Toxicological Profile for

2-Butanone

October 2020
2-BUTANONE ii

DISCLAIMER 

Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic 

Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human 

Services. 
2-BUTANONE iii

FOREWORD 

This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for these toxic substances described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented, but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; however, more comprehensive sources of specialty information are referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a relevance to public health discussion which would allow a public health professional to 

make a real-time determination of whether the presence of a particular substance in the environment 

poses a potential threat to human health. The adequacy of information to determine a substance's health 

effects is described in a health effects summary. Data needs that are of significance to the protection of 

public health are identified by ATSDR. 

Each profile includes the following:

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a toxic substance to ascertain the levels of significant 

human exposure for the substance due to associated acute, intermediate, and chronic 

exposures; 

(B) A determination of whether adequate information on the health effects of each substance 

is available or in the process of development to determine levels of exposure that present 

a significant risk to human health of acute, intermediate, and chronic health effects; and

(C) Where appropriate, identification of toxicologic testing needed to identify the types or 

levels of exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

local levels; interested private sector organizations and groups; and members of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR.

Patrick N. Breysse, Ph.D., CIH

Director, National Center for Environmental Health and

Agency for Toxic Substances and Disease Registry 

Centers for Disease Control and Prevention

Christopher M. Reh, Ph.D. 

Associate Director

Agency for Toxic Substances and Disease Registry 

Centers for Disease Control and Prevention
2-BUTANONE iv

*Legislative Background 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to “...effectuate and implement the health related 

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that 

pose the most significant potential threat to human health, as determined by ATSDR and the EPA. 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a 

toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare 

toxicological profiles for substances not found at sites on the NPL, in an effort to “...establish and 

maintain inventory of literature, research, and studies on the health effects of toxic substances” under 

CERCLA Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as 

otherwise necessary to support the site-specific response actions conducted by ATSDR. 
2-BUTANONE v

VERSION HISTORY

Date Description

October 2020 Final toxicological profile released

May 2019 Draft for public comment toxicological profile released

December 2010 Addendum to the toxicological profile released

July 1992 Final toxicological profile released
2-BUTANONE vi

CONTRIBUTORS & REVIEWERS 

CHEMICAL MANAGER TEAM

G. Daniel Todd, Ph.D. Julie Melia, Ph.D., D.A.B.T.

Jenny S. Crisman, B.S.

Lisa D. Ingerman, Ph.D., D.A.B.T

David W. Wohlers, Ph.D.

ATSDR, Office of Innovation and Analytics, 

Toxicology Section, Atlanta, GA 

SRC, Inc., North Syracuse, NY

REVIEWERS

Interagency Minimal Risk Level Workgroup: 

Includes ATSDR; National Center for Environmental Health (NCEH); National Institute for 

Occupational Safety and Health (NIOSH); U.S. Environmental Protection Agency (EPA); National 

Toxicology Program (NTP). 

Additional reviews for science and/or policy: 

ATSDR, Office of Community Health and Hazard Assessment; ATSDR, Office of Capacity 

Development and Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of 

Laboratory Science; NCEH, Division of Environmental Health Science and Practice.

PEER REVIEWERS

1. G.A. Shakeel Ansari, Ph.D.; Professor, Department of Pathology; University of Texas Medical

Branch; Galveston, Texas

2. F. Peter Guengerich, Ph.D.; Tadashi Inagami Professor of Biochemistry; Department of

Biochemistry; Vanderbilt University School of Medicine; Nashville, Tennessee

3. Dale Hattis, Ph.D.; Research Professor, George Perkins Marsh Institute; Clark University;

Worcester, Massachusetts

These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers 

were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, 

Compensation, and Liability Act, as amended. 

ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the 

profile based on comments. The peer reviewers’ comments and responses to these comments are part of 

the administrative record for this compound. 

The listing of peer reviewers should not be understood to imply their approval of the profile's final 

content. The responsibility for the content of this profile lies with ATSDR.
2-BUTANONE vii

CONTENTS

DISCLAIMER..............................................................................................................................................ii

FOREWORD...............................................................................................................................................iii

VERSION HISTORY...................................................................................................................................v

CONTRIBUTORS & REVIEWERS...........................................................................................................vi

CONTENTS................................................................................................................................................vii

LIST OF FIGURES .....................................................................................................................................ix

LIST OF TABLES........................................................................................................................................x

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................1

1.1 OVERVIEW AND U.S. EXPOSURES.........................................................................................1

1.2 SUMMARY OF HEALTH EFFECTS...........................................................................................1

1.3 MINIMAL RISK LEVELS (MRLs)..............................................................................................7

CHAPTER 2. HEALTH EFFECTS...........................................................................................................10

2.1 INTRODUCTION........................................................................................................................10

2.2 DEATH ........................................................................................................................................27

2.3 BODY WEIGHT..........................................................................................................................27

2.4 RESPIRATORY ..........................................................................................................................28

2.5 CARDIOVASCULAR.................................................................................................................30

2.6 GASTROINTESTINAL...............................................................................................................31

2.7 HEMATOLOGICAL ...................................................................................................................31

2.8 MUSCULOSKELETAL..............................................................................................................31

2.9 HEPATIC.....................................................................................................................................32

2.10 RENAL ........................................................................................................................................33

2.11 DERMAL.....................................................................................................................................33

2.12 OCULAR .....................................................................................................................................34

2.13 ENDOCRINE...............................................................................................................................35

2.14 IMMUNOLOGICAL ...................................................................................................................35

2.15 NEUROLOGICAL.......................................................................................................................36

2.16 REPRODUCTIVE .......................................................................................................................39

2.17 DEVELOPMENTAL...................................................................................................................40

2.18 OTHER NONCANCER...............................................................................................................42

2.19 CANCER......................................................................................................................................42

2.20 GENOTOXICITY........................................................................................................................43

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL 

INTERACTIONS...............................................................................................................46

3.1 TOXICOKINETICS.....................................................................................................................46

3.1.1 Absorption.............................................................................................................................46

3.1.2 Distribution ...........................................................................................................................48

3.1.3 Metabolism............................................................................................................................49

3.1.4 Excretion ...............................................................................................................................50

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models.............51

3.1.6 Animal-to-Human Extrapolations.........................................................................................54

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.....54

3.3 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................55

3.3.1 Biomarkers of Exposure........................................................................................................56
2-BUTANONE viii

3.3.2 Biomarkers of Effect.............................................................................................................57

3.4 INTERACTIONS WITH OTHER CHEMICALS .......................................................................57

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................64

4.1 CHEMICAL IDENTITY .............................................................................................................64

4.2 PHYSICAL AND CHEMICAL PROPERTIES ..........................................................................64

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE........................................................................66

5.1 OVERVIEW ................................................................................................................................66

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ..................................................68

5.2.1 Production .............................................................................................................................68

5.2.2 Import/Export........................................................................................................................69

5.2.3 Use ........................................................................................................................................70

5.2.4 Disposal.................................................................................................................................70

5.3 RELEASES TO THE ENVIRONMENT.....................................................................................70

5.3.1 Air .........................................................................................................................................71

5.3.2 Water.....................................................................................................................................71

5.3.3 Soil ........................................................................................................................................72

5.4 ENVIRONMENTAL FATE ........................................................................................................72

5.4.1 Transport and Partitioning.....................................................................................................72

5.4.2 Transformation and Degradation ..........................................................................................73

5.5 LEVELS IN THE ENVIRONMENT...........................................................................................75

5.5.1 Air .........................................................................................................................................76

5.5.2 Water.....................................................................................................................................77

5.5.3 Sediment and Soil .................................................................................................................79

5.5.4 Other Media ..........................................................................................................................79

5.6 GENERAL POPULATION EXPOSURE....................................................................................79

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ................................................81

CHAPTER 6. ADEQUACY OF THE DATABASE.................................................................................83

6.1 INFORMATION ON HEALTH EFFECTS.................................................................................83

6.2 IDENTIFICATION OF DATA NEEDS......................................................................................85

6.3 ONGOING STUDIES..................................................................................................................92

CHAPTER 7. REGULATIONS AND GUIDELINES ..............................................................................93

CHAPTER 8. REFERENCES ...................................................................................................................95

APPENDICES

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS ....................................................A-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR 2-BUTANONE.................................B-1

APPENDIX C. USER’S GUIDE.............................................................................................................C-1

APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS.......................................D-1

APPENDIX E. GLOSSARY ................................................................................................................... E-1

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ..................................................F-1
2-BUTANONE ix

LIST OF FIGURES

1-1. Health Effects Found in Humans and Animals Following Inhalation Exposure to 2-Butanone ..........2

1-2. Health Effects Found in Animals Following Oral Exposure to 2-Butanone ........................................3

1-3. Summary of Sensitive Targets of 2-Butanone – Inhalation..................................................................8

1-4. Summary of Sensitive Targets of 2-Butanone – Oral...........................................................................8

2-1. Overview of the Number of Studies Examining 2-Butanone Health Effects.....................................12

2-2. Levels of Significant Exposure to 2-Butanone – Inhalation...............................................................18

2-3. Levels of Significant Exposure to 2-Butanone – Oral........................................................................24

3-1. Proposed Metabolic Pathways for 2-Butanone...................................................................................50

5-1. Number of NPL Sites with 2-Butanone Contamination .....................................................................66

6-1. Summary of Existing Health Effects Studies on 2-Butanone By Route and Endpoint ......................84
2-BUTANONE x

LIST OF TABLES

1-1. Minimal Risk Levels (MRLs) for 2-Butanone .....................................................................................9

2-1. Levels of Significant Exposure to 2-Butanone – Inhalation...............................................................13

2-2. Levels of Significant Exposure to 2-Butanone – Oral........................................................................22

2-3. Levels of Significant Exposure to 2-Butanone – Dermal...................................................................26

2-4. Genotoxicity of 2-Butanone In Vivo...................................................................................................43

2-5. Genotoxicity of 2-Butanone In Vitro..................................................................................................44

4-1. Chemical Identity of 2-Butanone........................................................................................................64

4-2. Physical and Chemical Properties of 2-Butanone...............................................................................64

5-1. Facilities that Produce, Process, or Use 2-Butanone ..........................................................................69

5-2. Lowest Limit of Detection Based on Standards.................................................................................75

5-3. Summary of Environmental Levels of 2-Butanone ............................................................................76

5-4. 2-Butanone Levels in Water, Soil, and Air of National Priorities List (NPL) Sites...........................76

5-5. 2-Butanone Detected in Samples Collected Throughout the United States from 2010 to 2020.........78

7-1. Regulations and Guidelines Applicable to 2-Butanone......................................................................93
2-BUTANONE 1

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

1.1 OVERVIEW AND U.S. EXPOSURES

2-Butanone, also referred to as methyl ethyl ketone or MEK, is a common industrial solvent. Examples 

of specific applications include its use as a solvent for paints, lacquers, rubber cement, printing inks, paint 

removers, vinyl films, resins, rosins, polystyrene, chlorinated rubber, polyurethane, acrylic coatings, and 

cleaning solutions (Neier and Strehlke 1985; NLM 2020; 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 of lubricating oils, and as a solvent 

for the production of smokeless powders used as ammunition propellants.

2-Butanone is detected in environmental media, although usually at low levels. 2-Butanone is expected to 

rapidly volatilize from surface water and moist or dry soils and exists as a vapor in the atmosphere. 

2-Butanone displays a high mobility in soil and leaches readily into groundwater. 2-Butanone does not 

adsorb strongly to soils and sediments or bioconcentrate in aquatic organisms. The most likely routes of 

2-butanone exposure for the general public include ingestion of food, ingestion of contaminated drinking 

water, inhalation during household use of coating products, and dermal contact during the use of these 

products. High levels of occupational exposure to 2-butanone may occur by inhalation and dermal 

contact during the loading and unloading of large quantities of commercial coating materials during 

shipment. The application of commercial coatings containing 2-butanone without adequate protection 

may also lead to high levels of exposure, primarily by inhalation.

1.2 SUMMARY OF HEALTH EFFECTS

Information on the toxicity of 2-butanone comes primarily from inhalation studies in humans and 

laboratory animals and a limited number of oral studies in animals. The effects of 2-butanone in humans 

include neurological symptoms (headache, fatigue, feeling of intoxication) and mucous membrane 

irritation of the eyes, nose, and throat. Effects observed in animals include death, irritation of respiratory 

tissue, eyes, and skin, liver congestion, kidney congestion, corneal opacity, narcosis and incoordination, 

and fetotoxicity. As illustrated in Figure 1-1, clinical signs of neurotoxicity in humans (i.e., headache, 

fatigue, feeling of intoxication) and mucous membrane irritation (eyes, nose and throat) are the most 

sensitive effects in humans exposed by inhalation. Figure 1-2 illustrates that renal toxicity is the most 

sensitive effect following oral exposure in animals; however, studies of toxicity by the oral route are 
2-BUTANONE 2 

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-1. Health Effects Found in Humans and Animals Following Inhalation 

Exposure to 2-Butanone
2-BUTANONE 3 

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-2. Health Effects Found in Animals Following Oral Exposure to 

2-Butanone

1,080 Acute: Renal tubular necrosis

Acute: CNS depression, death

Dose (mg/kg/day) Effects in Animals

2,700-4,000
2-BUTANONE 4 

1. RELEVANCE TO PUBLIC HEALTH

generally lacking. Environmental exposure levels are typically lower than the concentrations used in 

animal studies.

Respiratory Effects. 2-Butanone is irritating to respiratory tissues. Upper respiratory tract irritation was 

noted in a case report of a patient with occupational 2-butanone exposure (concentration data were not 

reported) (Callender 1995). 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). Male and female volunteers exposed to 100 ppm 

2-butanone complained of slight nose and throat irritation, which became objectionable at 350 ppm 

(Nelson et al. 1943). Tomicic et al. (2011) also reported nose and throat irritation during a 6-hour 

exposure to 100 ppm 2-butanone with female subjects reporting higher symptom ratings than male 

subjects. Other studies reported the absence of an irritation effect in volunteers at concentrations up to 

200 ppm (Muttray et al. 2002; Seeber et al. 2002; van Thriel et al. 2002); however, these studies were 

conducted in male subjects only. Sensory irritation effects were seen in mice exposed to 2-butanone 

concentrations ≥3,809 ppm. A time- and concentration-dependent decrease in respiratory rate and tidal 

volume was observed (Hansen et al. 1992). Severe respiratory and eye irritation occurred in rats and 

guinea pigs exposed to 2-butanone concentrations ≥10,000 ppm (Altenkirch et al. 1978; Patty et al. 1935). 

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 exposure to 2-butanone are 

minimal. Liver congestion was found in guinea pigs exposed acutely by inhalation to ≥10,000 ppm (Patty 

et al. 1935). Serum concentrations of hepatic enzymes were not changed in rats after 2-butanone 

exposures of 300–5,000 ppm for 1–12 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). 

Exposure of female rats to 3,000 ppm (but not 1,000 ppm) 2-butanone for 15 days increased absolute and 

relative liver weight, but did not affect serum chemistry parameters (alanine transaminase [ALT], 

aspartate transaminase [AST], urea, and creatinine) or liver histopathology (Saillenfait et al. 2006). 

Relative liver weight was also increased in male rats exposed to 800 ppm 2-butanone for 4 weeks 

(Toftgard et al. 1981) and pregnant mice exposed to 3,000 ppm 2-butanone on gestation days (GDs) 6–15 

(NTP 1989; Schwetz et al. 1991). Liver weight increases in rodent studies may be related to induction of 

cytochrome P450 (CYP). 
2-BUTANONE 5

1. RELEVANCE TO PUBLIC HEALTH

2-Butanone alone is not highly hepatotoxic, but has a well-documented role in potentiating the 

hepatotoxicity of haloalkane compounds including chloroform and carbon tetrachloride (Brown and 

Hewitt 1984; Dietz and Traiger 1979; Hewitt et al. 1983, 1986, 1987; Tanii et al. 1986). 

Renal Effects. No studies were located regarding renal effects in humans after inhalation, oral, or dermal 

exposure to 2-butanone. Kidney congestion was found in guinea pigs exposed acutely by inhalation to 

≥10,000 ppm (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 90-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 a single gavage dose of 1,080 mg/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. Kidney toxicity in rats exposed to 

chloroform, assessed by a decreased accumulation of p-aminohippuric acid in renal cortical slices, was 

potentiated in rats that were pretreated with 2-butanone for 3 days prior to chloroform exposure 

(Raymond and Plaa 1995a).

Neurological Effects. Neurological symptoms were reported in some volunteer studies, but the results of 

neurobehavioral testing were similar to unexposed controls. Headache, fatigue, and feeling of 

intoxication were noted in volunteer subjects exposed to 100 ppm 2-butanone for 4 hours, with females 

scoring higher on symptom questionnaires compared with men (Tomicic et al. 2011). Headache and 

nausea were also reported by male subjects 2 hours after exposure to 200 ppm, compared with preexposure ratings (Muttray et al. 2002). In four separate studies, volunteers underwent a single 4-hour 

exposure to 200 ppm 2-butanone (Dick et al. 1984, 1988, 1989, 1992). 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. Regression analyses showed a significant linear relationship between blood concentrations of 

2-butanone in females and a small increase in the number of incorrect responses on the auditory portion 

of the dual task test (Dick et al. 1992).

Narcosis and incoordination were also observed in guinea pigs exposed to ≥10,000 ppm 2-butanone in air 

for a few hours (Patty et al. 1935). Juvenile baboons exposed continuously to 100 ppm for 7 days showed 

delayed reaction times in neurobehavioral tests (Geller et al. 1979). The neurological effects observed in 

this study could have resulted from narcosis or it is also possible that the baboons were distracted during 

the testing due to the irritating effects of 2-butanone on the respiratory system. Rats continuously 
2-BUTANONE 6

1. RELEVANCE TO PUBLIC HEALTH

exposed to 1,125 ppm for 5 months showed no signs of peripheral neuropathy on histological 

examination (Saida et al. 1976). Altenkirch et al. (1978) 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). No neurological effects were observed in rats after oral 

exposure to 1,725 mg/kg for 90 days (Ralston et al. 1985). 

2-Butanone potentiates the neurotoxicity of ethanol, n-hexane, methyl-n-butyl 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 n-hexane 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. 

Ocular Effects. 2-Butanone is irritating to the eyes. Mild eye irritation was noted in some volunteers 

exposed to 200 ppm 2-butanone for 3–5 minutes (Nelson et al. 1943). Discomfort in the eyes was also 

reported in human subjects exposed to 100 ppm 2-butanone for 6 hours, with females scoring 

significantly higher on symptom questionnaires compared to male subjects (Tomicic et al. 2011). Eye 

irritation was not reported in male subjects exposed to 2-butanone vapor for 4 hours under constant 

(10 ppm) or changing exposure conditions (peaks up to 380 ppm; time-weighted average [TWA] of 

189 ppm) (Seeber et al. 2002; van Thriel et al. 2002). 

Guinea pigs exposed to 2-butanone concentrations ≥10,000 ppm had eye irritation and lacrimation (Patty 

et al. 1935). Exposure to 100,000 ppm for ≥30 minutes caused corneal 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 of 2-butanone for 90 days (Cavender and Casey 

1981; Cavender et al. 1983).

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 or 

4,000 ppm during gestation resulted in fetotoxic effects, such as reduced fetal weight, skeletal variations, 

and delayed or incomplete ossification (Deacon et al. 1981; NTP 1989; Saillenfait et al. 2006; Schwetz et 

al. 1974). Delayed brain development was also observed in offspring exposed continuously 
2-BUTANONE 7

1. RELEVANCE TO PUBLIC HEALTH

(23 hours/day) throughout gestation (Stoltenburg-Didinger 1991). 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 suggests that such effects might occur in 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). An occupational cohort study of aircraft maintenance workers reported a 

statistically significant elevated rate ratio (RR) for multiple myeloma in females; however, the number of 

2-butanone exposed cases in the cohort was very small (Blair et al. 1998; Radican et al. 2008; Spirtas et 

al. 1991). Two case-control studies evaluated the relationship between 2-butanone exposure and 

childhood leukemia (Gao et al. 2014; Infante-Rivard et al. 2005). One study demonstrated an increased 

odds ratio (OR) for the relationship between measured household 2-butanone exposure and the diagnosis 

of acute childhood leukemia (Gao et al. 2014). The Infante-Rivard et al. (2005) study determined that 

case mothers were more often exposed to 2-butanone than control mothers (exposure coding by job title 

and household exposure); however, the number of cases exposed to 2-butanone was very low. No other 

studies were located regarding cancer in humans or animals following inhalation exposure to 2-butanone.

1.3 MINIMAL RISK LEVELS (MRLs)

The inhalation database was considered adequate for derivation of an acute-duration MRL, but inadequate 

for derivation of intermediate- or chronic-duration MRLs. As presented in Figure 1-3, the available acute 

inhalation data for 2-butanone indicate that the neurological effects are sensitive targets of toxicity. 

Clinical signs of neurotoxicity in humans (i.e., headache, fatigue, feeling of intoxication) and 

neurobehavioral effects in primates were reported at low concentrations. Respiratory and ocular irritation 

are also sensitive targets of toxicity in humans. In the case of intermediate- and chronic-duration 

exposure, target organs have not been sufficiently identified. In addition, nose, throat and eye irritation 

occurred in humans at exposure levels that were much lower than no-observed-adverse-effect level 

(NOAEL) values in animals in intermediate-duration studies. No studies were located regarding toxic 

effects in humans or animals after chronic inhalation exposure, precluding the derivation of a chronic 

inhalation MRL. 
2-BUTANONE 8

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-3. Summary of Sensitive Targets of 2-Butanone – Inhalation

Ocular, respiratory and neurological are the most sensitive targets of 2-butanone inhalation 

exposure.

Numbers in triangles and circles are the lowest LOAELs among health effects in humans and animals, 

respectively.

No acute, intermediate-, or chronic-duration oral MRLs were derived for 2-butanone. In the case of 

acute-duration oral exposure, target organs have not been sufficiently identified (see Figure 1-4). The 

paucity of information on toxic effects after intermediate- and chronic-duration oral exposure likewise 

precludes the derivation of MRLs for these durations.

Figure 1-4. Summary of Sensitive Targets of 2-Butanone – Oral

Renal is the most sensitive target of 2-butanone oral exposure. 

Numbers in circles are the lowest LOAELs for all health effects in animals.

No reliable dose response data were available for humans.
2-BUTANONE 9

1. RELEVANCE TO PUBLIC HEALTH

The acute-duration inhalation MRL value is summarized in Table 1-1 and discussed in greater detail in 

Appendix A.

Table 1-1. Minimal Risk Levels (MRLs) for 2-Butanonea

Exposure 

duration MRL Critical effect

Point of departure/ 

human equivalent 

concentration

Uncertainty

and modifying 

factor Reference

Inhalation exposure (ppm)

Acute 1 Neurological effects 

(headache, fatigue, 

feeling of intoxication)

LOAEL: 99.15 UF: 100 Tomicic et al. 

2011

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information. 

LOAEL = lowest-observed-adverse-effect level; UF = uncertainty factor
2-BUTANONE 10

CHAPTER 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 on the toxicology of 2-butanone. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

When available, mechanisms of action are discussed along with the health effects data; toxicokinetic 

mechanistic data are discussed in Section 3.1. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

To help public health professionals and others address the needs of persons living or working near hazardous 

waste sites, the information in this section is organized by health effect. These data are discussed in terms of 

route of exposure (inhalation, oral, and dermal) and three exposure periods: acute (≤14 days), intermediate 

(15–364 days), and chronic (≥365 days).

As discussed in Appendix B, a literature search was conducted to identify relevant studies examining health 

effect endpoints. Figure 2-1 provides an overview of the database of studies in humans or experimental 

animals included in this chapter of the profile. These studies evaluate the potential health effects associated 

with inhalation, oral, or dermal exposure to 2-butanone, but may not be inclusive of the entire body of 

literature. 

Animal inhalation studies are presented in Table 2-1 and Figure 2-2, and animal oral studies are presented 

in Table 2-2 and Figure 2-3. Animal dermal studies are presented in Table 2-3.

Levels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-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. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 
2-BUTANONE 11

2. HEALTH EFFECTS

considerable amount of judgment may be required in establishing whether an endpoint should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these endpoints. ATSDR believes 

that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less 

serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

A User's Guide has been provided at the end of this profile (see Appendix C). This guide should aid in 

the interpretation of the tables and figures for LSEs and MRLs.

Human and laboratory animal studies, primarily by the inhalation route, suggest potential associations 

between 2-butanone exposure and the following health outcomes:

• Neurological endpoint: Symptoms of neurotoxicity were reported in volunteers and 

neurobehavioral effects have been observed in laboratory animals.

• Respiratory endpoint: Nose and throat irritation were reported in volunteers exposed to 

2-butanone. Respiratory irritation was also seen in laboratory animal studies at high 

concentrations.

• Liver endpoint: Liver congestion and increased organ weight were observed in laboratory 

animal studies only. No data are available in humans.

• Kidney endpoint: Kidney congestion, mild renal necrosis and increased organ weight were 

observed in laboratory animal studies only. No data are available in humans.

• Ocular endpoint: Eye irritation is observed following inhalation exposure in humans and 

laboratory animals.

• Developmental endpoint: 2-Butanone was fetotoxic in rats. No data are available in humans. 
2-BUTANONE 12

2. HEALTH EFFECTS

Figure 2-1. Overview of the Number of Studies Examining 2-Butanone Health Effects

Most studies examined the potential respiratory, hepatic, dermal and neurological effects of 2-butanone

Fewer studies evaluated health effects in humans than animals (counts represent studies examining endpoint)

*Includes studies discussed in Chapter 2. A total of 42 studies (including those finding no effect) have examined toxicity; most studies examined multiple 

endpoints.
2-BUTANONE 13

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to 2-Butanone – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

ACUTE EXPOSURE

1 Human

16–143 M, 

F

1 day

4 hours/day

200 CS Neuro 200

Dick et al. 1984, 1988, 1989, 1992

2 Human

24 M

1 day

4 hours

10–380 CS Resp 189

Cardio 189

Ocular 189

Haumann et al. 2003; Seeber et al. 2002; van Thriel et al. 2002, 2003; Wiesmuller et al. 2002

3 Human

19 M

1 day

4 hours/day

200 BI, CS, OF Resp 200

Immuno 200

Muttray et al. 2002

4 Human

10 M, F

1 day

5 minutes/day

0, 100, 

200, 350

CS Resp 100 Nose/throat irritation

Ocular 200 Eye irritation

Nelson et al. 1943

5 Human

10 M, 15 F

1 day

6 hours/day

0, 100 CS Resp 100 Nose/throat irritation

Ocular 100 Eye irritation

Neuro 100b Headache, fatigue, feeling of 

intoxication

Tomicic et al. 2011

6 Monkey

(baboon)

4 M

7 days

24 hours/day

100 CS Neuro 100 Increased response time in 

neurobehavioral tests

Geller et al. 1979

7 Rat

(Wistar)

5 M

2–3 days

8 hour/day

10,000 CS Resp 10,000 Respiratory irritation

Altenkirch et al. 1978
2-BUTANONE 14

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to 2-Butanone – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

8 Rat

(SpragueDawley)

25 F (35 F 

controls)

10 days

GDs 6–15,

7 hours/day

0, 400, 

10,00, 

3,000

BW, OW,

FI, WI, CS,

FX, DX, MX, 

TG

Bd wt 1,000 3,000 Decreased maternal body weight

Develop 1,000 3,000 Extra ribs, delayed ossification

Deacon et al. 1981

9 Rat

(NS)

3 M, F

1 day

3 hours/day

92,239 LE Death 92,239

Klimisch 1988

10 Rat

(albino)

8 M

1 day

4 hours/day

0, 7,850, 

9,090, 

9,060, 

12,200, 

13,150, 

18,100, 

20,200

LE Death 11,700 LC50

LaBelle and Brieger 1955

11 Rat

(Wistar)

6–7 F

7 days

8 hours/day

0, 300 BC, BI Hepatic 300

Li et al. 1986

12 Rat

(SpragueDawley)

19–23 F

GDs 6–20

6 hours/day

0, 1,000, 

2,000, 

4,000, 

6,000

BW, DX, FI, 

FX, OW, MX, 

TG

Bd wt 2,000 4,000 Reduced food consumption (12%) 

and maternal body weight gain 

(52%)

Develop 2,000 4,000 Decreased fetal body weight (15% 

in males); incomplete ossification of 

the sternebrae

Saillenfait et al. 2006
2-BUTANONE 15

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to 2-Butanone – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

13 Rat

(NS)

21–23 F

(43 F 

controls)

GDs 6–15

7 hours/day

0, 1,000, 

3,000

BW, OW, FI, 

FX, MX, DX, 

TG

Develop 1,000 3,000 Gross malformations and sternebral 

anomalies

Schwetz et al. 1974

14 Rat

(NS)

6 M

1 day

8 hours/ day

8,000 LE Death 8,000 3/6 died

Smyth et al. 1962

15 Mouse

(NS)

50 M

1 day

4 hours/day

0, 1,602, 

1,848, 

2,050, 

2,438

CS, OF Neuro 1,602 Reduced immobility (antidepressant effect)

De Ceaurriz et al. 1983

16 Mouse

Ssc:CF-1

4 M

1 day

0.5 hours

0, 3,809, 

9,136, 

12,771, 

24,179, 

26,416

OF Resp 3,809 Reduced respiratory rate and tidal 

volume (sensory irritation effect)

Hansen et al. 1992

17 Mouse

(albino)

6 NS

43 minutes 103,000 LE Death 103,000

LaBelle and Brieger 1955

18 Mouse

(Swiss/ 

CD-1)

33 F

10 days

GDs 6–15

7 hours/day

0, 400, 

1,000, 

3,000

BW, DX, FX, 

OW, MX, TG

Bd wt 3,000

Hepatic 1,000 3,000 Increased relative liver weight in 

dams (7%)

Develop 1,000 3,000 Decreased fetal body weight (5% in 

males); misaligned sternebrae

NTP 1989; Schwetz et al. 1991
2-BUTANONE 16

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to 2-Butanone – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

19 Guinea pig

(NS)

6 NS

1 day

3–13.5 hours/

day

0, 3,300, 

10,000, 

3,3000, 

100,000

GN, CS Death 33,000

Resp 10,000 33,000 Gasping and death

Hepatic 3,300 10,000 Congestion

Renal 3,300 10,000 Congestions

Ocular 3,300 10,000 100,000 Eye irritation, lacrimation 

(10,000 ppm); corneal opacity and 

death (100,000 ppm)

Neuro 3,300 10,000 Narcosis, incoordination

Patty et al. 1935

INTERMEDIATE EXPOSURE

20 Rat

(NS)

19 NS

7 weeks

7 days/week

8 hours/day

6,000 HP, CS, LE Death 6,000 5/5 died

Neuro 6,000

Altenkirch et al. 1978, 1979

21 Rat

(Fischer)

15 M, F

90 days

5 days/week

6 hours/day

0, 1,250, 

2,500,

5,000

BW, OW,

FI, WI, GN,

HP, BC, CS,

BI, HE

Resp 5,000

Cardio 5,000

Gastro 5,000

Hemato 5,000

Musc/skel 5,000

Hepatic 5,000

Renal 5,000

Dermal 5,000

Immuno 5,000

Neuro 5,000

Repro 5,000

Other 

noncancer 

(not 

specified)

5,000

Cavender et al. 1983; Cavender and Casey 1981
2-BUTANONE 17

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to 2-Butanone – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

22 Rat

(SpragueDawley)

12 M

5 months

7 days/week

24 hours/day

1,125 HP Neuro 1,125

Saida et al. 1976

23 Rat

(SpragueDawley)

6 F

15 days

6 hours/day

0, 1,000, 

3,000

BC, HP, OW, 

UR

Hepatic 3,000

Renal 3,000

Saillenfait et al. 2006

24 Rat

(Wistar)

8 F

GDs 1–21

23 hours/day

0, 800, 

1,000–

1,500

DX, MX Develop 800 Delay in Purkinje cell outgrowth

Develop 800 Complete litter loss

Stoltenburg-Didinger et al. 1990; Stoltenburg-Didinger 1991

aThe number corresponds to entries in Figure 2-2. bAn acute-duration Minimal Risk Level (MRL) of 1 ppm was derived for 2-butanone based on reported neurological symptoms (headache, fatigue, feeling of 

intoxication) in volunteers. The MRL is based on the LOAEL (not adjusted for continuous exposure) of 99.15 ppm and a total uncertainty factor of 100 (10 for use 

of a LOAEL and 10 for human variability).

BC = serum (blood) chemistry); Bd wt or BW = body weight; BI = biochemical changes; Cardio = cardiovascular; CS = clinical signs; Develop = developmental; 

DX = developmental toxicity; F = female(s); FI = food intake; FX = fetal toxicity; Gastro = gastrointestinal; GD = gestational day; GN = gross necropsy; 

HE = hematology; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = lethal concentration, 50% kill; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); Musc/skel = musculoskeletal; MX = maternal toxicity; Neuro = neurological; NOAEL = no-observed-adverse-effect 

level; NS = not specified; OF = organ function; OW = organ weight; Repro = reproductive; Resp = respiratory; TG = teratogenicity; UR = urinalysis; WI = water 

intake
2-BUTANONE 18

2. HEALTH EFFECTS

Figure 2-2. Levels of Significant Exposure to 2-Butanone – Inhalation

Acute (≤14 days)
2-BUTANONE 19

2. HEALTH EFFECTS

Figure 2-2. Levels of Significant Exposure to 2-Butanone – Inhalation

Acute (≤14 days)
2-BUTANONE 20

2. HEALTH EFFECTS

Figure 2-2. Levels of Significant Exposure to 2-Butanone – Inhalation

Intermediate (15-364)
2-BUTANONE 21

2. HEALTH EFFECTS

Figure 2-2. Levels of Significant Exposure to 2-Butanone – Inhalation

Intermediate (15-364)
2-BUTANONE 22

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to 2-Butanone – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

ACUTE EXPOSURE

1 Rat

(Fischer)

6 M

1 day

(G)

0, 1,080 GN, HP, OF Hepatic 1,080

Renal 1,080 Tubular necrosis

Brown and Hewitt 1984

2 Rat

(SpragueDawley)

6 M

1 day

1 time/day

(GO)

0, 1,080 BI Hepatic 1,080

Hewitt et al. 1990

3 Rat

(SpragueDawley)

6 M, 6–

12 F

1 day

(G)

2,737 LE Death 2,737 LD50

Kimura et al. 1971

4 Rat

(NS)

4 M

3 days

1 time/day

(GW)

0, 1,130 BI Hepatic 1,130

Raunio et al. 1990

5 Rat

(F344)

3–4 M

1–7 days

1 time/day

(GW)

0, 1,500 BI Hepatic 1,500

Robertson et al. 1989

6 Rat

(albino)

5 M, F

1 day

(G)

0, 3670, 

7,340, 

14,680

BW Death 3,670 8/10 died

Neuro 3,670 CNS depression

Stillmeadow Inc. 1978

7 Rat

(NS)

56 M

1 day

1 time/day

(G)

0, 1,500 BI Hepatic 1,500

Traiger et al. 1989
2-BUTANONE 23

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to 2-Butanone – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

8 Mouse 1 day

(G)

Death 4,044 LD50

Tanii et al. 1986

INTERMEDIATE EXPOSURE

9 Rat

(Fischer)

20 M

13 weeks

5 days/week

(G)

0, 1,752 CS Neuro 1,725

Ralston et al. 1985

aThe number corresponds to entries in Figure 2-3.

BI = biochemical changes; BW = body weight; CNS = central nervous system; CS = clinical signs; F = female(s); (G) = gavage; GN = gross necropsy; 

(GO) = gavage in oil; (GW) = gavage in water; HP = histopathology; LD50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; 

M = male(s); NOAEL = no-observed-adverse-effect level; Neuro = neurological; NS = not specified; OF = organ function
2-BUTANONE 24

2. HEALTH EFFECTS

Figure 2-3. Levels of Significant Exposure to 2-Butanone – Oral 

Acute (≤14 days)
2-BUTANONE 25

2. HEALTH EFFECTS

Figure 2-3. Levels of Significant Exposure to 2-Butanone – Oral

Intermediate (15-364 days)
2-BUTANONE 26

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to 2-Butanone – Dermal

Species 

(strain)

No./group

Exposure 

parameters Doses

Parameters 

monitored Endpoint NOAEL 

Less 

serious 

LOAEL 

Serious 

LOAEL Effect

ACUTE EXPOSURE

Mouse

BALB/c

5 F

1 day

24 hours

0.08 mL 

(undiluted)

Dermal 0.08 Skin irritation

Iyadomi et al. 2000

Rabbit

(albino)

12 NS

24 hours 0.5 mL Dermal 0.5 Erythema

Hazelton Laboratories 1963a

Guinea pig

(Dunkin/Hartley)

10 F

3 days

3 times/day

10 μL/cm2 Dermal 10 Erythema

Anderson et al. 1986

Guinea pig

(NS)

6–9 NS

10 days

1 time/day

0.1 mL Dermal 0.1 Skin-fold thickening

Wahlberg 1984

INTERMEDIATE EXPOSURE

Human

NS

18 days

1 time/day

0.1 mL Dermal 0.1 

Wahlberg 1984

F = female(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; NS = not specified
2-BUTANONE 27

2. HEALTH EFFECTS

2.2 DEATH

No studies were located regarding death of humans following inhalation, oral, or dermal exposure to 

2-butanone. 

Acute inhalation exposure to ≥8,000 ppm 2-butanone resulted in death in rats, mice, and guinea pigs 

within a few hours (Klimisch 1988; LaBelle and Brieger 1955; Patty et al. 1935; Smyth et al. 1962). The 

4-hour LC50 in rats was 11,700 ppm (LaBelle and Brieger 1955). Death was also observed in rats 

exposed daily (8 hours/day) to 6,000 ppm for 7 weeks (Altenkirch et al. 1978, 1979). The cause of death 

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

and histologically. A repeat of this study gave the same results (i.e., death within 7 weeks coincident with 

confirmed bronchopneumonia) (Altenkirch et al. 1979).

Oral LD50 values for 2-butanone were similar (approximately 2,737 mg/kg) in three groups of SpragueDawley rats: immature (14 days old), young adult (80–160 g), and older adult (300–470 g) (Kimura et al. 

1971). 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 one male and one 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 <3,670 mg/kg, which is in agreement with the data reported in 

Kimura et al. (1971). 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).

No studies were located regarding death in animals after dermal exposure to 2-butanone. 

2.3 BODY WEIGHT

No studies were located regarding body weight changes in humans following inhalation, oral, or dermal 

exposure to 2-butanone. 

Maternal body weight was decreased in rats exposed by inhalation to 3,000 ppm for 7 hours/day during 

GDs 6–15 (Deacon et al. 1981; magnitude of change not reported). Maternal body weight gain was 

reduced by 52% in rats exposed to 4,000 ppm for 6 hours/day during GDs 6–20 (Saillenfait et al. 2006). 

Mice appeared to less sensitive to maternal body weight effects than rats. No effect on maternal body 

weight was observed in mice exposed to 3,000 ppm for 7 hours/day during GDs 6–15 (NTP 1989; 
2-BUTANONE 28

2. HEALTH EFFECTS

Schwetz et al. 1991). No effect on rats exposed to ≤5,000 ppm of 2-butanone for 90 days (Cavender and 

Casey 1981; Cavender et al. 1983). Furthermore, no specific effects on body weight were found. 

Terminal body weight was similar to controls in rats exposed to <5,000 ppm 2-butanone for 13 weeks 

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

No studies were located regarding body weight changes in animals after oral or dermal exposure to 

2-butanone. 

2.4 RESPIRATORY

2-Butanone is irritating to respiratory tissues. Upper respiratory tract irritation was noted in a case report 

of a patient with occupational 2-butanone exposure (concentration data were not reported) (Callender 

1995). 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). An increased prevalence of upper respiratory tract irritation (statistical 

significance not reported) was observed in a group of 41 workers exposed to 2-butanone (concentrations 

ranging from 51 to 116 ppm) at a cable factory, compared with a control group of 63 workers (Mitran et 

al. 1997). It should be noted that concerns regarding the study design of the Mitran et al. (1997) study 

were raised in a letter to the editor (Graham 2000) concluding that the study results should not be used to 

derive or modify health guidance values. 

Male and female volunteers (n=10) exposed to 100 ppm 2-butanone complained of slight nose and throat 

irritation, which became objectionable at 350 ppm (Nelson et al. 1943). Tomicic et al. (2011) also 

reported nose and throat irritation during a 6-hour exposure to 100 ppm 2-butanone with 15 female 

subjects reporting higher symptom ratings than 10 male subjects. Nasal irritation was not reported in 

24 male subjects exposed to 2-butanone vapor for 4 hours under constant (10 ppm) or changing exposure 

conditions (peaks up to 380 ppm; TWA of 189 ppm) (Seeber et al. 2002; van Thriel et al. 2002). 

Symptoms were scored as “hardly at all” for male subjects with self-reported multiple chemical 

sensitivity and “not at all” for the other subjects. The median symptom score in 19 males exposed to 

200 ppm for 4 hours was also 0 (no effect); however, a few of the subjects did report a significant 

increase in the severity of throat irritation after 4 hours of exposure (Muttray et al. 2002). Odor 

perception was reported by all subjects with the intensity influenced by concentration (10–380 ppm) and 

exposure duration (Seeber et al. 2002; van Thriel et al. 2002). Tomicic et al. (2011) reported that male 

subjects became tolerant to the odor of 2-butanone during the 6-hour exposure period (100 ppm), while 
2-BUTANONE 29

2. HEALTH EFFECTS

female subjects scored odor perception as high at the end of the exposure. The odor threshold for 

2-butanone falls in the range 5.4–8.25 ppm (Amoore and Hautala 1983; Doty et al. 1988). 

Nasal resistance was significantly increased in humans (12 males and 24 females) upon exposure to the 

odor threshold level of 2-butanone (5.4–8.25 ppm); this response reflects a nasopharyngeal reflex (Doty et 

al. 1988). A significant decrease in nasal flow was observed in anterior rhinomanometry of male subjects 

with self-reported multiple chemical sensitivity exposed to a TWA concentration of 189 ppm 2-butanone 

(Wiesmuller et al. 2002). This change was independent of the exposure concentration administered and 

may be related to odor perception. The nasal mucociliary transport time was increased in male subjects 

exposed to 200 ppm 2-butanone for 4 hours and the concentrations of IL-1β and IL-8 in nasal secretions 

were also increased (although not significantly) (Muttray et al. 2002). Concentrations of IL-8 and TNFα 

in nasal secretions were unchanged by 2-butanone exposure in this study (Muttray et al. 2002). Exposure 

of males to 2-butanone vapor for 4 hours under constant (10 ppm) or changing exposure conditions (peaks 

up to 380 ppm; TWA of 189 ppm) did not alter the concentrations of inflammatory biomarkers in nasal 

secretions (eosinophil cationic protein, myeloperoxidase, interleukin 1β, substance P, and neurokinin A) 

(van Thriel et al. 2003). Respiratory rate was not affected by 2-butanone exposure in these subjects 

(Haumann et al. 2003). 

The respiratory tract irritation noted in humans at ≥100 ppm does not necessarily imply that humans are 

more sensitive to the respiratory effects of 2-butanone than other species tested (see Table 2-1). Another 

possible explanation is that humans are better able to communicate the early signs of irritation compared 

with the other species tested. At high concentrations, 2-butanone is also irritating to respiratory tissues of 

animals. Guinea pigs exposed to 33,000 ppm had gasping respiration after 180 minutes of exposure and 

died after 200–260 minutes of exposure (Patty et al. 1935). Their lungs were emphysematous. Severe 

upper respiratory tract irritation was found after a few days in rats exposed to 10,000 ppm, 8 hours/day 

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

(1978), the exposure concentration was reduced to 6,000 ppm and the study continued. All of the rats 

died suddenly at 7 weeks with pathologically confirmed bronchopneumonia. This experiment was 

repeated and had the same results (Altenkirch et al. 1979). 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 
2-BUTANONE 30

2. HEALTH EFFECTS

bronchopneumonia in humans or animals. Rats appeared to tolerate intermittent exposures up to 

5,000 ppm. In a 90-day inhalation study, exposure of rats to 2-butanone concentrations of 0, 1,250, 

2,500, or 5,000 ppm for 6 hours/day, 5 days/week caused no signs of upper respiratory tract irritation or 

other respiratory effects assessed by clinical signs and histopathology evaluation (Cavender et al. 1983). 

2- Butanone produced a time- and concentration-dependent decrease in respiratory rate and tidal volume 

in mice exposed to 3,809, 9,136, 12,771, 24,179, or 26,416 ppm 2-butanone for 30 minutes followed by a 

20-minute recovery (Hansen et al. 1992). These effects were consistent with sensory irritation and 

desensitization occurred at the lowest concentrations used. 

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/100 mL. Slow infusion of sodium bicarbonate reduced the hyperventilation, and blood gases improved to 78 mmHg oxygen and 25mmHg carbon dioxide. Within 

12 hours, she had regained consciousness, made an 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 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. 

2.5 CARDIOVASCULAR

Heart rate was not affected in male volunteers exposed to 2-butanone vapor for 4 hours under constant 

(10 ppm) or changing exposure conditions (peaks up to 380 ppm; TWA of 189 ppm) (Haumann et al. 

2003). Histological examination of the hearts and aorta of rats exposed to ≤5,000 ppm of 2-butanone for 

90 days revealed no exposure-related lesions (Cavender and Casey 1981; Cavender et al. 1983). 

Cardiovascular effects observed in a 47-year-old 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 or animals following exposure to 2-butanone. 
2-BUTANONE 31

2. HEALTH EFFECTS

2.6 GASTROINTESTINAL

A higher prevalence of gastrointestinal symptoms (including loss of appetite, hyperacidity, bad taste, and 

abdominal pains) was observed in 41 workers exposed to 51–117 ppm of 2-butanone, compared with 

63 control workers (Mitran et al. 1997); statistical analysis of the prevalence data was not conducted. 

Concerns regarding the study design of the Mitran et al. (1997) study were raised in a letter to the editor 

(Graham 2000), which concluded that the study results should not be used to derive or modify health 

guidance values.

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 of 2-butanone for 90 days 

(Cavender and Casey 1981; Cavender et al. 1983). No other reports were located regarding 

gastrointestinal effects in humans or animals following exposure to 2-butanone. 

2.7 HEMATOLOGICAL

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 chemistry of rats exposed to 

≤5,000 ppm of 2-butanone for 90 days were normal (Cavender et al. 1983). No other reports were located 

regarding hematological effects in humans or animals following exposure to 2-butanone. 

2.8 MUSCULOSKELETAL

Increased pain in the bones, joints, and vertebral column and diffuse muscular pain were reported by a 

majority of 41 cable factory workers exposed to 2-butanone, compared with 63 controls (Mitran et al. 

1997). The exposure-level range throughout an 8-hour shift was 51–117 ppm. Concerns regarding the 
2-BUTANONE 32

2. HEALTH EFFECTS

study design of the Mitran et al. (1997) study were raised in a letter to the editor (Graham 2000), which 

concluded that the study results should not be used to derive or modify health guidance values. 

Histological examination of skeletal muscle and bone of rats exposed to ≤5,000 ppm of 2-butanone for 

90 days revealed no exposure-related lesions (Cavender and Casey 1981; Cavender et al. 1983). No other 

reports were located regarding musculoskeletal effects in humans or animals following exposure to 

2-butanone. 

2.9 HEPATIC

No studies were located regarding hepatic effects in humans after inhalation, oral and dermal 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 in guinea pigs from this 

study. Serum alkaline phosphatase activity was not altered in rats exposed 8 hours/day to 300 ppm 

2-butanone for 7 days compared to nonexposed control rats (Li et al. 1986). A statistically significant 

increase in absolute and relative liver weights of male and female rats (13–27%), but no change in serum 

levels of hepatic enzymes (ALT, AST, gamma-glutamyl transferase [GGT], and alkaline phosphatase), 

was observed in male rats at an exposure level of 5,000 ppm for 90 days (Cavender et al. 1983). A 

significant increase only in alkaline phosphatase (41% above controls) 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. Exposure of female rats to 3,000 ppm (but not 1,000 ppm) 2-butanone 6 hours/day 

for 15 days increased absolute and relative liver weight by 13–16% (Saillenfait et al. 2006). Serum 

chemistry parameters (ALT, AST, urea, and creatinine) and liver histopathology were not affected by 

2-butanone exposure in this study. Relative liver weight was also increased in male rats exposed to 

800 ppm 2-butanone 6 hours/day for 4 weeks (6% increase over control) (Toftgard et al. 1981) and 

pregnant mice exposed to 3,000 ppm 2-butanone for 7 hours/day on GDs 6–15 (7% increase over 

controls) (NTP 1989; Schwetz et al. 1991). Liver weight increases in rodent studies may be related to 

induction of cytochrome P450 (CYP) (see Section 3.1). 
2-BUTANONE 33

2. HEALTH EFFECTS

2-Butanone had no effect on liver weight, ALT, or serum ornithine carbamyl transferase activities 

measured 42 hours after oral exposure of rats to a single gavage dose of 1,080 mg/kg (Hewitt et al. 1983). 

Similarly, Brown and Hewitt (1984) observed normal ALT activity in rats exposed orally to 1,080 mg 

2-butanone/kg. 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). 

2.10 RENAL

No studies were located regarding renal effects in humans following inhalation, oral or dermal 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. Minimal kidney effects were observed in rats 

exposed to ≤5,000 ppm for 6 hours/day, 5 days/week for 13 weeks (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 ratio in male rats and the 

kidney/brain weight ratio in female rats were slightly, but significantly, elevated (6–11% increase over 

controls). Histopathological examination did not reveal any treatment-related renal lesion. In the absence 

of histopathological lesions or decrements in kidney function, the mild kidney effects observed in this 

study do not appear to be adverse. Exposure of female rats to 1,000 or 3,000 ppm 2-butanone 6 hours/day 

for 15 days did not affect kidney weight or produce renal histopathological lesions (Saillenfait et al. 

2006). 

Acute oral exposure of rats to 1,080 mg/kg 2-butanone caused mild renal tubular necrosis but had no 

effect on renal organic ion transport (p-aminohippuric acid, tetraethylammonium) or plasma creatinine 

(Brown and Hewitt 1984). No other studies were located regarding renal effects in animals after exposure 

to 2-butanone. 

2.11 DERMAL

A group of 41 workers exposed to 2-butanone reported a higher incidence of skin irritation, compared 

with a control group of 63 workers (Mitran et al. 1997). The exposure level range throughout an 8-hour 
2-BUTANONE 34

2. HEALTH EFFECTS

shift was 51–117 ppm. It should be noted that concerns regarding the study design of the Mitran et al. 

(1997) study were raised in a letter to the editor (Graham 2000) concluding that the study results should 

not be used to derive or modify health guidance values. Application of 0.1 mL undiluted 2-butanone once 

daily for 18 days to the forearm of volunteers did not result in erythema, an 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). Edema was detected in a mouse ear thickness 

test after application of 80 μL 2-butanone to the skin of the front and back of the ear (Iyadomi et al. 

2000). Ear thickness was maximal 2 hours after application and decreased to control levels by 24 hours. 

2.12 OCULAR

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. A group of 41 workers exposed to 2-butanone reported a higher incidence 

of ocular symptoms compared with a control group of 63 workers (Mitran et al. 1997). The exposurelevel range throughout an 8-hour shift was 51–117 ppm. It should be noted that concerns regarding the 

study design of the Mitran et al. (1997) study were raised in a letter to the editor (Graham 2000) 

concluding that the study results should not be used to derive or modify health guidance values. 

Mild eye irritation was noted in some volunteers exposed to 200 ppm 2-butanone for 3–5 minutes (Nelson 

et al. 1943). Discomfort in the eyes was also reported in human subjects exposed to 100 ppm 2-butanone 

for 6 hours with females scoring significantly higher on symptom questionnaires compared to male 

subjects (Tomicic et al. 2011). Eye irritation was not reported in male subjects exposed to 2-butanone 

vapor for 4 hours under constant (10 ppm) or changing exposure conditions (peaks up to 380 ppm; TWA 

of 189 ppm) (Seeber et al. 2002; van Thriel et al. 2002). 
2-BUTANONE 35

2. HEALTH EFFECTS

Guinea pigs exposed to 2-butanone concentrations ≥10,000 ppm had eye irritation and lacrimation (Patty 

et al. 1935). Exposure to 100,000 ppm for ≥30 minutes caused corneal 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 of 2-butanone for 90 days (Cavender and Casey 

1981; Cavender et al. 1983). 

2-Butanone instilled into the conjunctival sac of rabbits caused irritation, corneal 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 corneal damage after 7 and 14 days. On the basis of Draize 

scores in these studies, 2-butanone was classified as moderately irritating.

2.13 ENDOCRINE

No studies were located regarding endocrine effects in humans following inhalation, oral, or dermal 

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 of 2-butanone for 90 days (Cavender and 

Casey 1981; Cavender et al. 1983). 

2.14 IMMUNOLOGICAL

Inflammatory biomarkers were not significantly elevated in nasal secretions of volunteers exposed to 

2-butanone for 4 hours (Muttray et al. 2002 [200 ppm continuous]; van Thriel et al. 2003 [189 ppm 

TWA]). 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 of 2-butanone for 

90 days revealed no exposure-related lesions (Cavender and Casey 1981; Cavender et al. 1983). 

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 
2-BUTANONE 36

2. HEALTH EFFECTS

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. 

An in vitro study using granulocytes and monocytes isolated from human peripheral blood showed a 

concentration-dependent decrease in phagocytosis of oponized zymosan particles (0.0005–0.05 mM 

2-butanone). 2-Butanone also affected membrane integrity, glutathione homeostasis, and intracellular 

free calcium concentrations in an immortalized human T-lymphocyte cell line (>0.01 mM in Jurkat 

T cells) (McDermott et al. 2007).

2.15 NEUROLOGICAL

Neurotoxicity was reported in clinical case studies of occupational workers exposed to 2-butanone 

(exposure concentrations not reported). A worker exposed to 2-butanone fumes generated from burning 

fiberglass material (also occasionally to peroxides and acetone) reported severe chronic headache, 

dizziness, loss of balance, memory loss, fatigue, tremors, muscle twitches, visual disturbances, throat 

irritation, and tachycardia (exposure concentrations were not reported) (Callender 1995). 

Neurobehavioral tests revealed mild-to-moderate impairment of attention, psychomotor speed, short-term 

memory, and the ability to shift cognitive sets as processing demands increased, as well as significant 

mood disruption in the form of depression. Electroencephalography (EEG) and evoked potentials tests 

showed abnormalities that were consistent with behavioral effects. Additionally, motor and sensory 

polyneuropathy was found in nerve conduction velocity tests, and rotational and visual reflex testing 

results were consistent with peripheral labyrinthine dysfunction. The findings of a single-photon 

emission computerized tomography (SPECT) brain scan were consistent with small ischemic insults in 

both the right and left cerebral hemispheres. In another case report, a worker with inhalation and dermal 

exposure to solvents containing 100% 2-butanone for approximately 2 years reported dizziness, asthenia, 

anorexia, and weight loss (Orti-Pareja et al. 1996). Neurologic examination showed postural and action 

tremor in the hands, face, tongue, and voice; multifocal myoclonic jerks in the limbs; ocular flutter; and 

ataxic gait. 

Increases in several neurological symptoms, including mood disorder, irritability, memory difficulties, 

sleep disturbances, and headaches, were also reported for 41 workers at a cable factory compared to 

63 control workers (Mitran et al. 1997). The measured exposure-levels in this study ranged from 51 to 

117 ppm during an 8-hour work shift. In motor nerve conduction velocity tests, significant increases in 
2-BUTANONE 37

2. HEALTH EFFECTS

proximal latency in the median, ulnar, and peroneal nerves and distal latency in the median and ulnar 

nerves were observed; significant decreases in nerve conduction velocity in median, ulnar, and peroneal 

nerves were also observed. It should be noted that concerns regarding the study design of the Mitran et 

al. (1997) study were raised in a letter to the editor (Graham 2000) concluding that the study results 

should not be used to derive or modify health guidance values. Specific concerns were raised regarding 

the lack of a detailed description of the experimental conditions maintained during electrodiagnostic 

testing. 

Neurological symptoms were reported in some volunteer studies, but the results of neurobehavioral 

testing were similar to unexposed controls. Headache, fatigue, and feeling of intoxication were noted in 

volunteer subjects exposed to 100 ppm 2-butanone for 4 hours, with females scoring higher on symptom 

questionnaires compared with men (Tomicic et al. 2011). Headache and nausea were also reported by 

male subjects 2 hours after exposure to 200 ppm exposure, compared with pre-exposure ratings (Muttray 

et al. 2002). In four separate studies, groups of 16–25 volunteers underwent a single 4-hour exposure to 

200 ppm 2-butanone (Dick et al. 1984, 1988, 1989, 1992). 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. 

Regression analyses showed a significant linear relationship between blood concentrations of 2-butanone 

in females and a small increase in the number of incorrect responses on the auditory portion of the dual 

task test (Dick et al. 1992). In a study of 19 workers exposed to mixed solvents (2-butanone, 

cyclohexanone, tetrahydrofuran, and toluene), alterations in some neurobehavioral tests (Santa Ana 

dexterity test, digit span, and visual reproduction) were observed (Chia et al. 1993). However, there was 

no correlation between test score and mixed solvent exposure level.

Neurological effects have been observed in animals exposed by inhalation to 2-butanone. Exposure of 

mice to 2-butanone at concentrations ≥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 
2-BUTANONE 38

2. HEALTH 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. 

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 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 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 crossextensor 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 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. 1978). 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). 

No studies were located regarding neurological effects in humans after oral or dermal 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 ≥3,670 mg/kg (Stillmeadow Inc. 1978). Most of these rats died. No effects 

were observed in neurobehavioral tests, including hindlimb grasp, hindlimb place, balance beam, and 
2-BUTANONE 39

2. HEALTH EFFECTS

rotorod, in rats treated by gavage with 2-butanone at a TWA 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. 

In an intermediate study of dermal exposure, 1–2 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 (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.

2.16 REPRODUCTIVE

No studies were located regarding reproductive effects in humans after inhalation, oral, or dermal 

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 of 2-butanone for 90 days (6 hours/day, 5 days/week) revealed no exposurerelated lesions (Cavender and Casey 1981; Cavender et al. 1983). Complete litter loss was observed in 

rats exposed throughout gestation (23 hours/day, GDs 1–21) to 800 ppm (3/8 dams) and 1,000–1,500 ppm 

(4/8 dams) (Stoltenburg-Didinger et al. 1990). 

No studies were located regarding reproductive effects in animals after oral exposure to 2-butanone; 

however, Cox et al. (1975) describes a 2-generation drinking water study of 2-butanol in rats. 2-Butanol 

is metabolized to 2-butanone and its downstream metabolites within 16 hours following oral 

administration. In addition, peak blood concentrations of 2-butanone occurred within a similar time 

period following oral dosing of 2-butanol (7–8 hours) or 2-butanone (4–5 hours). The elimination 

kinetics for downstream urinary metabolites of both compounds (3-hydroxy-2-butanone and 

2,3-butanediol) were also similar for 2-butanol and 2-butanone (EPA 2003). The findings of this 

reproductive toxicity study of n-butanol (Cox et al. 1975) are presented here due to the absence of 

available studies for 2-butanone. Male and female Wistar rats were exposed to 0, 0.3, 1, or 3% 2-butanol 

in the drinking water for 8 weeks prior to mating and during gestation and lactation. The premating doses 

were reported as 0, 538, 1,644, and 5,089 mg/kg/day in males and 0, 594, 1,771, and 4,571 mg/kg/day in 

females. High-dose dams were given control drinking water for 2 weeks after delivery of the F1A litter, 
2-BUTANONE 40

2. HEALTH EFFECTS

and treatment was resumed at 2% 2-butanol prior to mating and examination of the F1B litter on GD 20 

(i.e., uterine contents examined after second mating). The F1 offspring used for mating and delivery of 

the F2 generation were also exposed to 2% 2-butanol as the highest drinking water concentration. 

Average daily doses were not reported for 2% 2-butanol in drinking water; however, EPA (2003) 

estimated doses of 3,384 mg/kg/day in males and 3,122 mg/kg/day in females based on a linear regression 

analysis of reported drinking water intake values. Body weight and body weight gain were reduced in 

male and female rats in the F0 generation following 8 weeks of exposure to 3% 2-butanol (12–16% 

decrease from controls). Maternal body weight on GD 20 was not affected by gestational exposure to 

concentrations <2% 2-butanol for the second mating (F1B generation). Reproductive parameters 

(e.g., pregnancy rate, implantations, resorptions, number of litters) were not altered at any treatment 

concentration in F0 or F1 rats (producing F1A, F1B, and F2 generations). Developmental effects 

observed in this study are described in Section 2.17. 

2.17 DEVELOPMENTAL

No studies were located regarding developmental effects in humans after inhalation, oral, or dermal 

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 two fetuses 

out of 21 litters, and brachygnathia was noted in two 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 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 and extra ribs, 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. 
2-BUTANONE 41

2. HEALTH EFFECTS

Groups of 33 pregnant Swiss mice were exposed to 0, 400, 1,000, or 3,000 ppm 2-butanone for 

7 hours/day on GDs 6–15; weights were measured on GDs 0, 6, 9, 15, and 18 and dams were euthanized 

on GD 18 (NTP 1989; Schwetz et al. 1991). No significant alterations in maternal body weight gain were 

observed with 2-butanone exposure, but a significant 7% increase in relative liver weight was observed at 

3,000 ppm. A small, but statistically significant, decrease in fetal body weight (approximately 5% lower 

than controls) was observed only in the male offspring of mice exposed to 3,000 ppm. A similar, but 

slightly smaller, decrease in fetal body weight was also observed in females, but the weights were not 

statistically significantly different from those of controls. No significant alterations in the number of 

fetuses or litters with malformations were found; however, a significant trend for increased incidence of 

misaligned sternebrae was observed at doses >400 ppm. 

Groups of 19–23 pregnant Sprague-Dawley rats were exposed to 0, 1,000, 2,000, 4,000, or 6,000 ppm 

2-butanone 6 hours/day on GDs 6–20 (Saillenfait et al. 2006). Significant decreases in maternal body 

weight gain (recorded on GDs 0, 6, 13, and 21) and food consumption (measured across GDs 6–13 and 

13–21) were observed at exposure levels of 4,000 and 6,000 ppm. Decreases in fetal body weight were 

observed at ≥4,000 ppm; fetal body weights were 4.4, 15, and 20% lower than the weights of controls in 

the 2,000, 4,000, and 6,000 ppm groups, respectively. No significant alterations in the total number of 

external, visceral, or skeletal variations were observed at any level of 2-butanone exposure. However, the 

study reported statistically significant increases in the incidence of incomplete sternebrae ossification in 

the 4,000 and 6,000 ppm groups. 

Following prenatal exposure to 2-butanone (23 hours/day GDs 1–21; 800 or 1,000–1,500 ppm), a delay 

was observed in the activity of succinic dehydrogenase and NADH tetrazolium reductase in the cerebellar 

cortex of offspring, suggesting a delay in the outgrowth of Purkinje cell apical dendritic tree (StoltenburgDidinger 1991). Histological examination of the cerebellar cortex showed a delay in the migration of the 

outer granular cells and a delay in the development of Purkinje cells (Stoltenburg-Didinger 1990). As 

discussed in Section 2.16, this exposure also resulted in an increase in the percentage of dams with 

complete litter loss.

No studies were located regarding developmental effects in animals after oral exposure to 2-butanone. 

The multigeneration drinking water study by Cox et al. (1975) (see study description in Section 2.16) 

reported decreased F1A and F2 pup body weights and decreased F1B fetal weights associated with 

2-butanol exposure. Mean F1A pup body weights measured on postnatal days (PNDs) 4 and 21 were 

reduced by 22 and 39%, respectively in the high-dose group (3% 2-butanol in drinking water). Body 
2-BUTANONE 42

2. HEALTH EFFECTS

weight was reduced by 13% in F2 pups on PND 21 in the high-dose group (2% 2-butanol in drinking 

water). F1B fetal body weight was reduced by 10% following gestational exposure to 2% 2-butanol. The 

F1B fetuses in the 2% group also showed increases in skeletal variations (missing sternebrae, wavy ribs, 

and incomplete vertebrae ossification) when compared with the 1% dose group; however, no difference 

was observed in comparison to the control group. 

2.18 OTHER NONCANCER

No studies were located regarding other systemic effects in humans or animals after inhalation, oral, or 

dermal exposure to 2-butanone. 

2.19 CANCER

Two retrospective studies of industrial workers chronically exposed to 2-butanone in facilities involved in 

dewaxing lubricating oil 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 1–4 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. The 

decrease in cancer-related mortality from these studies (Alderson and Rattan 1980; Wen et al. 1985) may 

be due to the “healthy worker effect” because the mortality of workers (a population considered to have a 

lower overall death rate than the general population) was compared to that of the general population. 

An occupational cohort study of >14,000 aircraft maintenance workers from Utah reported a statistically 

significant elevated rate ratio (RR) for multiple myeloma in females in the baseline study (Spirtas et al. 
2-BUTANONE 43

2. HEALTH EFFECTS

1991) and an extended follow-up study (Radican et al. 2008), but not the initial follow-up study (Blair et 

al. 1998). However, the number of 2-butanone-exposed cases in the cohort was very small (n=4; hazard 

ratio of 4.98 [95% confidence limits 1.24–19.93]). 

Two case-control studies evaluated the relationship between 2-butanone exposure and childhood 

leukemia (Gao et al. 2014; Infante-Rivard et al. 2005). In a case-control study of acute childhood 

lymphoblastic leukemia diagnosis in Canada (790 cases, 790 controls), case mothers were more often 

exposed than were control mothers (exposure coding by job title and household exposure); however, the 

number of cases exposed to 2-butanone was very low (4 versus 0 in controls) (Infante-Rivard et al. 2005). 

A case-control study of acute childhood leukemia diagnosis in Shanghai (105 cases, 105 controls), 

demonstrated an elevated odds ratio (OR) for the relationship between measured household 2-butanone 

exposure and the diagnosis of acute childhood leukemia (OR 3.89, 95% confidence interval 1.55–9.78) 

(Gao et al. 2014).

No animal studies evaluating the carcinogenicity potential of 2-butanone were located. 

EPA (IRIS 2003) concluded that the data are inadequate for an assessment of human carcinogenic 

potential of 2-butanone. 

2.20 GENOTOXICITY

In vivo and in vitro studies regarding the genotoxicity of 2-butanone are summarized in Tables 2-4 and 

2-5. Genotoxic effects including gene mutation, chromosome aberration, micronucleus frequency, 

deoxyribonucleic acid (DNA) damage, cell transformation, and unscheduled DNA synthesis were 

primarily negative. Three studies reported evidence for 2-butanone induction of chromosome effects in 

yeast, but the findings were inconsistent with other studies evaluating similar endpoints. 

Table 2-4. Genotoxicity of 2-Butanone In Vivo

Species (exposure route) Endpoint Results Reference

Mammals

Mouse Micronucleated erythrocytes – O’Donoghue et al. 1988

Hamster Micronucleated erythrocytes – Basler 1986

– = negative result
2-BUTANONE 44

2. HEALTH EFFECTS

Table 2-5. Genotoxicity of 2-Butanone In Vitro

Species (test system) Endpoint

Results

Reference

Activation

With Without

Prokaryotic organisms

Salmonella typhimurium Gene mutation – – Thorpe 1982

S. typhimurium (TA102) Gene mutation – – Jung et al. 1992

S. typhimurium Gene mutation – – O’Donoghue et al. 

1988

S. typhimurium (TA97, TA98, 

TA100, TA1535, TA1537)

Gene mutation – – Zeiger et al. 1992

Escherichia coli Gene mutation – – Thorpe 1982

Eukaryotic organisms

Fungi

Saccharomyces cerevisiae Gene mutation – – Thorpe 1982

S. cerevisiae Chromosomal 

aberrations 

(malsegregation)

No data + Liu et al. 1997

S. cerevisiae (D61.M) Mitotic chromosome 

loss

No data – Mayer and Groin

1994

S. cerevisiae (D61.M) Gene mutation or 

recombination

No data – Mayer and Groin

1994

S. cerevisiae Mitotic chromosome 

loss

No data + Whittaker et al. 

1990; Zimmermann 

et al. 1989

S. cerevisiae Aneuploidy No data + Mayer and Goin 

1987

Mammalian cells

Rat liver cells (RL4) Chromosomal 

aberrations

No data – Thorpe 1982

Rat hepatocytes Unscheduled DNA 

synthesis

No data – O’Donoghue et al. 

1988

BALB/3T3 Morphological 

transformation

No data – O’Donoghue et al. 

1988

Mouse lymphoma Gene mutation – – O’Donoghue et al. 

1988

V79 Chinese hamster 

fibroblasts

Micronucleus frequency No data – Kreja and Seidel 

2002

V79 Chinese hamster 

fibroblasts

DNA damage (comet 

assay)

No data – Kreja and Seidel 

2002

A549 cells DNA damage (comet 

assay)

No data – Kreja and Seidel 

2002

+ = positive results; – = negative results; DNA = deoxyribonucleic acid
2-BUTANONE 45

2. HEALTH EFFECTS

In vivo, 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. 2-Butanone was not mutagenic in 

bacteria (Salmonella typhimurium or Escherichia coli), yeast (Saccharomyces cerevisiae), or L5178Y 

mouse lymphoma cells with or without activation (O’Donoghue et al. 1988; Jung et al. 1992; Thorpe 

1982; Zeiger et al. 1992). 2-Butanone also did not induce unscheduled DNA synthesis in rat primary 

hepatocytes, transform BALB/3T3cells, or increase the frequency of chromatid gaps, chromatid breaks, or 

total chromatid aberrations in rat liver cells (Thorpe 1982). Tests for micronuclei and DNA damage in 

v79 Chinese hamster fibroblasts or human lung A549 cells were also negative (Kreja and Seidel 2002). 

2-Butanone produced mitotic chromosome loss in some (Liu et al. 1997; Whittaker et al. 1990; 

Zimmermann et al. 1989), but not all (Mayer and Groin 1994) studies. In both cases however, a positive 

induction of chromosome loss in the yeast cells was enhanced by coexposure to 2-butanone, and ethyl 

acetate, and propionitrile (Zimmermann et al. 1989), or with 2,5-hexanedione or 2-hexanone (Mayer and 

Groin 1994). Aneuploidy in S. cerevisiae (Mayer and Goin 1987) increased at high concentrations. The 

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

Goin 1987). 

No studies were located regarding genotoxic effects in humans or animals after inhalation, oral, or dermal 

exposure to 2-butanone. 
2-BUTANONE 46

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, 

BIOMARKERS, CHEMICAL INTERACTIONS 

3.1 TOXICOKINETICS 

Human studies of 2-butanone provide primarily qualitative information on absorption following 

inhalation exposure and limited quantitative data on urinary excretion kinetics following inhalation. 

2-Butanone toxicokinetics have been studied in rats following oral and inhalation exposure. An overview 

of these data is summarized below.

• 2-Butanone is rapidly absorbed following inhalation and dermal exposure in humans. 

Experiments in rats indicate that 2-butanone is rapidly absorbed and eliminated after oral 

administration. 

• Distribution has not been extensively studied following in vivo exposure; however, in vitro 

determinations of the 2-butanone tissue:air solubility ratios for human kidney, liver, muscle, lung, 

heart, fat, blood, and brain show similar solubility in all tissues. 2-Butanone did not accumulate 

in perirenal fat following repeat inhalation exposure in rats.

• Urinary metabolites of 2-butanone in humans include 3-hydroxy-2-butanone and 2,3-butanediol. 

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

Oxidation produces 3-hydroxy-2-butanone, which is then reduced to 2,3-butanediol, and 

2-butanone reduction produces 2-butanol. The metabolites of 2-butanone in guinea pigs were 

excreted in the urine as O-glucuronides or O-sulfates. 2-Butanone exposure induces CYP in the 

liver.

• 2-Butanone is removed rapidly from the blood and is excreted unchanged in expired air and urine. 

Metabolites of 2-butanone (3-hydroxy-2-butanone and 2,3-butanediol) with or without 

conjugation are also excreted in urine.

3.1.1 Absorption 

2-Butanone is well absorbed during inhalation exposure in humans. Pulmonary uptake ranged from 41 to 

56% of the inspired quantity (Liira et al. 1988a, 1988b, 1990a). Exercise increased the pulmonary uptake 

due to the greater ventilatory rate (Liira et al. 1988b). Several investigators have reported that exposure 

concentrations of 2-butanone are 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). In 

two subjects exposed to 25, 200, and 400 ppm on separate days for 4 hours/day (Liira et al. 1990b), blood 

levels increased continuously with increasing 2-butanone exposure. The increase in blood concentration 
2-BUTANONE 47

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS 

was steeper during exposure for 200 and 400 ppm compared to 25 ppm. Slower elimination from the 

blood after cessation of exposure was also seen at 400 ppm. These concentration-dependent changes in 

blood kinetics suggest that metabolic saturation may occur at higher exposure concentrations. Using 

physiologically based pharmacokinetic (PBPK) model simulations for 8-hour exposures, the investigators 

estimated that metabolic saturation may be approached at concentrations near 100 ppm at rest and 50 ppm 

during exercise (Liira et al. 1990b). 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 significantly correlated with breath levels 

(Brown et al. 1986). 

Information on the absorption of 2-butanone by animals after inhalation exposure is limited. Pulmonary 

and nasal uptake in dogs exposed to 500 ppm 2-butanone for 30 minutes was 25 and 36% of the total 

inhaled vapor concentration (Dahl et al. 1991). 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 high blood:air solubility ratio of 2-butanone also favors absorption (Saida et al. 1976; Perbellini et al. 

1984). Blood:air partition coefficients determined for humans, rats and dogs ranged from 138 to 

208 (Beliveau and Krishnan 2000; Dahl et al. 1991; Fisher et al. 1997; Mahle et al. 2007; Thrall et al. 

2002). The human blood:air partition coefficient was 2–4% higher in male and female pediatric subjects 

compared with adults (Mahle et al. 2007). A similar age-related pattern was observed in rats with a 4–6% 

higher blood:air coefficient observed in PND 10 males compared with adult and aged male rats. 

A woman who had metabolic acidosis after having accidentally ingested 2-butanone stored in a rum bottle 

had a blood concentration of 95 mg/100 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. 

Experiments in rats indicate that 2-butanone is rapidly absorbed and eliminated after oral administration. 

Gavage administration of 1,690 mg/kg 2-butanone in rats resulted in a plasma concentration of 
2-BUTANONE 48

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

94 mg/100 mL at 4 hours (Dietz and Traiger 1979). Within 18 hours, the plasma concentration decreased 

to 6.2 mg/100 mL (Dietz and Traiger 1979). A second, similar experiment in rats showed that, after oral 

administration of 1,690 mg/kg 2-butanone, the plasma concentration was 95 mg/100 mL; the 

concentration decreased to 7 mg/100 mL by 18 hours (Dietz et al. 1981). The peak exhaled breath 

concentration of 2-butanone was measured within 1 hour of gavage dosing with 50 mg/kg (Thrall et al. 

2002). Concentrations in expired breath decreased slowly over the next 3 hours. 

2-Butanone was rapidly absorbed following dermal exposure to the forearm skin of volunteers and was 

detected in expired breath within 2–3 minutes of exposure (Munies and Wurster 1965; Wurster and 

Munies 1965). Dermal penetration was enhanced by hydration and was lower when applied to dry skin. 

In subjects exposed to 200 ppm airborne 2-butanone for 4 hours, dermal absorption contributed 

approximately 1.2–9.6% (mean of 3.10–3.5%) of absorbed dose (Brooke et al. 1998). A dermal 

permeability constant (Kp) of 53 g/m2

/hour was reported for 2-butanone across excised human skin 

(Ursin et al. 1995). Schenk et al. (2018) reported an in vitro steady-state flux of 0.00143 g/cm2

/hour 

(14.3 g/m2

/hour) and permeability coefficient of 0.00175 cm/hour for 2-butanone across pig skin. 

3.1.2 Distribution 

No studies were located regarding the distribution of 2-butanone following inhalation, oral, or dermal 

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 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). In rats, 

tissue:air partition coefficients were similar for liver, kidney, fat, muscle, and brain (Mahle et al. 2007; 

Thrall et al. 2002). Tissue:air partition coefficients for muscle and brain were higher in PND 10 male rats 

compared with adult and aged male rats; however, older rats exhibited higher tissue:air partition 

coefficients for liver, kidney and fat (Mahle et al. 2007). 2-Butanone has been detected in human breast 

milk (Giroux et al. (1992). 

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 perirenal 

fat concentrations of 0.71 μmol/g after a single exposure and 0.70 μmol/g after repeated exposure. The 

similarity in fat concentrations after single and repeated intermittent exposure indicates that 2-butanone 

does not accumulate (Liira et al. 1991). Cosnier et al. (2018a) repeatedly exposed rats to 2-butanone by 
2-BUTANONE 49

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

inhalation at 20, 200, or 1,400 ppm. Similar blood levels of 2-butanone were observed following a single 

6-hour exposure or repeated exposures for up to 1 month. Brain concentrations were only slightly 

increased by repeated exposures for 1 month. 

3.1.3 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, 1990a). The 

urinary concentrations of these metabolites, however, represent only about 0.1–2% of the absorbed 

2-butanone. 2-Butanol was found in the blood of male volunteers exposed to 200 ppm 2-butanone for 

4 hours (Liira et al. 1990a). 

3-Hydroxy-2-butanone, 2,3-butanediol, and 2-butanol have also been found in the blood in guinea pigs 

(DiVincenzo et al. 1976) and rats (Dietz et al. 1981) exposed to 2-butanone. 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 3-1). 

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 O-glucuronides or O-sulfates (DiVincenzo et al. 1976). Cosnier et al. (2018a) 

detected 2-butanone, 2-butanol, and 3-hydroxy-2-butanone in rat urine, but only at 2-butanone inhalation 

levels resulting in metabolic saturation. Thrall et al. (2002) demonstrated that 2-butanone metabolism in 

rats is not completely eliminated by inhibition of the oxidative pathway using pyrazole. 

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 1,080–1,500 mg/kg/day for 1–7 days resulted in 

increased levels of CYP protein, increased activities of CYP-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). 2-Butanone also induced specific CYP isozymes in rat liver 

(CYP2B1 and CYP2B2) following daily intraperitoneal injections of 5 mmol/kg for 4 days (Imaoka and 

Funae 1991). Induction of microsomal enzymes did not occur in rats exposed to 2-butanone by 

inhalation. After exposure of rats to 800 ppm 2-butanone for 5 weeks (Toftgard et al. 1981) or 600 ppm 
2-BUTANONE 50

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

n-butanone for 8 days (Liira et al. 1991), no changes were observed in the content of hepatic CYP or in 

the CYP isozyme profile. However, Cosnier et al. (2018a) exposed rats to 2-butanone by inhalation and 

reported the exposure-related induction of both CYP1A2 and CYP2E1 enzymes, although total hepatic 

P450 enzyme concentration was not altered. Furthermore, exposure to 2-butanone at 1,400 ppm resulted 

in decreased hepatic glutathione concentration and glutathione S-transferase activity. 

Figure 3-1. Proposed Metabolic Pathways for 2-Butanone

Source: DiVincenzo et al. 1976

3CH C C

H2

CH3

O

3CH C C

H

CH3

O OH

3CH C

H

C

H2

CH3

OH

3CH C

H

C

H

CH3

OH OH

2-Butanone

2-Butanol 3-Hydroxy-2-butanone

2,3-Butanediol

(reduction)

(oxidation) (reduction)

3.1.4 Excretion 

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 (Kawai 

et al. 2003; Liira et al. 1988a, 1990a; Perbellini et al. 1984) and rats (Cosnier et al. 2018a). Unchanged 

2-butanone is excreted primarily through the lungs; the quantity eliminated by this route is an estimated 

20–40% (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, 

1990a). 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. 1990a). Therefore, 2-butanone would not be expected to accumulate with 

chronic exposure (Lowry 1987). Tomicic et al. (2011) measured urinary 2-butanone concentrations 
2-BUTANONE 51

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

before during and after a 6-hour exposure to 100 ppm 2-butanone. The urinary 2-butanone concentration 

was highest immediately following exposure and returned to pre-exposure levels by 6 hours after the 

cessation of exposure (urinary half-life was not determined). 2-Butanone concentrations were highest in 

women without hormonal contraceptives compared to women with hormonal contraceptives and men, 

suggesting an influence of sex hormones on 2-butanone metabolism. 

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 (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 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 

inhalation or oral exposure. 

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

PBPK models use mathematical descriptions of the uptake and disposition of chemical substances to 

quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK 

models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in 

risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that 

will be delivered to any given target tissue following various combinations of route, dose level, and test 

species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use 

mathematical descriptions of the dose-response function to quantitatively describe the relationship 

between target tissue dose and toxic endpoints. 

Several PBPK models of 2-butanone have been reported. These include human models simulating 

2-butanone kinetics following inhalation exposure (Liira 1990b; Jongeneelen et al. 2013; Tomicic and 

Vernez 2014) and rat models using data from multiple exposure routes (Dietz et al. 1981; Thrall et al. 
2-BUTANONE 52

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

2002). Risk assessment applications of these models are limited by the small number of data sets 

available for testing and model calibration.

Liira et al. (1990b)

Liira et al. (1990b) developed a PBPK model using blood concentration data for two male subjects 

exposed to 25, 100, or 200 ppm 2-butanone for 4 hours. Blood samples were collected during exposure 

and for 8 hours after exposure. The pulmonary ventilation rate of the subjects was measured at rest and 

during exercise. 2-Butanone metabolism was assumed to occur in the liver only and followed MichaelisMenten kinetics. The Km (2 μM) and Vmax (30 μmol/minute) were calculated from the best fit of the 

simulated blood concentrations. 2-Butanone was detected in blood (0.2–0.3 μM) prior to exposure 

suggesting some endogenous formation of this compound. This was treated as a continuous inhalation 

exposure in the PBPK model (1.25 ppm).

The elimination of 2-butanone from blood is slower at higher exposure concentrations, which is 

suggestive of metabolic saturation. The PBPK model was used to simulate blood concentrations for an 

8-hour continuous exposure at rest and during exercise. Metabolic saturation was estimated to occur at 

2-butanone concentrations of 100 ppm at rest and 50 ppm during exercise.

Tomicic and Vernez (2014); Jongeneelen et al. (2013)

Tomicic and Vernez (2014) and Jongeneelen et al. (2013) both utilized a generic PBPK model to evaluate 

human urinary biomarker data for 2-butanone obtained from volunteers exposed to 100 ppm for 6 hours 

(Tomicic et al. 2011). Tominic and Vernez (2014) used an inhalation model that describes absorption 

from air into a central compartment (representing the total body water) and distribution between the 

central compartment and a peripheral or storage compartment (representing fatty tissues). Absorption 

into the central compartment was calculated as a product of the mass concentration in air, the alveolar 

ventilation rate scaled to body weight, and the fraction absorbed by the lung (pulmonary retention of 

0.56 from Liira et al. 1988a). Metabolism is described by Michaelis-Menten kinetics (Km 45 mg/L and 

Vmax 22 mg/(hour*kg0.75) from Thrall et al. 2002) and elimination is represented by metabolism and 

excretion in expired air or urine. 

The sensitivity analysis, obtained by increasing each toxicokinetic parameter of the PBPK model by 10% 

indicated that the urinary 2-butanone concentration was especially sensitive to metabolism parameters 
2-BUTANONE 53

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

(Km and Vmax), cardiac output, and liver blood flow. A comparison of experimental data and model 

simulations showed adequate goodness of fit during the 6 hours exposure with poorer fit during the 

urinary elimination phase. Predictive simulations done for a work week (8 hours/day, 5 days at the 

Threshold Limit Value [TLV] concentration of 200 ppm) showed an overestimation of urinary 

2-butanone concentration for women without hormonal contraceptives compared to women with 

hormonal contraceptives and men.

Jongeneelen et al. (2013) used a generic model with 11 body compartments (lung, heart, brain, skin, 

adipose tissues, muscles, bone, bone marrow, stomach and intestines, liver, and kidney). This model used 

Michaelis-Menten kinetic constants for liver metabolism of 2-butanone (Km 4 μmol/L, Vmax

1,800 μmol/kg tissue/hour) and liver metabolism of 2,3-butanediol (Km 50 μmol/L, Vmax 300 μmol/kg 

tissue/hour). Model simulations for women were similar to the experimental data for women volunteers 

from the Tomicic et al. (2011) study. The model predicted higher urinary 2-butanone concentrations in 

men compared with experimental data.

Dietz et al. (1981)

A flow-limited PBPK model was used to describe blood concentrations of 2-butanol, 2-butanone, 

3-hydroxy-2-butanone, and 2,3-butanediol in Sprague-Dawley rats after gavage administration of 

2-butanol (1,776 mg/kg) or 2-butanone (1,776 mg/kg) or intravenous injection of 3-hydroxy-2-butanone 

(400 mg/kg) and 2,3-butanediol (800 mg/kg) were administered by intravenous injection. The model 

assumed distribution to liver and body water (including blood) and metabolism in liver only. MichaelisMenten kinetics were used to describe metabolism, and rate constants for each metabolite were estimated 

by curve fitting of the experimental blood concentration data. The model was adjusted to account for the 

lower than expected concentration of 3-hydroxy-2-butanone in blood suggested to result from 

partitioning, binding, or decreased transport from the liver. The competitive inhibition of 2-butanone 

oxidation by 2-butanol was also accounted for. Model adjustments were shown to improve the fit of the 

simulation compared with the experimental data used to derive the model.

Thrall et al. (2002)

The PBPK model developed by Thrall et al. (2002) consisted of four tissue compartments (fat, liver, 

rapidly perfused tissues, and slowly perfused tissues) and a description of the exchange of 2-butanone 

between lung blood and alveolar air. Pulmonary uptake of 2-butanone was evaluated in Fisher 344 rats 
2-BUTANONE 54

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

exposed to concentrations ranging from 100 to 2,000 ppm. Exhaled breath concentration were considered 

a surrogate measure of blood concentration. Michaelis-Menten metabolic rate constants were obtained by 

model simulation of the gas uptake data (best fit values of Km 0.63 mg/L, Vmax 5.44 mg/hour/kg). The 

PBPK model was calibrated using experimental data for expired breath concentrations in rats exposed by 

intravenous injection (25 mg/kg), intraperitoneal injection (50 mg/kg), and gavage (50 mg/kg). Rate 

constants calculated for oral and intraperitoneal absorption were 1.9 and 0.91 hours-1

, respectively.

3.1.6 Animal-to-Human Extrapolations 

The toxicokinetics of 2-butanone in humans are similar to those that have been observed in rats and 

guinea pigs. Metabolites of both oxidation and reduction reactions are found in all species. 

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. Potential effects on offspring resulting from exposures of parental 

germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal 

exposure during gestation and lactation. Children may be more or less susceptible than adults to health 

effects from exposure to hazardous substances and the relationship may change with developmental age. 

This section also discusses unusually susceptible populations. A susceptible population may exhibit 

different or enhanced responses to certain chemicals than most persons exposed to the same level of these 

chemicals in the environment. Factors involved with increased susceptibility may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters can reduce detoxification or excretion or compromise organ function. 

Populations at greater exposure risk to unusually high exposure levels to 2-butanone are discussed in 

Section 5.7, Populations with Potentially High Exposures.

The human blood:air partition coefficient was 2–4% higher in male and female pediatric subjects 

compared with adults and a similar age-related pattern was observed in rats, with a 4–6% higher blood:air 

coefficient observed in PND 10 males compared with adult and aged male rats (Mahle et al. 2007). These 

data suggest that pulmonary uptake following inhalation may be slightly higher in children compared to 

adults. Tomicic et al. (2011) suggested that individuals with a genetic polymorphism in the gene for 
2-BUTANONE 55

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

CYP2E1 (mutant allele CYP2E1*6) may exhibit enhanced oxidative metabolism of 2-butanone; however, 

the findings were limited by the small number of study participants (n=25). Experimental animal studies 

suggest that inhalation exposure to 2-butanone during pregnancy may lead to developmental effects; 

however, these effects were only seen at very high concentrations (>2,000 ppm).

3.3 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as biomarkers of exposure, biomarkers of effect, and biomarkers 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, substance-specific metabolites in readily obtainable body fluid(s), or excreta. Biomarkers of 

exposure to 2-butanone are discussed in Section 3.3.1. The National Report on Human Exposure to 

Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable sample of 

the U.S. population to environmental chemicals using biomonitoring (see http://www.cdc.gov/

exposurereport/). If available, biomonitoring data for 2-butanone from this report are discussed in 

Section 5.6, General Population Exposure. 

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 not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effect caused 

by 2-butanone are discussed in Section 3.3.2.

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, a decrease in the 
2-BUTANONE 56

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.2, Children and Other Populations that are Unusually Susceptible.

3.3.1 Biomarkers of Exposure

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; Kawai et al. 2003; 

Miyasaka et al. 1982; Sia et al. 1991). Personal dosimetry was used to measure exposure to 2-butanone 

among 27 furniture makers (Kawai et al. 2003), 50 magnetic videotape factory workers (Sia et al. 1991), 

62 printing plant workers (Miyasaka et al. 1982), 72 printing plant workers (Yoshikawa et al. 1995), 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 values ranging from 0.774 to 0.889). Miyasaka et al. (1982) concluded, however, that 

estimating exposure from urinary levels was reliable on a group basis, but not an individual basis. In a 

study of eight aircraft maintenance workers, Lemasters et al. (1999) suggested that breath measurements 

were more sensitive than urine and blood measurements following low-level exposure to 2-butanone 

(<20 ppm). 

A significant correlation between workroom and urinary 2-butanone concentrations was observed in shoe 

factory workers (r=0.6877, p<0.001) (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<0.001). Another 2-butanone metabolite, 2,3-butanediol, has also 

been identified in the urine of humans (Liira et al. 1988a, 1988b); however, no studies have examined the 

correlation between exposure to 2-butanone and urinary levels of this metabolite. 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. 1985); therefore, these compounds may confound assessment of exposure to

2-butanone. The urinary concentration of 2-butanone measured immediately after a 6-hour exposure to 

100 ppm 2-butanone was similar in women using hormonal contraceptives and men of similar age, but 

was higher in women not using hormonal contraceptives (Tomicic et al. 2011). This finding suggests that 

the presence of sex hormones may increase 2-butanone metabolism by CYP2E1; however, interpretation 

of study findings is limited by the small number of study participants (n=25). Creatinine adjustment of 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

this exposure biomarker was not necessary due to the passive process of elimination by the kidney 

(i.e., dependent on urine flow rate only). 

Blood and breath levels of 2-butanone were significantly correlated (r=0.78, p<0.001) in volunteers 

exposed to 200 ppm 2-butanone for 4 hours (Brown et al. 1986). 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).

2-Butanone is endogenously produced during the catabolism of isoleucine and is considered a normal 

constituent of urine (Tsao and Pfeiffer 1957). A study of National Health and Nutrition Examination 

Survey (NHANES) participants found an association between daily consumption of >20 mL alcohol and 

blood 2-butanone levels (Churchill et al. 2001).

3.3.2 Biomarkers of Effect

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 identified 

that would be useful as biomarkers to characterize effects of 2-butanone.

3.4 INTERACTIONS WITH OTHER CHEMICALS

The neurological and hepatic effects of 2-butanone alone are minimal (Altenkirch et al. 1978; Saida et al. 

1976). This compound, however, is frequently mixed with other chemicals such as n-hexane or methyln-butyl ketone for various commercial and industrial applications, which can then lead to serious toxic 

effects. Exposure to mixed solvents is most likely to occur in occupational settings or at a hazardous 

waste site. Clinical reports, animal studies, and some in vitro tests have shown that 2-butanone 

potentiates or enhances the neurotoxicity of ethanol, n-hexane, and methyl-n-butyl ketone, ethyl-n-butyl 

ketone, and toluene; the hepatotoxicity of carbon tetrachloride, chloroform, n-hexane, and 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

dimethylformamide; and the renal toxicity of methanol, and chloroform. These studies emphasize the 

potential public health hazard of mixed solvent exposure including 2-butanone. 

Interactions Potentially Influencing Neurotoxicity. Based on several case studies and clinical case 

reports, there is some evidence to suggest an interaction between 2-butanone and n-hexane and 

2-butanone and methyl-n-butyl ketone, which potentiates neurotoxic effects. Altenkirch et al. (1977) 

investigated a large outbreak of toxic polyneuropathies in a group of West Berlin "glue sniffers." Until 

the fall of 1975, the major constituents of the glue were n-hexane, toluene, ethyl acetate, and benzene. 

The development of neuropathies (muscular atrophy, paresthesia, paresis, quadriplegia) coincided with 

the addition of 2-butanone to the mixture. Similar outcomes were described in a clinical case report of 

three men exhibiting “glue sniffing neuropathy” following the addition of 2-butanone to the glue 

formulation (King et al. 1985), and also in workers from a coated fabrics plant who exhibited peripheral 

nephropathy when a methyl-n-butyl ketone solvent was introduced that contained high concentrations of 

2-butanone (Allen et al. 1975; Billmaier et al. 1974). In another case, a 39-year-old woman who had 

worked for several years gluing shoes using a glue containing 20% 2-butanone and 8% n-hexane, 

developed polyneuropathy after a few weeks of work in a poorly ventilated shop (Vallat et al. 1981). 

Laboratory animal studies demonstrated 2-butanone potentiation of n-hexane, methyl-n-butyl ketone, and 

ethyl-n-butyl ketone neurotoxicity (Altenkirch et al. 1978, 1982; O'Donoghue et al. 1984; Saida et al. 

1976; Schmidt et al. 1984). A study exposing rats to either 10,000 ppm n-hexane or a combination of 

1,000 ppm 2-butanone and 9,000 ppm n-hexane reported that the co-exposed animals developed paresis 

more rapidly and in greater numbers than rats exposed to n-hexane only (Altenkirch et al. 1978). In the 

same study, rats exposed to 6,000 ppm 2-butanone alone showed no signs of neurotoxicity up to 7 weeks, 

when all of 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 (4:1 or 3:2) or 700 ppm (5:2) caused clinical 

signs of neuropathy 1–5 weeks earlier than 500 ppm n-hexane alone (Altenkirch et al. 1982). 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 and 

mixed nerve conduction velocity in rats exposed to 300 ppm n-hexane:2-butanone (1:2) compared with 

rats exposed to 200 ppm 2-butanone alone or 100 ppm n-hexane alone (measured after 20 and 24 weeks 

of exposure). Finally, 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).
2-BUTANONE 59

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

A marked potentiation of peripheral neurotoxicity was reported when rats were exposed to methyl-n-butyl 

ketone:2-butanone (225:1,125 ppm) (Saida et al. 1976). Rats exposed to methyl-n-butyl ketone alone

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. (1982), which included paranodal axon swelling, 

accumulation of neurofilaments, and demyelination. Subcutaneous injection of methyl-n-butyl ketone 

alone increased distal motor latency and decreased motor fiber conduction velocity in male Donryu strain 

rats; these effects were enhanced with concomitant exposure to 2-butanone (Misumi and Nagano 1985). 

Oral administration of ethyl-n-butyl ketone in rats for several weeks caused paranodal axon swelling and 

neurofilamentous hyperplasia characteristic of n-hexane and methyl-n-butyl ketone neurotoxicity 

(O'Donoghue et al. 1984). Oral administration of 2-butanone potentiated the development of clinical and 

histological signs of ethyl-n-butyl ketone neurotoxicity.

In vitro studies support the hypothesis that 2-butanone potentiates both 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 n-hexane 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.

The precise mechanisms behind 2-butanone potentiation of n-hexane and methyl-n-butyl ketone 

neurotoxicity remain unclear; however, several studies suggest that 2-butanone alters the metabolism and 

elimination kinetics of these compounds. Biotransformation of n-hexane, methyl-n-butyl ketone, and 

ethyl-n-butylketone can produce the neurotoxic metabolite, 2,5-hexanedione (2,5-HD) (Couri et al. 1978; 

DiVincenzo et al. 1976; Robertson et al. 1989). The concentrations of the n-hexane metabolites, 2,5-HD 

and 2,5-dimethylfuran, were significantly higher in the blood and sciatic nerves of rats pretreated by 

gavage with 2-butanone before inhalation exposure to n-hexane, compared to concentrations in rats 

exposed to n-hexane alone (Robertson et al. 1989). Shibata et al. (1990a, 1990b) observed changes in 

urine n-hexane metabolite profiles in rats co-exposed to 2-butanone for 8 hours, indicating an overall 

decrease in both the production and clearance of 2,5-HD. Similar urine metabolite changes were seen in a 

controlled, acute 2-butanone/n-hexane co-exposure inhalation study in four human subjects (Shibata et al. 

2002). In other acute single-dose studies in laboratory animals, concomitant oral administration of 

2-butanone and 2,5-HD in rats reduced blood 2,5-HD clearance (Ralston et al. 1985). In Wistar rats co-
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

exposed interperitoneally to 2,5-HD and 2-butanone, reductions in of 2,5-HD clearance was observed in 

all tissues examined including serum, urine, and sciatic nerve tissue (Aoki et al. 1996; Yasui et al. 1995; 

Zhao et al. 1998a, 1998b). Concomitant inhalation exposure to ethyl-n-butyl ketone and 2-butanone 

(700:700 ppm) for 4 consecutive days caused a 2.6-fold increase in the serum concentration of 

2,5-heptanedione, which can be further metabolized to 2,5-HD (O’Donoghue et al. 1984). A metabolic 

study in vitro was done to evaluate the effect of 2-butanone on n-hexane metabolism in rat liver S9 

fractions using a head-space vial equilibration technique (Mortensen et al. 1998). Liver S9 fractions were 

isolated from rats orally exposed (pretreated) in vivo to a vehicle control or to 2-butanone. S9 fractions 

where then exposed in closed test tubes to either n-hexane vapors alone or to an n-hexane:2-butanone 

mixture. Consistent with metabolism studies done in vivo, the total amount of n-hexane metabolized from 

the head space was higher in 2-butanone pretreated liver S9 fractions than in untreated fractions, and the 

levels of the n-hexane metabolite, 2,5-HD, was approximately 3.5 times higher. 2,5-HD levels increased 

further with increasing concentrations of 2-butanone vapors added in vitro (Mortensen et al. 1998).

The impact of reduced 2,5-HD clearance on neurotoxicity becomes more evident in longer studies. A 

20-week subchronic inhalation study in rats exposed to n-hexane and 2-butanone reported a biphasic 

response, and an initial decrease in 2,5-HD concentrations in urine, similar to the observations from acute 

studies, was followed by an overall increase in 2,5-HD over time (Ichihara et al. 1998). The rise in 

2,5-HD coincided with decreased motor nerve velocity and increased distal latency of the tail nerve, 

measures of n-hexane neurotoxicity (Ichihara et al. 1998). Collectively, these studies indicate that the 

potentiating effects of 2-butantone on n-hexane, methyl-n-butyl ketone, and ethyl-n-butyl ketone 

neurotoxicity may be mediated by increased persistence of the 2,5-HD metabolite.

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 decreased the 

rate of ethanol elimination in mice in vivo and inhibited the in vitro activity of alcohol dehydrogenase, the 

primary mechanism for ethanol elimination. These results suggest that 2-butanone may potentiate the 

neurotoxicity of ethanol by inhibiting its metabolism by alcohol dehydrogenase.

Cosnier et al. (2014) reported significant increases in blood toluene levels at both 1 and 5 days after 

exposure by inhalation to binary mixtures of toluene and 2-butanone, compared to those exposed to 

toluene alone. Cosnier et al. (2018b) found that toluene inhibited 2-butanone metabolism and that 
2-BUTANONE 61

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

2-butanone inhibited toluene metabolism in rats exposed by inhalation to both substances. However, the 

studies of Cosnier and coworkers did not include evaluation of neurological endpoints.

Interactions Potentially Influencing Liver Toxicity. 2-Butanone alone is not highly hepatotoxic 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) alone caused a 9-fold increase in rat ALT activity (Brown and Hewitt 1984). In 

contrast, chloroform injection caused a 195-fold increase in rat ALT activity if administered 18 hours 

after oral administration of 2-butanone. Similarly, intraperitoneal injection of chloroform increased rat 

plasma ornithine carbamyl transferase activity 215-fold if given 18 hours after oral administration of 

2-butanone (Hewitt et al. 1983). The severity of hepatotoxicity appears to be dependent on dose and the 

length of time between 2-butanone pretreatment and subsequence chloroform exposure (Hewitt et al. 

1987). 2-Butanone also potentiates carbon tetrachloride-induced hepatotoxicity in the rat (Dietz and 

Traiger 1979; Raymond and Plaa 1995a; Traiger et al. 1989). Significant increases in rat plasma ALT 

activity and hepatic triglyceride content, both suggestive of liver damage, were observed following the 

administration of 2-butanone either for 16 hours (Traiger et al. 1989) or for a duration of 3 days 

(Raymond and Plaa 1995a) before intraperitoneal injection of carbon tetrachloride. An in vitro study by 

Kim et al. (2014) suggests a possible interaction between 2-butanone and dimethylformamide (DMF) in 

HepG2 cells. Additional studies will be needed to determine what effect this interaction, if any, will have 

on DMF-mediated liver toxicity in vivo. 

The potentiation of liver toxicity by ketones like 2-butanone is thought to be due to CYP induction. 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. Liver 

microsomes extracted from rats pretreated with 2-butanone, however, did not have increased CYP content 

compared with controls (Raymond and Plaa 1995b). Additionally, 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 CYP system, or depletion of liver glutathione

(Hewitt et al. 1987). To explore other possibilities, Raymond and Plaa (1996) tested whether 2-butantone 

altered the adverse impacts of carbon tetrachloride treatment on liver membrane integrity. Purified liver 

membranes from controls or rats pretreated with 2-butanone were monitored for membrane fluidity and 

measured for membrane enzymes including 5’-nucleotidase, leucine aminopeptidase, and alkaline 
2-BUTANONE 62

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

phosphatase (Raymond and Plaa 1996). 2-Butanone had no significant impact on the membrane integrity 

status influenced by carbon tetrachloride; therefore, increased membrane sensitivity is not likely a 

mechanism contributing to 2-butanone potentiation of carbon tetrachloride hepatotoxicity. 

Another hypothesis is that the observed 2-butanone potentiation of chloroform and carbon tetrachloride 

hepatotoxicity may be related to biotransformation of the 2-butanone to its metabolite, 2,3-butanediol. 

Carbon tetrachloride increased rat ALT 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 

(Traiger et al. 1989).

Interactions Potentially Influencing Kidney Toxicity. Few studies have evaluated the impact of 

2-butanone interactions on kidney toxicity. In a case-report, a 42-year-old male who ingested a cleaning 

solution that contained methanol and 2-butanone became tachycardic, with a hyperosmolar coma without 

anion gap metabolic acidosis. The study authors suggested that the osmolar gap, in the absence of 

metabolic acidosis, could be due to 2-butanone inhibition of methanol metabolism (Price et al. 1994). 

Kidney toxicity, assessed by a decreased accumulation of p-aminohippuric acid in renal cortical slices in 

rats exposed to chloroform, was potentiated in rats that were pretreated with 2-butanone for 3 days prior 

to chloroform exposure (Raymond and Plaa 1995a). Unlike in the liver, total CYP content and aniline 

hydroxylase levels were increased in kidney microsomes extracted from rats pretreated with 2-butanone, 

compared to controls. These data suggest a role for CYP induction in the potentiation of chloroform 

kidney toxicity by 2-butanone (Raymond and Plaa 1995b).

Interactions Potentially Influencing Other Toxicity. Pretreatment of ddY mice with carbon tetrachloride 

24 hours before oral administration of 2-butanone reduced the 2-butanone LD50 about 20% (Tanii et al. 

1986). The mechanism of this effect was not investigated.

Exposure of pregnant rats continuously to n-hexane alone (1,000–1,500 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 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

to quadriplegia in all dams during the postpartum exposure period was observed with the solvent mixture, 

while only hindlimb weakness was observed in the dams exposed to n-hexane alone.

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-BUTANONE 64

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY

Data pertaining to the chemical identity of 2-butanone are listed in Table 4-1. 

Table 4-1. Chemical Identity of 2-Butanone

Characteristic Information Reference

Chemical name 2-Butanone CAS 1989

Synonym(s) and registered 

trade name(s)

Methyl ethyl ketone; MEK; ethyl methyl 

ketone; methyl acetone; and others; 

Meetco

CAS 1989; SANSS 1989; 

Chemline 1989; OHM/TADS 

1989

Chemical formula C4H8O CAS 1989

Chemical structure

CAS Registry Number 78-93-3 CAS 1989

CAS = Chemical Abstracts Service 

4.2 PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of 2-butanone are presented in Table 4-2. 

Table 4-2. Physical and Chemical Properties of 2-Butanone

Property Information Reference

Molecular weight 72.11 Weast et al. 1988

Color Colorless Sax and Lewis 1987

Physical state Liquid Sax and Lewis 1987

Melting point -86.3°C Weast et al. 1988

Boiling point 79.6°C Weast et al. 1988

Density (liquid) at 20°C 0.8054 Weast et al. 1988

Odor Acetone-like Sax and Lewis 1987

Odor threshold:

Water 8.4 ppm Amoore and Hautala 1983

Air 5.4 ppm Amoore and Hautala 1983

3CH C C

H2

CH3

O
2-BUTANONE 65

4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of 2-Butanone

Property Information Reference

Solubility:

Water at 25°C 136,000 mg/L Tewari et al. 1982

Organic solvents Benzene, alcohol, ether, oils, most 

organic solvents

Sax and Lewis 1987; Neier and 

Strehlke 1985

Partition coefficients:

Log Kow 0.29 Hansch et al. 1995

Log Koc 0.55 Roy and Griffin 1985

Vapor pressure at 25°C 90.6 mmHg Riddick et al. 1986

Henry's law constant at 25°C 5.77x10-5 atm m3/mol Rathbun and Tai 1987

Autoignition temperature 515°C Sax and Lewis 1987

Flashpoint:

Closed cup -2°C Riddick et al. 1986

Open cup 1°C Riddick et al. 1986

Flammability limits in air 2–10% Sax and Lewis 1987

Conversion factors:

ppm (v/v) to mg/m3 in air 

(20°C)

1 ppm=2.95 mg/m3

mg/m3 to ppm (v/v) in air 

(20°C)

1 mg/m3=0.339 ppm

Bioconcentration factor 0.98 (calculated from Kow) Lyman et al. 1982

Explosive limits 1.4–11.4% at 200°F NIOSH 2019
2-BUTANONE 66

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW

2-Butanone has been identified in at least 526 of the 1,867 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (ATSDR 2019). However, the number of sites in which 

2-butanone has been evaluated is not known. The number of sites in each state is shown in Figure 5-1. Of 

these sites, 523 are located within the United States and 3 are located in Puerto Rico (not shown). 

Figure 5-1. Number of NPL Sites with 2-Butanone Contamination

• The most likely routes of 2-butanone exposure for the general public include ingestion of food, 

ingestion of contaminated drinking water, inhalation during household use of coating products, 

and dermal contact during the use of these products. High levels of occupational exposure to 

2-butanone may occur by inhalation and dermal contact during the loading and unloading of large 

quantities of commercial coating materials during shipment. The application of commercial 

coatings containing 2-butanone without adequate protection may also lead to high levels of 

exposure, primarily by inhalation. 

• 2-Butanone is detected in environmental media, although usually at low levels. 2-Butanone is 

expected to rapidly volatilize from surface water and moist or dry soils and exists as a vapor in 

the atmosphere. 2-Butanone displays a high mobility in soil and leaches readily into 

groundwater. 2-Butanone does not adsorb strongly to soils and sediments or bioconcentrate in 

aquatic organisms. 
2-BUTANONE 67

5. POTENTIAL FOR HUMAN EXPOSURE

• 2-Butanone undergoes degradation in the atmosphere although the mechanisms responsible for 

this process are not known. Biodegradation is expected to occur in soil and water under both 

aerobic and anaerobic conditions. 

2-Butanone may be released to the atmosphere in fugitive emissions during its production, transport, and 

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 wastewater 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. 

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 or 

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 vaporphase 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.
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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.

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 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

No information is available in the TRI database on facilities that manufacture or process 2-butanone 

because this chemical is not required to be reported under Section 313 of the Emergency Planning and 

Community Right-to-Know Act (Title III of the Superfund Amendments and Reauthorization Act of 

1986) (EPA 2005).

According to the most recent edition of U.S. Chemical Data Reporting on chemical production and use in 

the United States (EPA 2020), the National Aggregate Production Volume of 2-butanone in 2015 was

100,000,000–250,000,000 pounds. The National Aggregate Production Volumes of 2-butanone were

282,480,991, 100,000,000–250,000,000, 100,000,000–250,000,000, and 50,000,000–100,000,000 pounds 

in 2011, 2012, 2013, and 2014, respectively. U.S. facilities that produced, processed, or used 2-butanone 

in 2015 are included in Table 5-1. 
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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Facilities that Produce, Process, or Use 2-Butanone

State Number of facilities 

Alabama 1

Arkansas 1

California 2

Delaware 1

Florida 3

Illinois 2

Indiana 2

Kentucky 2

Louisiana 1

Massachusetts 1

Minnesota 1

Missouri 1

New Jersey 8

New York 2

Ohio 6

Oregon 2

Pennsylvania 2

South Carolina 1

Texas 9

Washington 1

Wisconsin 3

Source: EPA 2020

2-Butanone is produced on a commercial scale by one of two processes. The catalytic dehydrogenation 

of 2-butanol in the gas-phase accounts for 92% of 2-butanone production (2006). The remaining 8% of 

2-butanone is produced by a process in which liquid n-butane is oxidized catalytically to produce acetic 

acid and 2-butanone as a byproduct (Hoell et al. 2012). 

5.2.2 Import/Export

No publicly accessible data were located to indicate the amount of 2-butanone exported or imported from 

or to the United States.
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5. POTENTIAL FOR HUMAN EXPOSURE

5.2.3 Use

2-Butanone is an important solvent with properties similar to those of acetone. 2-Butanone exhibits a 

very high power of dissolution. Some natural substances, plastics, and resins can be dissolved in 

2-butanone. Areas of application are production of paints, lacquers, varnishes, paint thinners and 

removers, adhesives, cements, sealants, magnetic tapes, artificial leather, transparent paper, printing inks, 

cleaner for electronic equipment, cosmetics, pharmaceuticals; degreasing of metal surfaces; extraction of 

fats, oils, waxes, natural resins; and dewaxing of mineral oils or lube oils. Additionally, it is used as a 

synthetic flavoring agent in foods and pharmaceuticals and as a sterilizer for bacterial spores on surgical 

instruments, hypodermic needles and syringes, and dental instruments. It is also used in the 

manufacturing of smokeless powders (Hoell et al. 2012), which are ammunition propellants. 

5.2.4 Disposal

Incineration can be used to dispose of 2-butanone by spraying into incinerators or burning in paper 

packaging (NLM 2020). 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. 

5.3 RELEASES TO THE ENVIRONMENT

Manufacturing and processing facilities are required to report information to the TRI only if they employ 

≥10 full-time employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 

(except 1011, 1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal 

and/or oil for the purpose of generating electricity for distribution in commerce), 4931 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4939 (limited to facilities that combust coal and/or oil for the purpose of generating 

electricity for distribution in commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 

U.S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 

7389 (limited to facilities primarily engaged in solvents recovery services on a contract or fee basis); and 

if their facility produces, imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses 

>10,000 pounds of a TRI chemical in a calendar year (EPA 2005). 
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5. POTENTIAL FOR HUMAN EXPOSURE

5.3.1 Air

There is no information on releases of 2-butanone to the atmosphere from manufacturing and processing 

facilities because these releases are not required to be reported (EPA 2005). 

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 (EPA 1987a; 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. 

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 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 was reported in the emissions of common 

household wastes (Wilkins and Larsen 1995, 1996) and in aerobic composting at a rate of 22 g/ton of 

waste, 0.8 g/ton in phase I of combined anaerobic/aerobic composting processes, and 0.1 g/ton in phase II 

(Smet et al. 1999). 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). 

5.3.2 Water

There is no information on releases of 2-butanone to water from manufacturing and processing facilities 

because these releases are not required to be reported (EPA 2005). 

Limited data are available regarding the release of 2-butanone to surface and groundwaters. It has been 

detected in wastewater 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 
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5. POTENTIAL FOR HUMAN EXPOSURE

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 rainwater (Grosjean and Wright 1983). 

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 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). 

5.3.3 Soil

There is no information on releases of 2-butanone to soil from manufacturing and processing facilities 

because these releases are not required to be reported (EPA 2005).

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 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). 

5.4 ENVIRONMENTAL FATE

5.4.1 Transport and Partitioning

Air. 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 gasphase concentration of 2-butanone in Los Angeles, California was 220–3,000 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 
2-BUTANONE 73

5. POTENTIAL FOR HUMAN EXPOSURE

atmosphere. 2-Butanone has been identified in rainwater (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, <1 day, 

suggests that it is not transported long distances from its original point of release.

Water. 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/second with a wind velocity of 3 m/second, is approximately 15 hours (Lyman et al. 1982). 

Sediment and Soil. 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.

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 (Hansch et al. 1995), and an appropriate 

regression equation (Lyman et al. 1982). 

5.4.2 Transformation and Degradation

Air. 2-Butanone is expected to undergo atmospheric destruction by the gas phase reaction with 

photochemically produced hydroxyl radicals. Rate constants for this reaction ranging from 1.85x10-11 to 

9.8x10-13 atm/molecule-second in the temperature range of 22–32°C have appeared in the literature (Cox 

et al. 1980, 1981; EPA 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/moleculesecond 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 
2-BUTANONE 74

5. POTENTIAL FOR HUMAN EXPOSURE

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. 

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. 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 fermenter using a domestic sludge inoculum that had been adapted to acetate (Chou et al. 

1978).

An experimentally determined rate constant of 5.4x108 L/mol-second 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 (EPA 1987b), indicating that this process 

does not occur in the environment. By analogy to the gas phase 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. 
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5. POTENTIAL FOR HUMAN EXPOSURE

The chemical alteration of 2-butanone in rainwater has been postulated. In acid rain, hydroxy sulfonates 

may be formed by their action 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 

rainwater than in surface water; therefore, a more rapid rate of reaction would be expected in rain.

Sediment and 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 in soil. 

5.5 LEVELS IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to 2-butanone depends, in part, on the reliability 

of supporting analytical data from environmental samples and biological specimens. Concentrations of 

2-butanone in unpolluted atmospheres and in pristine surface waters are often so low as to be near the 

limits of current analytical methods. In reviewing data on 2-butanone levels monitored or estimated in 

the environment, it should also be noted that the amount of chemical identified analytically is not 

necessarily equivalent to the amount that is bioavailable.

Table 5-2 shows the lowest limit of detections that are achieved by analytical analysis in environmental 

media. An overview summary of the range of concentrations detected in environmental media is 

presented in Table 5-3. 

Table 5-2. Lowest Limit of Detection Based on Standardsa 

Media Detection limit Reference

Air 4 μg NIOSH 1996

Air 8 ppb Jonsson et al. 1985

Drinking water No data Wallace et al. 1984

Surface water and groundwater 10 ppb EPA 1988

Soil 10 ppb EPA 1988
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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-2. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Sediment 10 ppb EPA 1988

Whole blood 0.01 ppm Van Doorn et al. 1989

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

Table 5-3. Summary of Environmental Levels of 2-Butanone

Media Low High Mean

Outdoor air (ppb) 0.5 14 2.8

Indoor air (ppb) No data No data No data

Surface water (ppb) No data No data 11

Groundwater (ppb) No data No data 302

Drinking water (ppb) No data No data 1.6

Soil (ppb) No data No data 87

Detections of 2-butanone in air, water, and soil at NPL sites are summarized in Table 5-4. 

Table 5-4. 2-Butanone Levels in Water, Soil, and Air of National Priorities List 

(NPL) Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

quantitative 

measurements NPL sites

Water (ppb) 200 401 26.9 158 94

Soil (ppb) 550 1,700 65.7 119 93

Air (ppbv) 15.9 16.8 21.4 33 20

aConcentrations found in ATSDR site documents from 1981 to 2019 for 1,867 NPL sites (ATSDR 2019). Maximum 

concentrations were abstracted for types of environmental media for which exposure is likely. Pathways do not 

necessarily involve exposure or levels of concern.

5.5.1 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 of 

2-butanone measured in Los Angeles air in 1980 was 0–14 ppb in 70 samples (Grosjean 1982). An 
2-BUTANONE 77

5. POTENTIAL FOR HUMAN EXPOSURE

average concentration of 0.638 ppb of 2-butanone was obtained from 714 atmospheric samples in the 

United States (EPA 1988). The average concentration of 2-butanone at 25 urban locations in the United 

States was 1.4 μg/m3 (0.48 ppb) (Kelly et al. 1993). 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, 2-butanone 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); in samples surrounding the site, concentrations 

were 0.5–33 μg/m3

 (0.17–11.3 ppb) (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 (EPA 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. 

5.5.2 Water

From water quality data collected across the United States, 2-butanone was found at <2.0 μg/L (detection 

limit) in 1 of 107 samples of finished water (NWQMC 2020). 2-Butanone was identified as 

an ozone disinfection byproduct in drinking water (Richardson et al. 1999). 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. 
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5. POTENTIAL FOR HUMAN EXPOSURE

2-Butanone has been qualitatively detected in rainwater 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). 

Water quality data compiled from the STORET Data Warehouse and the U.S. Geological Survey (USGS) 

National Water Information System (NWIS) reports are summarized in Table 5-5. These data are 

comprised of water quality data from water resource management groups across the country. 

Table 5-5. 2-Butanone Detected in Samples Collected Throughout the United 

States from 2010 to 2020

Type Number of samples Number of positive Concentration range

Groundwater 21,395 3,072 0.09–5000 ppb

Surface water 1,093 66 0.3–<50 ppb

Storm water 9 9 <1.9–<50 ppb

Leachate 60 60 <50–2,450 ppb

Municipal waste 2 0 1.5 ppb (detection limit)

Sediment 37 0 0.89–4.30 ppb (detection limit)

Soil 18 0 1.1–330 ppb (detection limit)

Drinking watera 107 1 <2.0 ppb (detection limit)

aSamples taken 1998–2009; no results were reported for 2010–2020. 

Source: NWQMC (2020).

2-Butanone has been detected in the effluent of various industrial processes. It was found in six of seven 

wastewater samples from energy-related processes at a concentration up to 645 ppb (Pellizzari et al. 

1979). 2-Butanone was detected in the wastewater 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 wastewater 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 in the 

wastewater entering Cincinnati treatment plants (Dunovant et al. 1986). 

2-Butanone was qualitatively detected in the Black Warrior River, located in Tuscaloosa, Alabama 

(Bertsch et al. 1975) and in Newark Bay, New Jersey (Gunster et al. 1993). It was also detected in 
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5. POTENTIAL FOR HUMAN EXPOSURE

seawater from the straits of Florida at 0–22 ppb in 1968 (Corwin 1969) and in the Potomac River at 

<40 μg/L (Hall et al. 1987). 

5.5.3 Sediment and Soil

2-Butanone has been reported in soil samples collected from various mines and waste disposal facilities in 

the United States at concentrations ranging from 32 to 38,000 μg/kg (EPA 1987c, 1987d, 1988b, 1989). 

5.5.4 Other 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 tree-ripened nectarines (Dumont and 

Adda 1978; Gordon and Morgan 1972; Grey and Shrimpton 1967; Keen et al. 1974; Kinlin et al. 1972; 

Sosulski and Mahmoud 1979; Takeoka et al. 1988). The mean concentrations of 2-butanone in dried 

beans, split peas, and lentils were 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). 2-Butanone is a 

constituent of plant families including Lamiaceae, Solanaceae, Myrtaceae, and Grossulariaceae (USDA

2020). It has also been detected in cigarette smoke (Higgins et al. 1983; Osborne et al. 1956). 

5.6 GENERAL POPULATION 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 four 

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). 
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5. POTENTIAL FOR HUMAN EXPOSURE

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). 

However, in 107 finished water samples collected across the United States from 1990 to 2020, 2-butanone 

was detected in only one sample at <2 ppb (NWQMC 2020). 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 in water is expected to rapidly volatilize; thus, there is potential for inhalation exposure 

during showering and bathing. ATSDR’s three-compartment Shower and Household-Use Exposure 

(SHOWER) model predicts air concentrations in the shower stall, bathroom, and main house throughout 

the day by estimating the contribution from showering or bathing and the contribution from other water 

sources in the house, such as the dishwasher, clothes washer, and faucets. This information along with 

human activity patterns are used to calculate a daily time-weighted average exposure concentration via 

inhalation exposure and from dermal uptake from skin contact. ATSDR’s SHOWER model is available 

by sending a request to showermodel@cdc.gov. The SHOWER model predicts 40% volatilization of 

2-butanone while showering and about 30% from taking a tub bath. 

Vapor intrusion may also be a potential source of 2-butanone exposure, as vapor intrusion has been 

observed for several volatile organic chemicals (VOCs) with similar properties. EPA’s compilation of 

four studies of background indoor air concentrations found a 79–91% detection rate for 2-butanone in 

802 U.S. resident samples between 1990 and 2005 (EPA 2011). The background medians ranged from 

2.7 to 6.5 μg/m3

, 95th percentiles ranged from 21 to 39 μg/m3, and maximum values ranged from 76 to 

890 μg/m3

. ATSDR extracted environmental data from 135 ATSDR reports evaluating the vapor 

intrusion pathway at 121 sites published between 1994 and 2009 (Burk and Zarus 2013). The data set 

contained the maximum measured 2-butanone indoor air data at 11 vapor intrusion sites and ranged from 

0.06 to 96 μg/m3 (ATSDR 2005a, 2005b). ATSDR’s findings for 2-butanone from the 121 vapor 

intrusion sites generally fell within EPA’s background ranges, although the 95th percentile was about 

2 times greater than background, indicating some potential vapor intrusion impact on indoor air 

concentrations. 

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 1972; 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 81

5. POTENTIAL FOR HUMAN EXPOSURE

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). 

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Exposure to both 2-butanone and n-hexane 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.

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. 

Occupational exposure to 2-butanone is expected to occur by inhalation and dermal contact. High levels 

of occupational exposure could occur during the loading and unloading of large quantities of this material 

during shipment and during the application of commercial coatings containing 2-butanone without 

adequate protection. According to the National Occupational Exposure Survey (NOES) conducted by the 

National Institute for Occupational Safety and Health (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. More recent occupational survey data were not identified.

Similarly, recent occupational monitoring data were not identified for 2-butanone. 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 wastewater treatment plants in 1982; 3 of 17 samples were positive at 
2-BUTANONE 82

5. POTENTIAL FOR HUMAN EXPOSURE

concentrations ≤5.7 ppb (Dunovant et al. 1986). It has also been detected in the air above shale oil 

wastewaters (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, 1973–1974, 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 <0.01 to 1.2 ppm 

(Decker et al. 1983). 
2-BUTANONE 83

CHAPTER 6. 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 NTP, is required to assure the initiation of a program of research 

designed to determine the adverse health effects (and techniques for developing methods to determine 

such health effects) of 2-butanone. 

Data needs are defined as substance-specific informational needs that, if met, would reduce the 

uncertainties of human health risk assessment. This definition should not be interpreted to mean that all 

data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.1 INFORMATION ON HEALTH EFFECTS

Studies evaluating the health effects of inhalation, oral, and dermal exposure of humans and animals to 

2-butanone that are discussed in Chapter 2 are summarized in Figure 6-1. The purpose of this figure is to 

illustrate the information concerning the health effects of 2-butanone. The number of human and animal 

studies examining each endpoint is indicated regardless of whether an effect was found and the quality of 

the study or studies. 

As illustrated in Figure 6-1, most of the data on the toxicity of 2-butanone come from inhalation studies in 

humans and laboratory animals. The most commonly examined endpoints were respiratory and 

neurological effects. Developmental effects and liver toxicity were also studied in animals only. A small 

number of oral studies in animals evaluated hepatic, renal, and neurological effects. No reports of 

systemic toxicity are available for dermal exposure. 
2-BUTANONE 84

6. ADEQUACY OF THE DATABASE

Figure 6-1. Summary of Existing Health Effects Studies on 2-Butanone By Route 

and Endpoint* 

Potential respiratory, hepatic, and neurological effects were the most studied endpoints 

The majority of the studies examined inhalation exposure in animals (versus humans) 

*Includes studies discussed in Chapter 2. The number of studies include those 

finding no effect; many studies examined more than one endpoint. 
2-BUTANONE 85

6. ADEQUACY OF THE DATABASE

6.2 IDENTIFICATION OF DATA NEEDS

Missing information in Figure 6-1 should not be interpreted as a “data need.” A data need, as defined in 

ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological 

Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public 

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature.

Acute-Duration MRLs. A number of studies have evaluated the acute-duration toxicity of inhaled 

2-butanone in humans, primates, rats, mice, and guinea pigs. The data were considered adequate for 

derivation of an acute-duration inhalation MRL. The acute oral toxicity of 2-butanone was evaluated in 

rats; most of these studies involved a single gavage exposure. An acute-duration oral MRL was not 

derived because the oral database was considered inadequate to identify target organs or establish doseresponse relationships.

Intermediate-Duration MRLs. 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 or histological, were observed in several studies of intermediate exposures to high concentrations 

of 2-butanone up to 6,000 ppm (Altenkirch et al. 1978, 1979; 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 intermediateduration inhalation MRL was not derived because neurological symptoms (i.e., headache, fatigue, feeling 

of intoxication) and 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 5.5); 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), 
2-BUTANONE 86

6. ADEQUACY OF THE DATABASE

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 MRLs. No studies were located regarding the health effects of chronic exposure to 

2-butanone by any route in humans or animals. 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 5.5), 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 

be 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, 

genotoxic effects including gene mutation, chromosome aberration, micronucleus frequency, DNA 

damage, cell transformation, and unscheduled DNA synthesis were primarily negative (see Section 2.20). 

Three studies reported evidence for 2-butanone induction of chromosome effects in yeast, but the findings 

were inconsistent with other studies evaluating similar endpoints. On the basis of this information, 

2-butanone does not appear to be carcinogenic. 

Health Effects. 

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 (NIOSH 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 
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6. ADEQUACY OF THE DATABASE

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 with 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; 

Saillenfait et al. 2006; Schwetz et al. 1974) and mice (NTP 1989; Schwetz et al. 1991) following 

inhalation exposure of pregnant rats and mice to 3,000 or 4,000 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 and brain development was delayed in 

offspring of rats that delivered pups (Stoltenburg-Didinger 1991; Stoltenburg-Didinger 1990). In 

addition, 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 investigate 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 found 

at or near hazardous waste sites.

Immunotoxicity. There are limited data on the potential immunotoxicity of 2-butanone. A 

case report of an individual reported 2-butanone-induced contact urticaria (Varigos and Nurse 

1986). Studies in rats reported no histological alterations of immune and lymphoreticular tissues 

following intermediate-duration inhalation exposure (Cavender and Casey 1981; Cavender et al. 
2-BUTANONE 88

6. ADEQUACY OF THE DATABASE

1983). Because these studies did not evaluate immune function, they are not considered adequate 

for evaluating potential immunotoxicity of 2-butanone. Studies evaluating potential impairment 

of 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 male volunteers (Dick et al. 1984, 1988, 1989, 1992). However, 

symptoms of neurotoxicity (headache, fatigue, feeling of intoxication) were reported by subjects 

exposed to 100 ppm (Tomicic et al. 2011). Neurobehavioral effects have been observed in mice 

(1,602 ppm) (De Ceaurriz 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). Most of the available information on the neurotoxicity of 2-butanone is derived from 

studies conducted over 30 years ago when neurobehavioral screening tests were not as sensitive 

as currently available tests. Additional studies using sensitive measures could provide 

information on potential subtle neuropathological alterations. 2-Butanone is not generally 

regarded as being highly neurotoxic when administered alone. In acute and intermediate 

exposure studies, 2-butanone markedly potentiated the neurotoxicity of n-hexane and methyl-nbutyl ketone both in humans and animals. A comprehensive study of acute, intermediate, and 

chronic exposures to mixtures of 2-butanone, n-hexane, and methyl-n-butyl ketone by inhalation, 

oral, and dermal routes would provide valuable information regarding the neurotoxicity of these 

compounds. Such a study would be particularly valuable because 2-butanone is often found 

occupationally in mixtures containing n-hexane and methyl-n-butyl ketone, and these chemicals 

would probably be found together at hazardous waste sites. 

Epidemiology and Human Dosimetry Studies. Studies with male and female volunteers 

determined that inhalation exposure to 100 ppm produced neurological symptoms (i.e., headache, fatigue, 

feeling of intoxication) (Tomicic et al. 2011) and was irritating to the eyes, nose, and throat (Nelson et al. 

1943; Tomicic et al. 2011). Other studies reported the absence of neurological and irritation effects in 

volunteers at concentrations up to 200 ppm (Muttray et al. 2002; Seeber et al. 2002; van Thriel et al. 

2002); however, these studies were conducted in male subjects only. Female subjects were reported to be 

more sensitive than males to neurological symptoms and the respiratory and eye irritation effects of 

2-butanone (Tomicic et al. 2011). In four separate studies, volunteers exposed to 200 ppm had no 
2-BUTANONE 89

6. ADEQUACY OF THE DATABASE

neurobehavioral effects (Dick et al. 1984, 1988, 1989, 1992). Several epidemiological studies of 

occupational workers exposed to 2-butanone showed inconclusive results regarding increased risk of 

cancer (Alderson and Rattan 1980; Blair et al. 1998; Radican et al. 2008; Wen et al. 1985). Two casecontrol studies evaluating the relationship between 2-butanone exposure and childhood leukemia were 

also inconclusive (Gao et al. 2014; Infante-Rivard et al. 2005). 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, 1990a, 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 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 
2-BUTANONE 90

6. ADEQUACY OF THE DATABASE

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. 1990a). 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.

Children’s Susceptibility. The human blood:air partition coefficient was 2–4% higher in male and 

female pediatric subjects compared with adults and a similar age-related pattern was observed in rats with 

a 4–6% higher blood:air coefficient observed in PND 10 males compared with adult and aged male rats 

(Mahle et al. 2007). These data suggest that pulmonary uptake following inhalation may be slightly 

higher in children compared to adults. Although several animal studies have evaluated the potential 

developmental toxicity of 2-butanone, no studies were identified that evaluated potential age-related 

differences. Additional studies in young animals would be useful to address potential concerns that 

children may be more susceptible to the toxicity of 2-butanone than adults. 

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, Release, 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 compound. 

The production, use, and international trading of 2-butanone is well described in the available literature 

(Kavaler 1987; Neier and Strehlke 1985; Papa and Sherman 1981; USITC 1987, 1988, 1989). Methods 
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6. ADEQUACY OF THE DATABASE

for the disposal of 2-butanone are established (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.

Environmental Fate. There is sufficient predictive information to indicate that 2-butanone is not likely 

to partition from water (Hansch et al. 1995; Lyman et al. 1982; Roy and Griffin 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 has not yet been 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 (Lyman et al. 1982). Given the potential for exposure to 

2-butanone because of its prevalence in commercial products available to the public, 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 et al. 1995; 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 

environmental media (Grosjean and Wright 1983; EPA 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. Quantitative determination of the levels of 2-butanone in environmental media and foods will 

allow the estimation of human intake levels of this compound from each media. Studies evaluating 
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6. ADEQUACY OF THE DATABASE

potential exposure via vapor intrusion or volatilization during showering/bathing would provide valuable 

information regarding potential human exposure pathways. 

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 study is needed to evaluate 

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 aid in the determination of human exposure levels. 

Exposures of Children. No studies are available to assess whether children are at a higher exposure 

risk than adults to 2-butanone. Studies examining potential exposure sources for children would be 

useful.

6.3 ONGOING STUDIES

No ongoing studies of 2-butanone were identified by the National Institutes of Health (NIH) (RePORTER

2020).
2-BUTANONE 93

CHAPTER 7. REGULATIONS AND GUIDELINES 

Pertinent international and national regulations, advisories, and guidelines regarding 2-butanone in air, 

water, and other media are summarized in Table 7-1. This table is not an exhaustive list, and current 

regulations should be verified by the appropriate regulatory agency. 

ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on 

the MRLs for 2-butanone. 

Table 7-1. Regulations and Guidelines Applicable to 2-Butanone

Agency Description Information Reference

Air

EPA RfC 5 mg/m3 (1.7 ppm) IRIS 2003

WHO Air quality guidelines Not listed WHO 2010

Water & Food

EPA Drinking water standards and health advisories EPA 2018a

1-Day health advisory (10-kg child) 75 mg/L

10-Day health advisory (10-kg child) 7.5 mg/L

DWEL 20 mg/L

Lifetime health advisory 4 mg/L

10-4 Cancer risk No data

National primary drinking water regulations Not listed EPA 2009

RfD 0.6 mg/kg/day IRIS 2003

WHO Drinking water quality guidelines Not listed WHO 2017

FDA Substances Added to Fooda Approved under food 

additive and GRAS 

regulations

FDA 2020

Cancer

HHS Carcinogenicity classification No data NTP 2016

EPA Carcinogenicity classification Data are inadequate for 

an assessment of human 

carcinogenic potential

IRIS 2003

IARC Carcinogenicity classification No data IARC 2020

Occupational

OSHA PEL (8-hour TWA) for general industry, 

shipyards, and construction

200 ppm OSHA 2019a, 

2019b, 2019c

NIOSH REL (up to 10-hour TWA) 200 ppm NIOSH 2019

STEL (15-minute TWA) 300 ppm

IDLH 3,000 ppm NIOSH 1994
2-BUTANONE 94

7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to 2-Butanone

Agency Description Information Reference

Emergency Criteria

EPA AEGLs-air EPA 2018b

AEGL 1b

10-minute, 30-minute, 60-minute, 

4-hour, and 8-hour

200 ppm

AEGL 2b

10-minute 4,900 ppmc

30-minute 3,400 ppmc

60-minute 2,700 ppmc

4-hour 1,700 ppm

8-hour 1,700 ppm

AEGL 3b

10-minute 10,000 ppmd

30-minute 10,000 ppmd

60-minute 4,000 ppmc

4-hour 2,500 ppmc

8-hour 2,500 ppmc

DOE PACs-air DOE 2018a

PAC-1e 200 ppm

PAC-2e 2,700 ppm

PAC-3e 4,000 ppm

aThe Substances Added to Food inventory replaces EAFUS and contains the following types of ingredients: food and 

color additives listed in FDA regulations, flavoring substances evaluated by FEMA or JECFA, GRAS substances 

listed in FDA regulations, substances approved for specific uses in food prior to September 6, 1958, substances that 

are listed in FDA regulations as prohibited in food, delisted color additives, and some substances "no longer FEMA 

GRAS". 

bDefinitions of AEGL terminology are available from U.S. Environmental Protection Agency (EPA 2018c). cConcentration is ≥10% of the Lower Explosive Limit (LEL) of 18,000 ppm for methyl ethyl ketone. Safety 

considerations against the hazard of explosion must be taken into account.

dConcentration is ≥50% of the LEL of 18,000 ppm for methyl ethyl ketone. Extreme safety considerations against the 

hazard of explosion must be taken into account.

cDefinitions of PAC terminology are available from U.S. Department of Energy (DOE 2018b). 

AEGL = acute exposure guideline levels; DOE = Department of Energy; DWEL = drinking water equivalent level; 

EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; FDA = Food and 

Drug Administration; FEMA = Flavor and Extract Manufacturers Association of the United States; GRAS = generally 

recognized as safe; HHS = Department of Health and Human Services; IARC = International Agency for Research 

on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System; 

JECFA = Joint FAO/WHO Expert Committee on Food Additives; NIOSH = National Institute for Occupational Safety 

and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; 

PAC = protective action criteria; PEL = permissible exposure limit; REL = recommended exposure limit; 

RfC = inhalation reference concentration; RfD = oral reference dose; STEL = short-term exposure limit; TWA = timeweighted average; WHO = World Health Organization
2-BUTANONE 95

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dewaxing plants. Br J Ind Med 37(1):85-89. http://doi.org/10.1136/oem.37.1.85. 

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2-BUTANONE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS 

MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the 

most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an 

estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk 

of adverse noncancer health effects over a specified route and duration of exposure. MRLs are based on 

noncancer health effects only; cancer effects are not considered. These substance-specific estimates, 

which are intended to serve as screening levels, are used by ATSDR health assessors to identify 

contaminants and potential health effects that may be of concern at hazardous waste sites. It is important 

to note that MRLs are not intended to define clean-up or action levels. 

MRLs are derived for hazardous substances using the NOAEL/uncertainty factor approach. They are 

below levels that might cause adverse health effects in the people most sensitive to such chemicalinduced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic 

(≥365 days) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal 

route of exposure are not derived because ATSDR has not yet identified a method suitable for this route 

of exposure. MRLs are generally based on the most sensitive substance-induced endpoint considered to 

be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or 

birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not 

mean that adverse health effects will occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 
2-BUTANONE A-2 

APPENDIX A

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Office of Innovation and Analytics, Toxicology Section, expert panel peer reviews, and agency-wide 

MRL Workgroup reviews, with participation from other federal agencies and comments from the public. 

They are subject to change as new information becomes available concomitant with updating the 

toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously 

published MRLs. For additional information regarding MRLs, please contact the Office of Innovation 

and Analytics, Toxicology Section, Agency for Toxic Substances and Disease Registry, 1600 Clifton 

Road NE, Mailstop S102-1, Atlanta, Georgia 30329-4027. 
2-BUTANONE A-3 

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 2-Butanone 

CAS Numbers: 78-93-3 

Date: October 2020 

Profile Status: Final

Route: Inhalation 

Duration: Acute

MRL 1 ppm 

Critical Effect: Neurological (headache, fatigue, feeling of intoxication) 

Reference: Tomicic et al. 2011 

Point of Departure: LOAEL of 99.15 ppm 

Uncertainty Factor: 100 

LSE Graph Key: 5 

Species: Humans 

MRL Summary: An acute-duration inhalation MRL of 1 ppm was derived for 2-butanone based on 

reported neurological symptoms (headache, fatigue, feeling of intoxication) in volunteers. The MRL is 

based on the LOAEL (not adjusted for continuous exposure) of 99.15 ppm and a total uncertainty factor 

of 100 (10 for use of a LOAEL and 10 for human variability). 

Selection of the Critical Effect: Clinical signs of neurotoxicity in humans (i.e., headache, fatigue, feeling 

of intoxication) are a sensitive effect of 2-butanone exposure (Tomicic et al. 2011). Neurobehavioral 

effects in primates (Geller et al. 1979) were also reported at low concentrations (increased response time 

in match-to-sample tasks). 

Selection of the Principal Study: Tomicic et al. (2011) was selected as the principal study because 

neurological effects were reported in volunteers exposed to 100 ppm. 

Summary of the Principal Study:

Tomicic C, Berode M, Oppliger A, et al. 2011. Sex differences in urinary levels of several biological 

indicators of exposure: A human volunteer study. Toxicol Lett 202:218-225. 

Volunteers (10 males and 10 females using hormonal contraceptives and 5 females without hormonal 

contraceptives) were exposed to 100 ppm 2-butanone for 6 hours (measured concentration 

99.15±5.29 ppm). Urinary 2-butanone concentrations were measured every 2 hours before, during, and 

after exposure (24 hours total). A symptom questionnaire was administered every 2 hours during 

exposure. The symptoms rated on a visual analog scale (graded from “not at all” to “almost unbearable”) 

included headache, fatigue, nausea, dizziness, feeling of intoxication, discomfort in the eyes, in the nose, 

or in the throat or airways, breathing difficulty, and solvent smell. The quantitative symptom ratings were 

not reported; however, a statistically significant difference between men and women was indicated for 

neurological effects and irritation symptoms (eyes, nose, and throat) with females giving higher ratings 

than males. Specific ratings that were described as higher in females compared to males included 

headache after 4 and 6 hours, fatigue and feeling of intoxication after 6 hours and discomfort in the eyes 

after 2 and 4 hours.

Selection of the Point of Departure for the MRL: The LOAEL of 100 ppm for neurological effects 

(headache, fatigue, feeling of intoxication) was selected as the point of departure (POD) for the acuteduration inhalation MRL.
2-BUTANONE A-4 

APPENDIX A

Calculations: Not applicable.

Intermittent Exposure: Because of the reversible nature of mucous membrane irritation, adjustment for 

intermittent exposure was not necessary.

Human Equivalent Concentration: The POD was derived from human exposure studies (no conversion 

required).

Uncertainty Factor: The LOAEL is divided by a total uncertainty factor of 100: 

• 10 for use of a LOAEL 

• 10 for human variability

MRL = LOAEL ÷ UFs

 99.15 ppm ÷ (10x10) = 1 ppm 

Other Additional Studies or Pertinent Information that Lend Support to this MRL: Neurobehavioral 

testing was conducted in four baboons exposed to 100 ppm 2-butanone 24 hours/day for 7 days (Geller et 

al. 1979). A decrease in the mean response time for a match-to-sample task was observed. Nelson et al. 

(1943) exposed 10 subjects (both male and female) to 2-butanone at concentrations of 100, 200, or 

350 ppm for 3–5 minutes. Symptom classifications were no reaction, slightly irritating, and very 

irritating. At 100 ppm, slight nose and throat irritation were reported. At 200 ppm, mild eye irritation 

appeared in some subjects. Exposure to 350 ppm was conclusively rejected as not tolerable for an 8-hour 

workday. No further details were reported. Sensory irritation effects were seen in mice exposed to 

2-butanone concentrations ≥3,809 ppm. A time- and concentration-dependent decrease in respiratory rate 

and tidal volume was observed (Hansen et al. 1992). Severe respiratory and eye irritation occurred in rats 

and guinea pigs exposed to 2-butanone concentrations ≥10,000 ppm (Altenkirch et al. 1978; Patty et al. 

1935). 

Agency Contacts (Chemical Managers): G. Daniel Todd
2-BUTANONE A-5 

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 2-Butanone 

CAS Numbers: 78-93-3 

Date: October 2020 

Profile Status: Final

Route: Inhalation 

Duration: Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL.

Rational for Not Deriving an MRL: Target organs have not been sufficiently identified. In addition, 

clinical signs of neurotoxicity (i.e., headache, fatigue, feeling of intoxication) and nose, throat, and eye 

irritation occurred in humans at exposure levels that were much lower than NOAEL values in animals in 

intermediate-duration studies. 

Agency Contacts (Chemical Managers): G. Daniel Todd 
2-BUTANONE A-6 

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 2-Butanone 

CAS Numbers: 78-93-3 

Date: October 2020 

Profile Status: Final

Route: Inhalation 

Duration: Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL. 

Rational for Not Deriving an MRL: No chronic-duration studies examining noncarcinogenic effects 

following inhalation exposure were identified. 

Agency Contacts (Chemical Managers): G. Daniel Todd 
2-BUTANONE A-7 

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 2-Butanone 

CAS Numbers: 78-93-3 

Date: October 2020 

Profile Status: Final

Route: Oral

Duration: Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL. 

Rational for Not Deriving an MRL: Target organs have not been sufficiently identified and doseresponse data are lacking.

Agency Contacts (Chemical Managers): G. Daniel Todd 
2-BUTANONE A-8 

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 2-Butanone 

CAS Numbers: 78-93-3 

Date: October 2020 

Profile Status: Final

Route: Oral

Duration: Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL.

Rational for Not Deriving an MRL: Target organs have not been sufficiently identified and doseresponse data are lacking.

Agency Contacts (Chemical Managers): G. Daniel Todd 
2-BUTANONE A-9 

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 2-Butanone 

CAS Numbers: 78-93-3 

Date: October 2020 

Profile Status: Final

Route: Oral

Duration: Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL. 

Rational for Not Deriving an MRL: No chronic-duration studies examining noncarcinogenic effects 

following oral exposure were identified. 

 

Agency Contacts (Chemical Managers): G. Daniel Todd 
2-BUTANONE B-1 

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR 2-BUTANONE 

The objective of the toxicological profile is to evaluate the potential for human exposure and the potential 

health hazards associated with inhalation, oral, or dermal/ocular exposure to 2-butanone. 

B.1 LITERATURE SEARCH AND SCREEN 

A literature search and screen was conducted to identify studies examining health effects, toxicokinetics, 

mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical 

properties, production, use, environmental fate, environmental releases, and environmental and biological 

monitoring data for 2-butanone. ATSDR primarily focused on peer-reviewed articles without publication 

date or language restrictions. Non-peer-reviewed studies that were considered relevant to the assessment 

of the health effects of 2-butanone have undergone peer review by at least three ATSDR-selected experts 

who have been screened for conflict of interest. The inclusion criteria used to identify relevant studies 

examining the health effects of 2-butanone are presented in Table B-1. 

Table B-1. Inclusion Criteria for the Literature Search and Screen

Health Effects

Species

Human

Laboratory mammals

Route of exposure

Inhalation

Oral

Dermal (or ocular)

Parenteral (these studies will be considered supporting data)

Health outcome

Death

Systemic effects

Body weight effects 

Respiratory effects

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects

Other noncancer effects
2-BUTANONE B-2 

APPENDIX B

Table B-1. Inclusion Criteria for the Literature Search and Screen

Cancer

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

PBPK models

Biomarkers

Biomarkers of exposure

Biomarkers of effect

Interactions with other chemicals

Potential for human exposure

Releases to the environment

Air

Water

Soil

Environmental fate

Transport and partitioning

Transformation and degradation

Environmental monitoring

Air

Water

Sediment and soil

Other media

Biomonitoring

General populations

Occupation populations

B.1.1 Literature Search

The current literature search was intended to update the draft toxicological profile for 2-butanone released 

for public comment in May 2019. The following main databases were searched in October 2019: 

• PubMed 

• National Library of Medicine’s TOXLINE

• Scientific and Technical Information Network’s TOXCENTER 

The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers, 

synonyms, Medical Subject Headings (MeSH) headings, and keywords for 2-butanone. The query 

strings used for the literature search are presented in Table B-2. 

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS), 

NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures 

and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases 
2-BUTANONE B-3 

APPENDIX B

were searched in the creation of various tables and figures, such as the TRI Explorer, the Substance 

Priority List (SPL) resource page, and other items as needed. Regulations applicable to 2-butanone were 

identified by searching international and U.S. agency websites and documents.

Review articles were identified and used for the purpose of providing background information and 

identifying additional references. ATSDR also identified reports from the grey literature, which included 

unpublished research reports, technical reports from government agencies, conference proceedings and 

abstracts, and theses and dissertations. 

Table B-2. Database Query Strings 

Database

search date Query string

PubMed

10/2019 (78-93-3[rn] AND 2017:3000[mhda]) OR (("2 butanone"[tw] OR "2-butanon"[tw] OR "2-

butanone"[tw] OR "3-butanone"[tw] OR "acetone, methyl-"[tw] OR "butan-2-one"[tw] OR 

"butanon"[tw] OR "butanona"[tw] OR "butanone"[tw] OR "ethyl methyl ketone"[tw] OR 

"ethylmethyl ketone"[tw] OR "ketone, ethyl methyl"[tw] OR "methyl acetone"[tw] OR " 

methyl ethyl ketone"[tw] OR "methylethyl ketone"[tw] OR "methylethylketone"[tw] OR 

"metyl ethyl ketone"[tw]) AND (2017:3000[crdat] OR 2017:3000[edat]))

Toxline

10/2019 ( 78-93-3 [rn] OR "2 butanone" OR "2-butanon" OR "2-butanone" OR "3-butanone" OR 

"acetone methyl-" OR "butan-2-one" OR "butanon" OR "butanona" OR "butanone" OR 

"ethyl methyl ketone" OR "ethylmethyl ketone" OR "ketone ethyl methyl" OR "methyl 

acetone" OR " methyl ethyl ketone" OR "methylethyl ketone" OR "methylethylketone" OR 

"metyl ethyl ketone" ) AND 2017:2019 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS 

[org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HAPAB [org] OR HEEP [org] 

OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR 

NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart 

[org]

Limited to: YEAR of PUBLICATION of 2017-2019; and unchecked: synonyms, include 

pubmed

Toxcenter

10/2019 FILE 'TOXCENTER' ENTERED AT 08:01:10 ON 18 OCT 2019

CHARGED TO COST=EH038.06.01.OD

L1 9677 SEA FILE=TOXCENTER 78-93-3 

L2 9423 SEA FILE=TOXCENTER L1 NOT TSCATS/FS 

L3 6574 SEA FILE=TOXCENTER L2 NOT PATENT/DT 

L4 358 SEA FILE=TOXCENTER L3 AND ED>=20170101 

 ACTIVATE TOXQUERY/Q

 ---------

L5 QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR 

 BIOMARKER? OR NEUROLOG?) 

L6 QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR 

EPIDEMIOLOGY/ST,CT,

 IT) 

L7 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR 

 LC(W)50) 

L8 QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT 

L9 QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?) 

L10 QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?) 
2-BUTANONE B-4 

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

L11 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS 

OR 

 DIETARY OR DRINKING(W)WATER?) 

L12 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR 

PERMISSIBLE))

L13 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?) 

L14 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? 

OR 

 OVUM?) 

L15 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L16 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

L17 QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR 

SPERMAS? OR 

 SPERMATOB? OR SPERMATOC? OR SPERMATOG?) 

L18 QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR 

SPERMATOX? OR 

 SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?) 

L19 QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR 

DEVELOPMENTAL?) 

L20 QUE (ENDOCRIN? AND DISRUPT?) 

L21 QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR 

INFANT?) 

L22 QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?) 

L23 QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?) 

L24 QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? 

OR 

 NEOPLAS?) 

L25 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR 

CARCINOM?) 

L26 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR 

GENETIC(W)TOXIC?) 

L27 QUE (NEPHROTOX? OR HEPATOTOX?) 

L28 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?) 

L29 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?) 

L30 QUE L5 OR L6 OR L7 OR L8 OR L9 OR L10 OR L11 OR L12 OR L13 OR 

 L14 OR L15 OR L16 OR L17 OR L18 OR L19 OR L20 OR L21 OR L22 OR 

 L23 OR L24 OR L25 OR L26 OR L27 OR L28 OR L29 

L31 QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR 

MURIDAE 

 OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR 

SWINE 

 OR PORCINE OR MONKEY? OR MACAQUE?) 

L32 QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR 

LAGOMORPHA 

 OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE) 

L33 QUE L30 OR L31 OR L32 

L34 QUE (NONHUMAN MAMMALS)/ORGN 

L35 QUE L33 OR L34 
2-BUTANONE B-5 

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

L36 QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? 

OR 

 PRIMATES OR PRIMATE?) 

L37 QUE L35 OR L36 

 ---------

L38 150 SEA FILE=TOXCENTER L4 AND L37 

L39 10 SEA FILE=TOXCENTER L38 AND MEDLINE/FS 

L40 14 SEA FILE=TOXCENTER L38 AND BIOSIS/FS 

L41 126 SEA FILE=TOXCENTER L38 AND CAPLUS/FS 

L42 0 SEA FILE=TOXCENTER L38 NOT (MEDLINE/FS OR BIOSIS/FS OR 

 CAPLUS/FS) 

L43 147 DUP REM L39 L40 L41 (3 DUPLICATES REMOVED)

L*** DEL 10 S L38 AND MEDLINE/FS

L*** DEL 10 S L38 AND MEDLINE/FS

L44 10 SEA FILE=TOXCENTER L43 

L*** DEL 14 S L38 AND BIOSIS/FS

L*** DEL 14 S L38 AND BIOSIS/FS

L45 12 SEA FILE=TOXCENTER L43 

L*** DEL 126 S L38 AND CAPLUS/FS

L*** DEL 126 S L38 AND CAPLUS/FS

L46 125 SEA FILE=TOXCENTER L43 

L47 137 SEA FILE=TOXCENTER (L44 OR L45 OR L46) NOT MEDLINE/FS 

 SAVE TEMP L47 BUTANONE/A

 D SCAN L47

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

TSCATS via ChemView

10/2019 Compounds searched: 78-93-3

NTP

10/2019 "78-93-3" "methyl ethyl ketone" "2 butanone" "2-butanone" 

"acetone, methyl-" "methylethyl ketone" "methylethylketone" "methyl acetone"

"methylethyl ketone" "methylethylketone" "metyl ethyl ketone" "2-butanon"

"butan-2-one" "butanon" "butanona" "butanone" "ethyl methyl ketone" 

"ethylmethyl ketone" "ketone, ethyl methyl" "methyl acetone"

NIH RePORTER

04/2020 Search Criteria: Text Search: "2 butanone" OR "2-butanon" OR "2-butanone" OR "3-

butanone" OR "acetone methyl-" OR "butan-2-one" OR "butanon" OR "butanona" OR 

"butanone" OR "ethyl methyl ketone" OR "ethylmethyl ketone" OR "ketone ethyl 

methyl" OR "methyl acetone" OR " methyl ethyl ketone" OR "methylethyl ketone" OR 

"methylethylketone" OR "metyl ethyl ketone" (Advanced), Search in: Projects 

AdminIC: All, Fiscal Year: Active Projects

Other Identified throughout the assessment process
2-BUTANONE B-6 

APPENDIX B

The 2019 results were: 

• Number of records identified from PubMed, TOXLINE, and TOXCENTER (after duplicate 

removal): 740 

• Number of records identified from other strategies: 47 

• Total number of records to undergo literature screening: 787 

B.1.2 Literature Screening 

A two-step process was used to screen the literature search to identify relevant studies on 2-butanone: 

• Title and abstract screen

• Full text screen

Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually for 

relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the

second step of the literature screening process. Studies were excluded when the title and abstract clearly 

indicated that the study was not relevant to the toxicological profile. 

• Number of titles and abstracts screened: 787 

• Number of studies considered relevant and moved to the next step: 50 

Full Text Screen. The second step in the literature screening process was a full text review of individual 

studies considered relevant in the title and abstract screen step. Each study was reviewed to determine 

whether it was relevant for inclusion in the toxicological profile. 

• Number of studies undergoing full text review: 50 

• Number of studies cited in the pre-public draft of the toxicological profile: 266 

• Total number of studies cited in the profile: 303 

A summary of the results of the literature search and screening is presented in Figure B-1. 
2-BUTANONE B-7 

APPENDIX B

Figure B-1. October 2019 Literature Search Results and Screen for 2-Butanone
2-BUTANONE C-1 

APPENDIX C. USER'S GUIDE

Chapter 1. Relevance to Public Health

This chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information, and an overview of the minimal risk 

levels. This is designed to present interpretive, weight-of-evidence discussions for human health 

endpoints 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?

Minimal Risk Levels (MRLs)

Where sufficient toxicologic information is available, ATSDR derives MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a hazardous substance emission, given the concentration of a contaminant in air or the estimated daily 

dose in water. MRLs are based largely on toxicological studies in animals and on reports of human 

occupational exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. 

Section 1.2, Summary of Health Effects, contains basic information known about the substance. Other 

sections, such as Section 3.2 Children and Other Populations that are Unusually Susceptible and 

Section 3.4 Interactions with Other Substances, 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 that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, 

represents the most sensitive human health 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 systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

of 10 must be employed. Additional uncertainty factors of 10 must be used both 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 

inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a 
2-BUTANONE C-2

APPENDIX C

substance-specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables

that are provided in Chapter 2. Detailed discussions of the MRLs are presented in Appendix A.

Chapter 2. Health Effects

Tables and Figures for Levels of Significant Exposure (LSE)

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species and MRLs to humans for noncancer 

endpoints. 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. All entries in these tables and figures represent studies that provide reliable, quantitative 

estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE tables and figures follow. The numbers in the left column of the legends correspond to 

the numbers in the example table and figure.

TABLE LEGEND

See Sample LSE Table (page C-5)

(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. 

Typically, when sufficient data exist, 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 figures are limited to the inhalation and oral routes. Not 

all substances will have data on each route of exposure and will not, therefore, have all five of the 

tables and figures. Profiles with more than one chemical may have more LSE tables and figures.

(2) Exposure period. Three exposure periods—acute (<15 days), intermediate (15–364 days), and 

chronic (≥365 days)—are presented within each relevant route of exposure. In this example, two

oral studies of chronic-duration exposure are reported. For quick reference to health effects 

occurring from a known length of exposure, locate the applicable exposure period within the LSE 

table and figure.

(3) Figure key. 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 51 identified NOAELs and less serious LOAELs (also see the three

"51R" data points in sample LSE Figure 2-X).

(4) Species (strain) No./group. The test species (and strain), whether animal or human, are identified 

in this column. The column also contains information on the number of subjects and sex per 

group. Chapter 1, Relevance to Public Health, covers the relevance of animal data to human 

toxicity and Section 3.1, Toxicokinetics, contains any available information on comparative 

toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated 

to equivalent human doses to derive an MRL.

(5) Exposure parameters/doses. The duration of the study and exposure regimens are provided in 

these columns. This permits comparison of NOAELs and LOAELs from different studies. In 

this case (key number 51), rats were orally exposed to “Chemical X” via feed for 2 years. For a 
2-BUTANONE C-3

APPENDIX C

more complete review of the dosing regimen, refer to the appropriate sections of the text or the 

original reference paper (i.e., Aida et al. 1992).

(6) Parameters monitored. This column lists the parameters used to assess health effects. Parameters 

monitored could include serum (blood) chemistry (BC), behavioral (BH), biochemical changes 

(BI), body weight (BW), clinical signs (CS), developmental toxicity (DX), enzyme activity (EA), 

food intake (FI), fetal toxicity (FX), gross necropsy (GN), hematology (HE), histopathology 

(HP), lethality (LE), maternal toxicity (MX), organ function (OF), ophthalmology (OP), organ 

weight (OW), teratogenicity (TG), urinalysis (UR), and water intake (WI).

(7) Endpoint. This column lists the endpoint examined. The major categories of health endpoints 

included in LSE tables and figures are death, body weight, respiratory, cardiovascular, 

gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, ocular, endocrine, 

immunological, neurological, reproductive, developmental, other noncancer, and cancer. "Other

noncancer" refers to any effect (e.g., alterations in blood glucose levels) not covered in these 

systems. In the example of key number 51, three endpoints (body weight, hematological, and 

hepatic) were investigated.

(8) NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in the 

organ system studied. The body weight effect reported in key number 51 is a NOAEL at

25.5 mg/kg/day. NOAELs are not reported for cancer and death; with the exception of these two 

endpoints, this field is left blank if no NOAEL was identified in the study.

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused an adverse 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 endpoint used to 

quantify the adverse effect accompanies the LOAEL. Key number 51 reports a less serious 

LOAEL of 6.1 mg/kg/day for the hepatic system, which was used to derive a chronic exposure, 

oral MRL of 0.008 mg/kg/day (see footnote "c"). MRLs are not derived from serious LOAELs. 

A cancer effect level (CEL) is the lowest exposure level associated with the onset of 

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious 

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report 

doses not causing measurable cancer increases. If no LOAEL/CEL values were identified in the 

study, this field is left blank.

(10) Reference. The complete reference citation is provided in Chapter 8 of the profile.

(11) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. For example, footnote "c" indicates that the LOAEL of 6.1 mg/kg/day in key 

number 51 was used to derive an oral MRL of 0.008 mg/kg/day.

FIGURE LEGEND

See Sample LSE Figure (page C-6)

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods.

(13) Exposure period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the chronic exposure period are illustrated.
2-BUTANONE C-4

APPENDIX C

(14) Endpoint. These are the categories of health effects for which reliable quantitative data exist. 

The same health effect endpoints appear in the LSE table.

(15) Levels of exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day.

(16) LOAEL. In this example, the half-shaded circle that is designated 51R identifies a LOAEL

critical endpoint in the rat upon which a chronic oral exposure MRL is based. The key number 

51 corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) to 

the MRL of 0.008 mg/kg/day (see footnote "c" in the sample LSE table).

(17) CEL. Key number 59R is one of studies for which CELs were derived. The diamond symbol 

refers to a CEL for the test species (rat). The number 59 corresponds to the entry in the LSE 

table.

(18) Key to LSE figure. The key provides the abbreviations and symbols used in the figure.
2

-BUTANONEC-5

APPENDIX C
2-BUTANONE C-6 

APPENDIX C
2-BUTANONE D-1 

APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances may find the following information helpful for fast 

answers to often-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview 

of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity 

data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.

Chapter 2: Health Effects: Specific health effects identified in both human and animal studies are 

reported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of 

exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, and 

chronic). 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. 

Pediatrics: 

Section 3.2 Children and Other Populations that are Unusually Susceptible

Section 3.3 Biomarkers of Exposure and Effect

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) 

Internet: http://www.atsdr.cdc.gov 

The following additional materials are available online: 

Case Studies in Environmental Medicine are self-instructional publications designed to increase primary 

health care providers’ knowledge of a hazardous substance in the environment and to aid in the 

evaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html). 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident (see https://www.atsdr.cdc.gov/MHMI/index.asp). Volumes I and II are planning guides 

to assist first responders and hospital emergency department personnel in planning for incidents 

that involve hazardous materials. Volume III—Medical Management Guidelines for Acute 

Chemical Exposures—is a guide for health care professionals treating patients exposed to 

hazardous materials.

Fact Sheets (ToxFAQsTM) provide answers to frequently asked questions about toxic substances (see 

https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
2-BUTANONE D-2 

APPENDIX D

Other Agencies and Organizations

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA

30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015 • Web Page: 

https://www.cdc.gov/nceh/. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 395 E Street, S.W., Suite 9200, 

Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO 

(800-232-4636) • Web Page: https://www.cdc.gov/niosh/. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212 • Web Page: 

https://www.niehs.nih.gov/. 

Clinical Resources (Publicly Available Information) 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266 • Web Page: 

http://www.acoem.org/. 

The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians with 

recognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard, 

Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page: 

http://www.acmt.net. 

The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists 

who respond to questions from public health professionals, clinicians, policy makers, and the 

public about the impact of environmental factors on the health of children and reproductive-aged 

adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html. 

The American Association of Poison Control Centers (AAPCC) provide support on the prevention and 

treatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA 

22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page: 

http://www.aapcc.org/. 
2-BUTANONE E-1 

APPENDIX E. GLOSSARY 

Absorption—The process by which a substance crosses biological membranes and enters systemic 

circulation. Absorption can also refer to the taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of ≤14 days, as specified in the Toxicological 

Profiles.

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

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 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.

Benchmark Dose (BMD) or Benchmark Concentration (BMC)—is the dose/concentration 

corresponding to a specific response level estimate using a statistical dose-response model applied to 

either experimental toxicology or epidemiology data. For example, a BMD10 would be the dose

corresponding to a 10% benchmark response (BMR). The BMD is determined by modeling the doseresponse curve in the region of the dose-response relationship where biologically observable data are 

feasible. The BMDL or BMCL is the 95% lower confidence limit on the BMD or BMC. 

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. 

Biomarkers—Indicators signaling events in biologic systems or samples, typically classified as markers 

of exposure, effect, and susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of a 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.

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-control study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without the outcome. 

Case Report—A report that describes a single individual with a particular disease or exposure. These 

reports may suggest some potential topics for scientific research, but are not actual research studies.

Case Series—Reports that describe the experience of a small number of individuals with the same 

disease or exposure. These reports may suggest potential topics for scientific research, but are not actual 

research studies.
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APPENDIX E

Ceiling Value—A concentration that must not be exceeded.

Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.

Clastogen—A substance that causes breaks in chromosomes resulting in addition, deletion, or 

rearrangement of parts of the chromosome.

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome, and who are disease-free at start of follow-up. Often, at 

least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a 

continuous variable and analyses are directed towards analyzing an exposure-response coefficient.

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at a specific point in time.

Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties of 

human health risk assessment.

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.

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the response or amount of the response.

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 

effect occurs. Effects include malformations and variations, altered growth, and in utero death.

Epidemiology—The investigation of factors that determine the frequency and distribution of disease or 

other health-related conditions within a defined human population during a specified period. 

Excretion—The process by which metabolic waste products are removed from the body.

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome.

Half-life—A measure of rate for the time required to eliminate one-half of a quantity of a chemical from 

the body or environmental media.

Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by 

EPA and 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.

Immediately Dangerous to Life or Health (IDLH)—A condition that poses a threat of life or health, or 

conditions that pose an immediate threat of severe exposure to contaminants that are likely to have 

adverse cumulative or delayed effects on health.
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APPENDIX E

Immunotoxicity—Adverse effect on the functioning of the immune system that may result from 

exposure to chemical substances. 

Incidence—The ratio of new cases of individuals in a population who develop a specified condition to 

the total number of individuals in that population who could have developed that condition in a specified 

time period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles.

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) (LCLO)—The lowest concentration of a chemical in air that 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 

has been reported to have caused death in humans or animals.

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population.

Lethal Time(50) (LT50)—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 exposure level 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.

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus.

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function.

Metabolism—Process in which chemical substances are biotransformed in the body that could result in 

less toxic and/or readily excreted compounds or produce a biologically active intermediate.

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure.

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1.
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APPENDIX E

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in 

a specific population.

Mortality—Death; the mortality rate is a measure of the number of deaths in a population during a 

specified interval of time.

Mutagen—A substance that causes mutations, which are changes in the DNA sequence of a cell’s DNA. 

Mutations can lead to birth defects, miscarriages, or cancer.

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

hazardous substance.

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a 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. Although effects may be produced at this dose, 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.

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An odds ratio that is greater than 1 is considered to indicate greater risk of 

disease in the exposed group compared to the unexposed group.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air 

averaged over any 8-hour work shift of a 40-hour workweek.

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests (insects or other organisms harmful to cultivated plants or animals).

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body.

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic 

endpoints. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
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APPENDIX E

Physiologically Based Pharmacokinetic (PBPK) Model—A type of physiologically based doseresponse model that is comprised of a series of compartments representing organs or tissue groups with 

realistic weights and blood flows. These models require a variety of physiological information, including

tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly 

membrane permeabilities. The models also utilize biochemical information, such as blood:air partition 

coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry 

models.

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which a group is followed over time and the pertinent 

observations are made on events occurring after the start of the study. 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek.

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation RfC is expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily oral exposure of the human population to a potential hazard that is likely to be without risk of 

deleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are 

(1) ≥1 pound or (2) for selected substances, an amount established by regulation either under CERCLA or 

under Section 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 hazardous substance. The toxicity may be directed to the reproductive organs and/or 

the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual 

behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the 

integrity of this system.

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous 

substance.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health 

condition, or an inborn or inherited characteristic that is associated with an increased occurrence of 

disease or other health-related event or condition.
2-BUTANONE E-6

APPENDIX E

Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the 

risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease 

in the exposed group compared to the unexposed group.

Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be 

exceeded at any time during a workday. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population.

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)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which it is believed that nearly all workers may be repeatedly 

exposed, day after day, for a working lifetime without adverse effect. The TLV may be expressed as a 

Time-Weighted Average (TLV-TWA), as a Short-Term Exposure Limit (TLV-STEL), or as a ceiling 

limit (TLV-C).

Time-Weighted Average (TWA)—An average exposure within a given time period. 

Toxicokinetic—The absorption, distribution, metabolism, and elimination of toxic compounds in the 

living organism.

Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and 

pollution prevention activities reported by industrial and federal facilities. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),

Reference Dose (RfD), or Reference Concentration (RfC) 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 lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis (3 being the approximate logarithmic 

average of 10 and 1).

Xenobiotic—Any substance that is foreign to the biological system.
2-BUTANONE F-1

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ACMT American College of Medical Toxicology

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AEGL Acute Exposure Guideline Level

AIC Akaike’s information criterion 

AIHA American Industrial Hygiene Association

ALT alanine aminotransferase

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BCF bioconcentration factor

BMD/C benchmark dose or benchmark concentration

BMDX dose that produces a X% change in response rate of an adverse effect

BMDLX 95% lower confidence limit on the BMDX

BMDS Benchmark Dose Software 

BMR benchmark response

BUN blood urea nitrogen 

C centigrade

CAA Clean Air Act

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

cm centimeter

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DWEL drinking water exposure level

EAFUS Everything Added to Food in the United States

ECG/EKG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

ERPG emergency response planning guidelines

F Fahrenheit

F1 first-filial generation

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register
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APPENDIX F

FSH follicle stimulating hormone

g gram

GC gas chromatography

gd gestational day

GGT γ-glutamyl transferase 

GRAS generally recognized as safe

HEC human equivalent concentration 

HED human equivalent dose 

HHS Department of Health and Human Services

HPLC high-performance liquid chromatography

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health

IRIS Integrated Risk Information System 

Kd adsorption ratio

kg kilogram

kkg kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 metric ton

Koc organic carbon partition coefficient

Kow octanol-water partition coefficient

L liter

LC liquid chromatography

LC50 lethal concentration, 50% kill

LCLo lethal concentration, low

LD50 lethal dose, 50% kill

LDLo lethal dose, low

LDH lactic dehydrogenase

LH luteinizing hormone

LOAEL lowest-observed-adverse-effect level

LSE Level of Significant Exposure

LT50 lethal time, 50% kill

m meter

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factor

mg milligram

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

MRL Minimal Risk Level

MS mass spectrometry

MSHA Mine Safety and Health Administration

Mt metric ton

NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NCEH National Center for Environmental Health

ND not detected

ng nanogram

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences
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APPENDIX F

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

TLV threshold limit value

TLV-C threshold limit value-ceiling value

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time-weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey

USNRC U.S. Nuclear Regulatory Commission
2

-BUTANONEF-4

APPENDIX F

VOC volatile organic compound

WBC white blood cell

WHO World Health Organization > greater than ≥ greater than or equal to = equal to < less than ≤ less than or equal to % percent α alpha β beta γ gamma δ delta

μm micrometer

μg microgram q1* cancer slope factor – negative + positive

(+) weakly positive result (–) weakly negative result