water and air are not sensitive enough to
 

determine background levels of this compound. Existing methods are
 

satisfactory for measuring levels at which health effects occur.
 

The precision, accuracy, reliability, and specificity of methods to
 

determine 2-hexanone in water and air are not well documented, and additional
 

work is needed in this area.
 
70
 

6. ANALYTICAL METHODS
 

Methods for determining the parent compound, 2-hexanone, in water, air,
 

and waste samples are available (Badings et al. 1985; EPA 1986; Hawthorne et
 

al. 1985; NIOSH 1984). Sampling methodologies for compounds such as 2-hexanone
 

continue to pose problems such as nonrepresentative samples, insufficient
 

sample volumes, contamination, and labor-intensive, tedious extraction and
 

purification procedures (Green and Le Pape 1987). It would be helpful to have
 

means to measure organic compounds such as 2-hexanone in situ in water and
 

other environmental media without the need for sampling and extraction
 

procedures to isolate the analyte prior to analysis.
 

6.3.2 On-going Studies
 

There are no known on-going studies to improve methods of analysis for
 

2-hexanone or its metabolites in biological or environmental samples.
 
71
 

7. REGULATIONS AND ADVISORIES
 

Because of the potential of 2-hexanone to cause adverse health effects
 

in exposed people, a number of regulations and guidelines have been
 

established by various national and state agencies. These values are
 

summarized in Table 7-1.
 

73
 

8. REFERENCES
 

Abdel-Rahman MS, Hetland LB, Couri D. 1976. Toxicity and metabolism of methyl
 

n-butyl ketone. Am Ind Hyg Assoc J 37:95-102.
 

*Abdel-Rahman MS, Saladin JJ, Bohman CE, et al. 1978. The effect of 2-hexanone
 

and 2-hexanone metabolites on pupillomotor activity and growth. Am Ind Hyg
 

Assoc J 39:94-99.
 

*Abdo KM, Graham DG, Timmons PR, et al. 1982. Neurotoxicity of continuous (90
 

days) inhalation of technical grade methyl butyl ketone in hens. J Toxicol
 

Environ Health 9:199-215.
 

Abe K, Misumi J, Kawakami M, et al. 1980. Effects of n-hexane, methyl n-butyl
 

ketone, and 2,5-hexanedione on the excitability of sweat glands in rats to
 

mecholyl. Jap J Ind Health 22:380-381.
 

Abou-Donia MB. 1983. Interaction between neurotoxicities induced by
 

organophosphorus and long-chain hexacarbon compounds. Neurotoxicity 4:117-135.
 

Abou-Donia MB, Nomeir AA. 1986. The role of pharmacokinetic and metabolism in
 

species sensitivity to neurotoxic agents. Fundam Appl Toxicol 6:190-207.
 

*Abou-Donia MB, Makkawy H-AM, Graham DB. 1982. The relative neurotoxicities of
 

n-hexane, methyl n-butyl ketone, 2,5-hexanediol, and 2,5-hexanedione following
 

oral or intraperitoneal administration in hens. Toxicol Appl Pharmacol 62:369­

389.
 

*Abou-Donia MB, Lapadula DM, Campbell G, et al. 1985a. The joint neurotoxic
 

action of inhaled methyl butyl ketone vapor and dermally applied 0-ethyl 0-4­

nitrophenyl phenylphosphonothioate in hens: Potentiating effect. Toxicol Appl
 

Pharmacol 79:69-82.
 

*Abou-Donia MB, Makkawy H-AM, Campbell GM. 1985b. Pattern of neurotoxicity
 

of n-hexane, methyl n-butyl ketone, 2,5-hexanediol, and 2,5-hexanedione alone
 

and in combination with 0-ethyl 0-4-nitrophenyl phenylphosphonothioate in
 

hens. J Toxicol Environ Health 16:85-100.
 

*Abou-Donia MB, Lapadula DM, Campbell G, et al. 1985c. The synergism of
 

n-hexane-induced neurotoxicity by methyl isobutyl ketone following subchronic
 

(90 days) inhalation in hens: Induction of hepatic microsomal cytochrome P450. Toxicol Appl Pharmacol 81:1-16.
 

* Cited in text
 
74
 

8. REFERENCES
 

*ACGIH. 1986. Documentation of the threshold limit values and biological
 

exposure indices. 5th ed. American Conference of Governmental Industrial
 

Hygienists. Cincinnati, OH.
 

Allen N, Mendell JR, Billmaier D, et al. 1974. An outbreak of a previously
 

undescribed toxic polyneuropathy due to industrial solvent. Transactions of
 

the American Neurological Association 99:74-79.
 

*Allen N, Mendell JR, Billmaier DJ, et al. 1975. Toxic polyneuropathy due to
 

methyl n-butyl ketone: An industrial outbreak. Arch Neurol 32:209-218.
 

Altenkirch H, Mager J, Stoltenburg G, et al. 1977. Toxic polyneuropathies
 

after sniffing a glue thinner. J Neurol 214:137-152.
 

*Ambrose D, Ellender JH, Lees EB, et al. 1975. Thermodynamic properties of
 

organic oxygen compounds. XXXVIII. Vapour pressures of some aliphatic ketones.
 

J Chem Thermodynamics 7:453-472.
 

*Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor
 

thresholds compared with threshold limit values and volatilities for 214
 

industrial chemicals in air and water dilution. J Appl Toxicol 3:272-290.
 

*Anderson RA, Harland WA. 1980. The analysis of volatiles in blood from fire
 

fatalities. In: Proceedings of the Forensic Toxicology European Meeting, Int
 

Assoc Toxicol, 279-292.
 

Anger WK, Lynch DW. 1977. The effect of methyl n-butyl ketone on response
 

rates of rats performing on a multiple schedule of reinforcement. Environ Res
 

14:204-211.
 

Anonymous. 1974. Solvent causes motor neuropathy in workers at clothing
 

factory. J Am Med Assoc 229:247-248.
 

Anonymous. 1979. Hexacarbon neuropathy. The Lancet 2(November 3):942-943.
 

Anthony DC, Boekelheide K, Anderson CW, et al. 1983. The effect of 3,4­

dimethyl substitution on the neurotoxicity of 2,5-hexanedione. II. Dimethyl
 

substitution acccelerates pyrrole formation and protein crosslinking.
 

[Abstract] Toxicol Appl Pharmacol 71:372-382.
 

Asbury AK. 1979. Pathology of industrial toxic neuropathies. Acta Neurol Stand
 

Suppl 60:52-53.
 

ASTM. 1987a. Standard practice for sampling atmospheres to collect organic
 

compound vapors (activated charcoal tube adsorption method) - method D 3686­

84. In: 1987 annual book of ASTM standards. Vol. 11.03. Atmospheric analysis;
 

occupational health and safety. Philadelphia, PA: American Society for Testing
 

and Materials, 326-336.
 
75
 

8. REFERENCES
 

ASTM. 1987b. Standard practice for analysis of organic compound vapors
 

collected by the activated charcoal tube adsorption method - method D 3687-84.
 

In: 1987 annual book of ASTM standards. Vol. 11.03. Atmospheric analysis;
 

occupational health and safety. Philadelphia, PA: American Society for Testing
 

and Materials, 337-344.
 

ASTM. 1988. Standard practice for measuring volatile organic matter in water
 

by aqueous-injection gas chromatography - method D 2908-87. In: 1988 annual
 

book of ASTM standards. Vol. 11.02. Water II. Philadelphia, PA: American
 

Society for Testing and Materials, 46-51.
 

*Atkinson R, Carter WP, Aschmann SM, et al. 1985. Atmospheric fates of organic
 

chemicals: Prediction of ozone and hydroxyl radical reaction rates and
 

mechanisms. Report to U.S. Environmental Protection Agency, Office of Research
 

and Development, Research Triangle Park, NC, by Statewide Air Pollution
 

Research Center, University of California, Riverside, CA. EPA/600/3-85/063.
 

NTIS Publication No. PB85-241529.
 

*Babeu L, Vaishnav DD. 1987. Prediction of biodegradability for selected
 

organic chemicals. J Ind Microbial 2:107-115.
 

*Badings HT, De Jong C, Dooper RP. 1985. Automatic system for rapid analysis
 

of volatile compounds by purge-and-cold trapping/capillary gas chromatography.
 

J High Resolut Chromatogr Commun 8:755-763.
 

Baker EL Jr. 1983. Neurological disorders. In: Rom WN et al., eds.
 

Environmental and Occupational Medicine. Boston, MA: Little, Brown and
 

Company, 313-327.
 

Baker EL, Fine LJ. 1986. Solvent neurotoxicity: The current evidence. J Occup
 

Med 28:126-129.
 

*Barnes D, Bellin J, DeRosa C, et al. 1988. Reference dose (RfD): Description
 

and use in health risk assessments. Vol. I. Appendix A: Integrated risk
 

information system supportive documentation. Washington, DC: U.S.
 

Environmental Protection Agency, Office of Health and Environmental
 

Assessment. EPA/600/8-88/032a.
 

Bierbaum PJ. 1973. Survey of Columbus Coated Fabrics, Newark, California.
 

Cincinnati, OH: National Institute for Occupational Safety and Health,
 

Division of Field Studies and Clinical Investigations. NTIS No. PB81-229601.
 

*Bierbaum PJ, Marceleno T. 1973. Survey of Brammer Manufacturing Company,
 

Davenport, Iowa. Cincinnati, OH: National Institute for Occupational Safety
 

and Health, Division of Field Studies and Clinical Investigations. NTIS No.
 

PB81-231318.
 
76
 

8. REFERENCES
 

Bierbaum PJ, Parnes WD. 1974. Survey of Electrical Division of Bristol Brass
 

Corporation, South Windsor, Connecticut. Cincinnati, OH: National Institute
 

for Occupational Safety and Health, Division of Field Studies and Clinical
 

Investigations. NTIS No. PB-82-110073.
 

*Billmaier D, Yee HT, Allen N, et al. 1974. Peripheral neuropathy in a coated
 

fabrics plant. J Occup Med 16:665-671.
 

*Boekelheide K. 1987. 2,5-Hexanedione alters microtubule assembly. I.
 

Testicular atrophy, not nervous system toxicity, correlates with enhanced
 

tubulin polymerization. Toxicol Appl Pharmacol 88:370-382.
 

*Branchflower RV, Pohl IX. 1981. Investigation of the mechanism of the
 

potentiation of chloroform-induced hepatotoxicity and nephrotoxicity by methyl
 

a-butyl ketone. Toxicol Appl Pharmacol 61:407-413.
 

Branchflower RV, Schulick RD, George JW, et al. 1983. Comparison of the
 

effects of methyl-n-butyl ketone and phenobarbital on rat liver cytochromes P450 and the metabolism of chloroform to phosgene. Toxicol Appl Pharmacol
 

71:414-421.
 

*Bronstein AC, Currance PL. 1988, Emergency care for hazardous materials
 

exposure. St, Louis, MO: The C.V. Mosby Company, 65, 215-216.
 

*Brown EM, Hewitt WR. 1984. Dose-response relationships in ketone-induced
 

potentiation of chloroform hepato- and nephrotoxicity. Toxicol Appl Pharmacol
 

76:437-453.
 

*Brown KW, Donnelly KC. 1988. An estimation of the risk associated with the
 

organic constituents of hazardous and municipal waste landfill leachates.
 

Hazardous Wastes and Hazardous Materials 5:1-30.
 

Browning E. 1965. Toxicity and metabolism of industrial solvents. London,
 

England: Elsevier Publishing Company, 428-429.
 

*Calvert JG, Pitts JN. 1966. Photochemistry of the polyatomic molecules. In:
 

Photochemistry. New York, NY: John Wiley & Sons, Inc.
 

*CLPSD. 1989, Contract Laboratory Program Statistical Database. Viar and
 

Company, Management Services Division, Alexandria, VA. June 1986.
 

Couri D, Milks M. 1982. Toxicity and metabolism of the neurotoxic hexacarbons
 

n-hexane, 2-hexanone, and 2,5-hexanedione. Ann Rev Pharmacol Toxicol 22:145­

166.
 
77
 

8. REFERENCES
 

Couri D, Hetland LB, O'Neill JJ, et al. 1974. Comments on a plastics industry
 

neurotoxicity in relationship to methylbutyl ketone. Wright-Patterson Air
 

Force Base, OH: Aerospace Medical Research Laboratory. NTIS No. ADA-011857.
 

*Couri D, Hetland LB, Abdel-Rahman MS, et al. 1977. The influence of inhaled
 

ketone solvent vapors on hepatic microsomal biotransformation activities.
 

Toxicol Appl Pharmacol 41:285-289.
 

Couri D, Abdel-Rahman MS, Hetland LB. 1978. Biotransformation of n-hexane and
 

methyl n-butyl ketone in guinea pigs and mice. Am Ind Hyg Assoc J 39:295-300.
 

*Cowlen MS, Hewitt WR, Schroeder F. 1984a. 2-Hexanone potentiation of
 

[14
C]chloroform hepatotoxicity: Covalent interaction of a reactive intermediate
 

with rat liver phospholipid. Toxicol Appl Pharmacol 73:478-491.
 

*Cowlen MS, Hewitt WR, Schroeder F. 1984b. Mechanisms in 2-hexanone
 

potentiation of chloroform hepatotoxicity. Toxicol Lett 22:293-299.
 

Craft BF. 1973. Summary status report of an investigation of an incident of
 

toxic polyneuropathy at the Borden Chemical Company's Columbus Coated Fabrics
 

Division, Columbus, Ohio. Cincinnati, OH: National Institute for Occupational
 

Safety and Health. NTIS No. PB89-122915.
 

Davenport JG, Farrell DF, Sumi SM. 1976. Giant axonal neuropathy caused by
 

industrial chemicals: Neurofilamentous axonal masses in man. Neurology 26:919­

923.
 

*Day EA, Anderson DF. 1965. Gas chromatographic and mass spectral
 

identification of natural components of the aroma fraction of blue cheese. J
 

Agric Food Chem 13:2-4.
 

*DeCaprio AP, Olajos EJ, Weber P. 1982. Covalent binding of a neurotoxic nhexane metabolite: Conversion of primary amines to substituted pyrrole adducts
 

by 2,5-hexanedione. Toxicol Appl Pharmacol 65:440-450.
 

*DeCaprio AP, Briggs RG, Jackowski SJ, et al. 1988. Comparative neurotoxicity
 

and pyrrole-forming potential of 2,5-hexanedione and perdeuterio-2,5­

hexanedione in the rat. Toxicol Appl Pharmacol 92:75-85.
 

DeJesus C, Pleasure DF, Asbury AK, et al. 1977. Effects of methyl butyl ketone
 

on peripheral nerves and its mechanism of action. Report to National Institute
 

of Occupational Safety and Health, Cincinnati, OH, by Yale University of
 

Medicine, New Haven, CT and Veterans Administration Hospital, West Haven, CT.
 

NTIS No. PB83-105148.
 
78
 

8. REFERENCES
 

*DiVincenzo GD, Kaplan CJ, Dedinas J. 1976. Characterization of the
 

metabolites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl
 

ethyl ketone in guinea pig serum and their clearance. Toxicol Appl Pharmacol
 

36:511-522.
 

*DiVincenzo GD, Hamilton ML, Kaplan CJ, et al. 1977. Metabolic fate and
 

disposition of 14C-labeled methyl n-butyl ketone in the rat. Toxicol Appl
 

Pharmacol 41:547-560.
 

*DiVincenzo GD, Hamilton ML, Kaplan CJ, et al. 1978. Studies on the
 

respiratory uptake and excretion and the skin absorption of methyl n-butyl
 

ketone in humans and dogs. Toxicol Appl Pharmacol 44:593-604.
 

DiVincenzo GD, Hamilton ML, Kaplan CJ, et al. 1980. Characterization of the
 

metabolites of methyl n-butyl ketone. In: Spencer PS, Schaumburg HH, eds.
 

Experimental and clinical neurotoxicology. Baltimore, MD: Williams and Wilkins
 

Company, 846-855.
 

Duckett S, Williams N, Francis S. 1974. Peripheral neuropathy associated with
 

inhalation of methyl-n-butyl ketone. Experientia 30:1283-1284.
 

*Duckett S, Streletz IJ, Chambers RA, et al. 1979. 50 ppm MnBK subclinical
 

neuropathy in rats. Experientia 35:1365-1367.
 

Dumdei BE, Henderson R. 1988. Air toxics monitoring program during
 

bioremediation of a Superfund site. Proceedings of the 81st Annual Meeting of
 

Air Pollution Control Association, Dallas, TX. June, 1988.
 

*Dumont JP, Adda J. 1978. Occurrence of sesquiterpenes in mountain cheese
 

volatiles. J Agric Food Chem 26:364-367.
 

Durham HD, Pena SD J, Ecobichon DJ. 1988. Hexahydrocarbon effects on
 

intermediate filament organization in human fibroblasts. Muscle Nerve 11:160­

165.
 

*Eben A, Flucke W, Mihail F, et al. 1979. Toxicological and metabolic studies
 

of methyl n-butylketone, 2,5-hexanedione, and 2,5-hexanediol in male rats.
 

Ecotoxicol Environ Safety 3:204-217.
 

*Egan G, Spencer P, Schaumburg H, et al. 1980. n-Hexane-"free" hexane mixture
 

fails to produce nervous system damage. Neurotoxicology 1:515-524.
 

*Ellenhorn MJ, Barceloux DG. 1988. Medical toxicology: Diagnosis and treatment
 

of human poisoning. New York, NY: Elsevier, 999-1000.
 

*EPA. 1981. Chemical hazard information profile: Draft report methyl n-butyl
 

ketone. Washington, DC: U.S. Environmental Protection Agency, Office of
 

Pesticides and Toxic Substances.
 
79
 

8. REFERENCES
 

*EPA. 1986. Gas chromatography/mass spectrometry for volatile organics ­

method 8240. In: Test methods for evaluating solid waste. 3rd ed. SW-846.
 

Washington, DC: U.S. Environmental Protection Agency, Office of Solid Waste
 

and Emergency Response.
 

*EPA. 1987a. U.S. Environmental Protection Agency: Part II. Federal Register
 

52:25942-25953.
 

*EPA. 1987b. U.S. Environmental Protection Agency. Federal Register 52:11823­

11826.
 

*EPA. 1989. Interim methods for development of inhalation reference doses.
 

Washington, DC: U.S. Environmental Protection Agency, Office of Health and
 

Environmental Assessment. EPA 600/8-88/066F.
 

*Fedtke N, Bolt HM. 1986. Methodological investigations on the determination
 

of E-hexane metabolites in urine. Int Arch Occup Environ Health 57:149-158.
 

Garman JR, Freund T, Lawless EW. 1987. Testing for groundwater contamination
 

at hazardous waste sites. J Chromatogr Sci 25:328-337.
 

Genter MB, Szakal-Quin G, Anderson W, et al. 1986. Evidence that pyrrole
 

formation is a pathogenetic step in gamma-diketone neuropathy. [Abstract]
 

Toxicol Appl Pharmacol 87:351-362.
 

Goldberg AM. 1980. Mechanisms of neurotoxicity as studied in tissue culture
 

systems. Toxicology 17:201-208.
 

Goldstein MN. 1981. Effect of methyl-n-butyl ketone and other ketone
 

homologues on mammalian cells in culture. Report to National Institute of
 

Occupational Health and Safety, Cincinnati, OH, by Washington University, St.
 

Louis, MO. NTIS No. PB81-225997.
 

Gosselin RE, Smith RP, Hodge HC, et al. 1984. Clinical toxicology of
 

commercial products. 5th ed. Baltimore, MD: Williams and Wilkins, 11-185-11­

186.
 

Graedel TE. 1978. Aliphatic ketones. In: Chemical compounds in the atmosphere.
 

New York, NY: Academic Press, 181, 184-185.
 

*Green DR, Le Pape D. 1987. Stability of hydrocarbon samples on solid-phase
 

extraction columns. Anal Chem 59:699-703.
 

*Grey TC, Shrimpton DH. 1967. Volatile components of raw chicken breast
 

muscle. Br Poult Sci 8:23-33.
 
80
 

8. REFERENCES
 

*Hassett JJ, Banwart WL, Griffin RA. 1983. Correlation of compound properties
 

with sorption characteristics of nonpolar compounds by soils and sediments:
 

Concepts and limitations. In: Francis CW, Auerbach SI, Jacobs VA, eds.
 

Environment and solid wastes: Characterization, treatment, and disposal.
 

Boston, MA: Butterworths, 161-176.
 

*Hawthorne SB, Sievers RE, Barkley RM. 1985. Organic emissions from shale oil
 

wastewaters and their implications for air quality. Environ Sci Technol
 

19:992-997.
 

*Hewitt WR, Miyajima H, Cote MG, et al. 1980a. Acute alteration of chloroform-


induced hepato- and nephrotoxicity by n-hexane, methyl n-butyl ketone and 2,5­

hexanedione. Toxicol Appl Pharmacol 53:230-248.
 

*Hewitt WR, Miyajima H, Cote MG, et al. 1980b. Modification of haloalkaneinduced hepatotoxicity by exogenous ketones and metabolic ketosis. Fed Proc
 

39:3118-3123.
 

*Hewitt WR, Brown EM, Plaa GL. 1983. Relationship between the carbon skeleton
 

length of ketonic solvents and potentiation of chloroform-induced
 

hepatotoxicity in rats. Toxicol Lett 16:297-304.
 

*Hewitt LA, Ayotte P, Plaa GL. 1986. Modifications in rat hepatobiliary
 

function following treatment with acetone, 2-butanone, 2-hexanone, mirex, or
 

chlordecone and subsequently exposed to chloroform. Toxicol Appl Pharmacol
 

83:465-473.
 

*HSDB. 1989. Hazardous Substances Data Bank. National Library of Medicine,
 

National Toxicology Information Program, Bethesda, MD. September 5, 1989.
 

IRPTC. 1989. International Register of Potentially Toxic Chemicals. United
 

Nations Environment Programme, Geneva, Switzerland. September 1989.
 

*Johnson BL, Setzer JV, Lewis TR, et al. 1977. Effects of methyl n-butyl
 

ketone on behavior and the nervous system. Am Ind Hyg Assoc J 38:567-579.
 

Johnson BL, Setzer JV, Lewis TR, et al. 1978. An electrodiagnostic study of
 

the neurotoxicity of methyl n-amyl ketone. Am Ind Hyg Assoc J 39:866-872.
 

Johnson BL, Anger WK, Setzer JV, et al. 1979. Neurobehavioral effects of
 

methyl n-butyl ketone and methyl n-amyl ketone in rats and monkeys: A summary
 

of NIOSH investigations. J Environ Pathol Toxicol 2:113-133.
 

*Katz GV, O'Donoghue JL, DiVincenzo GD, et al. 1980. Comparative neurotoxicity
 

and metabolism of ethyl n-butyl ketone and methyl n-butyl ketone in rats.
 

Toxicol Appl Pharmacol 52:153-158.
 
81
 

8. REFERENCES
 

*King JW. 1989. Fundamentals and applications of supercritical fluid
 

extraction in chromatographic science. J Chromatogr Sci 27:355-364.
 

*Kinlin TE, Muralidhara R, Pittet AO, et al. 1972. Volatile components of
 

roasted filberts. J Agr Food Chem 20:1021-1028.
 

Konasewich D, Traversy W, Zar H. 1978. Status report on organic and heavy
 

metal contaminants in the Lakes Erie, Michigan, Huron and Superior basins.
 

Great Lakes Water Quality Board.
 

*Krasavage WJ, O'Donoghue JL, DiVincenzo GD, et al. 1980. The relative
 

neurotoxicity of methyl-n-butyl ketone, n-hexane and their metabolites.
 

Toxicol Appl Pharmacol 52:433-441.
 

*Laity JL, Burstain IG, Appel BR. 1973. Photochemical smog and the atmospheric
 

reactions of solvents. In: Tess RW, ed. Solvents theory and practice. Advances
 

in Chemistry Series 124, Washington, DC: American Chemical Society, 95-112.
 

*Lande SS, Durkin PR, Christopher DE, et al. 1976. Investigation of selected
 

potential environmental contaminants: Ketonic solvents. Washington, DC: U.S.
 

Environmental Protection Agency, Office of Toxic Substances. EPA-560/2-76-003.
 

NTIS No. TR 76-500.
 

*Lapin EP, Weissbarth S, Maker HS, et al. 1982. The sensitivities of creatine
 

and adenylate kinases to the neurotoxins acrylamide and methyl n-butyl ketone.
 

Environ Res 28:21-31.
 

Leo A, Hansch C, Elkins D. 1971. Partition coefficients and their uses. Chem
 

Rev 71:525,563.
 

Lloyd AC. 1979. Tropospheric chemistry of aldehydes. Washington, DC: National
 

Bureau of Standards. Special Publication No. 557.
 

*Lowery CE Jr., Foster JW, Jurtshuk P. 1968. The growth of various filamentous
 

fungi and yeasts on n-alkanes and ketones: I. Studies on substrate
 

specificity. Arch Mikrobiol 60:246-254.
 

*Lucas SV. 1984, GC/MS analysis of organics in drinking water concentrates and
 

advanced waste treatment concentrates. Vol. 1. Analysis results for 17
 

drinking water, 16 advanced waste treatment and 3 process blank concentrates.
 

Report to U.S. Environmental Protection Agency, Office of Research and
 

Development, Research Triangle Park, NC, Battelle Columbus
 

Laboratories, Columbus, OH. EPA-600/l-84-020a. NTIS No. PB85-128221.
 

*Lukins HB, Foster JW. 1963. Methyl ketone metabolism in hydrocarbonutilizing
 

mycobacteria. J Bacterial 85:1074-1087.
 
82
 

8. REFERENCES
 

*Mabey WR, Smith JH, Pod011 RT, et al. 1982. Aquatic fate process data for
 

organic priority pollutants. Report to U.S. Environmental Protection Agency,
 

Office of Water Regulations and Standards, Washington, DC, by SRI
 

International, Menlo Park, CA. EPA 440/4-81-014. NTIS No. PB87-169090.
 

*MacLeod H, Jourdain JL, Poulet G, et al. 1984. Kinetic study of reactions of
 

some organic sulfur compounds with OH radicals. Atmos Environ 18:2621-2626.
 

Makkawy HM, Graham DG, Abou-Donia MB. 1981. Differential neuro toxicity of n ­

hexane methyl-E-butyl ketone, 2,5-hexanediol and 2,5-hexanedione following
 

subchronic 90 days oral administration in hens. Fed Proc 40:678.
 

Mallov JS. 1976. MBK neuropathy among spray painters. J Am Med Assoc 235:1455­

1457.
 

Mallov JS, Marceleno T, Fontaine R. 1975. Methyl n-butyl ketone and peripheral
 

neuropathy: A summary report. Cincinnati, OH: U.S. Department of Health,
 

Education, and Welfare, Division of Field Studies and Clinical Investigations.
 

NTIS No. PB81-229981.
 

*Marceleno T, Bierbaum PJ, Mallov JS. 1974. Survey of Premium Finishes,
 

Incorporated, Cincinnati, OH. Cincinnati, OH: National Institute for
 

Occupational Safety and Health, Division of Field Studies and Clinical
 

Investigations. NTIS No. PB81-242729.
 

McDonough JR. 1974. Possible neuropathy from methyl butyl ketone. N Engl J Med
 

290:695.
 

Mendell JR, Duckett S, Williams N, et al. 1974a. Neuropathy and methyl n-butyl
 

ketone. N Engl J Med 290:1263-1264.
 

*Mendell JR, Saida K, Ganansia MF, et al. 1974b. Toxic polyneuropathy produced
 

by methyl n-butyl ketone. Science 185:787-789.
 

Mendell JR, Sahenk Z, Saida K, et al. 1977. Alterations of fast axoplasmic
 

transport in experimental methyl n-butyl ketone neuropathy. Brain Res 133:107­

118.
 

Michael LC, Pellizzari ED, Wiseman RW. 1988. Development and evaluation of a
 

procedure for determining volatile organics in water. Environ Sci Technol
 

22:565-570.
 

Misumi J, Nagano M. 1984. Neurophysiological studies on the relation between
 

the structural properties and neurotoxicity of aliphatic hydrocarbon compounds
 

in rats. Br J Ind Med 41:526-532.
 
83
 

8. REFERENCES
 

Misumi J, Nagano M. 1985. Experimental study on the enhancement of the
 

neurotoxicity of methyl n-butyl ketone by non-neurotoxic aliphatic
 

monoketones. Br J Ind Med 42:155-161.
 

*Morrison RT, Boyd RN. 1974. Organic chemistry. 3rd ed. Boston, MA: Allyn and
 

Bacon, Inc., 620.
 

*Myers VB. 1983. Remedial activities at the Miami Drum site, Florida. In:
 

National conference on management of uncontrolled hazardous waste sites.
 

Silver Springs, MD: Hazardous Materials Control Research Institute, 354-357.
 

Nachtman JP, Couri D. 1984. An electrophysiological study of 2-hexanone and
 

2,5-hexanedione neurotoxicity in rats. Toxicol Lett 23:141-145.
 

*NAS/NRC. 1989. Biologic markers in reproductive toxicology. Washington, DC:
 

National Academy of Sciences, National Research Council, National Academy
 

Press.
 

*NATICH. 1989. National Air Toxics Information Clearinghouse: NATICH database
 

report on state, local and EPA air toxics activities. Report to U.S.
 

Environmental Protection Agency, Office of Air Quality Planning and Standards,
 

Research Triangle Park, NC, by Radian Corporation, Austin, TX. EPA-450/3-89­

29.
 

*Neely WB, Branson DR, Blau GE. 1974. Partition coefficient to measure
 

bioconcentration potential of organic chemicals in fish. Environ Sci Technol
 

8:1113-1115.
 

Nelson BK. 1986. Developmental neurotoxicology of in utero exposure to
 

industrial solvents in experimental animals. Neurotoxicology 7:441-448.
 

NIOSH. 1978a. Criteria for a recommended standard: Occupational exposure to
 

ketones. Cincinnati, OH: U.S. Department of Health, Education and Welfare,
 

National Institute for Occupational Safety and Health. DHEW (NIOSH)
 

Publication No. 78-173.
 

*NIOSH. 1978b. Criteria for a recommended standard: Occupational exposure in
 

coal gasification plants. Cincinnati, OH: National Institute for Occupational
 

Safety and Health. DHEW (NIOSH) Pub No. 78-191.
 

*NIOSH. 1984. Ketones I - method 1300. In: NIOSH manual of analytical methods.
 

3rd ed. Vol. 2. Cincinnati, OH: U.S. Department of Health and Human Services,
 

National Institute for Occupational Safety and Health.
 

*NIOSH. 1985. Pocket guide to chemical hazards. Washington, DC: U.S.
 

Department of Health and Human Services, National Institute for Occupational
 

Safety and Health. DHHS (NIOSH) Publication No. 85-114.
 
84
 

8. REFERENCES
 

NIOSH. 1987. Organic solvent neurotoxicity. Cincinnati, OH: U.S. Department of
 

Health and Human Services, National Institute for Occupational Safety and
 

Health. Current Intelligence Bulletin 48. DHHS (NIOSH) Publication No. 87-104.
 

*NIOSH. 1989. National Occupational Exposure Survey. National Institute of
 

Occupational Safety and Health, Cincinnati, OH. October 18, 1989.
 

*NLM , 1989. Chemline. National Library of Medicine, Bethesda, MD. September
 

1989.
 

*NOHS. 1989. National Occupational Hazard Survey. National Institute of
 

Occupational Safety and Health, Cincinnati, OH. October 18, 1989.
 

*Nomeir AA, Abou-Donia MB. 1985. Analysis of D-hexane, 2-hexanone, 2,5­

hexanedione, and related chemicals by capillary gas chromatography and high
 

performance liquid chromatography. Anal Biochem 151:381-388.
 

*O'Donoghue, JL. 1985. Alkanes, alcohols, ketones, and ethylene oxide. In:
 

O'Donoghue JL, ed. Neurotoxicity of industrial and commercial chemicals. Vol.
 

II. Boca Raton, FL: CRC Press, Inc. 61-97.
 

O'Donoghue JL, Krasavage WJ, DiVincenzo GD, et al. 1984. Further studies on
 

ketone neurotoxicity and interactions. Toxicol Appl Pharmacol 72:201-209.
 

O'Donoghue JL, Haworth SR, Curren RD, et al. 1988. Mutagenicity studies on
 

ketone solvents: Methyl ethyl ketone, methyl isobutyl ketone, and isophorone.
 

Mutat Res 206:149-161.
 

*OSHA. 1989. Occupational Safety and Health Administration: Part III. Federal
 

Register 54:2940.
 

*Pankow JF, Rosen ME. 1988. Determination of volatile compounds in water by
 

purging directly to a capillary column with whole column cryotrapping. Environ
 

Sci Technol 22:398-405.
 

*Pellizzari ED, Castillo NP, Willis S, et al. 1979. Identification of organic
 

components in aqueous effluents from energy-related processes. In: Van Hall
 

CE, ed. Measurement of organic pollutants in water and wastewater.
 

Philadelphia, PA: American Society for Testing and Materials, 256-274. ASTM
 

Special Technical Publication No. 686.
 

*Perry JJ. 1968. Substrate specificity in hydrocarbon utilizing
 

microorganisms. Antonie Van Leeuwenhoek 34:27-36.
 
85
 

8. REFERENCES
 

*Perry DL, Chuang CC, Jungclaus GA, et al. 1979. Identification of organic
 

compounds in industrial effluent discharges. Athens, GA: U.S. Environmental
 

Protection Agency, Office of Research and Development, Environmental Research
 

Laboratory. EPA-600/4-79-016. PB-294794.
 

*Peters MA, Hudson PM, Dixon RL. 1981. The effect totigestational exposure to
 

methyl n-butyl ketone has on postnatal development and behavior. Ecotoxicol
 

Environ Safety 5:291-306.
 

Pilon D, Charbonneau M, Brodeur J, et al. 1986. Metabolites and ketone body
 

production following methyl n-butyl ketone exposure as possible indices of
 

MnBK potentiation of carbon tetrachloride hepatotoxicity. Toxicol Appl
 

Pharmacol 85:49-59.
 

Politis MJ, Pellegrino RG, Spencer PS. 1980. Ultrastructural studies of the
 

dying-back process. 5. Axonal neurofilaments accumulate at sites of 2,5­

hexanedione application: Evidence for nerve fibre dysfunction in experimental
 

hexacarbon neuropathy. [Abstract] J Neurocytol 9:505-516.
 

Prockop L, Couri D. 1977. Nervous system damage from mixed organic solvents.
 

In: Sharp CW, ed. Review of inhalants: Euphoria to dysfunction. Washington,
 

DC: U.S. Government Printing Office, 185-198.
 

Proctor NH, Hughes JP, Fischman ML. 1988. Chemical hazards of the workplace.
 

2nd edition. Philadelphia, PA: J. B. Lippincott Company, 324-325.
 

Puskar MA, Levine SP, Lowry SR. 1987. Qualitative screening of hazardous waste
 

mixtures. Environ Sci Technol 21:90-96.
 

Raisbeck MF. 1984. Effects of 2-hexanone upon hepato- and nephrotoxicity of
 

several haloalkanes and cephaloridine. Diss Abstr Int B 46:1083.
 

Raisbeck MF, Brown EM, Hewitt WR. 1986. Renal and hepatic interactions between
 

2-hexanone and carbon tetrachloride in F-344 rats. Toxicol Lett 31:15-21.
 

Raleigh RL, Spencer PS, Schaumburg HH. 1975. Toxicity of methyl- n-butyl
 

ketone. Arch Environ Health 30:317-318.
 

Roy WR, Griffin RA. 1985. Mobility of organic solvents in water-saturated soil
 

materials. Environ Geol Water Sci 7:241-247.
 

*Sabri MI. 1984. In vitro effect of n-hexane and its metabolites on selected
 

enzymes in glycolysis, pentose phosphate pathway and citric acid cycle. Brain
 

Res 297:145-150.
 
86
 

8. REFERENCES
 

Sabri MI, Moore CL, Spencer PS. 1979a. Studies on the biochemical basis of
 

distal axonopathies-I. Inhibition of glycolysis by neurotoxic hexacarbon
 

compounds. J Neurochem 32:683-689.
 

*Sabri MI, Ederle K, Holdsworth CE, et al. 1979b. Studies on the biochemical
 

basis of distal axonipathies. II. Specific inhibition of fructose-6-phosphate
 

kinase by 2,5-hexanedione and methyl-butyl ketone. Neurotoxicologly 1:285­

297.
 

*Saida K, Mendell JR, Weiss HS. 1976. Peripheral nerve changes induced by
 

methyl E-butyl ketone and potentiation by methyl ethyl ketone. Neuropathol Exp
 

Neurol 35:207-225.
 

*Sate A, Nakaj ima T. 1979. Partition coefficients of some aromatic
 

hydrocarbons and ketones in water, blood and oil. Br J Ind Med 36:231-234.
 

*Sax NI. 1984. Dangerous properties of industrial materials. 6th ed. New York:
 

Van Nostrand Reinhold Company, 1526-1527.
 

*Sax NI, Lewis RJ Sr. 1987. Hawley's condensed chemical dictionary. 11th ed.
 

New York: Van Nostrand Reinhold Company, 762.
 

Sayre LM, Shearson CM, Wongmongkolrit T, et al. 1986. Structural basis of
 

gamma-diketone neurotoxicity: Non-neurotoxicity of 3,3-dimethyl-2,5­

hexanedione, a gamma-diketone incapable of pyrrole formation. [Abstract]
 

Toxicol Appl Pharmacol 84:36-44.
 

Schrenk HH, Yant WP, Patty FA. 1936. Acute response of guinea pigs to vapors
 

of some new commercial organic compounds. Public Health Rep 51:624-631.
 

Selkoe DJ, Luckenbill-Edds L, Shelanski ML. 1978. Effects of neurotoxic
 

industrial solvents on cultured neuroblastoma cells: Methyl n-butyl ketone, nhexane and derivatives. J Neuropathol Exp Neurol 37:768-789.
 

*Shackelford WM, Keith LH. 1976. Frequency of organic compounds identified in
 

water. Athens, GA: U.S. Environmental Protection Agency, Office of Research
 

and Development. EPA-600/4-76-062. NTIS No. PB-165470.
 

Sharkawi M, Elfassy B. 1985. Inhibition of mouse liver alcohol dehydrogenase
 

by methyl n-butyl ketone. Toxicol Lett 25:185-189.
 

*Smyth HF, Carpenter CP, Weil CS, et al. 1954. Range-finding toxicity data:
 

List V. Arch Ind Hyg Occup Med 10:61-68.
 

Spector WS, ed. 1956. Lethal doses of solid and liquid compounds: Laboratory
 

animals. In: Spector WS, ed. Handbook of Toxicology. Vol. I. Philadelphia, PA:
 

W.B. Saunders and Company 5, 156-157, 321, 338-339.
 
87
 

8. REFERENCES
 

Spencer PS, Schaumburg HH. 1976. Feline nervous system response to chronic
 

intoxication with commercial grades of methyl n-butyl ketone, methyl isobutyl
 

ketone, and methyl ethyl ketone. Toxicol Appl Pharmacol 37:301-311.
 

Spencer PS, Schaumburg HH. 1977a. Ultrastructural studies of the dying-back
 

process. III. The evolution of experimental peripheral giant axonal
 

degeneration. J Neuropathol Exp Neurol 36:276-299.
 

*Spencer PS, Schaumburg HH. 1977b. Ultrastructural studies of the dying-back
 

process. IV. Differential vulnerability of PNS and CNS fibers in experimental
 

central-peripheral distal axonopathies. J Neuropathol Exp Neurol 36:300-320.
 

*Spencer PS, Schaumburg HH, Raleigh RL, et al. 1975. Nervous system
 

degeneration produced by the industrial solvent methyl n-butyl ketone. Arch
 

Neurol 32:219-222.
 

*Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-


hospital care. 2nd ed. Beltsville, MD: Bradford Communications Corporation,
 

312-313.
 

*Takeoka GR, Flath RA, Guntert M, et al. 1988. Nectarine volatiles: Vacuum
 

steam distillation versus headspace sampling. J Agric Food Chem 36:553-560.
 

Thomas RD, ed. 1986. Drinking water and health. Vol. 6. Washington, DC:
 

National Academy Press, 130.
 

Thorn P, Gardener H, Hrutfiord B. 1977. Odorous compounds from magnefite
 

pulping. Pulp and Paper Canada 78:93-95.
 

TRI. 1989. Toxic Chemical Release Inventory. National Library of Medicine,
 

National Toxicology Information Program, Bethesda, MD.
 

*Upreti RK, Shanker S. 1987. 2,5-Hexanedione-induced immunomodulatory effect
 

in mice. Environ Res 43:48-59.
 

*Upreti RK, Singh KP, Saxena AK, et al. 1986. Effect of 2,5-hexanedione on
 

lymphoid organs of rats: A preliminary report. Environ Res 39:188-198.
 

Vaishnav DD, Boethling RS, Babeu L. 1987. Quantitative
 

structurebiodegradability relationships for alcohols, ketones and alicyclic
 

compounds. Chemosphere 16:695-703.
 

Veronesi B, Peterson ER, Bornstein MB, et al. 1983. Ultrastructural studies of
 

the dying-back process. VI. Examination of nerve fibers undergoing giant
 

axonal degeneration in organotypic culture. J Neuropathol Exp Neurol 42:153­

165. [Abstract]
 
88
 

8. REFERENCES
 

*Verschueren K. 1983. Handbook of environmental data on organic chemicals. 2nd
 

ed. New York: Van Nostrand Reinhold Company, 320.
 

*View Database. 1989. Agency for Toxic Substances and Disease Registry
 

(ATSDR), Office of External Affairs, Exposure and Disease Registry Branch,
 

Atlanta GA. September 25, 1989.
 

*Weast RC, ed. 1985. CRC Handbook of chemistry and physics. Boca Raton, FL:
 

CRC Press, Inc., C-307.
 

*West C. 1990. Written communication (March 5) to Barry L. Johnson, Agency for
 

Toxic Substances and Disease Registry, regarding regulatory information of
 

hazardous substances. Department of Environmental Quality Engineering, The
 

Commonwealth of Massachusetts, Boston, MA.
 

*White EL, Bus JS, Heck HD. 1979. Simultaneous determination of n-hexane, 2­

hexanone and 2,5-hexanedione in biological tissues by gas chromatography mass
 

spectrometry. Biomed Mass Spectrum 6:169-172.
 

*Wieboldt RC, Adams GE, Later DW. 1988. Sensitivity improvement in infrared
 

detection for supercritical fluid chromatography. Anal Chem 60:2422-2427.
 

*Windholz M, ed. 1983. The Merck index: An encyclopedia of chemicals, drugs,
 

and biologicals. 10th ed. Rahway, NJ: Merck and Company, Inc., 5909.
 
89
 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as
 

specified in the Toxicological Profiles.
 

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical adsorbed
 

per unit weight of organic carbon in the soil or sediment to the concentration
 

of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
 

soil (i.e., the solid phase) divided by the amount of chemical in the solution
 

phase, which is in equilibrium with the solid phase, at a fixed solid/solution
 

ratio. It is generally expressed in micrograms of chemical sorbed per gram of
 

soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete time
 

period of exposure divided by the concentration in the surrounding water at
 

the same time or during the same period.
 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group
 

of studies, that produces significant increases in the incidence of cancer (or
 

tumors) between the exposed population and its appropriate control.
 

Carcinogen -- A chemical capable of inducing cancer.
 

Ceiling Value -- A concentration of a substance that should not be exceeded,
 

even instantaneously.
 

Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified
 

in the Toxicological Profiles.
 

Developmental Toxicity -- The occurrence of adverse effects on the developing
 

organism that may result from exposure to a chemical prior to conception
 

(either parent), during prenatal development, or postnatally to the time of
 

sexual maturation. Adverse developmental effects may be detected at any point
 

in the life span of the organism.
 

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a
 

result of prenatal exposure to a chemical; the distinguishing feature between
 

the two terms is the stage of development during which the insult occurred.
 

The terms, as used here, include malformations and variations, altered growth,
 

and in utero death.
 

EPA Health Advisory -- An estimate of acceptable drinking water levels for a
 

chemical substance based on health effects information. A health advisory is
 

not a legally enforceable federal standard, but serves as technical guidance
 

to assist federal, state, and local officials.
 
90
 

9. GLOSSARY
 

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
 

concentration of a contaminant from which one could escape within 30 min
 

without any escape-impairing symptoms or irreversible health effects.
 

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days
 

as specified in the Toxicological Profiles.
 

Immunologic Toxicity -- The occurrence of adverse effects on the immune system
 

that may result from exposure to environmental agents such as chemicals.
 

In Vitro -- Isolated from the living organism and artificially maintained, as
 

in a test tube.
 

In Viva -- Occurring within the living organism.
 

Lethal Concentration (LC (LO) Lo
) -- The lowest concentration of a chemical in air


which has been reported to have caused death in humans or animals.
 

Lethal Concentration (LC (50) 50
) -- A calculated concentration of a chemical in


air to which exposure for a specific length of time is expected to cause death
 

in 50% of a defined experimental animal population.
 

Lethal Dose (LD (LO) LO
) -- The lowest dose of a chemical introduced by a route


other than inhalation that is expected to have caused death in humans or
 

animals.
 

Lethal Dose (LD (50) 50
) -- The dose of a chemical which has been calculated to
 

cause death in 50% of a defined experimental animal population.
 

Lethal Time (LT (50) 50
) -- A calculated period of time within which a specific


concentration of a chemical is expected to cause death in 50% of a defined
 

experimental animal population.
 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in
 

a study or group of studies, that produces statistically or biologically
 

significant increases in frequency or severity of adverse effects between the
 

exposed population and its appropriate control.
 

Malformations -- Permanent structural changes that may adversely affect
 

survival, development, or function.
 

Minimal Risk Level -- An estimate of daily human exposure to a chemical that
 

is likely to be without an appreciable risk of deleterious effects
 

(noncancerous) over a specified duration of exposure.
 

Mutagen -- A substance that causes mutations. A mutation is a change in the
 

genetic material in a body cell. Mutations can lead to birth defects,
 

miscarriages, or cancer.
 
91
 

9. GLOSSARY
 

Neurotoxicity -- The occurrence of adverse effects on the nervous system
 

following exposure to chemical.
 

No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which
 

there were no statistically or biologically significant increases in frequency
 

or severity of adverse effects seen between the exposed population and its
 

appropriate control. Effects may be produced at this dose, but they are not
 

considered to be adverse.
 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the
 

concentrations of a chemical in n-octanol and water, in dilute solution.
 

Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace
 

air averaged over an 8-hour shift.
 

q1* -- The upper-bound estimate of the low-dose slope of the dose-response
 

curve as determined by the multistage procedure. The qI* can be used to
 

calculate an estimate of carcinogenic potency, the incremental excess cancer
 

risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and
 

pg/m3 for air).
 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an
 

order of magnitude) of the daily exposure of the human population to a
 

potential hazard that is likely to be without risk of deleterious effects
 

during a lifetime. The RfD is operationally derived from the NOAEL (from
 

'animal and human studies) by a consistent application of uncertainty factors
 

that reflect various types of data used to estimate RfDs and an additional
 

modifying factor, which is based on a professional judgment of the entire
 

database on the chemical. The RfDs are not applicable to nonthreshold effects
 

such as cancer.
 

Reportable Quantity (RQ) -- The quantity of a hazardous substance that is
 

considered reportable under CERCLA. Reportable quantities are: (1) 1 lb or
 

greater or (2) for selected substances, an amount established by regulation
 

either under CERCIA or under Sect. 311 of the Clean Water Act. Quantities are
 

measured over a 24-hour period.
 

Reproductive Toxicity -- The occurrence of adverse effects on the reproductive
 

system that may result from exposure to a chemical. The toxicity may be
 

directed to the reproductive organs and/or the related endocrine system. The
 

manifestation of such toxicity may be noted as alterations in sexual behavior,
 

fertility, pregnancy outcomes, or modifications in other functions that are
 

dependent on the integrity of this system.
 

Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers
 

can be exposed for up to 15 min continually. No more than four excursions are
 

allowed per day, and there must be at least 60 min between exposure periods.
 

The daily TLV-TWA may not be exceeded.
 
92
 

9. GLOSSARY
 

Target Organ Toxicity -- This term covers a broad range of adverse effects on
 

target organs or physiological systems (e.g., renal, cardiovascular) extending
 

from those arising through a single limited exposure to those assumed over a
 

lifetime of exposure to a chemical.
 

Teratogen -- A chemical that causes structural defects that affect the
 

development of an organism.
 

Threshold Limit Value (TLV) -- A concentration of a substance to which most
 

workers can be exposed without adverse effect. The TLV may be expressed as a
 

TWA, as a STEL, or as a CL.
 

Time-weighted Average (TWA) -- An allowable exposure concentration averaged
 

over a normal 8-hour workday or-40-hour workweek.
 

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route
 

other than inhalation, which is expected to cause a specific toxic effect in
 

50% of a defined experimental animal population.
 

Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
 

from experimental data. UFs are intended to account for (1) the variation in
 

sensitivity among the members of the human population, (2) the uncertainty in
 

extrapolating animal data to the case of human, (3) the uncertainty in
 

extrapolating from data obtained in a study that is of less than lifetime
 

exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data.
 

Usually each of these factors is set equal to 10.
 
A-l
 

APPENDIX A
 

USER'S GUIDE
 

Chapter 1
 

Public Health Statement
 

This chapter of the profile is a health effects summary written in
 

nontechnical language. Its intended audience is the general public especially
 

people living in the vicinity of a hazardous waste site or substance release.
 

If the Public Health Statement were removed from the rest of the document, it
 

would still communicate to the lay public essential information about the
 

substance. The major headings in the Public Health Statement are useful to
 

find specific topics of concern. The topics are written in a question and
 

answer format. The answer to each question includes a sentence that will
 

direct the reader to chapters in the profile that will provide more
 

information on the given topic.
 

Chapter 2
 

Tables and Figures for Levels of Significant Exposure (LSE)
 

Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize
 

health effects by duration of exposure and endpoint and to illustrate
 

graphically levels of exposure associated with those effects. All entries in
 

these tables and figures represent studies that provide reliable, quantitative
 

estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-ObservedAdverse-Effect Levels (LOAELs) for Less Serious and Serious health effects, or
 

Cancer Effect Levels (CELs). In addition, these tables and figures illustrate
 

differences in response by species, Minimal Risk Levels (MRLs) to humans for
 

noncancer end points, and EPA's estimated range associated with an upper-bound
 

individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE
 

tables and figures can be used for a quick review of the health effects and to
 

locate data for a specific exposure scenario. The LSE tables and figures
 

should always be used in conjunction with the text.
 

The legends presented below demonstrate the application of these tables and
 

figures. A representative example of LSE Table 2-l and Figure 2-l are shown.
 

The numbers in the left column of the legends correspond to the numbers in the
 

example table and figure.
 

LEGEND
 

See LSE Table 2-l
 

(1) 	 Route of Exposure One of the first considerations when reviewing
 

the toxicity of a substance using these tables and figures should
 

be the relevant and appropriate route of exposure. When sufficient
 

data exist,
 
A-2
 

APPENDIX A
 

three LSE tables and two LSE figures are presented in the document. The
 

three LSE tables present data on the three principal routes of exposure,
 

i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3,
 

respectively). LSE figures are limited to the inhalation (LSE Figure 2-l)
 

and oral (LSE Figure 2-2) routes.
 

(2). Exoosure Duration Three exposure periods: acute (14 days or less);
 

intermediate (15 to 364 days); and chronic (365 days or more) are
 

presented within each route of exposure. In this example, an inhalation
 

study of intermediate duration exposure is reported.
 

(3). Health Effect The major categories of health effects included in LSE
 

tables and figures are death, systemic, immunological, neurological,
 

developmental, reproductive, and cancer. NOAELs and LOAELs can be
 

reported in the tables and figures for all effects but
 

cancer. Systemic effects are further defined in the "System" column of
 

the LSE table.
 

(4). Key to Figure Each key number in the LSE table links study information to
 

one or more data points using the same key number in the corresponding
 

LSE figure. In this example, the study represented by key number 18 has
 

been used to define a NOAEL and a Less Serious LOAEL (also see the two
 

"18r" data points in Figure 2-l).
 

(5). Species The test species, whether animal or human, are identified in this
 

column.
 

(6). Exposure Frequency/Duration The duration of the study and the weekly and
 

daily exposure regimen are provided in this column. This permits
 

comparison of NOAELs and LOAELs from different studies. In this case (key
 

number la), rats were exposed to [substance x] via inhalation for 13
 

weeks, 5 days per week, for 6 hours per day.
 

(7). System This column further defines the systemic effects. These systems
 

include: respiratory, cardiovascular, gastrointestinal, hematological,
 

musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any
 

systemic effect (e.g., a decrease in body weight) not covered in these
 

systems. In the example of key number 18, one systemic effect
 

(respiratory) was investigated in this study.
 

(8). NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure
 

level at which no harmful effects were seen in the organ system studied.
 

Key number 18 reports a NOAEL of 3 ppm for the respiratory system which
 

was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm
 

(see footnote "c").
 

(9) 	 LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest
 

exposure level used in the study that caused a harmful health effect.
 

LOAELs have been classified into "Less Serious" and "Serious" effects.
 

These,,distinctions help readers identify the levels of exposure at which
 

adverse health effects first appear and the gradation of effects with
 

increasing dose. A brief description of the specific end point used to
 
A-3
 

APPENDIX A
 

quantify the adverse effect accompanies the LOAEL. The "Less Serious"
 

respiratory effect reported in key number 18 (hyperplasia) occurred at a
 

LOAEL of 10 ppm.
 

(10) Reference The complete reference citation is given in Chapter 8 of the
 

profile.
 

(11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated
 

with the onset of carcinogenesis in experimental or epidemiological
 

studies. CELs are always considered serious effects. The LSE tables and
 

figures do not contain NOAELs for cancer, but the text may report doses
 

which did not cause a measurable increase in cancer.
 

(12) Footnotes . Explanations of abbreviations or reference notes for data in
 

the LSE tables are found in the footnotes. Footnote "c" indicates the
 

NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm.
 

LEGEND
 

See LSE Figure 2-l
 

LSE figures graphically illustrate the data presented in the corresponding LSE
 

tables. Figures help the reader quickly compare health effects according to
 

exposure levels for particular exposure duration.
 

(13) Exposure Duration The same exposure periods appear as in the LSE table.
 

In this example, health effects observed within the intermediate and
 

chronic exposure periods are illustrated.
 

(14) Health Effect 	 These are the categories of health effects for which
 

reliable quantitative data exist. The same health effects appear in the
 

LSE table.
 

(15) Levels of Exposure 	 Exposure levels for each health effect in the LSE
 

tables are graphically displayed in the LSE figures. Exposure levels are
 

reported on the log scale "y" axis. Inhalation exposure is reported in
 

mg]m3 or ppm and oral exposure is reported in mg/kg/day.
 

(16) NOAEL In this example, 18r NOAEL is the critical end point for which an
 

intermediate inhalation exposure MRL is based. As you can see from the
 

LSE figure key, the open-circle symbol indicates a NOAEL for the test
 

species (rat). The key number 18 corresponds to the entry in the LSE
 

table. The dashed descending arrow indicates the extrapolation from the
 

exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005
 

ppm (see footnote "b" in the LSE table).
 

(17) CEL Key number 38r is one of three studies for which Cancer Effect Levels
 

(CELs) were derived. The diamond symbol refers to a CEL for the test
 

species (rat). The number 38 corresponds to the entry in the LSE table.
 
A-4
 

APPENDIX A
 

(18). Estimated Upper-Bound Human Cancer Risk Levels This is the range
 

associated with the upper-bound for lifetime cancer risk of 1 in 10,000
 

to 1 in 10,000,000. These risk levels are derived from EPA's Human Health
 

Assessment Group's upper-bound estimates of the slope of the cancer dose
 

response curve at low dose levels (q1*).
 

(19). Key to LSE Figure The Key explains the abbreviations and symbols used in
 

the figure.
 


A-7
 

APPENDIX A
 

Chapter 2 (Section 2.4)
 

Relevance to Public Health
 

The Relevance to Public Health section provides a health effects summary based
 

on evaluations of existing toxicological, epidemiological, and toxicokinetic
 

information. This summary is designed to present interpretive, weight-ofevidence discussions for human health end points by addressing the following
 

questions.
 

1. 	 What effects are known to occur in humans?
 

2.	 What effects observed in animals are likely to be of concern to
 

humans?
 

3. 	 What exposure conditions are likely to be of concern to humans,
 

especially around hazardous waste sites?
 

The section discusses health effects by end point. Human data are presented
 

first, then animal data. Both are organized by route of exposure (inhalation,
 

oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro
 

data and data from parenteral routes (intramuscular, intravenous,
 

subcutaneous, etc.) are also considered in this section. If data are located
 

in the scientific literature, a table of genotoxicity information is included.
 

The carcinogenic potential of the profiled substance is qualitatively
 

evaluated, when appropriate, using existing toxicokinetic, genotoxic, and
 

carcinogenic data. ATSDR does not currently assess cancer potency or perform
 

cancer risk assessments. MRLs for noncancer end points if derived, and the end
 

points from which they were derived are indicated and discussed in the
 

appropriate
 

section(s).
 

Limitations to existing scientific literature that prevent a satisfactory
 

evaluation of the relevance to public health are identified in the
 

Identification of Data Needs section.
 

Interpretation of Minimal Risk Levels
 

Where sufficient toxicologic information was available, MRLs were derived.
 

MRLs are specific for route (inhalation or oral) and duration (acute,
 

intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all
 

six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic;
 

Oral - acute, - intermediate, - chronic). These MRLs are not meant to support
 

regulatory action, but to aquaint health professionals with exposure levels at
 

which adverse health effects are not expected to occur in humans. They should
 

help physicians and public health officials determine the safety of a
 

community living near a substance emission, given the concentration of a
 

contaminant in air or the estimated daily dose received via food or water.
 

MRLs are based largely on toxicological studies in animals and on reports of
 

human occupational exposure.
 
A-8
 

APPENDIX A
 

MRL users should be familiar with the toxicological information on which the
 

number is based. Section 2.4, "Relevance to Public Health," contains basic
 

information known about the substance. Other sections such as 2.6,
 

"Interactions with Other Chemicals" and 2.7, "Populations that are Unusually
 

Susceptible" provide important supplemental information.
 

MRL users should also understand the MRL derivation methodology. MRLs are
 

derived using a modified version of the risk assessment methodology used by
 

the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA
 

1989a) to derive reference doses (RfDs) for lifetime exposure.
 

To derive an MRL, ATSDR generally selects the end point which, in its best
 

judgement, represents the most sensitive humanhealth effect for a given
 

exposure route and duration. ATSDR cannot make this judgement or derive an MRL
 

unless information (quantitative or qualitative) is available for all
 

potential effects (e.g., systemic, neurological, and developmental). In order
 

to compare NOAELs and LOAELs for specific end points, all inhalation exposure
 

levels are adjusted for 24hr exposures and all intermittent exposures for
 

inhalation and oral routes of intermediate and chronic duration are adjusted
 

for continous exposure (i.e., 7 days/week). If the information and reliable
 

quantitative data on the chosen end point are available, ATSDR derives an MRL
 

using the most sensitive species (when information from multiple species is
 

available) with the highest NOAEL that does not exceed any adverse effect
 

levels. The NOAEL is the most suitable end point for deriving an MRL. When a
 

NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and
 

an uncertainty factor (UF) of 10 is employed. MRLs are not derived from
 

Serious LOAELs. Additional uncertainty factors of 10 each are used for human
 

variability to protect sensitive subpopulations (people who are most
 

susceptible to the health effects caused by the substance) and for
 

interspecies variability (extrapolation from animals to humans). In deriving
 

an MRL, these individual uncertainty factors are multiplied together. The
 

product is then divided into the adjusted inhalation concentration or oral
 

dosage selected from the study. Uncertainty factors used in developing a
 

substance-specific MRL are provided in the footnotes of the LSE Tables.
 



C-l
 

APPENDIX C
 

PEER REVIEW
 

A peer review panel was assembled for 2-hexanone. The panel consisted of
 

the following members: Dr. Richard J. Bull, Associate Professor, Department of
 

Pharmacology and oxicology, Washington State University, Pullman, Washington;
 

Dr. Anthony DeCaprio, Private Consultant, Albany, New York; Dr. Theodore Mill,
 

Director, Physical Organic Chemistry Department, SRI International, Menlo
 

Park, California. A second panel of reviewers was assembled to review the
 

sections on mitigation of effects. This panel consisted of: Dr. Brent Burton,
 

Medical Director, Oregon Poison Center, Oregon Health Sciences University,
 

Portland, Oregon; Dr. Alan Hall, Private Consultant, Evergreen, Colorado; and
 

Dr. Alan Woolf, Director of Clinical Pharmacology and Toxicology,
 

Massachusetts Poison Control System, The Children's Hospital, Boston,
 

Massachusetts. These experts collectively have knowledge of 2-hexanone's
 

physical and chemical properties, toxicokinetics, key health end points,
 

mechanisms of action, human and animal exposure, and quantification of risk to
 

humans. All reviewers were selected in conformity with the conditions for peer
 

review specified in Section 104(i)(13) of the Comprehensive Environmental
 

Response, Compensation, and Liability Act, as amended.
 

Scientists from the Agency for Toxic Substances and Disease Registry
 

(ATSDR) have reviewed the peer reviewers' comments and determined which
 

comments will be included in the profile. A listing of the peer reviewers'
 

comments not incorporated in the profile, with a brief explanation of the
 

rationale for their exclusion, exists as part of the administrative record for
 

this compound. A list of databases reviewed and a list of unpublished
 

documents cited are also included in the administrative record.
 

The citation of the peer review panel should not be understood to imply
 

its approval of the profile's final content. The responsibility for the
 

content of this profile lies with the ATSDR.