TOXICOLOGICAL PROFILE FOR 

2-BUTANONE 

Agency for Toxic Substances and Disease Registry

U.S. Public Health Service 

July 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-butanone(methyl

ethyl ketone) 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-butanone has been found at 137 of

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

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

which 2-butanone is found may change. The information is important for you because

2-butanone may cause harmful health effects and because these sites are potential

or actual sources of human exposure to 2-butanone. 

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 are 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 substance such as 2-butanone, 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-BUTANONE? 

2-Butanone, also known as methyl ethyl ketone (MEK), is a colorless liquid

with a sweet, but sharp odor. 2-Butanone is manufactured in large amounts for use

in paints, glues, and other finishes because it rapidly evaporates and will

dissolve many substances, It will quickly evaporate into the air. 2-Butanone is

often found dissolved in water or as a gas in the air. 2-Butanone is also a 

natural product made by some trees and is found in some fruits and vegetables. The

exhausts of cars and trucks release 2-butanone into the air. 2-Butanone is usually

found in the air, water, and soil of landfills and hazardous waste sites. 

In water, 2-butanone can be changed to a more simple chemical form by natural

biological processes and will be broken down in about 2 weeks. It will not be

deposited in the sediment of rivers or lakes, and it is not expected to concentrate

in fish. In air, 2-butanone will break down under the influence of sunlight,

although it does not react with sunlight directly. One-half of any given amount of

2-butanone in the air will break down in 1 day or less. It is not known if 2­

butanone changes to a more simple form by 
2 

1. PUBLIC HEALTH STATEMENT 

natural biological processes in soil, but it is expected to do so because

similar substances are broken down by these processes. 2-Butanone will not

stick to soil, and if it is spilled onto soil, it will travel through the

soil into underground water sources. Some of the 2-butanone found in soil

or water will also evaporate to the air. 

You will find more information on the chemical properties of 2­

butanone in Chapter 3. The uses of 2-butanone are given in Chapter 4. More

information on how 2-butanone behaves in the environment is found in 

Chapter 5. 

1.2 HOW MIGHT I BE EXPOSED TO 2-BUTANONE? 

2-Butanone can enter the environment in a number of different ways.

It can enter the air or water from the waste of manufacturing plants. 2­

Butanone is present in many different types of paints and glues used both

in the home and in industry. As these products dry, 2-butanone will enter

the air. 2-Butanone is also in air because it is released in the exhaust 

of cars and trucks. Some trees in the forest release 2-butanone to the 

air. 

We do not know the background levels of 2-butanone in air, water, or

soil. We know that 2-butanone is found naturally in some foods. We know 

it is found at hazardous waste sites, and it is also found occasionally in

drinking water and often in the air of cities. You may also be exposed to

2-butanone by smoking cigarettes. 

You may be exposed to higher levels of 2-butanone if you use glues of

coatings containing it in a small enclosed area that does not have good air

flow, People who use it at work have a good chance of being exposed to 2­

butanone. 2-butanone is used in such industries as shoes factories, printing

plants, plastics factories, and sporting goods manufacturers. People who live

near a toxic waste site where 2-butanone is kept may breathe it if it

evaporates into the air, or drink it if it gets into the water supply,

especially when the water supply comes from wells. 

You can find more information on how much 2-butanone is in the 

environment and how you can be exposed to it in Chapter 5. 

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

2-butanone can enter your body if you breathe air that contains it, through

your skin if it touches you, or through your mouth if you eat food or drink water

that has 2-butanone in it. Studies have shown that, if there is 2-butanone in the

air you breathe, at least half of what you breathe in will enter your body. The

other half will leave in the air you breathe out. We do not know how much

2-butanone will stay in your body if you drink it or if it touches your skin. The

amount of 2-butanone that actually enters your body depends on how much is in the

air you breathe, how much is in your food or 
3 

1. PUBLIC HEALTH STATEMENT 

water, or how much gets on your skin. The amount of 2-butanone that enters your body

also depends on how long you breathe it or how long it is on your skin before you wash

it off. Your body gets rid of 2-butanone in urine and in the air you breathe out. 2­

Butanone is not a chemical that stays in your body for very long; it will be gone by

the next day. For more information on how 2-butanone gets into and leaves your body,

see Chapter 2. 

1.4 HOW CAN 2-BUTANONE AFFECT MY HEALTH? 

Some people who breathed air that contained 2-butanone first noticed its sweet,

sharp odor at a concentration of 5-8 parts of 2-butanone per million parts of air (5-8

ppm). The main health effects that have been seen in humans who breathed higher

concentrations of 2-butanone are mild irritation of the nose, throat, eyes, and skin. 

Serious health effects in animals have been seen only at very high

concentrations of 2-butanone. These high concentrations are not expected in the usual

use of 2-butanone or in the vicinity of hazardous waste sites. Studies in animals 

have shown that 2-butanone does not cause serious damage to the nervous system or the

liver, but mice that breathed low levels for a short time had temporary behavioral

effects. 2-Butanone alone does not have serious effects on the liver or nervous 

system, but it can cause other chemicals to become more harmful to these systems. 

Guinea pigs, rats, and mice that breathed high levels of 2-butanone for a short

time became unconscious and died. Pregnant rats and mice that breathed air containing

high levels of 2-butanone had underdeveloped fetuses. The rats that swallowed very

high concentrations of 2-butanone in water also developed signs of nervous system

effects such as inactivity, drooping eye lids, and uncoordinated muscle movement. Some

rats and mice that swallowed water containing high concentrations of 2-butanone died.

Rats that received water containing a lower concentration of 2-butanone had mild

kidney damage. Skin irritation developed in rabbits and guinea pigs that had small

amounts of 2-butanone dropped on their skin. Rabbits that had small amounts of 2­

butanone dropped in their eyes had serious eye irritation. We do not know whether 2­

butanone causes birth defects or affects reproduction in humans. Reproductive effects

were not seen in animals exposed to 2-butanone. We have no information about whether

2-butanone causes cancer in humans or animals. 

A more complete discussion of the health effects of 2-butanone in humans and

animals can be found in Chapter 2. 

1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 2-BUTANONE? 

No specific medical test is available to determine whether you have been exposed

to 2-butanone. Studies in humans and animals have shown that it is possible to detect

2-butanone or its breakdown products in the blood, breath, 
4 

1. PUBLIC HEALTH STATEMENT 

and urine. The levels of 2-butanone found in the blood, breath, and urine

are usually associated with the levels of exposure found in the workplace,

but this is more useful for determining exposure of groups of people

rather than individuals. Tests for 2-butanone in blood, urine, or breath

are useful only for recent exposure because 2-butanone and its breakdown

products leave the body rapidly. These considerations are discussed in

more detail in Chapters 2 and 6. 

1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? 

The Occupational Safety and Health Administration (OSHA) has set an

occupational exposure limit of 200 ppm of 2-butanone in the air. The

National Institute for Occupational Safety and Health (NIOSH) has also

recommended 200 ppm of 2-butanone as the limit for up to a 10-hour work

shift in a 40-hour workweek. Because of its odor, you can smell 2-butanone

before it harms you. Further information on governmental recommendations

can be found in Chapter 7. 

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-butanone (methyl

ethyl ketone) 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

butanone based on toxicological studies and epidemiological

investigations.

 2-Butanone alone is a relatively safe chemical widely used as a

insolvent industry. For some uses, 2-butanone is combined with other

chemicals thathave serious neurotoxic and hepatotoxic effects. Clinical

reports and animal studies have clearly shown that exposure to 2-butanone

alone causes minimal chronic neurological or hepatic deficits, if any. It

does potentiate both the neurotoxicity of n-hexane and methyl-n-butyl

ketone and the hepatotoxicity of carbon tetrachloride and chloroform. The

potentiation of neurotoxicity and hepatotoxicity by 2-butanone is

discussed in Section 2.6 (Interactions with other Chemicals). 

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 no-observedadverse-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 take at hazardous waste

sites may want information on levels of exposure associated with more subtle

effects in humans or animals (LOAEL) or exposure 
6 

2. HEALTH EFFECTS 

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 1989a), 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 

2.2.1.1 Death 

No studies were located regarding death of humans following

inhalation exposure to 2-butanone.

 Acute (4-hour) exposure to 2,000 ppm 2-butanone caused the death of up to 4

of 6 rats within a 14-day observation period after exposure (Carpenter et al.

1949). The cause of death was not reported, but gross necropsy and histopathology

confirmed that extraneous infections were not involved. In contrast, exposure of 6

rats to 8,000 ppm 2-butanone for 8 hours resulted in the death of half of the rats

(Smyth et al. 1962). Furthermore, the 4-hour LC50 in rats, calculated from the doseresponse curve, was 11,700 ppm (LaBelle and Brieger 1955). The LC50 was determined 

using similar rats and the same exposure methods used by Carpenter et al. (1949).

Mice exposed to a saturated vapor of 2-butanone (estimated concentration: 103,000

ppm) showed a mean survival time of 43 minutes (LaBelle and Brieger 1955). The LT50 

and LT50 in rats exposed to 92,239 ppm 2-butanone were 3 and 0.5 hours, respectively

(Klimisch 1988). The LT50 represents the time of exposure after which 50% of the

animals died within 14 days following exposure. The LT0 represents the time of

exposure after which no animals died within 14 days following exposure. No deaths

were reported after a 4-hour exposure of mice to 2,438 ppm 2-butanone (De Ceaurriz

et al. 1983). Death of guinea pigs occurred within 45 minutes of exposure to

100,000 ppm 2-butanone and within 200 minutes of exposure to 33,000 ppm (Patty et

al. 1935). Gasping respiration was observed at concentrations of 33,000 ppm and

higher about 10 minutes before the guinea pigs died. 
7 

2. HEALTH EFFECTS 

In intermediate duration studies, no deaths occurred during a 90-day exposure

of rats to 5,000 ppm or less, 5 days/week for 6 hours/day (Cavenderet al. 1983). In

contrast, five of five rats died within 7 weeks of a planned 15-week exposure to

6,000 ppm, 7 days/week, 8 hours/day (Altenkirch et al. 1978a). The cause of death

for all rats exposed to 2-butanone in this study was severe bronchopneumonia

confirmed pathologically and histologically. In the same study, rats exposed to nhexane or a combination of n hexane and 2-butanone did not develop

bronchopneumonia. A repeat of this study gave the same results, i.e., death within

7 weeks coincident with confirmed bronchopneumonia (Altenkirch et al. 1978b). Saida

et al. (1976) reported no deaths or change in clinical signs in rats exposed to

1,125 ppm 2-butanone continuously for 5 months. Similar results were reported by

several groups after intermediate exposures ranging from 200 to 800 ppm in rats and

guinea pigs, i.e., no deaths and no change in clinical signs (LaBelle and Brieger

1955; Takeuchi et al. 1983; Toftgard et al. 1981). The LC50 the highest NOAEL

values, and all reliable LOAEL values for death in each species and duration

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

2.2.1.2 Systemic Effects 

The systemic effects of 2-butanone following inhalation exposure are

discussed below. No studies were located regarding cardiovascular,

gastrointestinal, musculoskeletal, hepatic, or renal effects in humans after

inhalation exposure to 2-butanone. The highest NOAEL values and all reliable LOAEL

values for each systemic effect for each species and duration category are recorded

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

Respiratory Effects. 2-Butanone is irritating to respiratory tissues. A

clinical case report of three men exposed to 2-butanone fumes while removing paint

from an airplane hangar noted mild respiratory symptoms but did not further

describe the nature or extent of the symptoms (Berg 1971). Volunteers exposed to

100 ppm 2-butanone complained of slight nose and throat irritation, which became

objectionable at 300 ppm (Nelson et al. 1943). The respiratory tract irritation

noted in humans at 100 ppm does not imply that humans are more sensitive to the

respiratory effects of 2-butanone than other species tested (see Table 2-l).

Another possible explanation is that humans are better able to communicate the 

early signs of irritation compared with the other species tested. Nasal resistance

was significantly increased in humans upon exposure to the threshold level of 2­

butanone; this response reflects a nasopharyngeal reflex (Doty et al. 1988). The 

odor threshold for 2-butanone falls in the range 5.4-8.25 ppm (Amoore and Hautala

1983; Doty et al. 1988). 

At high concentrations, 2-butanone is also irritating to respiratory tissues

of animals. Severe upper respiratory tract irritation was found after a few days in

rats exposed to 10,000 ppm, 8 hours/day (Altenkirch et al. 1978a). Guinea pigs

exposed to 33,000 ppm had gasping respiration after 180 minutes of exposure and

died after 200-260 minutes of exposure. Their 





13 

2. HEALTH EFFECTS 

lungs were emphysematous. Rats seem to tolerate concentrations that are still high,

but substantially lower than the acute exposures when exposed intermittently in

intermediate duration studies. In a 90-day inhalation study, exposure of rats to 2­

butanone concentrations of 5,000 ppm or less caused no signs of upper respiratory

tract irritation or other respiratory effects (Cavender et al. 1983). Due to the

irritation observed at 10,000 ppm in the study by Altenkirch et al. (1978a), the

exposure concentration was reduced to 6,000 ppm and the study continued. All the

rats died suddenly at 7 weeks with pathologically confirmed bronchopneumonia. This

experiment was repeated and had the same results (Altenkirch et al. 1978b).

Furthermore, rats exposed to n-hexane or a combination of n-hexane and 2-butanone

did not develop bronchopneumonia, suggesting that a factor other than poor animal

maintenance precipitated the bronchopneumonia. The Wistar rats used in this study

may possibly have been derived from a stock that was particularly susceptible to

infection. The initial exposure to a high concentration of 2-butanone may have

weakened their immune system allowing infection to develop. No other studies were

located that reported a link between 2-butanone exposure and bronchopneumonia in

humans or animals. 

Cardiovascular Effects. No studies were located regarding cardiovascular

effects in humans after inhalation exposure to 2-butanone. 

Histological examination of the hearts and aortae of rats exposed to 5,000

ppm or less of 2-butanone for 90 days revealed no exposure-related lesions

(Cavender and Casey 1981; Cavender et al. 1983). 

Gastrointestinal Effects. No studies were located regarding gastrointestinal

effects in humans after inhalation exposure to 2-butanone. 

No histopathological lesions were found in the esophagus, salivary glands,

ileum, duodenum, jejunum, cecum, large or small intestines, or pancreas of rats

exposed to 5,000 ppm or less of 2-butanone for 90 days(Cavender and Casey 1981;

Cavender et al.1983). 

Hematological Effects. Information regarding hematological effects of 2­

butanone exposure in humans is limited to a case report in which a normal

hematological profile and blood chemistry were found in an 18-year-old seaman

exposed to 2-butanone while removing paint from an airplane hangar (Berg 1971). 2­

Butanone exposure in this case was linked to retrobulbar neuritis and severely

impaired vision. However, because methanol was found in the blood of the patient,

consumption or exposure to methanol cannot be ruled out.

 Studies in animals also indicate that 2-butanone does not produce

hematological effects. No effect on hemoglobin concentration, or on red blood cell,

white blood cell, neutrophil, lymphocyte, or monocyte populations were observed in

rats exposed intermittently to 235 ppm 2-butanone for 12 weeks(LaBelle and Brieger

1955). Similarly, the hematological profile and serum 
14 

2. HEALTH EFFECTS 

chemistry of rats exposed to 5,000 ppm or less of 2-butanone for 90 days

were normal (Cavender et al. 1983). 

Musculoskeletal Effects. No studies were located regarding musculoskeletal

effects in humans after inhalation exposure to 2-butanone. 

Histological examination of skeletal muscle and bone of rats exposed to 5,000

ppm or less of 2-butanone for 90 days revealed no exposure-related lesions

(Cavender and Casey 1981; Cavender et al. 1983). 

Hepatic Effects. No studies were located regarding hepatic effects in

humans after inhalation exposure to 2-butanone. 

Most of the hepatic effects of inhalation exposure to 2-butanone observed in

animals are minimal and probably not adverse, although acute exposure of guinea

pigs to a high concentration (10,000 ppm) caused liver congestion (Patty et al.

1935). Exposure to 3,300 ppm had no effects. Serum alkaline phosphatase activity

was not different in rats exposed intermittently to 300 ppm 2-butanone for 7 days

compared to nonexposed control rats (Li et al. 1986). There was no change in the

isozymes of cytochrome P-450 or in the total concentration of cytochrome P-450 in

rats exposed to 800 ppm for 4 weeks(Toftgard et al. 1981). 2-Butanone, however,

altered the metabolism of androstenedione by increasing the formation of two

metabolites and decreasing the formation of two other metabolites. Furthermore,

liver weight was increased in the 2-butanone-exposed rats (Toftgard et al. 1981). A

small but statistically significant increase in absolute and relative liver weights

of male and female rats, but no change in serum levels of hepatic enzymes (serum

glutamic-oxaloacetic transaminase [SGOT], serum glutamic-pyruvic

transaminase[SGPT], serum gamma-glutamyl transpeptidase [SGGT], and alkaline

phosphatase)in male rats, was observed at an exposure level of 5,000 ppm for 90

days (Cavender et al. 1983). A significant increase only in alkaline phosphatase

was noted in the female rats. Histopathological examination did not reveal any

hepatic lesion aside from those expected in Fischer rats of this age. Exposure to

2,500 ppm 2-butanone had no effect on any hepatic parameter (Cavender et al. 1983).

In the absence of histopathological liver lesions, the mild liver effects observed

at 5,000 ppm were probably not adverse. 

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

following inhalation exposure to 2-butanone. 

Acute inhalation exposure of guinea pigs to 10,000 ppm 2-butanone

resulted in congestion of the kidney (Patty et al. 1935). No effects were

observed at 3,300 ppm. In an intermediate duration study, only minimal

kidney effects were observed in rats exposed to 5,000 ppm or less

(Cavender et al. 1983). Blood urea nitrogen determinations and urinalysis

including urine volume, specific gravity, and pH showed that all values

were within normal limits for male and female rats; the exception was that

urine volume in the females was slightly but significantly increased. The

kidney/body weight 
15

 2. HEALTH EFFECTS 

ratio in male rats and the kidney/brain weight ratio in female rats were

slightly but significantly elevated. Histopathological examination did not

reveal any treatment-related renal lesion. In the absence of histopathological

lesions or decrements in kidney function, these mild kidney effects do not

appear to be adverse. No other studies were located regarding the renal effects

of inhalation exposure to 2-butanone. 

Dermal/Ocular Effects. Two men exposed to 2-butanone while removing paint

from an airplane hangar had conjunctival irritation (Berg 1971). A

third man had severe loss of vision. Within 36 hours, the man's vision was

completely restored. However, because methanol was found in the blood of the

man with vision loss, exposure to methanol cannot be ruled out. No other

studies were located regarding dermal/ocular effects in humans following

inhalation exposure to 2-butanone. 

Guinea pigs exposed to 2-butanone. concentrations of 10,000 ppm or

greater had eye irritation and lacrimation (Patty et al. 1935). Exposure to

100,000 ppm for 30 minutes or more caused cornea1 opacity. This condition

gradually improved in guinea pigs that lived to 8 days after exposure. No

effects occurred when guinea pigs were exposed to 3,300 ppm. Ophthalmological

examination of the eyes and histological examination of the skin revealed no

effects in rats exposed to 5,000 ppm or less of 2-butanone for 90 days

(Cavender and Casey 1981; Cavender et al. 1983). No other studieswere

located regarding dermal/ocular effects in animals following inhalation

exposure to 2-butanone. 

Other Systemic Effects. No studies were located regarding other systemic

effects in humans after inhalation exposure to 2 butanone. 

In rats, no histopathological lesions were found in the thyroid,

parathyroid, pituitary gland, adrenal glands, ears, or Zymbal glands

of rats exposed to 5,000 ppm or less of 2-butanone for 90 days

(Cavender and Casey 1981; Cavender et al. 1983). Furthermore, no

specific effects on body weight were found. 

2.2.1.3 Immunological Effects 

No studies were located regarding immunological effects in humans

following inhalation exposure to 2-butanone. 

Although no specific tests for immunological effects were

performed, histological examination of lymph nodes, thymus, spleen,

and bone marrow of rats exposed to 5,000 ppm or less of 2-butanone for

90 days revealed no exposure-related lesions (Cavender and Casey 1981;

Cavender et al. 1983). This NOAEL value is recorded in Table 2-l and

plotted in Figure 2-l.

,’ 
16 

2. HEALTH EFFECTS 

2.2.1.4 Neurological Effects 

In three separate studies, volunteers underwent a single 4-hour

exposure to 200 ppm 2-butanone (Dick et al. 1984, 1988, 1989). No

differences were observed between exposed and control groups on

neurobehavioral tests including psychomotor tests (choice reaction time,

visual vigilance, dual task, and memory scanning), postural sway, and a

profile of mood states. No other studies were located regarding

neurological effects after inhalation exposure to 2-butanone. 

Neurological effects have been observed in animals exposed by inhalation to

2-butanone. Exposure of mice to 2-butanone at concentrations greater than or equal

to 1,602 ppm for 4 hours caused a dose-related reduction in the duration of

immobility in a "behavioral despair" swimming test (De Ceaurriz et al. 1983). The

authors noted that the effect of 2-butanone was similar to that of antidepressants.

In guinea pigs exposed acutely to 10,000 ppm 2-butanone, incoordination occurred

within 90 minutes and unconsciousness occurred within 240-280 minutes (Patty et al.

1935). These signs occurred earlier at higher concentrations, but no neurological

signs were observed at 3,300 ppm. Juvenile baboons exposed continuously to 100 ppm

for 7 days showed early signs of narcosis, incoordination, and a loss of time

perception in neurobehavioral tests (Geller et al. 1979). The neurological effects

observed in this study could have resulted from narcosis. It is also possible that

the baboons were distracted during the testing due to the irritating effects of 2­

butanone on the respiratory system. Furthermore, the effects of 2-butanone observed

at 100 ppm in the baboons do not imply that baboons are more sensitive to 2­

butanone than other species tested. Since the baboons were evaluated with a complex

discriminant behavioral task, it is possible that subtle neurobehavioral effects

could be observed. However, it should be noted that only one exposure level was

tested, only one baboon of four tested showed consistently different results from

the controls throughout the study, and no statistical tests were performed. These

limitations preclude definitive conclusions. 

Intermediate duration exposures to 2-butanone were not neurotoxic in rats.

Male Sprague-Dawley rats exposed continuously to 1,125 ppm 2-butanone for periods

of 5 months or less showed no signs of peripheral neuropathy following histological

examination (Saida et al. 1976). The neurotoxicity of n-butyl ketone, however, was

markedly potentiated by 2-butanone. No differences were observed in nerve fiber

preparations from male and female Fischer 344 rats exposed to 5,000 ppm or less 2­

butanone for 90 days (Cavender and Casey 1981; Cavender et al. 1983). Furthermore,

no histopathological lesions were found in the brain, sciatic nerve, tibia1 nerve,

spinal cord, or optic nerves. No effects were observed in posture, gait, tone, and

symmetry of the facial muscles, or in the pupillary, palpebral, extensor thrust,

and cross-extensor thrust reflexes. The only effect recorded was a slight but

statistically significant increase in brain weight in female rats exposed to 5,000

ppm. No clinical signs and no histological evidence of neuropathy in 
17 

2. HEALTH EFFECTS 

peripheral nerves from the brachial plexus, sciatic nerve, spinal cord, and medulla

were observed in rats exposed to 6,000 ppm for 7 weeks compared with rats exposed

to n-hexane or a combination of n-hexane and 2-butanone(Altenkirch et al. 1978a).

In contrast, 2-butanone potentiated the neurotoxicity of n-hexane. No

neuropathological changes were found on light microscope and electron microscope

examination of teased tail nerves after exposure of a rat to 200 ppm 2-butanone for

24 weeks (Takeuchi et al. 1983). At 4 weeks, significant increases in motor nerve

conduction velocity and mixed nerve conduction velocity were found, while distal

motor latency was decreased. These changes in nerve conduction velocity were not

seen beyond 4 weeks. The transient increase in nerve conduction velocity may have

been due to an effect of 2-butanone on the axonal membrane (Takeuchi et al. 1983).

The highest NOAEL values and all reliable LOAEL values for neurological

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

and plotted in Figure 2-l. 

2.2.1.5 Developmental Effects 

No studies were located regarding developmental effects in humans

after inhalation exposure to 2-butanone. 

Several studies in rats and mice were located regarding developmental effects

after inhalation exposure. Exposure of pregnant rats to 1,000 or 3,000 ppm 2­

butanone during gestation resulted in a slight increase in the incidence of

malformations at 3,000 ppm; acaudia and imperforate anus were found in 2 fetuses

out of 21 litters, and brachygnathia was noted in 2 other fetuses (Schwetz et al.

1974). A low incidence of sternebral anomalies was also noted in the 3,000 ppm

group. Although the incidence of malformations was not high enough to support a

positive correlation, it may have indicated a slight teratogenic effect in rats. A

second study by the same group supported the previous findings of skeletal

anomalies (Deacon et al. 1981). No statistically significant differences in

external or soft tissue abnormalities were found in the offspring of dams exposed

to 3,000 ppm or less during gestation, No effect was observed on the number of live

fetuses/litter or on fetal crown-rump length. Skeletal abnormalities, including

delayed ossification of the cervical centra, sternebral malformations, and

asymmetric pelvis were observed at 3,000 ppm. Decreased body weight gain and

increased water consumption in the pregnant rats at 3,000 ppm 2-butanone indicated

that some maternal toxicity may have occurred at this exposure level. Deacon et al.

(1981) concluded 2-butanone was slightly fetotoxic, but not embryotoxic or

teratogenic at 3,000 ppm. Mean fetal body weight was reduced in the male and female

offspring of mouse dams exposed to 3,000 ppm butanone, but was significantly

reduced only in the males(Mast et al. 1989). A statistically significant increase

in the incidence of misaligned sternebrae was observed in the 3,000 ppm group. No

effects were observed at 1,000 ppm. Thus, 2-butanone was fetotoxic in both rats and

mice. In pregnant rats, continuous exposure to 800 ppm 2-butanone throughout

gestation resulted in the failure of three of eight of the rats to deliver 
18 

2. HEALTH EFFECTS 

litters. While all 8 of the control dams in the experiment for 2-butanone delivered

litters, 6 of 16 control dams in an experiment with n-hexane in the same study also

failed to produce litters. Therefore, the reliability of the results in the 2­

butanone exposed group is questionable (Stoltenburg-Didinger et al. 1990). The

reliable NOAEL and LOAEL values for developmental effects 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-butanone. 

Although no tests for reproductive function were performed, histological

examination of the testes, epididymides, seminal vesicles, vaginas, cervices,

uteri, oviducts, ovaries, or mammary glands of rats exposed to 5,000 ppm or less

of 2-butanone for 90 days revealed no exposure-related lesions (Cavender and Casey

1981; Cavender et al. 1983). 

2.2.1.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or

animals after inhalation exposure to 2-butanone. 

Genotoxicity studies are discussed in Section 2.4. 

2.2.1.8 Cancer 

Two retrospective studies of industrial workers chronically exposed to 2­

butanone in dewaxing plants reported that deaths due to cancer were less than

expected. In a cohort of 446 males employed by Shell Chemical Company, 13 deaths

were due to cancer, whereas 14.26 were expected; the standard mortality ratio

(SMR) was 0.91 (Alderson and Rattan 1980). In the same cohort, 2 cases of buccal

or pharyngeal neoplasms were found; 0.13 were expected to exist, and the' SMR was

15.38. There were 4 cases of stomach, colon, or rectal cancer; 3.18 were expected,

and the SMR was 1.28. The incidence of buccal or pharyngeal neoplasms was

statistically significant but was regarded by the authors as due to chance because

of the small number of individuals affected and the number of separate comparisons

made between observed and expected rates. Furthermore, the use of tobacco was not

discussed in this study. The incidence of stomach, colon, or rectal cancer was not

statistically significant. The authors concluded that there was no clear evidence

of a cancer hazard at this dewaxing plant. A retrospective cohort study of 1,008

male oil refinery workers occupationally exposed to an estimated l-4 ppm of 2­

butanone in a dewaxing-lubricating oil plant was also conducted (Wen et al. 1985).

The overall cancer-related mortality was less than expected. The increased

incidence of buccal and pharyngeal neoplasms reported by Alderson and Rattan

(1980) was not confirmed in this study. 
19

 2. HEALTH EFFECTS 

No studies were located regarding cancer in animals following

inhalation exposure to 2-butanone. 

2.2.2 Oral Exposure 

2.2.2.1 Death 

No studies were located regarding death of humans following oral

exposure to 2-butanone. 

Oral LD50 values for 2-butanone were similar (approximately 2,737

mg/kg) in three groups of Sprague-Dawley rats: immature (14 days old),

young adult(80-160 g), and older adult (300-470 g) (Kimura et al.

1971). The oral LD50 could not be determined in newborn rats because of 

volume limitations; it was estimated to be less than 805 mg/kg, Most

of the Sprague-Dawley rats receiving 3,670, 7,340, or 14,680 mg/kg by

gavage died within 1 hour at each dose, except 1 male and 1 female at

the lowest dose; these rats survived until sacrifice at 14 days

(Stillmeadow Inc. 1978). The data were insufficient for determination

of an LD50, but the authors estimated the acute oral LD50 to be less 

than 3,670 mg/kg, which is in agreement with the data reported in

Kimura et al. (1971). The LD50 in Carworth-Wistar rats was 5,522 mg/kg

(Smyth et al. 1962), which may represent a strain difference. In two

separate experiments, 1,080 mg 2-butanone/kg administered by gavage in

corn oil produced no deaths in male Fischer rats (Brown and Hewitt

1984) or in male Sprague-Dawley rats(Hewitt et al. 1983). Tanii et al.

(1986) determined the oral LD50 for 2-butanone in mice as 4,044 mg/kg

(95% confidence limits - 3,200-5,111 mg/kg). The acute duration LD50 

values and the LOAEL value for death in rats are recorded in Table 2-2 

and plotted in Figure 2-2. 

2.2.2.2 Systemic Effects 

The systemic effects of 2-butanone after oral exposure are

discussed below. No studies were located regarding gastrointestinal,

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

animals after oral exposure to 2-butanone. The highest NOAEL values

and all reliable LOAEL values for each systemic effect after oral

exposure in each species and duration category are recorded in Table

2-2 and plotted in Figure 2-2.

 Respiratory Effects. One clinical report of oral exposure to 2-butanone in

humans was located. A 47-year-old woman accidentally ingested an unknown volume of

2-butanone that had been stored in a rum bottle (Kopelman and Kalfayan 1983). She

was admitted to an emergency ward unconscious and hyperventilating. Blood gases

were 85 mmHg oxygen and 24 mmHg carbon dioxide. Analysis of her blood showed a 2­

butanone plasma concentration of 95 mg/lOO mL. Slow infusion of sodium bicarbonate

reduced the hyperventilation, and blood gases improved to 78 mmHg oxygen and 25

mmHg carbon dioxide. Within 12 hours, she had regained consciousness, made an 



23 

2. HEALTH EFFECTS 

uneventful recovery over the next few days, and was discharged after 1

week(Kopelman and Kalfayan 1983). 

All albino rats receiving 3,670 mg/kg or more had labored breathing, and

most of them died within 1 hour (Stillmeadow Inc. 1978). It is'not clear

whether the labored breathing represented a respiratory or a neurological

response to a high dose. No other studies were located regarding respiratory

effects after oral exposure to 2-butanone. 

Cardiovascular effects. Cardiovascular effects observed in a 47-yearold woman after accidental ingestion of 2-butanone were decreased blood

pressure and increased pulse rate (Kopelman and Kalfayan 1983). No other

reports were located regarding cardiovascular effects in humans following oral

exposure to 2-butanone. 

No studies were located regarding cardiovascular effects in animals

following oral exposure to 2-butanone.
 

Hepatic Effects. No studies were located regarding hepatic effects

in humans following oral exposure to 2-butanone. 

2-Butanone had no effect on liver weight, SGPT, or serum ornithine

carbamyl transferase activities measured 42 hours after oral exposure of rats

to 1,080 mg/kg (Hewitt et al. 1983). Similarly, Brown and Hewitt (1984)observed

normal SGPT activity in rats exposed orally to 1,080 mg 2-butanone/kg. Although

histological examination was not performed, 2-butanone appears to have a low

order of hepatic toxicity in inhalation studies. Several studies have shown

that 2-butanone has the ability to induce microsomal liver enzymes. Acute oral

treatment of rats with 2-butanone at doses of 1,080 to 1,500 mg/kg/day for l-7

days resulted in increased levels of cytochrome P-450, increased activities of

cytochrome P-450-dependent monooxygenases (Brady et al. 1989; Raunio et al.

1990; Robertson et al. 1989; Traiger et al. 1989) and proliferation of the

smooth endoplasmic reticulum(Traiger et al. 1989). In the absence of clinical

or histological evidence of liver damage, induction of microsomal enzymes

probably represents a normal physiological response to xenobiotics rather than

an adverse effect. Furthermore, oral treatment of rats with 1,080 mg/kg

2-butanone had no effect on the fragility of hepatic lysosomes or on the

calcium uptake by mitochondria or microsomes (Hewitt et al. 1990). Therefore,

the doses of 1,080-1,500 mg/kg can be considered acute oral NOAEL values for

hepatic effects.

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

following oral exposure to 2-butanone.

 Oral exposure of rats to 1,080 mg 2-butanone/kg caused mild renal tubular

necrosis but had no effect on renal organic ion transport(PAH, TEA) or

plasmacreatinine (Brown and Hewitt 1984). No other studies were located

regardingrenal effects in animals after oral exposure to 2-butanone. 
24 

2. HEALTH EFFECTS 

2.2.2.3 Immunological Effects

 No studies were located regarding immunological effects in humans or

animals after oral exposure to 2-butanone. 

2.2.2.4 Neurological Effects

 No studies were located regarding neurological effects in humans after

oral exposure to 2-butanone.

 In animals, clinical signs of central nervous system toxicity including

lethargy, labored breathing, ptosis, lacrimation, exophthalmos, ataxia,

salivation, and piloerection were observed in rats treated by gavage with

2-butanone at doses greater than or equal to 3,670 mg/kg (Stillmeadow Inc.1978).

Most of these rats died. No effect was observed on neurobehavioral tests 

including hindlimb grasp, hindlimb place, balance beam, and roto-rod in rats

treated by gavage with 2-butanone at a time-weighted average dose of 173

mg/kg/day for 90 days (Ralston et al. 1985). No other studies were located

regarding neurological effects in animals after oral exposure to 2-butanone. The

NOAEL value and LOAEL value for neurological effects are recorded in Table 2-2

and plotted in Figure 2-2. 

No studies were located regarding the following health effects in humans

or animals after oral exposure to 2-butanone: 

2.2.2.5 Developmental Effects

2.2.2.6 Reproductive Effects

2.2.2.7 Genotoxic Effects 

Genotoxicity studies are discussed in Section 2.4. 

2.2.2.8 Cancer 

No studies were located regarding cancer in humans or animals after oral

exposure to 2-butanone. 

2.2.3 Dermal Exposure 

2.2.3.1 Death 

No studies were located regarding death in humans after dermal exposure

to 2-butanone. One study reported the dermal LD50 for 2-butanone in rabbits to be 

greater than 10 mL/kg (Smyth et al. 1962). No other studies were located

regarding death in animals after dermal exposure to 2-butanone. 
25 

2. HEALTH EFFECTS 

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-butanone. 

The only systemic effects of dermal exposure studied were dermal and

ocular. The highest NOAEL value and all reliable LOAEL values for dermal

and ocular effects in each species and duration category are recorded in

Table 2-3. 

Dermal/Ocular Effects. Application of 0.1 mL undiluted 2-butanone

once daily for 18 days to the volar forearm of volunteers did not result

in erythema, increase in skin-fold thickness, or edema over the 18-day

exposure period Wahlberg (1984). Further details regarding the number of

volunteers were not reported. 

In rabbits and guinea pigs, application of undiluted 2-butanone

caused minimal skin irritation, erythema, and/or increase in skin-fold

thickness (Anderson et al. 1986; Hazleton Laboratories 1963a; Wahlberg

1984). Slight desquamation occurred in guinea pigs after 31 weeks of

dermal exposure to increasing amounts of 2-butanone (Eastman Kodak 1978).

Abraded skin areas were slightly more sensitive to the application of 2­

butanone (Hazleton Laboratories 1963a). 

2-Butanone instilled into the conjunctival sac of rabbits caused

irritation, cornea1 opacity, and conjunctivitis (Davis and Baker 1975;

Haskell Laboratories 1971; Hazleton Laboratories 1963b; Kennah et al.

1989). These effects were generally reversible in 7-14 days. Hazleton

Laboratories (1963b) reported that one of six rabbits had persistent

cornea1 damage after 7 and 14 days. On the basis of Draize scores in these

studies, 2-butanone was classified as moderately irritating. 

2.2.3.3 Immunological Effects 

One clinical report of 2-butanone-evoked contact urticaria was

located. A 48-year-old man employed as a painter complained of severe

irritation when he handled 2-butanone (Varigos and Nurse 1986). A small

amount of 2-butanone applied to his forearm produced a bright red area at

the site of application. The area became itchy, but no induration or

edema was noted. After 15 minutes, the reaction subsided. Two days later,

the test was repeated with the same result. Five volunteers were later

tested for sensitivity to 2-butanone by the same method, but no response

was observed. 

No studies were located regarding immunological effects in animals

after dermal exposure to 2-butanone. 

27 

2. HEALTH EFFECTS 

2.2.3.4 Neurological Effects 

No studies were located regarding neurological effects in humans

after dermal exposure to 2-butanone. 

In an intermediate study of dermal exposure, l-2 mL of undiluted 2­

butanone was applied in increasing amounts to shaved areas on the backs of

guinea pigs 5 days/week for 31 weeks or less (Eastman Kodak 1978). No

clinical signs of neurotoxicity were observed. No evidence of

neurotoxicity was noted on examination of Epon sections of the medulla

oblongata and tibia1 nerve by light microscopy (Eastman Kodak 1978). The

details of 2-butanone application, however, were not clear in this report. 

No studies were located regarding the following health effects in

humans or animals after dermal exposure to 2-butanone: 

2.2.3.5 Developmental Effects 

2.2.3.6 Reproductive Effects 

2.2.3.7 Genotoxic Effects 

Genotoxicity studies are discussed in Section 2-4. 

2.2.3.8 Cancer 

No studies were located regarding cancer in humans or animals after

dermal exposure to 2-butanone. 

2.3 TOXICOKINETICS 

2.3.1 Absorption 

2.3.1.1 Inhalation Exposure 

2-Butanone is well absorbed during inhalation exposure. Pulmonary

uptake in humans ranged from 41% to 56% of the inspired quantity (Liira et

al. 1988a, 1988b, 1990). Exercise increased the pulmonary uptake due to

the greater ventilatory rate (Liira et al. 1988b). The high blood/air

solubility ratio of 2-butanone also favors absorption (Saida et al. 1976;

Perbellini et al. 1984). Several investigators have reported that

exposure concentrations of Z-butanoneare significantly correlated with

blood concentrations in humans (Brown et al. 1986; Brugnone et al. 1983;

Ghittori et al. 1987; Liira et al. 1988a, 1988b;Lowry 1987; Miyasaka et

al. 1982; Perbellini et al. 1984; Tolos et al. 1987). Exposure of humans

to 200 ppm 2-butanone for 4 hours resulted in blood concentrations of 3.5­

7.2 μg/mL (Liira et al. 1988a, 1988b; Lowry 1987). Occupational

concentrations are significantly correlated with blood and urine

concentrations of unmetabolized 2-butanone (Brugnone et al. 1983; Ghittori

et al. 1987; Miyasaka et al. 1982). Blood levels of 2-butanone are also 
28 

2. HEALTH EFFECTS 

significantly correlated with breath levels (Brown et al. 1986). These

data indicate that 2-butanone is absorbed upon inhalation.

 Information on the absorption of 2-butanone by animals after

inhalation exposure is limited. Rats that were exposed to 600 ppm 2­

butanone for 6 hours on 1 day or for 6-10 hours/day for 8 days had blood

concentrations of 1,041 μmol/L after a single exposure and 1,138 μmol/L

after repeated exposure(Liira et al. 1991). The similarity in blood

concentrations after single and repeated intermittent exposure indicates

that 2-butanone does not accumulate. 

2.3.1.2 Oral Exposure 

A woman who had metabolic acidosis after having accidentally

ingested 2-butanone stored in a rum bottle had a blood concentration of 95

mg/lOO mL(13.2 mM) (Kopelman and Kalfayan 1983). A man who intentionally

ingested 100 mL of liquid cement containing a mixture of acetone (18%), 2

butanone (28% or about 37 mg/kg), and cyclohexanone (39%) had a plasma

level of 2-butanone of about 110 μg/mL at 5 hours after ingestion (Sakata

et al. 1989). These reports provide qualitative evidence that 2-butanone

is absorbed following oral exposure in humans, but do not provide

information regarding the extent of absorption. In the first case, the

quantity ingested was unknown, while in the second case, the man was

treated by gastric lavage at 2 hours after ingestion.

 Oral administration (gavage) of 1,690 mg 2-butanone/kg in rats

resulted in a plasma concentration of 94 mg/lOO mL at 4 hours (Dietz and

Traiger 1979). Within 18 hours, the plasma concentration decreased to 6.2

mg/lOO mL (Dietzand Traiger 1979). A second, similar experiment in rats

showed that, after oral administration of 1,690 mg 2-butanone/kg, the

plasma concentration was 95 mg/lOO mL; the concentration decreased to 7

mg/lOO mL by 18 hours (Dietz et al. 1981). These data indicate that 2­

butanone is rapidly absorbed and eliminated after oral administration. 

2.3.1.3 Dermal Exposure 

No studies were located regarding the rate or extent of absorption

of 2-butanone in humans or animals following dermal exposure. 

2.3.2 Distribution 

2.3.2.1 Inhalation Exposure 

No studies were located regarding the distribution of 2-butanone

following inhalation exposure in humans.

 In vitro determinations of the 2-butanone tissue/air solubility ratio

for human kidney, liver, muscle, lung; heart, fat, and brain show that the

solubility is similar in all tissues, and that the ratio is nearly equal

to 
29 

2. HEALTH EFFECTS 

200 (Perbellini et al. 1984). Blood/tissue solubility ratios are all near

unity; therefore, 2-butanone is not expected to concentrate in any one

tissue(Perbellini et al. 1984).

 Information regarding distribution of 2-butanone in animals after

inhalation exposure is limited. Rats that were exposed to 600 ppm

2-butanone for 6 hours on 1 day or for 6-10 hours/day for 8 days had blood

concentrations of 1,041 μmol/L after a single exposure and 1,138 μmol/L

after repeated exposure (Liira et al. 1991). The concentration of 2­

butanone in perirenal fat was 0.71 μmol/g after a single exposure and 0.70 

μmol/g after repeated exposure. The similarity in blood and perirenal

concentrations after single and repeated intermittent exposure indicates

that 2-butanone does not accumulate. 

2.3.2.2 Oral Exposure 

No studies were located regarding the distribution of 2-butanone

following oral exposure in humans or animals. 

2.3.2.3 Dermal Exposure 

No studies were located regarding the distribution of 2-butanone

following dermal exposure in humans or animals. 

2.3.3 Metabolism 

Few studies exist regarding the metabolism of 2-butanone in humans. Two

metabolites of 2-butanone have been identified in human urine after 

inhalation exposure. They are 3-hydroxy-2-butanone (Brugnone et al. 1983;

Perbellini et al. 1984) and 2,3-butanediol (Liira et al. 1988a, 1988b,

1990). The urinary concentrations of these metabolites, however, represent

only about 0.1%-2% of the absorbed 2-butanone. P-Butanol was found in the

blood of male volunteers exposed to 200 ppm 2-butanone for 4 hours (Liira

et al. 1990). In addition to 3-hydroxy-2-butanone and 2,3-butanediol, a

third metabolite, 2-butanol, has been found in the blood in guinea pigs

(DiVincenzo et al. 1976)and rats (Dietz et al. 1981). About 30% of the 2­

butanone administered orally in rats was converted to 2,3-butanediol; 4%

was converted to 2-butanol, and 4% was converted to 3-hydroxy-2-butanone

(Dietz et al. 1981). 

In guinea pigs, 2-butanone was metabolized by both oxidative and

reductive pathways (Figure 2-3). Oxidation produces 3-hydroxy-2-butanone,

which is then reduced to 2,3-butanediol (DiVincenzo et al. 1976).

Reduction of 2-butanone produces 2-butanol. The metabolites of 2-butanone

in guinea pigs were excreted in the urine as 0-glucuronides or O-sulfates. 

31 

2. HEALTH EFFECTS 

2.3.4 Excretion 

2.3.4.1 Inhalation Exposure 

Urinary excretion of unchanged 2-butanone and its metabolites, 3­

hydroxy-2-butanone and 2,3-butanediol, accounts for only 5% or less of the

2-butanone absorbed by inhalation in humans (Liira et al. 1988a,

1990;Perbellini et al. 1984). Unchanged 2-butanone is excreted primarily

through the lungs; the quantity eliminated by this route is an estimated

20X-40% (Browning 1965; Riihimaki 1986); however, only about 3% of

absorbed 2-butanone was excreted unchanged in the expired air of humans

exposed to 200 ppm for 4 hours (Liira et al. 1988a, 1990). 2-Butanone is

rapidly cleared from the blood with a reported plasma half-life in humans

of 49-96 minutes (Brown et al. 1986; Liira et al. 1988a; Lowry 1987) and

an apparent clearance rate of 0.60 L/minute (Liira et al. 1990).

Therefore, 2-butanone would not be expected to accumulate with chronic

exposure (Lowry 1987).

 No studies were located regarding excretion of 2-butanone in

animals after inhalation exposure. 

2.3.4.2 Oral Exposure 

Information regarding the excretion of 2-butanone after oral

exposure in humans is limited. A man who intentionally ingested 100 mL of

liquid cement containing a mixture of acetone (18X), 2-butanone (28% or

about 37 mg/kg), and cyclohexanone (39%) had a plasma level of 2-butanone

of about 110 μg/mL at 5 hours after exposure (Sakata et al. 1989). The

plasma level declined to about 95 μg/mL at 12 hours and to <20 μg/mL at 18

hours, where it remained until about 25 hours and slowly declined to <5 

μg/mL at 48 hours. Urine levels of 2-butanone decreased gradually from 123 

μg/mL at 5 hours to 61 μg/mL at 19 hours. Disappearance from the urine

then became more rapid with about 10 μg/mL excreted at 48 hours. While

this study provided information on the elimination of 2-butanone from

plasma and urine of a human orally exposed, coexposure to the other

components of the cement could have influenced the elimination. 

No studies were located regarding the rate or extent of excretion of

2-butanone in animals following oral exposure. 

2.3.4.3 Dermal Exposure 

No studies were located regarding the rate or extent of excretion of

2-butanone in humans or animals following dermal exposure. 

2.4 RELEVANCE TO PUBLIC HEALTH

 The only known effects of 2-butanone in humans are related to its

irritating properties on the respiratory and dermal/ocular systems.

Effects 
32 

2. HEALTH EFFECTS 

observed in animals include death, irritation of respiratory tissue, eyes,

and skin, liver congestion, kidney congestion, cornea1 opacity, narcosis

and incoordination, and fetotoxicity. 

No acute-, intermediate-, or chronic-duration inhalation MRLs were

derived for 2-butanone. In the case of acute-duration inhalation exposure,

target organs have not been sufficiently identified. Intermediate-duration

inhalation studies likewise failed to identify target organs, and nose and

throat irritation occurred in humans exposed for 5 minutes to exposure

levels that were much lower than NOAEL values in animals in intermediateduration studies. No studies were located regarding toxic effects in

humans or animals after chronic inhalation exposure, precluding the

derivation of a chronic inhalation MRL. No acute, intermediate-, or

chronic-duration oral KRLs were derived for 2-butanone. In the case of 

acute-duration oral exposure, target organs have not been sufficiently

identified. The paucity of information on toxic effects after

intermediate- and chronic-duration oral exposure likewise

precludes the derivation of MRLs for these durations. Acute-duration,

intermediate-duration, and chronic-duration dermal MRLs were not derived

for 2-butanone due to the lack of appropriate methodology for the

development of dermal MRLs. 

Death. No studies were located regarding death of humans after

inhalation, oral, or dermal exposure to 2-butanone. Death of rats and mice

occurred within a few hours during acute inhalation exposure to very high

concentrations (greater than or equal to 90,000 ppm) (Klimisch 1988;

LaBelle and Brieger 1955). The inhalation 4-hour LC50 in rats was 11,700

ppm (LaBelle and Brieger 1955). In the intermediate-duration studies, no

rats died after exposure to 5,000 ppm or less for 6 hours/day, 5 days/week

for 90 days(Cavender et al. 1983), but all rats exposed to 6,000 ppm, 8

hours/day, 7 days/week died from bronchopneumonia (Altenkirch et al.

1978a, 1978b). The bronchopneumonia may have been caused by the 2-butanone

exposure because the results were reproducible and did not occur in rats

exposed to n-hexane or the combination of 2-butanone and n-hexane

(Altenkirch et al. 1978a, 1978b). The concentration of 2-butanone that

would cause death in humans after inhalation is not known. It does not 

seem likely that humans would be exposed to the high concentrations that

are fatal to animals except in an occupational accident. 2-Butanone has a

half-life in air of only 14 hours; therefore, in the vicinity of toxic

waste sites, ambient concentrations would be expected to be low. 

Information regarding death from oral and dermal exposure is limited

to LD50 determinations. Oral LD50 values have been reported to be

approximately 2,740 mg/kg in immature, young adult, and older SpragueDawley rats (Kimura et al. 1971), 5,542 mg/kg in Wistar rats (Smyth et al.

1962), and 4,044 mg/kg in mice (Tanii et al. 1986). The dermal LD50 in 

rabbits is greater than 10 mL/kg (Smyth et al. 1962). Oral exposure of

humans to 2-butanone might occur through drinking water if this chemical

seeped from a waste site, for example, into the groundwater. 2-Butanone is

highiy water soluble and is 
33 

2. HEALTH EFFECTS 

expected to have a high soil mobility. Exposure through drinking water

is,therefore, possible, but fatal concentrations are unlikely

Dermalexposure of humans is unlikely to result in death. 

Systemic Effects. There are few known systemic effects of 2-butanone

exposure in humans. Three men exposed to 2-butanone vapors while removing

paint from an airplane hangar developed mild respiratory symptoms;

however, the nature and extent of these symptoms were not described (Berg

1971). One of the men suffered a loss of vision secondary to retrobulbar

neuritis, but this was reversed within 36 hours. Furthermore, exposure to

methanol could not be ruled out. Nelson et al. (1943) reported that 100

ppm 2-butanone caused slight nose and throat irritation, and that some

subjects complained of mild eye irritation at 200 ppm. Subjects could not

tolerate 350 ppm 2-butanone. For this study, it was estimated that 200 ppm

would be the maximum concentration of 2-butanone tolerable for an 8-hour 

exposure period. No adverse effects were reported in several studies

exposing volunteers to 200 ppm 2-butanone for 4 hours (Dick et al. 1984,

1988, 1989; Liira et al. 1988a, 1988b). In contrast, sporting goods

manufacturing plant workers exposed to 250 ppm or less complained of skin,

eye, nose, and throat irritation, and central nervous system symptoms

(headache, dizziness, fatigue)(Lee and Murphy 1982). One worker in this

group complained of "acting differently," but the change in behavior was

not described. These exposures were in enclosed areas with poor

ventilation. Exposure at the sporting goods factory was not to 2-butanone

exclusively; other solvent vapors were also present. Therefore, the

central nervous system symptoms described may not have been due solely to

2-butanone. 

Respiratory Effects. The respiratory effects observed in humans are

discussed above. Upper respiratory tract irritation was reported in rats

exposed for a few hours to 10,000 ppm 2-butanone (Altenkirch et al.

1978a). After the concentration was lowered to 6,000 ppm, all the rats

died suddenly at 7 weeks. Bronchopneumonia was confirmed pathologically as

the cause of death. In contrast, no respiratory tract irritation or

infection was observed in rats,exposed to 5,000 ppm 2-butanone for 90 days

(Cavender et al. 1983). Patty et al. (1935) reported that acute

inhalation exposure of guinea pigs to 10,000 ppm or more of 2-butanone

produced gasping respiration, emphysematous lungs, ocular irritation, and

lacrimation. Exposure to 100,000 ppm for 30 minutes or more caused cornea1

opacity, a condition which gradually improved in guinea pigs that lived 8

days after exposure. Since 2-butanone exposure is not tolerable to humans

at concentrations of 350 ppm (Nelson et al. 1943), it is highly unlikely

that inhalation exposure could result in respiratory, dermal, or ocular

effects more serious than minor irritation. Dermal exposure of humans,

rabbits, and guinea pigs has produced irritation to the skin (Anderson et

al. 1986; Hazleton Laboratories 1963a; Wahlberg 1984). Intraocular 

exposure of rabbits has resulted in cornea1 damage (Hazleton Laboratories

1963b; Kennah et al. 1989). Dermal and eye contact with liquid 2-butanone

is possible in occupational settings and at hazardous waste sites. 
34 

2. HEALTH EFFECTS 

Hepatic Effects. No studies were located regarding hepatic effects

in humans after inhalation, oral, or dermal exposure to 2-butanone. Animal

data indicate that hepatic effects after high-level exposure to 2-butanone

would be minimal in humans. Liver congestion was found in guinea pigs

exposed acutely by inhalation to 10,000 ppm or more (Patty et al. 1935).

Serum concentrations of hepatic enzymes were not changed in rats after 2­

butanone exposures of 300-5,000 ppm for l-12 weeks (Cavender et al. 1983;

Li et al. 1986; Schwetz et al. 1974). No lesions that could be linked to

2-butanone exposure were found following histological examination,

although a slight increase in absolute and relative liver weight was noted

(Cavender et al. 1983). After exposure of rats to 800 ppm 2-butanone for 5

weeks, no changes were observed in the content of hepatic cytochrome P-450

or in the cytochrome P-450 isozyme profile (Toftgard et al. 1981).

2-Butanone, however, altered the metabolism of androstenedione by

increasing the formation of two metabolites and decreasing the formation

of two other metabolites. Furthermore, liver weight was increased in the

2-butanone-exposed rats (Toftgard et al. 1981). While no induction of

microsomal enzymes was found in rats exposed to 2-butanone by inhalation,

several studies have shown that E-butanone has the ability to induce

microsomal liver enzymes in rats after acute oral exposure (Brady et al.

1989; Raunio et al. 1990; Robertson et al. 1989; Traiger et al. 1989).

These studies also suggested that 2-butanone potentiates the toxicity of

other chemicals, such as, carbon tetrachloride, n-hexane, m-xylene, and

chloroform, by increasing their metabolism to toxic metabolites. While

enzyme induction by itself represents a normal physiological response to a

xenobiotic rather than an adverse effect, the enzyme induction by 2­

butanone can be viewed as an adverse effect if coexposure to other

chemicals for which 2-butanone potentiates toxicity by this mechanism

occurs. Therefore, humans working or living near hazardous waste sites

where these chemicals are present along with 2-butanone may be at greater

risk of adverse hepatic effects. 

Renal Effects. Renal effects of 2-butanone exposure in humans would

probably be minimal based on animal data. Kidney congestion was found in

guinea pigs exposed acutely by inhalation to 10,000 ppm or more (Patty et

al. 1935). Cavender et al. (1983) assessed kidney function with

measurements of blood urea nitrogen, urine volume, urine specific gravity,

and pH after a go-day exposure to 5,000 ppm 2-butanone. All values were

within normal ranges, and no histopathological lesions attributable to 2­

butanone exposure were found. Oral exposure of rats to 1,080 mg 2­

butanone/kg caused mild renal tubule necrosis but had no effect on renal

organic ion transport or plasma creatinine; therefore, in spite of mild

necrosis, normal kidney functions were not impaired. Exposure of humans to

2-butanone at hazardous waste sites is, therefore, not likely to result in

severe kidney effects. 

Neurological Effects. The main neurological complaints of humans

exposed occupationally to 2-butanone are headaches, dizziness, nausea, and

fatigue (Lee and Frederick 1981; Lee and Parkinson 1982). However, these

symptoms were not reported in several inhalation studies in which humans

were exposed to 200 ppm of 2-butanone for 4 hours (Dick et al. 1984, 1988,

1989; Liira 
35 

2. HEALTH EFFECTS 

et al. 1988a, 1988b). In the occupational exposures cited, 2-butanone was

combined with several other solvents; therefore, a neurological effect

exclusive to 2-butanone cannot be inferred. Dick et al. (1984, 1988, 1989)

found that exposure to 2-butanone had no effect on any neurobehavioral

measurement. Nevertheless, early signs of narcosis and incoordination

based on a battery of neurobehavioral tests were described in juvenile

baboons after continuous exposure to 100 ppm 2-butanone for 7 days (Geller

et al. 1979). It is also possible that the baboons were distracted during

testing by the irritant effects of 2-butanone on the respiratory tract and

were not, as the investigators concluded, in a state of narcosis. 

Narcosis and incoordination were also observed in guinea pigs

exposed to 10,000 ppm or more 2-butanone in air for a few hours (Patty et

al. 1935). 2-Butanone was not neurotoxic at lower concentrations in longer

duration studies in animals. Rats continuously exposed to 1,125 ppm for 5

months showed no signs of peripheral neuropathy on histological

examination (Saida et al. 1976). Altenkirch et al. (1978a) observed no

clinical signs of neuropathy in rats exposed for 7 weeks to 6,000 ppm. No

neurological effects were observed in rats exposed by inhalation to\ 5,000

ppm for 90.days (Cavender et al. 1983). Alterations in nerve conduction

velocity were seen in rats exposed by inhalation for 4 weeks to 200 ppm 2­

butanone (Takeuchi et al. 1983). The toxicological significance of this

observation is questionable because normal nerve conduction velocities

were observed at all time points beyond 4 weeks. No neurological effects

were observed in rats after oral exposure to 1,725 mg/kg for 90 days

(Ralston et al. 1985). Therefore, exposure of humans to 2-butanone alone

in the workplace or at hazardous waste sites is not likely to result in

serious neurological effects. 

Although exposure to 2-butanone appears relatively innocuous, this

ketone is very hazardous in combination with other solvents. 2-Butanone

markedly potentiates the neurotoxicity of ethanol, n-hexane, methyl-nbutyl ketone, and ethyl-n-butyl ketone (Altenkirch et al. 1977; Cunningham

et al. 1989; King et al. 1985; Ralston et al. 1985; Robertson et al. 1989;

Vallat et al. 1981). Glue formulations containing both 2-butanone and nhexane caused "glue sniffers' neuropathy" (Altenkirch et al. 1977; King et

al. 1985; Vallat et al. 1981). This neuropathy is characterized by motor

nerve dysfunction, paresis, paralysis, muscular atrophy, and neural tissue

morphology changes including paranodal axon swelling, neurofilamentous

hyperplasia, and demyelination (see Section 2.6). Therefore, humans

working or living near hazardous waste sites where methyl-n-butyl ketone,

ethyl-n-butyl ketone, or n-hexane is present or who frequently use alcohol

may be at greater risk for neurological effects if 2-butanone is also

present. 

Developmental Effects. No studies were located regarding

developmental effects in humans following inhalation, oral, or dermal

exposure to 2-butanone. Inhalation exposure of rats and mice to 3,000 ppm

during gestation resulted in fetotoxic effects, such as reduced fetal

weight, skeletal variations, and delayed ossification (Deacon et al. 1981;

Mast et al. 
36 

2. HEALTH EFFECTS 

1989; Schwetz et al. 1974). It is not known whether exposure of humans to

2-butanone by any route would result in fetotoxic effects, but the

presence of these effects in two animal species strongly suggests that

such effects might occur in humans. 

Reproductive Effects. No studies were located regarding reproductive

effects in humans following inhalation, oral, or dermal exposure to

2-butanone. The only study regarding reproductive effects in animals was a

go-day inhalation study in rats exposed to 5,000 ppm or less of 2-butanone

(Cavender and Casey 1981; Cavender et al. 1983). Histological examination

of male and female reproductive organs revealed no effects, but

reproductive function was not tested. 

Genotoxic Effects. In vivo and in vitro studies regarding the

genotoxicity of 2-butanone are summarized in Table 2-4. No induction of

micronuclei was found in the erythrocytes of mice (O'Donoghue et al. 1988)

or hamsters (Basler 1986) after intraperitoneal injection with 2-butanone.

&I vitro studies sponsored by the Chemical Manufacturers' Association

showed that 2-butanone was not mutagenic in the Salmonella/mammalianmicrosome preincubation mutagenicity assay (Ames test) or the L5178Y TK

+/- mouse lymphoma mutagenesis assay with or without activation

(O'Donoghue et al. 1988). 2-Butanone did not induce unscheduled DNA

synthesis in rat primary hepatocytes, and it did not transform BALB/3T3

cells. 2-Butanone did not increase the reverse mutation frequency in

Escherichia coli or Salmonella tvohimurium, with or without activation,

and did not increase the frequency of chromatid gaps, chromatid breaks, or

total chromatid aberrations in rat liver cells (Thorpe 1982). 2-Butanone

did not cause gene mutations in Saccharomvces cerevisiae (Thorpe 1982),

but cause mitotic chromosome loss (Whittaker et al. 1990; Zimmermann et

al. 1989) and aneuploidy in S. cerevisiae (Mayer and Goin 1987) at high

concentrations. The positive induction of chromosome loss in the yeast

cells was enhanced by coexposure to 2-butanone, ethyl acetate, and

propionitrile (Zimmermann et al. 1989). The positive induction of

aneuploidy was enhanced by coexposure to 2-butanone and nocodazole (Mayer

and Goin 1987). It appears, therefore, that 2-butanone alone is not

genotoxic to humans. 

Cancer. Two retrospective epidemiological studies of industrial

workers chronically exposed to 2-butanone in dewaxing plants reported that

deaths due to cancer were less than expected (Alderson and Rattan 1980;

Wen et al. 1985).

 No other studies were located regarding cancer in humans or animals

following inhalation exposure to 2-butanone. 

38 

2. HEALTH EFFECTS 

2.5 BIOMARRERS 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(s) 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-butanone 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 on

magnitude, can be recognized as an established or potential health

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

biochemical or cellular signals of tissue dysfunction (e.g., increased

liver enzyme activity or pathologic changes in female genital epithelial

cells), as well as 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-butanone 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." 
39 

2. HEALTH EFFECTS 

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

Inhalation exposure to 2-butanone correlates well with blood,

breath, and urinary concentrations of unchanged 2-butanone (Brown et al.

1986; Brugnone et al. 1983; Ghittori et al. 1987; Miyasaka et al. 1982).

Personal dosimetry was used to measure exposure to 2-butanone among 62

printing plant workers(Miyasaka et al. 1982) and 659 workers in plastic

boat, chemical, plastic button, paint, and shoe factories (Ghittori et al.

1987). The correlation between exposure levels and urinary concentration

of unchanged 2-butanone was strong in each study (r=O.774 and r=0.91,

respectively). Miyasaka et al. 1982) concluded, however, that estimating

exposure from urinary levels was reliable on a group basis but not an

individual basis. Blood and breath levels of 2-butanone were significantly

correlated (r=0.78, p<O.OOl) in volunteers exposed to 200 ppm 2-butanone

for 4 hours (Brown et al. 1986). A significant correlation between

workroom and urinary 2-butanone concentrations was observed in shoe

factory workers (r=0.6877, p<O.OOl) (Brugnone et al. 1983). In the same

study, a more significant correlation was observed between workroom

concentrations and a 2-butanone urinary metabolite, 3-hydroxy-2-butanone

(r=0.8179, p<O.OOl). Another 2-butanone metabolite, 2,3-butanediol, has

also been identified in the urine of humans (Liira et al. 1988a, 1988b).

No studies were located regarding the correlation between exposure to 2­

butanone and urinary levels of the metabolite, 2,3-butanediol. A third

metabolite, 2-butanol, was identified in guinea pig-blood; however, no

attempt was made to correlate 2-butanol blood levels with exposure to

2-butanone (DiVincenzo et al. 1976). Metabolism of alcohols, hydrocarbons,

and other ketones may also yield 2-butanone, 3-hydroxy-2-butanone, and

2,3-butanediol (Dietz and Traiger 1979; Tsukamoto et al. 1985a); therefore,

these compounds may confound assessment of exposure to 2-butanone. 

Measurements of tissue, blood, and excreta levels may not be an

accurate indication of past exposure to 2-butanone. Accumulation in target

tissues does not occur because tissue/blood solubility ratios are all near

unity; therefore, 2-butanone will not concentrate in specific tissues

(Perbellini et al. 1984). The serum half-life of 2-butanone in humans is

very short;estimates range from 49 to 96 minutes (Liira et al. 1988a;

Lowry 1987). Furthermore, 2-butanone was not detectable in blood or

breath measurements reported the morning after a 4-hour exposure to 200

ppm (Brown et al. 1987). 

No quantifiable effects that could be used as biomarkers of exposure

to 2-butanone were identified. 

2.5.2 Biomarkers Used to Characterize Effects Caused by 2-Butanone 

2-Butanone induces hepatic microsomal enzymes in rats after oral

exposure(Brady et al. 1989; Raunio et al. 1990, Robertson et al. 1989;

Traiger et al. 1989), but this enzyme induction has not been associated

with more severe liver effects. No other subtle biochemical effects of 2 

butanone have been 
40 

2. HEALTH EFFECTS 

identified that would be useful as biomarkers to characterize effects of 

2-butanone. 

2.6 INTERACTIONS WITH OTHER CHEMICALS 

The neurological and hepatic effects of 2-butanone alone are minimal.

For certain applications, 2-butanone is combined with other chemicals that

have serious neurotoxic or hepatotoxic effects. Clinical reports and animal

studies have clearly shown that 2-butanone potentiates both the neurotoxicity

of ethanol, n-hexane, and methyl-n-butyl ketone and the hepatotoxicity of

carbon tetrachloride and chloroform. 

Altenkirch et al. (1977) investigated a large outbreak of toxic

polyneuropathies in a group of West Berlin "glue sniffers." The development

of neuropathies (muscular atrophy, paresthesia, paresis, quadriplegia)

coincided with a change in the composition of a glue that was popular for

sniffing. Until the fall of 1975, the major constituents of the glue were nhexane, toluene, ethyl acetate, and benzene. At this time, 2-butanone was

added to the mixture and the sudden appearance of the toxic neuropathies

began. 

A 39-year-old woman who had worked for several years gluing shoes

developed polyneuropathy after a few weeks of work in a poorly ventilated shop

(Vallat et al. 1981). The glue she was using contained 20% 2-butanone and 8%

n-hexane. 

"Glue sniffing neuropathy" was also described in a clinical case report

of three men who had similar symptoms (King et al. 1985). All had been

sniffing the same brand of glue containing light, volatile hydrocarbons(CeC,), toluene, and 2-butanone. P-Butanone had recently been added to the glue

formulation, and the authors suggested that this may have increased the

neurotoxicity. A change in the formulation of a solvent compound also

precipitated a sudden outbreak of peripheral neuropathy in a coated fabrics

plant (Allen et al. 1975; Billmaier et al. 1974). Methyl-n-butyl ketone

introduced into a solvent used at the plant was implicated as the causative

agent; however, the solvent also contained high concentrations of 2-butanone.

Combined exposure to 2-butanone and methyl-n-butyl ketone has not been studied

meepidemiologically in humans; therefore, whether P-butanone potentiates methyln-butyl ketone neurotoxicity in humans is not known (Katz 1985). 

The potentiation of the neurotoxicity of n-hexane and methyl-n-butyl ketone

by 2-butanone is well-documented in animals (Altenkirch et al. 1978a, 1978b,

1982a, 1982b; Saida et al. 1976; Takeuchi et al. 1983). Altenkirch et al.

(1978a) exposed rats to either 10,000 ppm n-hexane or a combination of 1,000

ppm 2-butanone and 9,000 ppm n-hexane. A summary of three experiments under

these conditions showed that rats exposed to the combination of n-hexane and

2-butanone developed paresis more rapidly and in greater numbers than rats

exposed to n-hexane only. In the same study, rats exposed to 6,000 ppm 
41 

2. HEALTH EFFECTS 

2-butanone only showed no signs of neurotoxicity up to 7 weeks, when all

the rats in this group died suddenly of bronchopneumonia. These results

were confirmed in a second study; mixtures of 500 ppm n-hexane and 2­

butanone (4:l or 3:2) or 700 ppm (5:2) caused clinical signs of neuropathy

l-5 weeks earlier than 500 ppm n-hexane alone (Altenkirch et al. 1982a).

Histological examination revealed morphological changes in the rats

similar to those found in youths suffering from glue sniffing neuropathy,

including paranodal axon swelling, accumulation of neurofilaments in the

cytoplasm, and demyelination. Takeuchi et al. (1983) observed a

significant decrease in motor nerve conduction velocity in rats exposed to

300 ppm n-hexane:2-butanone (1:2). In this study, motor nerve conduction

velocity increased in rats exposed to 200 ppm 2-butanone alone and did not

change in rats exposed to 100 ppm n-hexane alone. Male Wistar rats exposed

to n-hexane or a combination of n-hexane and 2-butanone developed

ultrastructural changes in the intrapulmonary nerves characteristic of

hexacarbon neurotoxicity (Schmidt et al. 1984). Concomitant exposure to nhexane and 2-butanone decreased the onset of observable neuropathological

changes. 

Saida et al. (1976) reported a marked potentiation of peripheral

neurotoxicity when rats were exposed to methyl-n-butyl ketone:2-butanone

(225:1,125 ppm). Rats exposed to methyl-n-butyl ketone only developed

paralysis by 66 days. The combination caused paralysis in 25 days, while 

2-butanone alone had no effect up to 5 months. Histological examination of

neurons revealed morphological changes similar to those reported by

Altenkirch et al. (1982a), which included paranodal axon swelling,

accumulation of neurofilaments, and demyelination. Subcutaneous injection

of methyl-n-butyl ketone with or without 2-butanone increased distal motor

latency and decreased motor fiber conduction velocity in male Donryu

strain rats (Misumi and Nagano 1985). The combination of the two ketones

enhanced these effects. 

In vitro studies support the hypothesis that 2-butanone potentiates

n-hexane and methyl-n-butyl ketone neurotoxicity. Veronesi et al.

(1984)observed that, in tissues cultured from fetal mouse spinal cord,

dorsal root ganglia, and muscle, the combination of 2-butanone and nhexane produced giant axonal swellings more rapidly than cultures treated

with n-hexane alone. Furthermore, cultures exposed to nontoxic

concentrations of n-hexane also developed giant axonal swellings when 2­

butanone was administered concomitantly.

 Biotransformation of both n-hexane and methyl-n-butyl ketone can

produce 2,5-hexanedione (Couri et al. 1978; DiVincenzo et al. 1976;

Robertson et al. 1989). This compound is the most potent neurotoxic

metabolite of n-hexane and methyl-n-butyl ketone known (Katz 1985).

2-Butanone may potentiate n-hexane and methyl-n-butyl ketone neurotoxicity

by enhancing their metabolic conversion to 2,5-hexanedione. Combined

administration of methyl-n-butyl ketone and 2-butanone produced more

2,5-hexanedione than administration of methyl-n-butyl ketone alone (Couri

et al. 1978). The concentrations of the n-hexane metabolites

2,5-hexanedione and 2,5-dimethylfuran were significantly 
42 

2. HEALTH EFFECTS 

higher in the blood and sciatic nerve of rats pretreated by gavage with

2-butanone followed by inhalation exposure to n-hexane compared with rats

exposed to n-hexane alone (Robertson et al. 1989). In addition,

concomitant oral administration of 2-butanone and 2,5-hexanedione in rats

reduced blood 2,5-hexanedione clearance (Ralston et al. 1985). 

Ethyl-n-butyl ketone is a weak neurotoxin (O'Donoghue et al. 1984).

Oral administration in rats for several weeks caused the paranodal axon

swelling and neurofilamentous hyperplasia characteristic of n-hexane and

methyl-n-butyl ketone neurotoxicity. Biotransformation of ethyl-n-butyl

ketone produced two neurotoxic metabolites, 2,5-hexanedione and 2,5­

heptanedione. 2,5-Heptanedione can be further metabolized to 2,5

hexanedione. Concomitant inhalation exposure to 700 ppm ethyl-n-butyl

ketone and 700 ppm 2-butanone for 4 consecutive days caused a 2.6-fold

increase in the serum concentration of 2,5-heptanedione. Oral

administration of 2-butanone potentiated the development of clinical and

histological signs of ethyl-n-butyl neurotoxicity.

 2-Butanone has also been found to potentiate the neurotoxicity of

ethanol (Cunningham et al, 1989). Mice pretreated intraperitoneally with

2-butanone followed by intraperitoneal injection of ethanol 30 minutes

later showed prolonged loss of righting reflex induced by ethanol. 2­

Butanone also decreased the rate of ethanol elimination in mice in vivo 

and inhibited the in vitro activity of alcohol dehydrogenase, the main

mechanism for ethanol elimination. These results suggest that 2-butanone

potentiated the neurotoxicity of-ethanol by inhibiting its metabolism by

alcohol dehydrogenase. 

2-Butanone is not a universal potentiator of hydrocarbon- and

aliphatic ketone-induced neuropathies (O'Donoghue et al. 1982).

Concomitant oral administration of 2-butanone and 5-nonanone did not 

potentiate the neurotoxicity of 5-nonanone. 

2-Butanone alone is minimally neurotoxic (Altenkirch et al. 1978a;

Saida et al. 1976). This compound, however, is frequently mixed with nhexane and methyl-n-butyl ketone for various commercial and industrial

applications. The previous discussion emphasizes the public health hazard

of mixed solvent exposure to 2-butanone. Exposure to a mixed solvent is

more likely to occur in an occupational setting or at a hazardous waste

site, than exposure to 2-butanone alone. 

2-Butanone alone is not highly hepatotoxic (see the discussion of

Hepatic Effects in Section 2.2.1.2) but has a well-documented role in

potentiating haloalkane-induced hepatotoxicity (Brown and Hewitt 1984;

Dietz and Traiger 1979; Hewitt et al. 1983, 1986, 1987; Tanii et al.

1986). Intraperitoneal injection of chloroform (0.5 mL/kg) caused a ninefold increase in rat SGPT activity (Brown and Hewitt 1984). In contrast,

chloroform injection caused a 195-fold increase in rat SGPT activity if

administered 18 hours after oral administration of 2-butanone. Similarly,

intraperitoneal injection of 
43 

2. HEALTH EFFECTS 

chloroform increased rat plasma ornithine carbamyl transferase activity

215-fold if given 18 hours after oral administration of 2-butanone (Hewitt

et al. 1983). In addition to the doses administered, the length of time

between administration of 2-butanone and the chloroform injection

determined the severity of hepatotoxicity (Hewittet al. 1987).

Measurements of SGPT and plasma ornithine carbamyl transferase revealed

that 2-butanone is most efficacious for potentiation of chloroform-induced

hepatotoxicity if administered 18 hours before chloroform. 

2-Butanone also potentiates carbon tetrachloride-induced

hepatotoxicity (Dietz and Traiger 1979; Traiger et al, 1989). Measurement

of SGPT activity and hepatic triglyceride content showed that

administration of 2-butanone 16 hours before intraperitoneal injection of

carbon tetrachloride significantly enhanced liver damage. The mechanism of

P-butanone potentiation of chloroform and carbon tetrachloride

hepatotoxicity may be related to biotransformation of the ketone to its

metabolite, 2,3-butanediol. Carbon tetrachloride increased rat SGPT 164­

fold when injected 16 hours after oral administration of 2,3-butanediol.

Replacement of 2,3-butanediol with 2-butanone increased the transaminase

66-fold. Hepatic triglyceride content was potentiated to a similar degree

by both 2-butanone and 2,3-butanediol. However, the maximal potentiation

of carbon tetrachloride-induced hepatic injury by pretreatment with 2­

butanone coincided with increased microsomal enzyme activity within the

same time frame following exposure to 2-butanone alone (Traiger et al.

1989). This strongly suggests that 2-butanone potentiates the

hepatotoxicity of carbon tetrachloride by enhancing its metabolism to

toxic intermediates. The mechanism of 2-butanone potentiation of

chloroform-induced hepatotoxicity apparently does not involve

biotransformation of chloroform to a reactive intermediate, an alteration

of the cytochrome P-450 system, or depletion of liver glutathione (Hewitt

et al. 1987). It is possible that 2,3-butanediol also contributes to the

toxicity of chloroform. 

Pretreatment of ddY mice with carbon tetrachloride 24 hours before 

oral administration of 2-butanone reduced the 2-butanone LD,, about 20%

(Tanii et al. 1986). The mechanism of this effect was not investigated. 

Exposure of pregnant rats continuously to n-hexane alone (l,OOO1,500 ppm) or n-hexane and 2-butanone (1,200 ppm n-hexane, 300 ppm 2­

butanone) throughout gestation and/or during the postnatal period resulted

in reduced birth weight of pups, and weight gain reduction persisted

during the postnatal exposure period (Stoltenburg-Didinger et al. 1990).

The effect was more pronounced with the mixture of solvents. In addition,

hindlimb weakness in one dam during the gestational exposure period

progressing to quadriplegia in all dams during the postpartum exposure

period was for the solvent mixture, while only hindlimb weakness was

observed in the dams exposed observed n-hexane alone. 
44 

2. HEALTH EFFECTS

 Coexposure of S. cerevisiae to 2-butanone, ethyl acetate, and propionitrile

enhanced the induction of chromosome loss caused by 2-butanone (Zimmermann et

al. 1989). Coexposure of S. cerevisiae to 2-butanone and nocodazole enhanced the

induction of aneuploidy caused by 2-butanone alone (Mayer and Goin 1987). 

2.7 POPULATIONS THAT ABE UNUSUALLY SUSCEPTIBIE 

No studies were located that identified populations that are unusually

susceptible to adverse health effects after exposure to 2-butanone. The very

young and the very old are typically more susceptible to chemical, toxicity than

are older children, adolescents, and healthy adults. Individuals that are

alcoholics and those with existing liver disease would be expected to metabolize

2-butanone differently than the general population. Persons with existing

neuropathies may also be more susceptible. Exposure to both 2-butanone and nhexane or methyl-n-butyl ketone is possible in occupational settings and at

hazardous waste sites; thus, neurological effects of n-hexane and methyl-n-butyl

ketone may be greater with coexposure to 2-butanone. Likewise, occupational

exposure or exposure at hazardous waste sites to a combination of 2-butanone and

the haloalkanes, carbon tetrachloride, or chloroform, presents a greater risk

for liver damage. 

2.8 MITIGATION OF EFFECTS 

This section will describe clinical practice and research concerning

methods for reducing toxic effects of exposure to 2-butanone. This section is

intended to inform the public of existing clinical practice and the status of

research concerning such methods. However, because some of the treatments

discussed may be experimental and unproven, this section should not be used as a

guide for treatment of exposures to 2-butanone. When specific exposures have

occurred, poison control centers and medical toxicologists should be consulted

for medical advice. 

2-Butanone has a low order of systemic toxicity. The main effects in

humans are irritation of respiratory tissues and eyes and nonspecific

neurological effects, such as headache, dizziness, nausea, and fatigue. Such

effects are characteristic of solvent exposure and are mitigated primarily by

removing affected individuals from exposure conditions and decontaminating

exposed areas (Bronstein and Currance 1988; Stutz and Janusz 1988). For example,

contaminated clothing is removed and skin washed. If the eyes were exposed, they

are flushed with water. For ingestion of 2-butanone, there is controversy as to

whether or not to administer emetics. The controversy centers around the risk of

aspiration of vomitus into the lungs during emesis. Administration of activated

charcoal has been suggested to reduce gastrointestinal absorption. Please refer

to Bronstein and Currance (1988) and Stutz and Janusz (1988) for more complete

information.

 Although 2-butanone alone is not highly neurotoxic or hepatotoxic, it

potentiates the neurotoxicity of n-hexane and methyl-n-butyl ketone, and the

hepatotoxicity of chloroform and carbon tetrachloride (see Section 2.6).

Exposure to 2-butanone with other solvents is more likely than exposure to 2­

butanone alone in occupational and environmental settings. Since both n-hexane

and methyl-n-butyl ketone can be 
45 

2. HEALTH EFFECTS 

metabolized to 2,5-hexanedione (Couri et al. 1978; DiVincenzo et al 1976),

a potent neurotoxic agent (Katz 1985), 2-butanone may potentiate the

neurotoxicity of the other chemicals by enhancing the biotransformation of

n-hexane and methyl-n-butyl ketone to 2,5-hexanedione by inducing

microsomal enzymes. The potentiation of the hepatotoxicity of carbon

tetrachloride and chloroform by 2-butanone may be related to the

biotransformation of 2-butanone to 2,3-butanediol, a metabolite that

potentiates the hepatotoxicity of carbon tetrachloride to a greater extent

than does 2-butanone (Dietz and Traiger 1979). Alternatively, the

induction of microsomal enzymes by 2-butanone may enhance the

biotransformation of chloroform and carbon tetrachloride to toxic 

intermediates (Brady et al. 1989; Traiger et al. 1989). If carbon

tetrachloride or chloroform shift metabolic pathways of 2-butanone in

favor of greater formation of 2,3-butanediol, administration of an agent

that blocks this shift could mitigate the potentiation. 2-Butanone is

reduced to 2-butanol and oxidized to 3-hydroxy-2-butanone, which is

further reduced to 2,3-butanediol(DiVincenzo et al. 1976). However, the

enzyme systems involved in the biotransformation of 2-butanone have not

been characterized. Similarly, if 2-butanone enhances the metabolism of

chloroform and carbon tetrachloride by inducing microsomal enzymes, agents

that block this induction could mitigate this potentiation. 

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-butanone 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

butanone. 

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-Butanone 

The existing data on health effects of inhalation, oral, and dermal

exposure of humans and animals to 2-butanone are summarized in Figure 2-4. The

purpose of this figure is to illustrate the existing information concerning the

health effects of 2-butanone. 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.

 Studies regarding the adverse health effects of exposure to 2-butanone in humans

is limited (Figure 2-4). No reports exist regarding death in humans 

47 

2. HEALTH EFFECTS 

following exposure to 2-butanone by any route. Existing information

regarding systemic effects of 2-butanone exposure have come primarily from

two clinical reports involving accidental poisoning: one by oral exposure

and one by inhalation (Berg 1971; Kopelman and Kalfayan 1983). A clinical

study reported contact urticaria triggered by dermal -exposure to 2

butanone in a 48-year-old male painter (Varigos and Nurse 1986).

Intermediate dermal exposure to 2-butanone had no effect on humans

(Wahlberg 1984). Acute inhalation studies in humans showed no adverse

neurological effects (Dick et al. 1984, 1988, 1989). However, 2-butanone

produced nose, throat, and eye irritation in humans (Nelson et al. 1943).

Epidemiological studies showed no clear relationship between occupational

exposure to 2-butanone and the development of neoplasms (Alderson and

Rattan 1980; Wen et al. 1985). 

Animal studies regarding death after acute and intermediate exposure

to 2-butanone by inhalation, oral, dermal, and other routes are available.

Several studies are also available that show that acute and intermediate 

inhalation exposures have minimal or no systemic effects. Minimal effects

were limited to small increases in organ weight (Cavender et al. 1983;

Toftgard et al. 1981). Inhalation, oral, and dermal studies showed that

2-butanone is minimally neurotoxic in most species. Guinea pigs exposed

acutely to high concentrations (10,000 ppm) developed incoordination and

narcosis (Patty et al 1935). Juvenile baboons exposed to 100 ppm 2

butanone also appeared to show early signs of incoordination and narcosis

in a complex discriminant neurobehavioral test (Geller et al. 1979).

Histological examination of reproductive organs of male and female rats

exposed by inhalation to 5,000 ppm revealed no effects (Cavender and Casey

1981; Cavender et al. 1983). Studies of acute oral exposure showed that 2­

butanone caused renal tubular necrosis (Brown and Hewitt 1984; Hewitt et

al. 1983) and induced hepatic microsomal enzymes (Brady et al. 1989;

Raunio et al. 1990, Robertson et al. 1989; Traiger et al. 1989). One

intermediate oral exposure showed that 2-butanone was not neurotoxic

(Ralston et al, 1985). Acute and intermediate dermal exposures to 2­

butanone were mildly irritating to the skin of rabbits, rats, and guinea

pigs (Hazleton Laboratories 1963a; Wahlberg 1984). No reports of systemic

toxicity are available for dermal exposure. Several studies demonstrating

that 2-butanone is moderately irritating to the eyes of rabbits are

available. 2-Butanone was fetotoxic, causing delayed development in

fetuses of rats (Deacon et al. 1981; Schwetz et al. 1974) and mice (Mast

et al. 1989) exposed by inhalation. 

Several studies are available regarding 2-butanone potentiation of

n-hexane and methyl-n-butyl ketone neurotoxicity and 2-butanone

potentiation of haloalkane hepatotoxicity. 

2.9.2 Data Needs 

Acute-Duration Exposure. Several studies are available that report the

results of acute duration exposure to 2-butanone by inhalation, oral, and

dermal routes in both humans and animals. In acute inhalation studies, an 
48 

2. HEALTH EFFECTS 

LC50 value in rats (LaBelle and Brieger 1955) and other exposures that

caused death in rats (Klemisch 1988; Smyth et al. 1962), mice (LaBelle and

Brieger 1955), and guinea pigs (Patty et al. 1935) were identified. The

target organs identified in guinea pigs after acute inhalation exposure to

high concentrations of 2-butanone are the respiratory system, liver,

kidney, eye, and central nervous system Patty et al. 1935. Slight

neurotoxicity was also seen in mice and baboons exposed to low

concentrations (DeCeaurriz et al. 1983; Geller et al. 1979). Narcosis and

incoordination were observed in guinea pigs exposed acutely to high

concentrations of 2-butanone (Patty et al. 1935). An acute-duration

inhalation MRL was not derived because target organs of rats and mice have

not been sufficiently investigated. Although target organs of acute

inhalation exposure of rats and mice have not been sufficiently

investigated, intermediate duration studies indicate that effects on the

liver, kidney, respiratory system, and nervous system of rats are minimal.

In acute oral studies, LD50 values for rats (Kimura et al. 1971; Smyth et

al. 1962) and mice (Tanii et al. 1986) were available, and the kidney

was identified as a target (Brown and Hewitt 1984). No acute oral MRL was

derived because target organs have not been sufficiently investigated.

Furthermore, inhalation studies indicate that 2-butanone is a

developmental toxicant, but developmental effects after oral exposure were

not studied. Acute dermal studies have shown that 2-butanone is a skin 

and eye irritant in rabbits (Hazleton Laboratories 1963a, 1963b) and

guinea pigs (Anderson et al. 1986; Wahlberg 1984), but the systemic

toxicity of acute dermal exposure has not been investigated. The available

pharmacokinetic data are not sufficient to predict whether target organs

would be similar by the various routes of exposure. Acute exposure of

humans near a toxic waste site to 2-butanone alone would probably not have

serious clinical consequences. 2-Butanone is detectable by humans at

concentrations far below its OSHA and NIOSH permissible levels because of

its odor. Further acute exposure studies with 2-butanone alone would

probably not be useful. In contrast, further acute exposure studies by

oral, inhalation, and dermal routes of 2-butanone combined with such

hepatotoxins as chloroform and carbon tetrachloride, or with such

neurotoxins as n-hexane and methyl-n-butyl ketone would yield valuable

information on the potentiation of the hepatotoxicity and neurotoxicity,

resperhively, of the other-chemicals by 2-butanone. These chemicals are

often found together in formulations used occupationally and they might be

stored together at toxic waste sites. Therefore, workers and populations

surrounding hazardous waste sites might be exposed to these substances for

acute durations. 

Intermediate-Duration Exposure. A comprehensive 90-day inhalation

study in rats showed that 2-butanone did not have adverse effects in the

respiratory, cardiovascular, gastrointestinal, musculoskeletal,

hematological, hepatic, renal, or dermal/ocular systems (Cavender and

Casey 1981; Cavender et al. 1983). The most serious effect was slightly

increased liver weight at the highest concentration tested, 5,000 ppm.

Occupational exposures to concentrations this high are unlikely since

humans find 350 ppm 2-butanone intolerable (Nelson et al. 1943). No signs

of neurotoxicity, either clinical 
49 

2. HEALTH EFFECTS 

or histological, were observed in several studies of intermediate

exposures to high concentrations of 2-butanone up to 6,000 ppm (Altenkirch

et al. 1978a, 1978b; Cavender and Casey 1981; Cavender et al. 1983).

Therefore, most organs and tissues in humans probably would not be

adversely affected by intermediate 2-butanone exposures either

occupationally or near toxic waste sites. An intermediate duration

inhalation MRL was not derived because nose and throat irritation occurred 

in humans at acute inhalation exposure levels lower than the NOAEL values

for intermediate duration inhalation exposure in animals. No intermediate

oral or dermal studies investigated the systemic toxicity of 2-butanone by

these routes, and the available pharmacokinetic data are not. Sufficient 

to predict whether target organs would be similar by the various routes of

exposure. 2-Butanone has been detected in air, water, food, and soil (see

Section 5.4); therefore, exposures by the inhalation, oral, and dermal

routes are possible. From a public health perspective, exposure to solvent

mixtures is more likely than exposure to a single pure chemical.

Therefore, intermediate exposure studies of 2-butanone mixed with other

solvents (hexacarbons and haloalkanes), the toxicity of which is

potentiated by 2-butanone, would provide valuable information on

neurotoxicity and systemic toxicity. This information is important since

these chemicals are often found together in solvents used occupationally, 

and they might be stored together at hazardous waste sites where

surrounding populations could be exposed for intermediate durations. 

Chronic-Duration Exposure and Cancer. No studies were located 

regarding the health effects of chronic exposure to 2-butanone by any

route in humans or animals, but acute and intermediate duration inhalation

studies indicated that by itself, 2-butanone is minimally toxic.

Pharmacokinetic data are insufficient to predict the possible target

organs of chronic exposure by any route. Since 2-butanone has been

detected in air, water, food, and soil (see Section 5.4), exposures by the

inhalation, oral, and dermal routes are possible. 2-Butanone is often

found in formulations with other chemicals, such as chloroform, carbon

tetrachloride, n-hexane, and methyl-n-butyl ketone, the toxicities of

which -2-butanone potentiates. These chemicals may be stored together at

hazardous waste sites. Chronic inhalation, oral, and dermal studies in

which animals are administered these chemicals in combination with 2­

butanone may provide dose-response information for the potentiation of the

neurotoxicity and hepatotoxicity of these chemicals by 2-butanone. This

information is important because there are populations surrounding

hazardous waste sites that might by exposed to these chemicals for similar

durations. 

Although no cancer bioassays were available, preliminary

epidemiological studies suggest that occupational exposure to 2-butanone

does not increase the development of neoplasms. Furthermore, 2-butanone

was not genotoxic, either with or without metabolic activation, in several

microorganisms and cultured mammalian cells (O'Donoghue et al. 1988;

Thorpe 1982). Furthermore, no induction of micronuclei was found in the

erythrocytes of hamsters (Basler 1986) or mice (O'Donoghue et al. 1988)

after intraperitoneal injection with 
50 

2. HEALTH EFFECTS 

2-butanone. On the basis of this information, 2-butanone does not appear

to be carcinogenic. 

Genotoxicity. No induction of micronuclei was found in the 

erythrocytes of hamsters (Basler 1986) or mice (O'Donoghue et al. 1988)

after intraperitoneal injection with 2-butanone. A comprehensive battery

of in vitro tests showed that 2-butanone was not mutagenic in two

prokaryotic organisms and two eukaryotic organisms, did not transform

mammalian cells in culture, and did not induce unscheduled DNA synthesis

in rat primary hepatocytes (O'Donoghue et al. 1988; Thorpe 1982). 2­

Butanone did not cause gene mutations in S. cerevisiae (Thorpe 1982), but

caused mitotic chromosome loss (Whittaker et al. 1990; Zimmermann et al.

1989) and aneuploidy in S. cerevisiae (Mayer and Goin 1987) at high

concentrations. The positive induction of chromosome loss in the yeast

cells was enhanced by coexposure to 2-butanone, ethyl acetate, and

propionitrile (Zimmermann et al. 1989). The positive induction of

aneuploidy was enhanced by coexposure to 2-butanone and nocodazole (Mayer

and Goin 1987). Although 2-butanone contains an electrophilic center at

the carbonyl carbon, further testing for genotoxicity does not seem

warranted, except in combination with other solvents. 

Reproductive Toxicity. No studies were located regarding effects on

reproductive capacity or reproductive organs and tissues in humans

following exposure to 2-butanone. The authors of a health hazard

evaluation report for NIOSH concluded that a perceived increase in the

number of spontaneous abortions among female workers believed to result

from exposure to 2-butanone and several other volatile chemicals at a shoe

factory was not related to exposure (Tharr et al. 1982). No

histopathological lesions were found in male or female reproductive organs

of rats exposed to 5,000 ppm 2-butanone for 90 days (Cavender and Casey

1981; Cavender et al. 1983), but reproductive function was not assessed.

Further studies of the reproductive function of 2-butanone by all

durations and routes would provide valuable information particularly if

the studies include histological examination of the organs and tissues of

the reproductive. system. If reproductive organs were identified as

targets of 2-butanone toxicity, single or multigeneration reproductive

studies probably would be warranted. Since 2-butanone potentiates the

neurotoxicity or hepatotoxicity of certain chemicals, it would be valuable

to investigate the reproductive effects of mixed solvent exposures that

include 2-butanone. This investigation would be useful because 2-butanone

is often found in mixtures of other solvents in occupational settings, and

these mixtures may be found together at or near hazardous waste sites.

 Developmental Toxicity. Information regarding developmental toxicity

of 2-butanone in humans was not located. 2-Butanone was slightly fetotoxic

in rats (Deacon et al. 1981; Schwetz et al. 1979) and mice (Mast et al.

1989)following inhalation exposure of pregnant rats and mice to 3,000 ppm.

The fetotoxicity was related to delayed development. Furthermore, five of

eight pregnant rats exposed continuously to 800 ppm throughout gestation

failed to deliver litters (Stoltenburg-Didinger et al. 1990). In addition, 
51 

2. Health Effects 

developmental effects were more pronounced in pups born to rat dams

exposed to a mixture of n-hexane and 2-butanone than in pups born to dams

exposed to n-hexane alone (Stoltenburg-Didinger et al. 1990). This 

study, however, was very poorly reported, with very little information

provided on exposure to 2-butanone alone. No developmental or

distribution studies have been conducted by the oral route, but there is

no reason to believe that 2-butanone or its metabolites could not cross 

the placenta after administration by the oral route. Therefore, it is

likely that orally administered 2-butanone would be fetotoxic in these

species. Determination of the doses needed to produce the fetotoxicity by

the oral route would provide valuable information. Since 2-butanone 

potentiates the neurotoxicity or hepatotoxicity of certain chemicals, it

would be valuable to further investigage the developmental effects of

mixed solvent exposures that include 2-butanone. Such a study would be

useful because 2-butanone is often found in mixtures with other solvents 

in occupational settings, and these mixtures may be fould at or near

hazardous waste sites. 

Immunotoxicity. No studies were located regarding immunotoxicity

after oral exposure to 2-butanone. A clinical report of contact urticaria

in a 47-year-old painter exposed occupationally to 2-butanone (Varigos and

Nurse 1986) suggests that skin sensitivity requires more study.

Altenkirch et al. (1978a) reported that 19/19 rats died suddenly of

pathologically confirmed bronchopneumonia after 7 weeks of inhalation

exposure to 6,000 ppm 2-butanone. 2-butanone may weaken the immune

system, thus predisposing humans and animals to infection. No 

histopathological lesions were found in the thymus, lymph nodes, spleen,

or bone marrow of rats exposed to 5,000 ppm or less of 2-butanone for 90

days (Cavender and Casey 1981; Cavender et al. 1983), but tests for immune

function were not performed. Therefore, a study of the effects of

2-butanone on immune function (thymus, lymph nodes, peripheral blood

lymphocytes, etc.)would provide valuable information regarding the

immunotoxicity of 2-butanone. 

Neurotoxicity. 2-butanone was not neurotoxic at a concentration of 

200 ppm in several acute inhalation exposure studies in humans (Dick et

al. 1984, 1988, 1989). Neurobehavioral effects have been observed in mice 

(1,602 ppm) )DeCeaurriz et al. 1983) and baboons (100 ppm) (Geller et al.

1979) exposed acutely by inhalation. Guinea pigs displayed narcosis and

incoordination after acute inhalation exposure to high concentrations

(Patty et al. 1935). Clinical signs of neurotoxicity were also observed

in rats treated acutely by gavage with a high dose of 2-butanone

(Stillmeadow Inc. 1978). However, 2-butanone is not generally regarded as

being highly neurotoxic when administred alone. In acute and intermediate 

exposure studies in animals, it markedly potentiated the neurotoxicity of

n-hexane and methyl-n-butyl ketone both in humans and animals. A 

comprehensive study of acute, intermdiate, and chronic exposures to

mixtures of 2-butanone, n-hexane, and methyl-n-butyl ketone by inhalation,

oral, and dermal routes will provide valuable information regarding the

neurotoxicity of these compounds. Such a study would be particularly

valuable because 2-butanone is 
52 

2. HEALTH EFFECTS 

often found occupationally in mixtures containing n-hexane and methyl-nbutyl ketone, and these chemicals would probably be found together at

hazardous waste sites. 

Epidemiological and Human Dosimetry Studies. One study with humans

etermined that inhalation exposure to 100 ppm for 15 minutes was

irritating to the nose and throat, and exposure to 350 ppm was intolerable

(Nelson et al. 1943). In three separate studies, volunteers exposed to 200

ppm had no neurobehavioral effects (Dick et al. 1984, 1988, 1989). Two

epidemiological studies of chemical company workers exposed to 2-butanone

showed inconclusive results regarding increased risk of cancer (Alderson

and Rattan 1980; Wen et al. 1985). No epidemiological studies regarding

other health effects of 2-butanone exposure were located. Therefore,

valuable epidemiological information could be obtained from further

studies of cancer and other health effects, particularly neurotoxicity and

reproductive and developmental toxicity. 

Biomarkers of Exposure and Effect. The only known biomarkers of

2-butanone exposure are blood, breath, and urinary concentrations of

2-butanone and its metabolites (Brown et al. 1986; Brugnone et al. 1983;

Ghittori et al. 1987; Miyasaka et al. 1982). 2-Butanone is rapidly cleared

from the body, and existing studies show that accumulation of 2-butanone

in tissues does not occur to a significant extent. Furthermore, 2-butanone

alone is relatively free of adverse health effects. Therefore, development

of biomarkers of exposure to a battery of solvents often used

occupationally in combination with 2-butanone would be more valuable than

development of biomarkers for 2-butanone alone. 

2-Butanone exposure has no specific effects that can be used as

biomarkers for exposure by any route or for any duration of exposure. 

Absorption, Distribution, Metabolism, and Excretion. 2-Butanone is 

absorbed by inhalation (Liira et al. 1988a, 1988b, 1990, 1991) and oral

exposure (Brown and Hewitt 1984; Dietz and Traiger 1979; Dietz et al.

1981; Hewitt et al. 1983; Sakata et al. 1989). Net retention of inhaled 2­

butanone is approximately 50% in humans (Liira et al. 1988a, 1988b).

Studies of absorption after dermal exposure would provide valuable

information on this occupationally significant route of entry. Available

data regarding the relative rates or extent of absorption, metabolism,

distribution, and excretion by the three routes of exposure are not

sufficient to draw meaningful conclusions. 2-Butanone is equally soluble

in all tissues and organs measured (Perbellini et al. 1984). Therefore, 2­

butanone is probably evenly distributed throughout the body. The primary

route of excretion appears to be the lungs. The metabolic pathways for 2­

butanone have been thoroughly studied in rats (Dietz and Traiger 1979;

Dietz et al. 1981) and guinea pigs (DiVincenzo et al. 1976). Similar

metabolites have been identified in humans (Liira et al. 1988a, 1988b;

Miyasaka et al. 1982). In rats, 30% of an oral dose of 2-butanone was

converted to 2,3-butanediol (Dietz 
53 

2. HEALTH EFFECTS 

et al. 1981). Potentiation of the neurotoxicity of ethanol, n-hexane, and

methyl-n-butyl ketone and the hepatotoxicity of haloalkanes by 2-butanone

may involve interactions in the biotransformation of these compounds

(Brady et al. 1989; Cunningham et al. 1989; Raunio et al. 1990; Robertson

et al. 1989; Traiger et al. 1989). Further studies regarding the

interaction of hexacarbons, haloalkanes, and 2-butanone at the metabolic

level may provide valuable information. 

Comparative Toxicokinetics. Available human data show that 2 

butanone is metabolized primarily to 2,3-butanediol and 3-hydroxy-2­

butanone, but the extent of metabolism appears to be small (Liira et al.

1988a, 1988b). In an occupational exposure study of 2-butanone, only 3­

hydroxy-2-butanone was observed (Brugnone et al. 1983). In rats and guinea

pigs, a third metabolite, 2-butanol, was observed (Dietz et al. 1981;

DiVincenzo et al. 1976). About 30% of an oral dose of 2-butanone in rats

later appeared in plasma as 2,3-butanediol (Dietz et al. 1981). 2-Butanol

is also a product of 2-butanone metabolism in humans (Liira et al. 1990).

2-Butanone potentiates the neurotoxicity of n-hexane and methyl-n-butyl

ketone and the hepatotoxicity of haloalkanes. The 2-butanone metabolite,

2,3-butanediol, may be more efficacious for potentiating the

hepatotoxicity of the haloalkanes than 2-butanone. Therefore, valuable

information would be gained by toxicokinetic studies of 2-butanone and its

metabolites as they pertain to the toxicity of the hexacarbons and

haloalkanes. 

Mitigation of Effects. 2-Butanone by itself has a low order of

systemic toxicity. However, exposure to 2-butanone with other solvents,

which is more likely in occupational and environmental settings than is

exposure to 2-butanone alone, results in a potentiation of the

neurotoxicity and hepatotoxicity of the other solvents. Further studies

that investigate the mechanism by which 2-butanone potentiates the

toxicity of other ketones, n-hexane, chloroform, and carbon tetrachloride

would be useful in planning research aimed to develop agents that would

interfere with the mechanism, thereby mitigating the potentiation. 

2.9.3 On-going Studies

 No information regarding current studies of the health effects of

2-butanone was located. 

55 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY 

Data pertaining to the chemical identity of 2-butanone are listed in

Table 3-1. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES 

The physical and chemical properties of 2-butanone are presented in

Table 3-2. 



59 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.1 PRODUCTION 

According to the most recent edition of U.S. International Trade

Commission (USITC 1989), 482,028,000 pounds of 2-butanone were produced in

the United States in 1988. The production volume for 1986 and 1987 was

600,440,000 and 671,859,000 pounds, respectively (USITC 1987, 1988). Total

U.S. capacity for 1989 has been estimated at 622 million pounds (SRI

1989). Production of 2-butanone has been flat in the past decade, but it

is expected to grow at 2%-3% through 1991 (Chemical Marketing Reporter

2987). Current manufacturers of 2-butanone are included in Table 4-1.

According to the Toxic Release Inventory (TRI 1989), 2,218 facilities

manufacture or process 2-butanone. These facilities had a maximum amount

of 2-butanone on site of approximately 1,670,000,000 pounds in 1987. These

data are presented in Table 4-2. The quality of the data must be viewed

with caution since the 1987 data represent first-time, incomplete

reporting by these facilities. Not all facilities that should have

reported have done so. 

2-Butanone is produced on a commercial scale by one of two

processes. The vapor-phase dehydrogenation of set-butanol.(2-butanol),

itself obtained from the hydrolysis of butene, accounts for 88%

2-butanone production (Neier and Strehlke 1985; Papa and Sherman 1981). In

the other commercially significant process, 2-butanone is obtained as a

byproduct of acetic acid production. In this methodology, liquified butane

is subjected to catalytic oxidation. 

4.2 IMPORT/EXPORT 

Approximately 16% of the total U.S. production of 2-butanone is

exported to other countries (Chemical Marketing Reporter 1987). Imports

into the United States amounted to about 52 million pounds in 1986. 

4.3 USE 

2-Butanone exhibits outstanding solvent properties, and combined

with its low cost, it is often the choice solvent for various coating

systems (Neier and Strehlke 1985; Papa and Sherman 1981). Uses of

2-butanone can be broken down into the following categories: coatings

solvent, 50%; adhesives, 13%; magnetic tapes, 8%; lube oil dewaxing, 4%;

printing inks, 3%; exports, 16%; and miscellaneous, 6% (Chemical Marketing

Reporter 1987). Examples of specific applications include its use as a

solvent for nitrocellulose, lacquers, rubber cement, printing inks, paint

removers, vinyl films, resins, rosins, polystyrene, chlorinated rubber,

polyurethane, acrylic coatings, and cleaning solutions (Neier and Strehlke

1985; Papa and Sherman 1981; Sax and Lewis 1987). 2-Butanone is used in

the production of synthetic leathers, transparent paper, and aluminum

foil. It is also used in the degreasing of metals, as an extraction

solvent, in dewaxing applications, and as a solvent for the production of

smokeless powders. 




64 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.4 DISPOSAL 

Dilute solutions of 2-butanone can be discharged directly into

sewage treatment facilities, sprayed into incinerators, or burned in paper

packaging (OHM/TADS 1989). It can be destroyed in fluidized-bed

incinerators, rotary kiln incinerators, or liquid injection incinerators

using short residence times of a few seconds for either liquids or gases,

and longer residence times for contaminated solids, if applicable (HSDB

1989). 2-Butanone has been reported to be amenable to biological

degradation in sewage treatment plants (Babeu and Vaishnav 1987; Bridie et

al. 1979; Gaudy et al. 1963.; Price et al. 1974; Urano and Kato 1986;

Vaishnav et al. 1987; Young et al. 1968). No data are available regarding

the amount disposed by each of these methods, nor is any information

available regarding the trends in the disposal of 2-butanone. 
65 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

2-Butanone may be released to the atmosphere in fugitive emissions

during its production, transport, and use. It is widely used in coating

systems where its volatilization to the atmosphere is an intended outcome

of its use. In urban areas, it can exist in the atmosphere as a result of

automobile exhaust, the decomposition of other organic compounds, and from

natural sources. 

The release of 2-butanone to water or soil is not well documented. 

Release of 2-butanone to surface water may occur via industrial waste

water emissions. 2-Butanone may also be released to soil or water from a

spill or other catastrophic event. The leachate of landfills and hazardous

waste sites may result in 2-butanone contamination of soil and

groundwater. 

According to the SARA Section 313 TRI (1989), an estimated total of

149,678,423 pounds of 2-butanone was released to the environment in 1987

by facilities that manufacture or process this compound. Of this,

149,478,640 pounds were released to the atmosphere. The quality of the TRI

data must be viewed with caution since the 1987 data represent first-time,

incomplete reporting of estimated releases by these facilities. Not all

sources of chemical wastes are included and not all facilities. Only

certain types of facilities were required to report. This is not an

exhaustive list. These data are presented in Table 5-1. 

2-Butanone is expected to rapidly volatilize from surface water and

moist or dry soils to the atmosphere, In the atmosphere, this compound is

expected to exist predominantly in the vapor phase. Wet deposition may

return 2-butanone to the earth's surface. 

In soil, 2-butanone is expected to display very high mobility, and

it has the potential to leach into groundwater. This characteristic also

suggests that it does not significantly adsorb to sediment and suspended

organic matter in surface waters. 2-Butanone is not expected to

bioconcentrate in fish and aquatic organisms. 

Although the degradation of 2-butanone in the environment is

understood on a theoretical level, data are not available to quantify all

conclusions. In the atmosphere, 2-butanone is expected to undergo a

vapor-phase reaction with photochemically produced hydroxyl radicals; the

half-life for this process is approximately 1 day. However, laboratory

experiments have suggested that the atmospheric half-life of 2-butanone is

much shorter. 

In water, 2-butanone is expected to undergo microbial degradation

under both aerobic and anaerobic conditions. Chemical oxidation, direct

photolysis, and hydrolysis of 2-butanone under environmental conditions

are not expected to occur to any significant extent. Data on the fate of

2-butanone in soil are not available. 


68 

5. POTENTIAL FOR HUMAN EXPOSURE 

Various data are available regarding the concentration of 2-butanone

in environmental media. It has been qualitatively detected in U.S. drinking

water supplies and as a naturally occurring constituent of foods. It has

also been detected in the air. 

EPA has identified 1,177 NPL sites. 2-Butanone has been found at 137

out of the sites evaluated for its presence. However, we do not know how

many of the 1,177 NPL sites have been evaluated for this chemical. As more

sites are evaluated by EPA, this number may change (View 1989). The

frequency of these sites within the United States can be seen in Figure 5-l. 

The general population is exposed to 2-butanone by drinking

contaminated water or by the ingestion of food containing it. Members of the

general population living near hazardous waste sites may be exposed to

contaminated drinking water if their household water source is well water.

The general population is also expected to be exposed to 2-butanone by

inhalation, especially in urban areas. The use of commercial coatings

containing 2-butanone also results in exposure by inhalation, and possibly

by dermal contact as well. High levels of exposure may occur for members of

the general population if these coatings are used in an enclosed,

unventilated area. Occupational exposure to 2-butanone may occur by

inhalation during the production, formulation, use, or transport of this

compound. 

5.2 RELEASES TO THE ENVIRONMENT 

5.2.1 Air 

2-Butanone may be emitted to the atmosphere during its production,

formulation, storage, or use in commercial products. 2-Butanone may also be

released to the atmosphere as a result of its use as a solvent in commercial

products. It was identified as an emission from a variety of indoor building

materials: latex caulk, particle board, latex paint, and polyurethane floor

finish (Tichenor 1987; Tichenor and Mason 1988). Since 2-butanone is

prevalent in adhesives and coatings (Papa and Sherman 1981), it may be

released to the atmosphere during the curing of these products. 

According to the SARA Section 313 TRI (1989), an estimated total of

149,478,640 pounds of 2-butanone was released to the atmosphere in 1987 by

facilities that manufacture or process this compound. The quality of the TRI

data must be viewed with caution since the 1987 data represent first-time,

incomplete reporting of estimated releases by these facilities. Only certain

types of facilities were required to report. This is not an exhaustive list. 

2-Butanone is present in the exhaust of automobiles (Seizinger and

Dimitriades 1972). In a Swedish study, 2-butanone was detected in automobile

exhaust, although the ambient air levels measured in Stockholm did not

correlate with these emissions (Jonsson et al. 1985). Thus, the prevalence

of other sources is indicated, as the air levels of 2-butanone were higher

than 

70 

5. POTENTIAL FOR HUMAN EXPOSURE 

could be explained solely by automobile emissions. Other potential sources

of 2-butanone in the atmosphere include the burning of polyethylene

(Hodgkin et al. 1982) and the photochemical degradation of hydrocarbons

(Grosjean 1982), especially those emitted from motor vehicles. 2-Butanone

is also emitted to the atmosphere from such natural sources as European

firs, junipers, cedars, cypress trees, and ferns (Isidorov et al. 1985)

and ant secretions (Cammaerts et al. 1978). 

5.2.2 Water 

Limited data are available regarding the release of 2-butanone to

surface and groundwaters. It has been detected in waste water effluents

from commercial processes (Dunovant et al. 1986; Hawthorne and Sievers

1984; Jungclaus et al. 1978; Pellizzari et al. 1979). 2-Butanone may also

be present in water from the microbial oxidation of butane (Phillips and

Perry 1974). Its relatively high water solubility, 136,000 mg/L at 25°C

(Tewari et al. 1982), suggests that wet deposition of atmospheric

2-butanone results in the contamination of surface water. Evidence for 

this comes from the fact that 2-butanone has been detected in rain water 

(Grosjean and Wright 1983).

 According to the SARA Section 313 TRI (1989), an estimated total of

75,858 pounds of 2-butanone was released to water in 1987 by facilities

that manufacture or process this compound, a very small amount compared to

what is released to the atmosphere. The quality of the TRI data must be

viewed with caution since the 1987 data represent first-time, incomplete

reporting of estimated releases by these facilities. Only certain types of

facilities were required to report. This is not an exhaustive list. 

The contamination of groundwater with 2-butanone has occurred at

hazardous waste sites (Francis et al. 1980; Sawhney and Kozloski 1984) and

landfills (Sabel and Clark 1984) due to infiltration of contaminated

leachate. 2-Butanone was detected in 180 groundwater samples from 357

hazardous waste sites monitored by the Contract Laboratory Program (CLP)

at a geometric mean concentration of 302 ppb for the positive samples

(CLPSD 1988). Note that the CLPSD includes data from both NPL and non-NPL

sites. 2-Butanone is also likely to enter groundwater as a result of a

spill to soil during a catastrophic event, such as a tanker spill

(Halvorsen and Ohneck 1985). 

2-Butanone may also enter water from natural sources. It has been

detected in various species of macroalgae at concentrations as high as

2,600 ng/g (Whelan et al. 1982). 

5.2.3 Soil 

Limited data are available regarding the release of 2-butanone to

soil. The presence of this compound in the groundwater at hazardous waste

sites and landfills (Francis et al. 1980; Sabel and Clark 1984; Sawhney

and Kozloski 1984) suggests that leachate at these facilities will be a

source of 
71 

5. POTENTIAL FOR HUMAN EXPOSURE 

2-butanone release to soil. Wet deposition of atmospheric 2-butanone may

also result in its contamination of soil. 2-Butanone may enter soil during

a catastrophic event, such as a tanker spill (Halvorsen and Ohneck 1985).

2-Butanone has been found in 309 of 357 hazardous waste sites monitored by

the CLP at a geometric mean concentration of 87 ppb (CLPSD 1988). Note

that the CLPSD includes data from both NPL and non-NPL sites.

 According to the SARA Section 313 TRI (1989), an estimated total of

48,675 pounds of 2-butanone was released to soil in 1987 by facilities

that manufacture or process this compound; a very small amount compared to

what is released to the atmosphere. The quality of the TRI data must be

viewed with caution since the 1987 data represent first-time, incomplete

reporting of estimated releases by these facilities. Only certain types of

facilities were required to report. This is not an exhaustive list. 

5.3 ENVIRONMENTAL FATE 

5.3.1 Transport and Partitioning

 In the atmosphere, 2-butanone is expected to exist predominantly in

the vapor phase (Eisenreich et al. 1981; Riddick et al. 1986). This is

consistent with experimental data, which demonstrated that the gas-phase

concentration of 2-butanone in Los Angeles, California, was from 220 to

3,000 times greater than the particulate phase concentration (Grosjean

1982). The relatively high water solubility of 2-butanone, 136,000 mg/L at

25°C (Tewari et al. 1982), suggests that wet deposition may remove 2­

butanone from the atmosphere. 2-Butanone has been identified in rain 

water (Grosjean and Wright 1983). The absence of significant amounts of

particulate 2-butanone indicates that dry deposition to the earth's

surface is not an important fate process. The short residence time

expected for 2-butanone in the atmosphere, less than 1 day,suggests that

it is not transported long distances from its original point of

release. 

Based on an experimental soil adsorption coefficient (Koc) of 3.55

(Roy and Griffin 1985) 2-butanone is expected to display very high

mobility in soil (Swann et al. 1983). 2-Butanone was found in groundwater

samples shortly after a tanker spill (Halvorsen and Ohneck 1985) and in

the groundwater underneath hazardous waste sites and public landfills

(Francis et al. 1980; Sabel and Clark 1984; Sawhney and Kozloski 1984).

The vapor pressure of 2-butanone, 90.6 mmHg at 25°C (Riddick et al. 1986),

and the Henry's law constant, 5.77x10-5 atm m3

/mol at 25°C, suggest that

volatilization from either dry or moist soil to the atmosphere will be an

important environmental process. 

If 2-butanone is released to water it is expected to rapidly volatilize to

the atmosphere. Based on its Henry's law constant, an estimated

volatilization half-life from a model river 1 m deep, flowing at 1 m/set

with a wind velocity of 3 m/sec, is approximately 15 hours (Lyman et al.

1982). 
72 

5. POTENTIAL FOR HUMAN EXPOSURE 

2-Butanone is not expected to significantly adsorb to sediment and

suspended organic matter. It is also not expected to bioconcentrate in

fish and aquatic organisms (Lyman et al. 1982). These conclusions are

based on an experimental Koc of 3.55 (Roy and Griffin 1985), and a

calculated bioconcentration factor of 0.98 obtained from its octanol/water

partition coefficient, 0.29 (Hansh and Leo 1985), and an appropriate

regression equation (Lyman et al. 1982). 

5.3.2 Transformation and Degradation 

5.3.2.1 Air

 2-Butanone is expected to undergo atmospheric destruction by the

gasphase reaction with photochemically produced hydroxyl radicals. Rate 

constants for this reaction ranging from 1.85x10-11 to 9.8x10-13 

atm/molecule-sec in the temperature range of 22-32°C have appeared in the

literature (Cox et al. 1980, 1981; Edney and Corse 1986; Edney et al.

1986; Darnall et al. 1976; Gusten et al. 1984; Wallington and Kurylo 1987;

Wallington et al. 1988). Using a recommended rate constant of 1.85x10-11 

atm/molecule-sec at 25°C and an average atmospheric hydroxyl radical

concentration of 5x105

 molecule/cm3 (Atkinson 1985), a half-life of 21

hours for this reaction can be calculated. However, experiments performed

under simulated atmospheric conditions in the laboratory have shown that

2-butanone has a half-life of only 9.8 hours for photo-initiated processes

(Dilling et al. 1976). The rate of its destruction increased in the

presence of other anthropogenic compounds. The atmospheric destruction of

2-butanone as a result of direct irradiation is not expected to be

significant under atmospheric conditions (Cox et al. 1980). Therefore,

direct photolysis cannot account for the enhanced rate of atmospheric

destruction observed in the laboratory. However, the data suggest that

other mechanisms are responsible for the destruction of 2-butanone in the

atmosphere, which are yet to be defined. 

5.3.2.2 Water 

2-Butanone is expected to be removed from environmental waters by

microbial degradation under both aerobic and anaerobic conditions. Limited

data specific to the chemical degradation of 2-butanone in water are

available; however, it is not expected to occur to any significant extent. 

Numerous investigations have concluded that 2-butanone undergoes

biological degradation under aerobic conditions. At an initial

concentration of 1 ppm, 2-butanone completely degraded in aerated water

obtained from a deep Florida aquifer within 14 days after a 5-day lag

period (Delfino and Miles 1985). Screening studies using a microbial seed

from domestic waste treatment plants have indicated that 2-butanone has a

5-day biological oxygen demand (BOD5) which is between 59% and 74% of the

theoretical amount after a short lag period (Babeu and Vaishnav 1987;

Bridie et al. 1979; Gaudy et al. 1963; Price et al. 1974; Urano and Kato

1986; Vaishnav et al. 1987; Young et al. 
73 

5. POTENTIAL FOR HUMAN EXPOSURE 

1968). A pure culture study indicated that propionate is produced as a

result of the microbial oxidation of 2-butanone (Phillips and Perry 1974). 

2-Butanone has been listed as a compound amenable to degradation by

anaerobic biotechnology (Speece 1983). At an initial concentration of

500 ppm, 2-butanone was completely reduced to methane within 8 days in a

fermentor using a domestic sludge inoculum that had been adapted to

acetate (Chou et al. 1979). 

An experimentally determined rate constant of 5.4x108

 L/mol-sec has

been determined for the reaction of 2-butanone with hydroxyl radicals in

water (Anbar and Neta 1967). This value corresponds to a half-life of 4

years for this reaction, given a hydroxy radical concentration of 1x10-17 M 

(Mill et al. 1980). Hydrolysis of ketones is generally not believed to be

an environmentally important process (Lyman et al. 1982; Mill 1982). A

rate constant of 0 L/mol-year was listed for the hydrolysis of 2-butanone

under neutral, acidic, and basic conditions at 25°C (Kollig et al. 1987),

indicating that this process does not occur in the environment. By analogy

to the gasphase photolysis of 2-butanone (Cox et al. 1980), direct

photochemical breakdown of 2-butanone in water is not expected. Therefore,

the chemical degradation of 2-butanone in environmental waters is not

expected to occur to any significant extent. 

The chemical alteration of 2-butanone in rain water has been 

postulated. In acid rain, hydroxy sulfonates may be formed by the

reaction with bisulfite, and ammonia adducts may be formed in ammoniated

rain (Grosjean and Wright 1983). The concentration of these reactive

species is likely to be much higher in rain water than in surface water;

therefore, a more rapid rate of reaction would be expected in rain. 

5.3.2.3 Soil 

No specific data concerning the fate of 2-butanone in soil were

available. By analogy to the experimental results on the microbial

degradation of 2-butanone in water, this compound may degrade in soil

under aerobic and anaerobic conditions given suitable time for adaptation

of the microbial population. Again by using an analogy to the fate of 2­

butanone in aqueous systems, it is not expected to hydrolyze, photolyze on

the surface, or undergo chemical degradation. 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

5.4.1 Air

 2-Butanone has been detected in a limited number of sites in rural,

urban, and indoor locations. It was detected in 17 samples taken in

Tucson, Arizona, in 1982 at an average concentration of 2.8 ppb. In the

mountains of Arizona, the concentration was 0.50 ppb (Snider and Dawson

1985). The range 
74 

5. POTENTIAL FOR HUMAN EXPOSURE 

of 2-butanone measured in Los Angeles air in 1980 was.O-14 ppb in 70

samples (Grosjean 1982). 2-Butanone was found in one-third of samples

taken downwind of a solvent recycling facility in Maryland in 1970, at a

maximum concentration of 94 ppm (Smoyer et al. 1971). Although it has been

detected in the exhaust of gasoline engines, it was not found in the air

of a highway mountain tunnel (Hampton et al. 1982).

 2-Butanone was detected in the air of the Kin-But chemical waste 

site, located in New Jersey, at concentrations ranging from trace to 1.5

pg/m3 (0.51 ppb), and 0.5 to 33 μg/m3

 (0.17-11.3 ppb) in samples

surrounding the site (Pellizzari 1982). It was qualitatively detected in

the air at four of four hazardous waste sites and one landfill in New 

Jersey (LaRegina et al. 1986).

 In a survey of 36 homes taken in Chicago, Illinois, 2-butanone was

detected in the indoor air at 3 residences (Jarke et al. 1981). It was

also found in three outdoor samples in this survey. It is not clear,

however, if the positive indoor and outdoor samples were collected at the

same location. In a compilation and analysis of ambient monitoring data

collected from 1970 to 1987, the daily concentration of 2-butanone was 0

ppb in urban, suburban, and rural areas (Shah and Heyerdahl 1988). 2­

Butanone has been qualitatively detected in the indoor air of homes in

Chicago (Jarke et al. 1981) and in Canadian residential and office

buildings (Tsuchiya 1987).

 The sporadic ambient air monitoring data available for 2-butanone

suggest that the average background concentration of this compound may be

very low. However, the available data also suggest that there are

dramatic, temporal, and diurnal variations in its concentration. 

5.4.2 Water

 Numerous studies have qualitatively detected 2-butanone in drinking 

water supplies (Kool et al. 1982). It has been found in drinking water 

from the District of Columbia; Cincinnati, Ohio; Miami, Florida; Ottumwa,

Iowa; Philadelphia, Pennsylvania; Seattle, Washington; Tuscaloosa,

Alabama; and New Orleans, Louisiana (Bertsch et al. 1975; Coleman et al.

1976; EPA 1974, 1975; Kopfler et al. 1977; Scheiman et al. 1974). It was

detected in Des Moines, Iowa, drinking water samples at an estimated

concentration of 1.6 ppb (Ogawa and Fritz 1985). 2-Butanone was detected

in tap water 8 months after the installation of new polyvinyl chloride

(PVC) pipes at a concentration ranging from 0.4 to 4.5 ppm (Wang and

Bricker 1979). It resulted from the glue used to cement the water pipes

together. The concentration of 2-butanone in the water increased with the

amount of time the water sat in the pipes. 

2-Butanone has been qualitatively detected in rain water and the

clouds of Henninger, California, at 0.04 ppb, and in the mist of Long

Beach, California (Grosjean and Wright 1983). Trace amounts have also been

found in the ice in Fairbanks, Alaska (Grosjean and Wright 1983). 
75 

5. POTENTIAL FOR HUMAN EXPOSURE 

2-Butanone was listed as being detected in less than 5% of U.S.

groundwater supplies (Dyksen and Hess 1982). At U.S. hazardous waste

sites, 2-Butanone was listed as being frequently detected in the

groundwater (Garman et al. 1987). This statement should be interpreted

with caution, as "frequently" was defined as greater than 0.1%, of the

samples. 2-Butanone was detected in 180 groundwater samples from 357

hazardous waste sites monitored by the CLP at a geometric mean

concentration of 302 ppb in the positive samples (CLPSD 1988). Examples

of.the presence of 2-butanone at hazardous waste sites and landfills can

be found in Table 5-2. It was detected in groundwater samples underneath a

tanker truck spill at concentrations up to 2,200 ppm (Halvorsen and Ohneck

1985). Interpretation of the concentration of 2-butanone found in

groundwater samples should be made carefully, and should take into account

the experimental methods used in the determinations; results

may be skewed due to the presence of 2-butanone in the adhesives used to

cement PVC well pipes together (Sosebee et al. 1983).

 2-Butanone has been detected in the effluent of various industrial 

processes. It was found in six of seven waste water samples from

energyrelated processes at a concentration up to 645 ppb (Pellizzari et

al. 1979). 2-Butanone was detected in the waste water of a specialty

chemical manufacturing plant at a concentration of 8-20 ppm, but not in

the receiving river water or its sediment (Jungclaus et al. 1978). It was

also detected in the waste water from shale oil processing at a

concentration of 0.4-18 ppm (Hawthorne and Sievers 1984).In 1982, 2­

butanone was detected at concentrations of 83 ppb or less in the waste

water entering Cincinnati treatment plants (Dunovant et al. 1986). 

2-Butanone has been detected in 77 of 357 surface water samples at

U.S. hazardous waste sites at a geometric mean concentration of 11 ppb for

the positive samples (CLPSD 1988). It was qualitatively detected in the

Black Warrier River, located in Tuscaloosa, Alabama (Bertsch et al. 1975),

and in sea water from the straits of Florida at O-22 ppb in 1968 (Corwin

1969). 

5.4.3 Soil

 Limited data are available on the detection of 2-butanone in soil 

samples. It has been found in 309 of 357 hazardous waste sites monitored

by the CLP at a geometric mean concentration of 87 ppb for the positive

samples (CLPSD 1988). 

5.4.4 Other Environmental Media 

2-Butanone has been detected as a natural component of numerous

types of foods. It has been qualitatively identified as a volatile

constituent in raw chicken breast muscle, milk, roasted filberts (nuts),

Beaufort (Gruyere) and cheddar cheese, bread dough, and intact treeripened nectarines (Dumont and Adda 1978; Gordon and Morgan 1979; Grey and

Shrimpton 1967; Keen et al. 1974; 

77 

5. POTENTIAL FOR HUMAN EXPOSURE 

Kinlin et al. 1972; Sosulski and Mahmoud, 1979; Takeoka 'et al. 1988). The

mean concentration of 2-butanone in dried beans, split peas, and lentils

was 148, 110, and 50 ppm, respectively (Lovegren et al. 1979). 2-Butanone

has been detected in southern peas at a median concentration of 120 ppb

(Fisher et al. 1979), and it has been qualitatively detected in winged

beans and soybeans (Del Rosario et al. 1984). It has also been detected in

cigarette smoke (Higgins et al. 1983; Osborne et al. 1956). 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

 Available monitoring data suggest that the general population is

exposed to 2-butanone. In the early stages of the Total Exposure

Assessment Methodology (TEAM) study, 2-butanone was qualitatively detected

in 3 of 8 personal air samples, 5 of 12 breath samples, and 1 of 1

drinking water sample obtained from 12 volunteers living in urban areas of

New Jersey or North Carolina (Wallace et al. 1984). 2-Butanone has also

been detected in the expired air of 206 of 387 samples (53.2%) taken from

54 adult, nonsmoking, urban dwelling subjects, at an average concentration

of 3.6 ng/L (Krotoszynski et al. 1979). It was detected in the expired air

of six of eight male volunteers, three of whom were smokers (Conkle et al.

1975). 2-Butanone was found in 5 of 12 samples of human mothers' milk from

subjects in 4 different U.S. urban areas (Pellizzari et al. 1982). It has

been qualitatively detected in the indoor air of homes in Chicago (Jarke

et al. 1981) and in Canadian residential and office buildings (Tsuchiya

1987).

 Exposure to 2-butanone by the general population may occur by

ingestion of contaminated drinking water. This compound has been

identified in U.S. drinking water supplies (Bertsch et al. 1975; Coleman

et al. 1976; EPA 1974, 1975; Kopfler et al. 1977; Ogawa and Fritz 1985;

Scheiman et al. 1974). Inhalation is also a likely route of exposure to 2­

butanone, especially during the household use of commercial coatings that

use 2-butanone as a solvent. Exposure by dermal contact may also occur

during the use of such coatings.

 2-Butanone is a naturally occurring constituent in a variety of

common foods (Del Rosario et al. 1984; Dumont and Adda 1978; Gordon and

Morgan 1979; Grey and Shrimpton 1967; Keen et al. 1974; Kinlin et al.

1972; Lovegren et al. 1979; Takeoka et al. 1988). Ingestion of these foods

will result in exposure to 2-butanone. Exposure to 2-butanone may also

occur while smoking (Higgins et al. 1983; Osborne et al. 1956). Students

taking undergraduate general chemistry laboratory courses may be also

exposed to 2-butanone (Kolb 1988).

 According to the National Occupational Exposure Survey (NOES)

conducted by NIOSH between 1980 and 1983, 1,221,587 workers, of which

201,308 were women, were potentially exposed to 2-butanone during that

time period (NIOSH 1989). Of these workers, 84% (80% for the women) were

exposed during the use of trade name products containing 2-butanone.

Occupational exposure is expected to occur by inhalation and dermal

contact. 
78 

5. POTENTIAL FOR HUMAN EXPOSURE 

A study of three companies involved in spray painting and spray

gluing operations reported that, for 89 workers exposed to 2-butanone, the

mean air concentration was 0.3 ppm (Whitehead et al. 1984). 2-Butanone was

detected in the air of Cincinnati waste water treatment plants in 1982; 3

of 17 samples were positive at concentrations of 5.7 ppb or less (Dunovant

et al. 1986). It has also been detected in the air above shale oil waste

waters (Hawthorne and Sievers 1984). The breathing zone air for workers at

an organic solvent recycling plant averaged 11 ppm during drum decantation

operations, and 10 ppm during all other work activities (Kupferschmid and

Perkins 1986). The ambient concentration was not greater than exposure

limits of 200 ppm in any of these examples (NIOSH 1984). The

concentrations of 2-butanone in air samples obtained from the Skylab,

1973-74, ranged from 2.4 to 1,505 ppb (Liebich et al. 1975). Personal

exposure to 2-butanone at a waste solvent incineration facility ranged

from <O.Ol to 1.2 ppm (Decker et al. 1983). 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

For the general population, high levels of exposure to 2-butanone

may occur for those living near commercial settings where this compound is

used. For example, the downwind 2-butanone concentration near a solvent

recycling facility was measured at concentrations up to 94 ppm (Smoyer et

al. 1971). High levels of exposure may also occur during the use of

commercial coatings containing 2-butanone, especially when working in

enclosed, unventilated spaces. Members of the general population living

near hazardous waste sites and drawing their drinking water from

groundwater sources may be exposed to high levels of 2-butanone through

ingestion of contaminated water, although no information on the size of

the population can be provided. 

High levels of occupational exposure to 2-butanone may occur by inhalation

and dermal contact during the loading and unloading of large quantities of

this material during shipment. The application of commercial coatings

containing 2-butanone without adequate protection may also lead to high

levels of exposure, primarily by inhalation. 

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-butanone 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-butanone. 

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 
79 

5. POTENTIAL FOR HUMAN EXPOSURE 

the uncertainties of human health assessment. In the future, the

identified data needs will be evaluated and prioritized, and a substancespecific research agenda will be proposed. 

5.7.1 Data Needs 

Physical and Chemical Properties. The physical and chemical

properties of 2-butanone are well documented. The environmental fate of 2­

butanone can be predicted from these properties and compared to

experimental results once they are obtained in areas where deficiencies

exist. 

Production, Import/Export, Use, and Disposal. The significant

amounts of 2-butanone produced in the United States, combined with its

prevalence in commercial and household products, suggest that large

numbers of citizens are potentially exposed to,anthropogenic sources of

this $ompound. The production, use, and international trading of 2­

butanone is well described in the available literature (Chemical Marketing

Reporter 1987; Neir and Strehlke 1985; Papa and Sherman 1981; USITC 1987,

1988, 1989). Methods for the disposal of 2-butanone are established (HSDB

1989; OHM/TADS 1989), but the amounts processed by each method cannot be

ascertained. Therefore, disposal of 2-butanone cannot be compared to the

regulations controlling this practice. Knowing the amount of 2-butanone

released to the environment and its disposal pattern will aid in

determining routes and levels of exposure to the general population by

indicating which media should be monitored carefully. 

According to the Emergency Planning and Community Right-to-Know Act

of 1986, 42 U.S.C. Section 11023, industries are required to submit

chemical release and off-site transfer information to EPA. The Toxic 

Release Inventory (TRI), which contains this information for 1987, became

available in May of 1989. This database will be updated yearly and should

provide a list of industrial production facilities and emissions. 

Environmental Fate. There is sufficient predictive information to

indicate that 2-butanone is not likely to partition from water (Hansch and

Leo 1985; Lyman et al. 1982; Roy and Griffen 1985); yet, there are few

field studies to verify these predictions. Similarly, 2-butanone's

transport, transformation, and degradation in the environment can be

predicted (Atkinson 1985; Babeu and Vaishnav 1987; Cox et al. 1980;

Delfino and Miles 1985), but not as yet experimentally substantiated in

all areas. Experimental studies in this area would allow the determination

of 2-butanone's lifetime in the environment and aid in determining levels

and routes of human exposure.

 Bioavailability from Environmental Media. Numerous toxicokinetic and 

toxicity studies in humans and animals have demonstrated the

bioavailability of 2-butanone from air, ingestion of food and water, and

dermal contact. Absorption of 2-butanone after inhalation is well

established, and it appears to be adsorbed after ingestion. These

mechanisms are consistent with what one would expect, based on 2­

butanone's physical and chemical properties (Lyma 
80 

5. POTENTIAL FOR HUMAN EXPOSURE 

et al. 1982). Given the potential for exposure to 2-butanone because of

its prevalence in commercial products available to the public (Neier and

Strehlke 1985) and its ability to enter the immediate areas of the

environment (TRI 1989), further research on the bioavailability of this

compound will allow the quantification of human exposure and risk. 

Food Chain Bioaccumulation. 2-Butanone is not believed to 

appreciably bioconcentrate in fish and aquatic organisms (Hansch and Leo

1985; Lyman et al. 1982). It is also not expected to biomagnify in the

food chain. Quantitative data supporting these conclusions are not

available in the literature. Additional information on bioconcentration 

and biomagnification would be useful in confirming the predicted behavior

of this compound.

 Exposure Levels in Environmental Media. Data are available regarding

the level of 2-butanone in endronmental media (Grosjean and Wright 1983;

Shah and Heyerdahl 1988) and foods (Dumont and Adda 1978; Grey and

Shrimpton 1967; Kinlin et al. 1972; Lovegren et al. 1979; Takeoka et al.

1988); however, the data available are often qualitative and only

generalized trends regarding the occurrence of this compound can be

derived. Its presence in environmental media near hazardous waste sites is

not well documented (CLPSD 1988). Quantitative determination of the

levels of 2-butanone in environmental media and foods will allow the 

estimation of levels on human intake of this compound from each media. 

Exposure Levels in Humans. 2-Butanone has been found in the human 

blood samples of urban dwellers, but the observed levels have not been

correlated with personal activities. Studies on the level of 2-butanone in

human tissues near hazardous waste sites are not complete. A correlation

of the levels of 2-butanone in humans with their personal activities or

the areas where they live will allow an assessment of potential exposure

to the general population. Similarly, correlations of occupational

exposure by profession will allow a determination of human exposure

levels.

 Exposure Registries. No exposure registries for 2-butanone 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 National Exposure Registry facilitates the epidemiological research

needed to assess adverse health outcomes that may be related to the

exposure to the compound. 
81 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.7.2 On-going Studies 

On-going studies on water purification techniques and transformation

of 2-butanone in the environment have been identified (EPA 1989b),

although no specific information was provided. 

As part of the Third National Health and Nutrition Evaluation Survey

(NHANES III), the Environmental Health Laboratory Sciences Division of the

Center for Environmental Health and Injury Control, Centers for Disease

Control, will be analyzing human blood samples for 2-butanone and other

volatile organic compounds. These data will give an indication of the

frequency of occurrence and background levels of these compounds in the

general population. 

83 

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-butanone 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-butanone. 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-butanone 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 

Numerous procedures that detect-2-butanone in biological materials

have been reported in the literature. A summary of.these methods is found

in Table 6-l. In general, each technique appears to be capable of

determining 2-butanone in any type of biological matrix given suitable

modification of the sample collection/preparation step. 

Since 2-butanone is a volatile compound, analysis by headspace

sampling can be accomplished for both liquid matrices, such as blood and

urine (Deveaus and Huvenne 1987; Perbellini et al. 1984), and solid

matrices, such as soft tissue (Perbellini et al. 1984). For solid samples

such as soft tissue, better results are obtained if the sample is first

homogenized at low temperatures before analysis. The technique involves

gently heating the sample in a closed system, followed by withdrawing a

portion of the air above the sample (the headspace) by syringe. Separation

of 2-butanone from other compounds that may be present is then

accomplished by injecting the contents of the syringe directly into a gas

chromatograph (GC). As indicated in Table 6-2, successful quantification

of 2-butanone has been accomplished using a variety of detection systems,

including a flame ionization detector, mass spectrometer, or Fourier

transform infrared spectrometer. 

Analysis of 2-butanone in liquid samples can also be accomplished by

purge and trap methodology (Pellizzari et al. 1982). In this technique, an

inert gas is bubbled through the sample, liberating 2-butanone. The

contaminant is then trapped on an adsorbent cartridge, followed by thermal

desorption directly into a gas chromatograph (GC). This technique has been

successfully used for analysis of human milk samples (Pellizzari et al.

1982) 

Extractive techniques can also be used for the analysis of 2­

butanone in liquid samples (Kezic and Monster 1988; Van Doorn et al.

1989). The sample is shaken with an immiscible organic solvent into which

2-butanone partitions. 


86 

6. ANALYTICAL METHODS 

After concentrating the extract, the sample can be analyzed by different

methods. 2-Butanone can first be derivitized to increase its extraction 

efficiency, or to make it more visible to the detection system. 

Numerous types of detection and quantitation methods have been used

in the analysis of 2-butanone in biological samples. Gas chromatography

has been used to separate 2-butanone from other contaminants that may be

present. Direct quantitation can be made by using a flame ionization

detector (FID), tandem gas chromatography-mass spectrometry (GC-MS), or

tandem GC-fourier transform infrared spectrometry (GC-FTIR). The latter

two techniques also allow direct identification of the contaminants.

Analysis of derivitized 2-butanone can be accomplished using highperformance liquid chromatography (HPLC) equipped with an ultraviolet (WV)

detector. These detection systems are capable of measuring 2-butanone in

the sub-ppm range; the limits on the GC-FTIR system are slightly greater

than 1 ppm. 

Given the numerous techniques available for the determination of

2-butanone in biological samples, and the lack of any standardized method

for each individual matrix, the choice of an analysis technique appears to

be a function of the instrumentation and personal biases of the laboratory

performing the analysis. With the exception of the derivitization method,

all of the techniques described above are also capable of determining the

metabolites of 2-butanone (3-hydroxy-2-butanone, 2-butanol, and 2,3­

dihydroxybutane) in biological samples. 

6.2 ENVIRONMENTAL SAMPLES 

A short description of standardized methods that can be used for the

analysis of 2-butanone in environmental samples is presented in Table 6-2.

It should be noted that an extensive list of methods for the analysis of

2-butanone in environmental samples can be compiled from the literature.

In all of these methods, however, there is a consensus that, after the

sample preparation stage, mixture separation and quantitative analysis are

best determined by the use of a gas chromatograph coupled with any of an

assortment of detectors (Bertsch et al. 1975; Coleman et al. 1976; Corwin

1969; Dunovant et al. 1986; Hawthorne and Sievers 1984; Isidorov et al.

1985; Jonsson et al. 1985; Jungclaus et al. 1978; LaRegina et al. 1986;

Pellizzari 1982; Sawhney and Kozloski 1984; Smoyer et al. 1971; Snider and

Dawson 1985; Wallace et al. 1984; Wang and Bricker 1979).

 The analysis of 2 butanone in air can be accomplished by NIOSH method

2500 (NIOSH 1984). The sample is obtained in the field by the use of a

pumping system to pass a measurable quantity of air (approximately l-12 L)

through a tube loaded with a solid sorbent, Ambersorb XE-347. Extraction

of the tube with the solvent carbon disulfide liberates the 2-butanone,

and quantitation is achieved by GC using a flame ionization detector. 
87 

6. ANALYTICAL METHODS 

The analysis of 2-butanone in soil, sediment, and water samples at

hazardous waste sites is described in the Contract Laboratory Program

manual (EPA 1988). For the soil and sediment samples, the procedure begins

with the addition of a small portion of water to the sample. At this

point, all three matrices are subjected to a purge and trap cycle. An

inert gas is bubbled through the sample, volatilizing 2-butanone. The gas

stream is then passed through an adsorbent tube that recollects the 2­

butanone. The sorbent tube is attached to a gas chromatograph and heated

to flush the sample onto a GC column. Quantification can be accomplished

using either a flame ionization detector or a mass spectrometer, depending

on the total concentration of organics in the sample. Required

quantitation limits for this program are 10 ppm in all three matrices. No

other standardized methods for the determination of 2-butanone in 

environmental samples were located. 

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-butanone is available. Uhere 

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-butanone.

 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 substancespecific research agenda will be proposed. 

6.3.1 Data Needs

 Methods for Determining Biomarkers of Exposure and Effect. Numerous 

methods for the determination of 2-butanone in biological materials have

been described in the literature (Deveaux and Huvenne 1987; Kezic and

Monster 1988; Pellizzari et al. 1982; Perbellini et al. 1984; Van Doorn et

al. 1989). These methods are also appropriate for determining the

metabolites of 2-butanone, 3-hydroxy-2-butanone, 2-butanol, and 2,3­

dihydroxybutane, which also serve as biomarkers of exposure. These methods

display the requisite sensitivity to measure background levels in the

population and levels which may indicate a concern for biological effects.

Standardized methods for these procedures should be established as no

standardized methods could be located. Any methodology established for

determining biomarkers of exposure must take into account the short

biological half-life of 2-butanone, which may render these methods

inferior to direct measurements of exposure. 
88 

6. ANALYTICAL METHODS 

There are no known biomarkers of effect which are specific to 2-butanone. 

Methods for Determining Parent Compounds and Degradation Products in

Snvironmental Media. Numerous methods capable of detecting low levels of

2-butanone in environmental media have been described in the literature 

(Bertsch et al. 1975; Dunovant 1985; Hawthorne and Sievers 1984; LaRegina

et al. 1986; Pellizzari 1982; Wallace et al. 1984). Appropriate

standardized methods are available for the determination of 2-butanone in 

air (NIOSH 1984), water, soil, and sediments (EPA 1988) at levels that may

constitute a concern for human health. The methods for determining 2­

butanone in air, the medium that represents the most concern for exposure,

are highly sensitive, accurate, and reproducible. The exact levels of

detection for these methods in all media, however, are not described.

There are numerous reliable methods available in the literature that have 

been used to determine levels of 2-butanone in environmental media and 

foods at levels that may cause health effects to occur, but they have not

been standardized. 

6.3.2 On-going Studies 

The Environmental Health Laboratory Sciences Division of the Center

for Environmental Health and Injury Control, Centers for Disease Control,

is developing methods for the analysis of 2-butanone and other volatile

organic compounds in blood, These methods use purge and trap methodology

and magnetic sector mass spectrometry which gives detection limits in the

low parts per trillion range.

 On-going studies involving the development of analytical methods

have been identified (EPA 1989b), although no specific information was

provided. 
89 

7. REGULATIONS AND ADVISORIES

 International (World Health Organization) guidelines for 2-butanone

were not located. National and state regulations and guidelines pertinent

to human exposure to 2-butanone are summarized in Table 7-1. 

____________________ 

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pre-hospital care, 2nd ed. Beltsville MD: Bradford Communications

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*Swarm RL, Laskowski DA, McCall PJ, et al. 1983. A rapid method for the

estimation of the environmental parameters octanol/water partition

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*Takeoka GR, Flath RA, Guntert M, et al. 1988. Nectarine volatiles: Vacuum

steam distillation versus headspace sampling. J Agric Food Chem 36:553

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*Takeuchi Y, Ono Y, Hisanaga N, et al. 1983. An experimental study of the

combined effects of n-hexane and methyl ethyl ketone. Br J Ind Med

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*Tanii H, Tsuji H, Hashiomoto K. 1986. Structure-toxicity relationship of

monoketones. Toxicol Lett (AMST) 30:13-18. 

*Tewari YB, Miller MM, Wasik SP, et al. 1982. Aqueous solubility and

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Eng Data 27:451-454. 

Tham R, Bunnfors I, Eriksson B, et al. 1984. Vestibulo-ocular disturbances

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*Thorpe E. 1982. Toxicity studies with chemical solvents: short-term in

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*Tichenor BA. 1987. Organic emission measurements via small chamber

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*Tichenor BA, Mason MA. 1988. Organic emissions from consumer products and

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38:264-268. 

*Toftgard R, Nilsen 0, Gustafsson J-A. 1981. Changes in rat liver

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weeks. Stand J Work, Environ Health 7:31-37. 
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*Tolos W, Setzer J, MacKenzie B, et al. 1987. Biological monitoring of

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toluene. In: Ho M, Dillon H, ed., Biological monitoring of exposure to

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*TRI. 1989. Toxic Release Inventory. National Library of Medicine,

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Truong KN, Blackburn JW. 1984. The stripping of organic chemicals in

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*Tsuchiya Y, 1987. Volatile organic compounds in indoor air, New Orleans,

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*Tsukamoto S, Chiba S, Muto T, et al. 1985a. Study on the metabolism of

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*Urano K, Kato 2. 1986. Evaluation of biodegradation ranks of priority

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*Wen C, Tsai S, Weiss N, et al. 1985. Long-term mortality study of oil

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115 

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. 
116 

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 vivo -- Occurring within the living organism. 

Lethal Concentration (Lo)(LC(Lo) -- The lowest concentration of a chemical in 

air which has been reported to have caused death in humans or animals. 

Lethal Concentration(50) (LC50) -- 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(Lo) (LDLo) -- 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(50) (LD50) -- The dose of a chemical which has been calculated 

to cause death in 50% of a defined experimental animal population. 

Lethal Time(50) (LT(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. 
117 

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 doseresponse curve as determined by the multistage procedure. The ql* can 

be used to calculate an estimate of carcinogenic potency, the

incremental excess cancer risk per unit of exposure (usually ug/L for

water, mg/kg/day for food, and μg/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 nn a

professional judgment of the entire database on the chemical. The RfD

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 CERCLA 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 bedire.cted 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. 
118 

9. GLOSSARY 

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. 

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-Observed- Adverse-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, Minimai

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 2-1 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 2-1) and oral (LSE Figure 2-2) routes. 

(2)	 Exposure 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 Freauency/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 18), rats were exp'osed 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 Wc"). 

(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 ppm in key number 18 was used to derive an MRL of 0.005 ppm. 

LEGEND 

See LSE Figure 2-1 

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

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 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 e

the LSE table. 
A-4 

APPENDIX A 

(18). Estimated UDDer-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 derive.d 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-of-evidence 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 aquainthealth 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-butanone. The panel consisted of

the following members: Dr. Michael Norvell, Private Consultant, Ringoes,

New Jersey; Dr. Rolf Hartung, Department of Environmental and Industrial

Health, University of Michigan, Ann Arbor, Michigan; and Dr. Vincent

Garry, Director, Laboratory for Environmental Medicine and Pathology,

University of Minnesota, Minneapolis, Minnesota. These experts

collectively have knowledge of 2-butanone'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 the Comprehensive Environmental Response, Compensation, and

Liability Act of 1986, Section 104. 

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. 

‘U.S. Government Printing Wca: 1992- 636-281