Report on Carcinogens 

Monograph on 1-Bromopropane 

September 25, 2013 

Office of the Report on Carcinogens 

Division of the National Toxicology Program 

National Institute of Environmental Health Sciences 

U.S. Department of Health and Human Services 

NIH Publication No. 13-5982

ISSN 2331-267X
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RoC Monograph on 1-Bromopropane 9/25/13

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FOREWORD

The National Toxicology Program (NTP) is an interagency program within the Public 

Health Service (PHS) of the Department of Health and Human Services (HHS) and is 

headquartered at the National Institute of Environmental Health Sciences of the National 

Institutes of Health (NIEHS/NIH). Three agencies contribute resources to the program: 

NIEHS/NIH, the National Institute for Occupational Safety and Health of the Centers for 

Disease Control and Prevention (NIOSH/CDC), and the National Center for 

Toxicological Research of the Food and Drug Administration (NCTR/FDA). Established 

in 1978, the NTP is charged with coordinating toxicological testing activities, 

strengthening the science base in toxicology, developing and validating improved testing 

methods, and providing information about potentially toxic substances to health 

regulatory and research agencies, scientific and medical communities, and the public.

The Report on Carcinogens (RoC) is prepared in response to Section 301 of the Public 

Health Service Act, as amended. The RoC contains a list of identified substances (i) that 

either are known to be human carcinogens or are reasonably anticipated to be human 

carcinogens and (ii) to which a significant number of persons residing in the United 

States are exposed. The Secretary, Department of HHS, has delegated responsibility for 

preparation of the RoC to the NTP, which prepares the report with assistance from other 

Federal health and regulatory agencies and nongovernmental institutions. The most 

recent RoC, the 12th Edition (2011), is available at http://ntp.niehs.nih.gov/go/roc12.

Nominations for (1) listing a new substance, (2) reclassifying the listing status for a 

substance already listed, or (3) removing a substance already listed in the RoC are 

evaluated in a scientific review process (http://ntp.niehs.nih.gov/go/rocprocess) with 

multiple opportunities for scientific and public input using established listing criteria

(http://ntp.niehs.nih.gov/go/15209). A list of candidate substances under consideration for 

listing in (or delisting from) the RoC can be obtained by accessing 

http://ntp.niehs.nih.gov/go/37893.
9/25/13 RoC Monograph on 1-Bromopropane

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INTRODUCTION

1-Bromopropane (n-propyl bromide, CASRN 106-94-5) is a brominated hydrocarbon that 

is currently used as a solvent in a variety of industrial and commercial applications. 

Exposure to workers has been increasing in the past few years due to several new 

applications in which 1-bromopropane has been substituted for substances identified as 

suspect carcinogens or ozone-depleting chemicals. The available occupational exposure 

data indicate that workers can be exposed to high levels of 1-bromopropane.

1-Bromopropane was selected as a candidate substance for the Report on Carcinogens 

(RoC) due to the potential for substantial human exposure to 1-bromopropane in the 

United States, and an adequate database to evaluate its potential carcinogenicity. 

1-Bromopropane has been tested for carcinogenicity in rodents in a 2-year inhalation 

study (NTP 2011a). In addition, 1-bromopropane causes toxicity in people and 

experimental animals. Structurally related haloalkanes are carcinogenic in experimental 

animals.

Monograph contents

The RoC Monograph on 1-Bromopropane consists of the following components: (Part 1) 

the cancer evaluation component that reviews the relevant scientific information, assesses 

its quality, applies the RoC listing criteria to the scientific information, and gives the RoC 

listing status for 1-bromopropane, and (Part 2) the RoC monograph’s substance profile 

containing the NTP’s listing status decision, a summary of the scientific evidence 

considered key to reaching that decision, and data on properties, use, production, 

exposure, and Federal regulations and guidelines to reduce exposure to 1-bromopropane.

The cancer evaluation component for 1-bromopropane provides information on the 

following topics: human exposure and properties (Section 1), disposition and 

toxicokinetics (Section 2), cancer studies in experimental animals (Section 4), and studies 

of mechanisms and other related effects (Section 5), including relevant toxicological 

effects, genetic toxicology, and mechanisms of carcinogenicity. When human cancer 

studies are reviewed, they are discussed in Section 3; however, no cancer studies in 

humans with exposure specifically to 1-bromopropane were identified. The information 

in Sections 2 through 5 is synthesized in Section 6.

The information reviewed in Sections 2 through 5 (and synthesized in Section 6) came 

from publicly available, peer-reviewed sources. Information in Section 1, including 

chemical and physical properties, analytical methods, production, use, and occurrence 

came from publicly available, published or unpublished sources. 

The cancer evaluation for 1-bromopropane focuses on the evaluation of the cancer studies 

in experimental animals and mechanistic data, and also whether there is any evidence that 

the potential modes of action by which 1-bromopropane might cause cancer are not 

relevant to humans.
RoC Monograph on 1-Bromopropane 9/25/13

iii

Process for preparation of the cancer evaluation component

The process for preparing the cancer evaluation component of the monograph included 

approaches for obtaining public and scientific input and using systematic methods (e.g., 

standardized methods for identifying the literature, inclusion/exclusion criteria, extraction 

of data and evaluation of study quality using specific guidelines [see Appendix A], and 

assessment of the level of evidence for carcinogenicity using established criteria).

The Office of the Report on Carcinogens (ORoC) followed the approaches outlined in the 

concept document, which discusses the scientific issues and questions relevant to the 

evaluation of 1-bromopropane carcinogenicity, the scope and focus of the monograph, 

and the approaches to obtain scientific and public input to address the key scientific 

questions and issues, for preparing the cancer evaluation component of the draft 

monograph. The ORoC presented the draft concept document on 1-bromopropane to the 

NTP Board of Scientific Counselors (BSC) at the June 21–22, 2012 meeting that 

provided opportunity for written and oral public comments; the concept document is 

available on the RoC website (http://ntp.niehs.nih.gov/go/37896). The draft monograph 

was peer reviewed in a public forum in March 2013 (see ‘Peer Review of the Draft RoC 

Monograph on 1-Bromopropane’ below), revised accordingly, and presented to the BSC 

at a June 2013 meeting. 

Key scientific questions and issues relevant for the cancer evaluation

The cancer evaluation component of the monograph focuses on studies of 

1-bromopropane in experimental animals and mechanistic data. It also identifies and 

discusses human and animal studies of non-cancer endpoints, such as neurological or 

reproductive/developmental toxicity, immunosuppression, and studies of structurally 

related compounds and metabolites, to determine whether this information can inform 

mechanisms of carcinogenicity of 1-bromopropane. 

The key scientific questions identified in the concept, which concern the results in 

experimental animals and mechanisms of carcinogenicity are: 

What is the level of evidence (sufficient or not sufficient) for the 

carcinogenicity of 1-bromopropane from studies in experimental animals? 

What are the tissue sites?

What are potential mechanisms by which 1-bromopropane may cause cancer? 

o Do the mechanistic data in experimental animals support the cancer 

findings in humans? 

o Are there mechanistic data to suggest that the cancer findings in 

experimental animals are not relevant to humans?

o Does immunomodulation play a role in 1-bromopropane carcinogenicity? 

Approach for obtaining scientific and public input 

Additional scientific input was obtained for exposure and disposition and toxicokinetics 

of 1-bromopropane. (Technical advisors are identified on the “CONTRIBUTORS” page.)
9/25/13 RoC Monograph on 1-Bromopropane

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Public comments on scientific issues were requested on 1-bromopropane by Federal 

Register notices at several times prior to and during the development of the final RoC 

monograph, including a request for information on the nomination, and for comment on 

the draft concept document (which outlined the rationale and approach for conducting the 

scientific review) and comment on the draft RoC monograph. In addition, the NTP posted 

its preliminary literature search strategy and list of references for public input on the RoC 

webpage for 1-bromopropane (http://ntp.niehs.nih.gov/go/37896) several months prior to 

the release of the draft monograph. Four public comments were received in response to 

the Federal Register notices and are available at http://ntp.niehs.nih.gov/go/37663.

Methods for writing the cancer evaluation component of the monograph

The procedures by which relevant literature were identified, data were systematically 

extracted and summarized, and the monograph was written, together with the processes 

for scientific review, quality assurance, and assessment and synthesis of data, are 

described below.

The preparation of the RoC Monograph on 1-Bromopropane began with development of 

a literature search strategy for 1-bromopropane to obtain information relevant to the 

topics for monograph sections, as discussed above, using search terms developed in 

collaboration with a reference librarian (see Appendix A for a detailed description of the 

literature search strategy). The citations (N = 1,689) identified from these searches were 

uploaded to a web-based systematic review system for evaluation by two reviewers using 

inclusion/exclusion criteria, and 158 references were selected for final inclusion in the 

monograph using these criteria.

Information for the exposure, relevant cancer, and mechanistic sections was

systematically extracted in tabular format and/or summarized in the text, following 

specific procedures developed by ORoC, from studies selected for inclusion in the 

monograph. All sections of the monograph underwent scientific review and quality 

assurance (QA) (i.e., assuring that all the relevant data and factual information extracted 

from the publications have been reported accurately) by a separate reviewer. Any 

discrepancies between the writer and the reviewer were resolved by mutual discussion in 

reference to the original data source.

Strengths, weaknesses, and data quality of the cancer studies for 1-bromopropane in 

experimental animals were assessed based on a series of questions related to 

characterization of the substance tested, the features of animal husbandry, the design of 

the study, the methods for clinical observations and necropsy, and the manner in which 

the data were reported (see Appendix C). Relevant genotoxicity and mechanistic studies 

were also assessed for their strengths and weaknesses.
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Human exposure information was assessed to determine whether the evidence indicates 

that a significant number of persons residing in the United States are exposed to 

1-bromopropane (see Foreword for information regarding the congressional mandate for 

the RoC). However, for many 

substances, this information is not 

available, and typically, U.S. 

exposure can be inferred from data 

on use, production volume, 

occupational monitoring, 

environmental (occurrence), 

estimated daily intake, and 

biomonitoring. Because cancer has 

a long latency period, past 

exposure is also considered in the 

assessment.

RoC listing criteria (see text box) 

were applied to the available 

database of carcinogenicity data to 

assess the level of evidence

(sufficient or not sufficient) for the 

carcinogenicity of 1-bromopropane

from studies in experimental 

animals. This initial conclusion 

does not integrate the experimental 

animal and mechanism data. The 

evaluation of the mechanistic data 

included a discussion and 

assessment of the strength of 

evidence for potential modes of 

action of 1-bromopropane–induced 

neoplasia, including metabolic 

activation, cytotoxicity, and 

genetic effects and 

immunosuppression. In addition, 

human and animal studies of noncancerous endpoints, such as 

neurological or 

reproductive/developmental 

toxicity, as well as studies of 

structurally related compounds and 

metabolites, may be informative.

The RoC listing criteria were then 

applied to the available body of 

knowledge for 1-bromopropane to 

reach a listing recommendation.

RoC Listing Criteria 

Known To Be Human Carcinogen:

There is sufficient evidence of carcinogenicity from studies 

in humans*, which indicates a causal relationship between 

exposure to the agent, substance, or mixture, and human 

cancer.

Reasonably Anticipated To Be Human Carcinogen:

There is limited evidence of carcinogenicity from studies in 

humans*, which indicates that causal interpretation is 

credible, but that alternative explanations, such as chance, 

bias, or confounding factors, could not adequately be 

excluded, OR 

there is sufficient evidence of carcinogenicity from studies 

in experimental animals, which indicates there is an 

increased incidence of malignant and/or a combination of 

malignant and benign tumors (1) in multiple species or at 

multiple tissue sites, or (2) by multiple routes of exposure, 

or (3) to an unusual degree with regard to incidence, site, 

or type of tumor, or age at onset, OR

there is less than sufficient evidence of carcinogenicity in 

humans or laboratory animals; however, the agent, 

substance, or mixture belongs to a well-defined, structurally 

related class of substances whose members are listed in a 

previous Report on Carcinogens as either known to be a 

human carcinogen or reasonably anticipated to be a human 

carcinogen, or there is convincing relevant information that 

the agent acts through mechanisms indicating it would 

likely cause cancer in humans. 

Conclusions regarding carcinogenicity in humans or 

experimental animals are based on scientific judgment, 

with consideration given to all relevant information. 

Relevant information includes, but is not limited to, dose 

response, route of exposure, chemical structure, 

metabolism, pharmacokinetics, sensitive sub-populations, 

genetic effects, or other data relating to mechanism of 

action or factors that may be unique to a given substance. 

For example, there may be substances for which there is 

evidence of carcinogenicity in laboratory animals, but there 

are compelling data indicating that the agent acts through 

mechanisms which do not operate in humans and would 

therefore not reasonably be anticipated to cause cancer in 

humans.

*This evidence can include traditional cancer epidemiology 

studies, data from clinical studies, and/or data derived from 

the study of tissues or cells from humans exposed to the 

substance in question that can be useful for evaluating 

whether a relevant cancer mechanism is operating in 

people.
9/25/13 RoC Monograph on 1-Bromopropane

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CONTRIBUTORS

Office of the Report on Carcinogens (ORoC), Division of the National Toxicology 

Program (NTP) 

Conducted technical review and evaluation 

Diane L. Spencer, MS (Project Lead)

Ruth M. Lunn, DrPH (Director, ORoC) 

Gloria D. Jahnke, DVM, DABT

Integrated Laboratory Systems, Inc. (Support provided through NIEHS Contract 

Number HHSN273201100004C)

Conducted technical review and evaluation

Sanford Garner, PhD (Principal Investigator) 

Stanley Atwood, MS, DABT

Andrew Ewens, PhD, DABT

Jennifer Ratcliffe, PhD

Alton Peters, MS

Provided administrative support 

Ella Darden, BS

Tracy Saunders, BS

Technical Advisors: National Institute for Occupational Safety and Health

Provided scientific input on specific sections of the monograph 

Kevin Hanley, MSPH, CIH, REHS, RS

Centers for Disease Control, National Institute for Occupational Safety and Health

Division of Surveillance, Hazard Evaluations, and Field Studies

G. Scott Dotson, PhD, CIH

Centers for Disease Control, National Institute for Occupational Safety and Health

Education and Information Division 

Editorial Advisor 

Provided editorial support for the substance profile and key sections of the 

monograph 

Susan Dakin, PhD

Independent Consultant in Technical & Scientific Writing & Editing
RoC Monograph on 1-Bromopropane 9/25/13

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Peer Review of the Draft RoC Monograph on 1-Bromopropane

Peer review of the Draft RoC Monograph on 1-Bromopropane was conducted by an ad 

hoc expert panel at a public meeting held March 21–22, 2013, at the National Institute of 

Environmental Health Sciences, Keystone Building, Research Triangle Park, NC (see 

http://ntp.niehs.nih.gov/go/38854) for materials, minutes, and panel recommendations 

from the peer review meeting). The selection of panel members and conduct of the peer 

review were performed in accordance with the Federal Advisory Committee Act and 

Federal policies and regulations. The panel members served as independent scientists, not 

as representatives of any institution, company, or governmental agency.

In this capacity, panel members had the following major responsibilities in reviewing the 

draft RoC monograph: (1) to comment on the draft cancer evaluation components for 

1-bromopropane, specifically, whether they are technically correct and clearly stated, 

whether the NTP has objectively presented and assessed the scientific evidence, and 

whether the scientific evidence is adequate for applying the RoC listing criteria, and (2) 

to comment on the draft substance profile for 1-bromopropane, specifically, whether the 

scientific justification presented in the substance profile supports the NTP’s preliminary 

policy decision on the RoC listing status of 1-bromopropane. The panel was also asked to 

vote on the following questions: (1) whether the scientific evidence supports the NTP’s 

conclusion on the level of evidence for carcinogenicity from experimental animal studies 

on 1-bromopropane and (2) whether the scientific evidence supports the NTP’s 

preliminary listing decision for 1-bromopropane in the RoC. The panel agreed with the 

NTP conclusions that 1-bromopropane should be listed in the RoC based on sufficient 

evidence of carcinogenicity from studies in experimental animals, which found skin 

tumors in male rats, large intestine tumors in female and male rats, and lung tumors in 

female mice.
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Peer Review Panel Members

Lucy Anderson, PhD, DABT (Chair) Consultant for Biomedical Sciences and 

Toxicology

Catonsville, Maryland

Leo Thomas Burka, PhD Consultant

Cary, North Carolina

Michael Elwell, DVM, PhD Senior Pathologist 

Department of Pathology

Nonclinical Safety Assessment

Covance Laboratories Inc.

Chantilly, Virginia

Terry Gordon, PhD Professor

Department of Environmental Medicine

New York University School of Medicine

New York, New York

Lawrence H. Lash, PhD Professor and Associate Chair

Department of Pharmacology

Wayne State University School of Medicine

Detroit, Michigan

Stephen Nesnow, PhD Consultant

Chapel Hill, North Carolina

Wayne T. Sanderson PhD, CIH Professor and Chair

Department of Epidemiology

College of Public Health

University of Kentucky

Lexington, Kentucky

MaryJane K. Selgrade, PhD Senior Toxicologist

ICF International

Environmental Risk and Toxicology

Durham, North Carolina

Paul A. White, PhD Leader, Genetic Toxicology Group

Environmental Health Sciences and 

Research Bureau

Health Canada 

Ottawa, Ontario, Canada
RoC Monograph on 1-Bromopropane 9/25/13

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Part 1

RoC Cancer Evaluation

Properties and Human Exposure

Disposition (ADME) and Toxicokinetics

Human Cancer Studies

Studies in Experimental Animals

Mechanisms and Other Relevant Effects

Overall Cancer Evaluation
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RoC Monograph on 1-Bromopropane 9/25/13

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Table of Contents

1 Properties and Human Exposure................................................................................1

1.1 Chemical identification and properties ................................................................1

1.2 Uses and production............................................................................................2

1.3 Biological indices of exposure.............................................................................3

1.4 Characterization of exposure in the workplace ....................................................3

1.4.1 Adhesives use ...............................................................................................6

1.4.2 1-Bromopropane manufacturing ...................................................................9

1.4.3 Dry cleaning .................................................................................................9

1.4.4 Aerosol solvents .........................................................................................10

1.4.5 Vapor degreasing........................................................................................10

1.4.6 Cleaning and painting workshops ...............................................................11

1.5 Potential for environmental exposure ................................................................12

1.5.1 Release of 1-bromopropane to the environment ..........................................12

1.5.2 Fate, occurrence, and exposure ...................................................................12

1.6 Potential for exposure from other sources: consumer products ..........................12

1.7 Exposure levels for people ................................................................................12

1.8 Synthesis and summary.....................................................................................12

2 Disposition and Toxicokinetics ...............................................................................15

2.1 Absorption, distribution, and excretion..............................................................15

2.1.1 Absorption..................................................................................................15

2.1.2 Distribution ................................................................................................15

2.1.3 Excretion ....................................................................................................16

2.2 Metabolism.......................................................................................................16

2.2.1 Metabolites detected in humans ..................................................................17

2.2.2 In vivo studies in experimental animals.......................................................17

2.2.3 In vitro studies............................................................................................21

2.2.4 Studies of metabolizing enzymes................................................................22

2.2.5 Differences in metabolic pathways..............................................................23

2.3 Synthesis and summary.....................................................................................24

3 Human Cancer Studies............................................................................................25

4 Studies of Cancer in Experimental Animals.............................................................27

4.1 Studies in experimental animals: characteristics, methodology, and relevant nonneoplastic findings.....................................................................................................27

4.1.1 Rats............................................................................................................27

4.1.2 Mice ...........................................................................................................28

4.2 Assessment of neoplastic findings.......................................................................29

4.3 NTP level of evidence conclusion .......................................................................33

5 Mechanistic Data and Other Relevant Effects..........................................................35

5.1 Genetic and related effects ................................................................................35

5.1.1 DNA and protein adducts............................................................................35

5.1.2 In vitro studies in bacteria ...........................................................................36

5.1.3 In vitro studies in mammalian cells.............................................................37

5.1.4 In vivo studies in rodents............................................................................37
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5.1.5 Studies in exposed workers.........................................................................37

5.1.6 Genotoxic effects of 1-bromopropane metabolites ......................................38

5.1.7 Synthesis of results.....................................................................................39

5.2 Relevant toxicological effects ...........................................................................40

5.3 Mechanistic considerations ...............................................................................40

5.3.1 Metabolic activation and genotoxicity.........................................................41

5.3.2 Oxidative stress ..........................................................................................41

5.3.3 Immunosuppression and other factors.........................................................42

5.3.4 Sex differences in chemical carcinogenesis.................................................43

5.4 Carcinogenicity of 1-bromopropane metabolites and analogues.........................44

5.4.1 Metabolites.................................................................................................45

5.4.2 Analogues...................................................................................................45

6 Overall Cancer Evaluation – Synthesis of Animal, Human, and Mechanistic Data.......

................................................................................................................................47

6.1 Cancer studies in experimental animals.............................................................47

6.2 Mechanistic and other relevant data...................................................................47

6.3 NTP listing recommendation.............................................................................49

References.....................................................................................................................51

Appendix A: Literature Search Strategy ......................................................................A-1

Appendix B: Human Exposure Tables and Regulations and Guidelines.....................A-17

Appendix C: Assessment of the Quality of the Individual Animal Cancer Studies .....A-31

Appendix D: Genotoxicity Studies ............................................................................A-35

Appendix E: Relevant Toxicological Effects .............................................................A-45

List of Tables

Table 1-1. Chemical identification of 1-bromopropane ....................................................1

Table 1-2. Physical and chemical properties of 1-bromopropane .....................................2

Table 1-3. Production data for 1-bromopropane...............................................................3

Table 2-1. 1-Bromopropane metabolites........................................................................18

Table 4-1. Large intestine tumors observed in Fischer 344/N rats exposed to 

1-bromopropane by inhalation for 2 years...................................................30

Table 4-2. Skin tumors observed in Fischer 344/N rats exposed to 1-bromopropane by 

inhalation for 2 years..................................................................................31

Table 4-3. Malignant mesotheliomas and pancreatic islet-cell tumors observed in Fischer 

344/N rats exposed to 1-bromopropane by inhalation for 2 years................32

Table 4-4. Lung tumors observed in B6C3F1 mice exposed to 1-bromopropane by 

inhalation for 2 years..................................................................................33

Table 5-1. Summary of 1-bromopropane genotoxicity information................................39

Table 5-2. Summary of genotoxicity data for 1-bromopropane metabolitesa..................40

Table A-1. General sources checklist for: 1-Bromopropane ................................A-10

Table A-2. Exposure-related sources checklist for: 1-Bromopropane .........................A-12
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Table A-3. Data sources for 1-bromopropane searches ..............................................A-13

Table A-4. Literature search approach for 1-bromopropane .......................................A-13

Table A-5. Search terms for monograph topics for 1-bromopropane ..........................A-14

Table B-1. Adhesives applications – personal samples of 1-bromopropane in air, urinary 

biomarkers (AcPrCys and Br), and 1-bromopropane in blood and exhaled air

...............................................................................................................A-17

Table B-2. Adhesives applications – area samples.....................................................A-22

Table B-3. 1-Bromopropane manufacturing – personal samples ................................A-23

Table B-4. 1-Bromopropane manufacturing – area samples.......................................A-23

Table B-5. Dry-cleaning applications – personal samples of 1-bromopropane ...........A-24

Table B-6. Dry-cleaning applications – area samples of 1-bromopropane in air .........A-24

Table B-7. Vapor degreasing applications – personal samples of 1-bromopropane in air, 

of urinary biomarkers (AcPrCys and Br-), and of 1-bromopropane in exhaled 

air...........................................................................................................A-26

Table B-8. Vapor degreasing applications – area samples..........................................A-28

Table B-9. Existing U.S. standards and guidelines with exposure limits for 1-

bromopropane (ppm)a.............................................................................A-29

Table B-10. EPA SNAP program determinations regarding different end uses of 

1-bromopropane .....................................................................................A-30

Table D-1. In vitro studies of 1-bromopropane mutagenicity in bacteria ....................A-35

Table D-2. In vitro studies of 1-bromopropane in mammalian cells...........................A-38

Table D-3. In vivo studies of cytogenetic effects of 1-bromopropane in rodents.........A-39

Table D-4. In vivo studies of 1-bromopropane in humans..........................................A-41

Table D-5. Summary of in vitro and in vivo studies of 1-bromopropane metabolites..........

...............................................................................................................A-43

Table E-1a. 1-Bromopropane effects on sperm motility and glutathione levels in wildtype or Cyp2e1–/– mice............................................................................A-46

Table E-1b. Sperm motility following 2-hour incubations with 1-bromopropane or 1-

bromo-2-hydroxypropane .......................................................................A-46

Table E-2. 1-Bromopropane effects on serum enzymes in male ICR mice .................A-50

Table E-3. 1-Bromopropane effects on hepatic GSH and GSH conjugate (S-propyl GSH) 

levels in female BALB/c mice ................................................................A-51

Table E-4. Comparison of liver histopathology among three mouse strains exposed to 

1-bromopropane .....................................................................................A-52

Table E-5. Comparison of liver necrotic area in wild-type and Nrf2-null mice exposed to 

1-bromopropane .....................................................................................A-53

Table E-6. 1-Bromopropane effects on plasma enzymes in male Wistar rats..............A-54

Table E-7. Suppression of splenic IgM response to sheep RBC in rodents after inhalation 

exposure to 1-bromopropane for 10 weeks..............................................A-55

List of Figures

Figure 1-1. Chemical structure of 1-bromopropane..........................................................1

Figure 1-2. TWA 1-bromopropane air concentrations across industry sectors..................5

Figure 1-3. 1-Bromopropane air concentrations for first and second NIOSH facility 

surveys in the adhesives use sector ...............................................................8
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Figure 2-1. 1-Bromopropane metabolism in male F344 rats and B6C3F1 mice following 

inhalation exposure.....................................................................................20

Figure 2-2. Metabolic pathways of 1-bromopropane in male Sprague-Dawley rats 

following oral exposure ..............................................................................21

Figure A-1. Literature search strategy and review........................................................A-2
RoC Monograph on 1-Bromopropane 9/25/13 

1

1 Properties and Human Exposure

1-Bromopropane is a brominated hydrocarbon currently used as a solvent in several industrial 

sectors including adhesives, dry cleaning, vapor degreasing, and aerosol solvents. In recent 

years, occupational exposures to 1-bromopropane have increased due to new industrial and 

commercial applications for 1-bromopropane involving its use as a substitute for ozone-depleting 

chemicals or suspect carcinogens. 

This section describes the chemical and physical properties of 1-bromopropane (Section 1.1); its 

uses and production (Section 1.2); biological indices of exposure (Section 1.3); characterization 

of exposure in the workplace (Section 1.4); potential for environmental exposure, including 

sources of release of 1-bromopropane to the environment, and its fate, occurrence, and exposure 

(Section 1.5); potential for exposure from other sources such as consumer products (Section 1.6);

and exposure levels for people (Section 1.7). Section 1.8 summarizes the information in Sections 

1.1 to 1.7. Data tables with occupational exposure to 1-bromopropane are provided in Appendix 

B, and include individual (e.g., personal breathing zone [PBZ], urinary biomarker, serum 

bromide, and exhaled breath) and area concentration measurements in various industrial sectors. 

U.S. regulations and guidelines that potentially limit exposure to 1-bromopropane are also 

reported in Appendix B. 

1.1 Chemical identification and properties 

1-Bromopropane (Figure 1-1) is a bromoalkane or alkyl bromide. Table 1-1 contains some 

chemical identification information for 1-bromopropane. 

Figure 1-1. Chemical structure of 1-bromopropane 

Table 1-1. Chemical identification of 1-bromopropane 

Characteristic Information

Chemical Abstracts index name 1-Bromopropanea

CAS Registry number 106-94-5

a

Molecular formula C3H7Brb

Synonyms 1-BPb; Propyl bromideb; n-Propyl bromideb; Propane, 1-bromob; 

normal propyl bromidec; nPBd

Sources: aNTP 2003a, 

bHSDB 2006, cUNEP 2001, dEPA 2007. 
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1-Bromopropane exists as a colorless to pale yellow liquid with a strong, characteristic odor

(NTP 2011a). It is slightly soluble in water and in most organic solvents including acetone, 

ethanol, ether, benzene, chloroform, and carbon tetrachloride. It is less flammable than many 

other halogenated alkanes at room temperature. 1-Bromopropane’s thermal decomposition 

produces hydrogen bromide. 1-Bromopropane can react with oxidizing agents to form hazardous 

flammable compounds and with water to produce acids. Some physical and chemical properties 

for 1-bromopropane are listed in Table 1-2. 

Table 1-2. Physical and chemical properties of 1-bromopropane 

Property Information

Molecular weight 123.0b

Melting point -110 C

b

Boiling point 64.7 C

b

Vapor pressure (mm Hg) 110.8 at 20 C

b

Vapor density 4.25a

Specific gravity 1.353 at 20 C

b

Solubility in water (20°C) 2,450 mg/La

Octanol/water partition coefficient (log Kow) 2.10a

Henry’s law constant 0.0073 atm-m

3

/mol at 25 C

a

Conversion factors (1-bromopropane in air)

parts per million (ppm) to μg/m3

μg/m3to parts per million (ppm)

g/m3= 5,030.7 (ppm)c 

ppm = 1.988 10-4( g/m3)

c

Sources: aHSDB 2006, 

bNTP 2003a, c

SMARTe.org 2012.

1.2 Uses and production

1-Bromopropane is used primarily as a solvent cleaner in vapor and immersion degreasing 

operations to clean optics, electronics, and metals and as a solvent vehicle in industries using 

aerosol-applied adhesives such as foam cushion manufacturing; however, these uses might be 

impacted by an EPA proposed rule listing certain uses as unacceptable (see Appendix B, Table 

B-10). In recent years, 1-bromopropane usage has increased due to new industrial applications 

involving its use as a substitute for ozone-depleting chemicals or suspect carcinogens. For 

example, increased use of 1-bromopropane in the dry-cleaning industry has occurred in response 

to states considering and pursuing actions to ban the use of tetrachloroethylene 

(perchloroethylene or PERC) (Blando et al. 2010). 1-Bromopropane also has been reported to 

have other advantages as a replacement for other halogenated solvents, including lower energy 

costs due to lower boiling point and reduced drying time, low Global Warming Potential (GWP), 

and reduced water consumption (Craft 2013). 1-Bromopropane also has potential application as a 

spot remover in the textile industry, but an evaluation of 1-bromopropane as a substitute for 

trichloroethylene (TCE) concluded that chronic toxicity data were lacking and use of 

1-bromopropane was not recommended until more data were available (Mirza et al. 2000). In the 

past, 1-bromopropane was used primarily as a solvent for fats, waxes, or resins and as an 
RoC Monograph on 1-Bromopropane 9/25/13

3

intermediate in the synthesis of pharmaceuticals, insecticides, quaternary ammonium 

compounds, flavors, or fragrances in generally well-controlled, closed processes (Hanley et al.

2006a, NTP 2003a). 

1-Bromopropane is produced by reacting n-propyl alcohol with hydrogen bromide and then 

removing the water that forms in the process. 1-Bromopropane can also be produced by 

dehydrating propanol with bromine or hydrogen bromide in the presence of sulfur catalyst (NTP 

2003a). In 2012, 1-bromopropane was manufactured by at least 21 companies worldwide, 

including at least 1 company in the United States (SRI 2012). Production data for 

1-bromopropane are listed in Table 1-3. Production data are based on Internet searches of 

sources dated as noted; data are subject to change.

Table 1-3. Production data for 1-bromopropane 

Category Years covered Quantity in poundsa

U.S. EPA Chemical 

Data Reporting Ruleb

2006

2002, 1998

1994

1990, 1986

> 1 million to 10 million

1 million to < 10 million

> 500K to 1 million

10K to 500K

U.S. imports (recent)c2011 10.3 million

U.S. imports 

(historical)c

2007 10.9 million

U.S. exports (recent)c2011 15.1 million

U.S. exports (historical)c2007 8.8 million

Sources: EPA 2012, SRI 2012, USITC 2012.

a

From 10/2012 Internet searches; data subject to change.

b

Formerly called Inventory Update Rule.

cReported as brominated derivatives of acyclic hydrocarbons, which includes other 

chemicals in addition to 1-bromopropane.

1.3 Biological indices of exposure

Potential biological indices of exposure to 1-bromopropane include measurements of bromide 

ion (Br(-)), N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys) (see Section 2.2 for a description of the 

metabolism of 1-bromopropane), and 1-bromopropane in urine, and serum bromide levels

(Eisenberg and Ramsey 2010, Hanley et al. 2006a, Hanley et al. 2009, Kawai et al. 2001, 

Valentine et al. 2007). Urinary 3-bromopropionic acid (3-BPA) was not found to be an effective 

urinary biomarker for occupational exposure to 1-bromopropane from spray adhesives, because 

it was not detected in heavily exposed workers at foam cushion manufacturers. However, 

AcPrCys and bromide ion were effective biomarkers (Mathias et al. 2012). 

1.4 Characterization of exposure in the workplace

Occupational exposure to 1-bromopropane may occur through inhalation and dermal contact at 

workplaces where 1-bromopropane is produced or used (HSDB 2006), and extensive 

1-bromopropane occupational exposure-monitoring data are available. Many of the data either 
9/25/13 RoC Monograph on 1-Bromopropane

4

were submitted to the EPA under the Significant New Alternatives Policy (SNAP) program or 

collected during studies conducted under the NIOSH Health Hazard Evaluation (HHE) or 

Industrywide Studies Branch (IWSB) programs. (See Appendix B, Tables B-1 to B-8 for

personal samples (e.g., personal breathing zone [PBZ], urinary biomarker, serum bromide, and 

exhaled breath) as well as area samples for 1-bromopropane concentrations in various industrial 

sectors.)

Based on the available occupational exposure (as described in Tables B-1 to B-8), 8- to 12-hr 

time-weighted average (TWA) 1-bromopropane air concentrations across all sectors ranged from 

not detected to 380 ppm. Jobs requiring workers to spray 1-bromopropane adhesives have the 

highest exposures and jobs requiring workers to clean and assemble small parts used in radio 

frequency and microwave communication instruments (vapor degreasing operations) have the 

lowest exposures. In extreme cases, 1-bromopropane air concentrations during vapor degreasing 

may be as much as four orders of magnitude lower than during adhesives use. This could be due 

in part to exposure to 1-bromopropane during only part of the workday. For example, Hanley et 

al. (2010) reported that parts were cleaned on an as-needed basis in the facilities that they 

sampled, and use of degreasers was limited to 90 minutes or less for an entire work shift. Figure 

1-2 graphically depicts TWA 1-bromopropane air concentrations across industry sectors. The 

figure does not include all data for occupation exposure; thus, the highest air concentration 

shown is less than the maximum reported of 380 ppm.
RoC Monograph on 1-Bromopropane 9/25/13 

5

Figure 1-2. TWA 1-bromopropane air concentrations across industry sectors 

From Eisenberg and Ramsey 2010, Graul 2012, Hanley et al. 2006b, Hanley et al. 2010, Ichihara et al. 2004a, Kawai et al. 2001. Time-weightedaverage 1-bromopropane exposure levels as geometric means (Adhesives, Other, and Vap. Deg.); arithmetic mean (Dry Cln.); or not reported (Manuf. 

and Aer. Solv.). Note: the dashed, vertical line represents the ACGIH threshold limit value – time-weighted average (TLV-TWA) of 10 ppm. 
9/25/13 RoC Monograph on 1-Bromopropane

6

The Occupational Safety and Health Administration (OSHA) Chemical Exposure Health 

Dataset contains OSHA compliance monitoring program industrial hygiene samples.

1-Bromopropane concentration sampling data are available for 1998 to 2011. Of the 164 

total sample points for 1-bromopropane, 126 were personal breathing zone (PBZ) 

samples with detectable values from 18 facilities. PBZ samples with detectable values 

ranged from 0.0477 to 423 ppm. Sixty-two (62) samples from 9 of the facilities were 

above the American Conference of Governmental Industrial Hygienists (ACGIH) 

threshold limit value (TLV) of 10 ppm. Most of those facilities (7 of 9) were in the vapor 

degreasing or adhesives use sector (OSHA 2011).

1.4.1 Adhesives use 

1-Bromopropane–based adhesives are used most widely as spray adhesives for foam 

cushion manufacturing (e.g., the furniture industry) and to a lesser extent in laminate 

adhesives (FR 2007); however, no exposure data were identified for laminate adhesives. 

In furniture foam cushion manufacturing plants, cushions are generally assembled by 

gluing together pieces of cut flexible foam (Harney et al. 2002, Harney et al. 2003). Once 

the foam pieces are glued together, workers hand press the pieces to achieve a proper 

bond. The adhesive is spray-applied using a compressed air spray gun. Data were also 

identified for one adhesives and coatings manufacturer (Hanley et al. 2007, Hanley et al.

2010).

Personal samples (available data for personal breathing zone and exhaled breath

concentrations for 1-bromopropane as well as urinary biomarker and serum bromide

concentrations for the adhesives use sector) are provided in Appendix B, Table B-1. 

Eight- to twelve-hour TWA 1-bromopropane air concentrations for adhesives use ranged 

from 0.1 to 380 ppm. These data indicate that workers engaged in adhesive spraying are 

consistently exposed to higher concentrations than non-sprayers, in some cases by as 

much as three orders of magnitude. The higher exposures are reflected in higher levels of 

urinary biomarkers for both urinary Br(-)(Hanley et al. 2006a) and urinary AcPrCys 

concentrations (Hanley et al. 2009).

Pre- and post-shift 1-bromopropane breath concentrations have been measured for 

adhesives use. Available breath monitoring data indicate that post-shift 1-bromopropane 

concentrations were consistently higher than pre-shift concentrations, in many cases, 

more than 10 times higher. For example, Hanley et al. (2005) reported a pre-shift mean 

breath concentration of 0.96 ppm and a post-shift mean breath concentration of 15.4 ppm 

for a polyurethane seat cushion manufacturing plant. Further, breath concentrations for 

sprayers were consistently higher than concentrations for workers performing other jobs. 

Serum bromide concentration data indicated that concentrations are highest in the 

adhesives sector, for which values as high as 1,700 mg/L have been reported (Majersik et 

al. 2007) (see Appendix B, Table B-1). Based on NIOSH HHE data for one facility, the

average difference between end-of-week and start-of-week serum bromide concentrations 

for exposed workers was 23 mg/L compared with 3 mg/L for unexposed workers (Harney

et al. 2003).
RoC Monograph on 1-Bromopropane 9/25/13

7

1-Bromopropane air concentrations differed considerably before and after engineering 

controls (i.e., ventilation improvements, enclosure of spray tables, etc.) were 

implemented at two facilities studied in the NIOSH HHE program. Figure 1-3 depicts 

1-bromopropane air concentrations for first and second NIOSH facility surveys for the 

three known facilities in the adhesives use sector at which NIOSH conducted HHE 

assessments. In two cases (Custom Products and STN Cushion Company), the facilities 

adopted NIOSH recommendations concerning addition of engineering controls and 

TWAs decreased by 80% or greater. The results demonstrated reductions of mean TWA 

1-bromopropane air concentration from 168.9 ppm (N = 69) to 19.0 ppm (N = 30) for all 

workers at Custom Products Inc. and from 65.9 ppm (N = 12) to 16.6 ppm (N = 11) for 

sprayers at STN Cushion Company (Reh et al. 2002).

NIOSH also recommended similar controls for the third facility (Marx Industries), but the 

agency reported that they were unaware of any changes in controls or employee use of 

personal protective equipment during the time interval between the first and second 

survey for this facility, and only slight change in exposure for sprayers occurred between 

the first and second surveys. The mean TWA 1-bromopropane air concentration for all 

sprayers for the first survey (N = 12) was 107.6 ppm, and the mean for the second survey 

(N = 8) was 101.4 ppm (Harney et al. 2003).

According to a summary of workplace exposure data for 1-bromopropane submitted to 

EPA for the SNAP program (Graul 2012), initially, fewer than half the personal breathing 

zone (PBZ) sample concentrations were below 50 ppm (8-hr TWA); however, after 

ventilation improvements, 97% of the PBZ samples were less than 50 ppm and 78% were 

≤ 25 ppm. Further, the initial mean concentration was 141.7 ppm; after ventilation 

improvements, the mean concentration was 18.3 ppm (Graul 2012).
9/25/13 RoC Monograph on 1-Bromopropane

8

Figure 1-3. 1-Bromopropane air concentrations for first and second NIOSH facility surveys in the adhesives use sector

TWA concentrations reported for Custom Products, Inc. and STN Cushion Company are arithmetic means, and those reported for Marx Industries, Inc. are 

geometric means.
RoC Monograph on 1-Bromopropane 9/25/13

9

Concentration measurements for the adhesives use sector are shown in Appendix B, 

Table B-2. Area samples for 1-bromopropane for adhesives use ranged from 0.01 to 176 

ppm. The range of area samples reflects variation between facilities; however, differences 

within a facility appear to vary only minimally for the same task. 

1.4.2 1-Bromopropane manufacturing 

Personal samples (from the available data for personal breathing zone concentrations of

1-bromopropane) for the manufacturing sector in China are provided in Appendix B, 

Table B-3. No 1-bromopropane air concentration data were identified for 

1-bromopropane manufacturing plants in the United States, but Patent Number 5,773,672 

(June 30, 1998), which is assigned to a U.S. manufacturer of 1-bromopropane, contains 

descriptions of numerous control processes to contain 1-bromopropane in contrast with 

the more open processes described below. Eight- to twelve-hour TWA 1-bromopropane 

air concentrations for these facilities ranged from not detected to 170 ppm. Worker 

exposure was reported to occur from (1) adding chemicals into reaction pots, (2) sitting 

close to reaction pots when observing and recording the temperature, (3) removing crude 

product, (4) adding hydrogen carbonate and stirring, and (5) pouring the product into 

1000 L drums (Li et al. 2010b). In one plant, the highest concentrations were measured 

during the transfer of processed product into containers (Ichihara et al. 2004a). 

Area sample concentrations of 1-bromopropane for 1-bromopropane manufacturing 

ranged from not detected to 90.2 ppm (see Appendix B, Table B-4).

One study also examined biomarkers of 1-bromopropane exposure. Valentine et al.

(2007) measured globin S-propylcysteine (PrCys) adducts and urinary N-acetyl-Spropylcysteine (N-acetyl-S-(n-propyl)-L-cysteine or AcPrCys) for workers in a Chinese 

1-bromopropane manufacturing facility and reported a significant (P < 0.01) increase in 

PrCys adducts on 1-bromopropane manufacturing workers’ globin (1.52 pmol/mg globin) 

compared with control factory workers (0.11 pmol/mg globin) (N = 32 controls, N = 26 

exposed). Further, Valentine et al. (2007) determined that urinary AcPrCys levels 

increased as 1-bromopropane ambient exposure levels increased (N = 47 exposed); the 

exposure levels ranged from 0 to 170.54 ppm.

1.4.3 Dry cleaning 

The increased use of 1-bromopropane in the dry-cleaning industry has occurred in 

response to states considering and pursuing actions to ban the use of PERC (Blando et al.

2010). 1-Bromopropane has been reported to be the only PERC alternative that can be 

used in the original PERC machines with alterations; other cleaners would require the 

purchase of new machines (Eisenberg and Ramsey 2010).

Personal full- and partial-shift samples (available data for personal breathing zone 

concentrations of 1-bromopropane) for the dry-cleaning sector are provided in Appendix 

B, Table B-5. Eight- to twelve-hour TWA 1-bromopropane air concentration data 

identified in these dry-cleaning facilities ranged from < 0.004 to 56 ppm. Eisenberg and 

Ramsey (2010) reported a mean serum bromide concentration of 144 mg/L for a drycleaning facility owner who was converting his machine from PERC to 1-bromopropane 

(value reported as 144 mcg/mL). Worker exposure could occur from introduction of 
9/25/13 RoC Monograph on 1-Bromopropane

10

solvent to the cleaning machine, machine maintenance, unloading and handling of 

recently cleaned clothes, interrupting the machine wash cycle, and “cooking” the solvent 

(i.e., boiling the solvent to remove impurities) (Blando et al. 2010, Eisenberg and 

Ramsey 2010). Further, exposure could occur due to leaks resulting from normal machine 

wear with time, poor maintenance, and incompatibility of 1-bromopropane with system 

gasket materials and poor ventilation (Blando et al. 2010).

Reduced exposure due to improved ventilation procedures also has been illustrated for 

dry-cleaning applications. For example, Blando et al. (2010) (see Appendix B, Table B6) noted that building size, exhaust fan capacity and operation, and natural ventilation 

(i.e., opening doors and windows) were the determining factors for operator air 

concentrations in two of the three shops studied differing by as much as 4 orders of 

magnitude. Other studies have shown that dry cleaning operators often use natural 

ventilation (i.e., opening doors and windows) to control 1-bromopropane exposures.

However, weather conditions may prevent use of natural ventilation (Eisenberg and 

Ramsey 2010), which typically is not as effective as mechanical ventilation. 

Area sample concentrations for 1-bromopropane for dry cleaning ranged from < 0.004 to 

170 ppm and differences were mainly explained by characteristics of the individual 

facilities (see Appendix B, Table B-6). Area samples at Facility 1 in Eisenberg and 

Ramsey (2010) varied between morning and afternoon measurements. Measurements 

taken in the morning were higher because the facility closed the doors and did not operate 

the ventilation system at this time; only the front windows were open. However, in the 

afternoon, the facility operated the ventilation system and opened the back door. 

Variation in area samples at Facility 4 in Eisenberg and Ramsey (2010) might have been 

due to machine leaks as the owner converted the machine himself and reported that he 

had difficulties finding the correct conversion materials. Further, opening the front door 

and operating the exhaust fan produced a marked decrease in solvent odor at this facility 

(Eisenberg and Ramsey 2010). Findings reported by Blando et al. (2010) for dry-cleaning 

Shops A, B, and C were discussed above. 

1.4.4 Aerosol solvents 

1-Bromopropane has been reported to be used as a solvent in aerosol lubricants, coatings, 

or cleaning fluids for electrical or electronic equipment or aircraft maintenance, or in 

spinnerette lubricants and cleaning sprays used in synthetic fiber production (FR 2007). 

Spray-can aerosol solvents are normally used intermittently and for short periods of time 

(i.e., 1 to 2 minutes). In some cases, aerosol products are used in confined spaces without 

ventilation or fans where short-term worker exposure can be high. Although emissions 

from aerosol solvents typically are not controlled via engineering controls, aerosol users 

can reduce exposure levels through use of fume hoods and improving ventilation (FR 

2003). Eight- to twelve-hour TWA 1-bromopropane air concentration data identified for 

aerosol solvents ranged from 5 to 30.2 ppm (Graul 2012). Fifteen-minute STEL sample 

data ranged from 45.1 to 254 ppm. 

1.4.5 Vapor degreasing

In general, vapor degreasers use a refrigerated cooling coil around the top of the interior 

of the vapor chamber to condense heated 1-bromopropane vapor into liquid droplets on 
RoC Monograph on 1-Bromopropane 9/25/13

11

the cooler surface of parts to remove dirt, grease, and surface contaminants (Hanley and 

Dunn 2006). Excess 1-bromopropane drips back into the solvent sump and is recycled as 

the parts ascend from the vapor to condensing zones. Another function of the cooling coil 

is to control solvent vapor emissions by “capping” the heated vapor zone with a 

refrigerated air space.

For the vapor degreasing sector, personal samples of 1-bromopropane are provided in 

Appendix B, Table B-7. Eight- to twelve-hour GM TWA 1-bromopropane air 

concentration for vapor degreasing ranged from 0.077 to 21 ppm. In Hanley et al. (2010), 

workers near degreasers had personal breathing zone TWA 1-bromopropane 

concentrations higher (GM = 2.6 ppm) than workers away from degreasers (GM = 0.31

ppm), and urinary bromide and AcPrCys concentrations showed the same trend. 

A NIOSH HHE was conducted at a facility that used 1-bromopropane below its boiling 

point as a vapor degreaser (Reh and Nemhauser 2001). Eight- to twelve-hour TWA 

1-bromopropane air concentration data for this facility ranged from 0.01 to 0.63 ppm. 

Fifteen-minute sample data identified ranged from 2.3 to 8.4 ppm. This facility’s cleaning 

system was located in a special, enclosed room with a local exhaust ventilation system 

(FR 2003). The design of most vapor degreasers reduces emissions from equipment 

because the solvent is boiled and subsequently condensed rather than allowing vapors to 

be emitted. In general, it is expected to be more difficult to control emissions from 

cleaning equipment in which the solvent is not boiled and condensed (FR 2003). Both 

cleaning methods could benefit from the installation of well-maintained, effective local 

exhaust ventilation systems as these are the preferred method of solvent emission control. 

A summary of 500 personal samples for vapor degreasing by Graul (2012) reported that

> 87% of the personal samples were below 25 ppm on an 8-hour TWA basis and

approximately 75% of those samples were below 10 ppm on an 8-hour TWA basis.

1-Bromopropane emissions exposure to vapor degreasing workers can be reduced 

through changes in equipment and operating practices (FR 2003, Hanley and Dunn 

2007). For example, additional condensation coils can be installed to prevent vapors from 

leaving the degreaser. Further, workers can tilt pieces to be cleaned to increase solvent 

drainage inside the vapor degreaser instead of leaving 1-bromopropane on the pieces to 

evaporate outside the degreaser where workers can inhale the vapors. A mechanical hoist 

operated at a controlled rate is also advantageous so that workers cannot raise the parts 

basket too quickly, which may circumvent effective vapor control of the condensing 

zone.

Area sample concentrations for 1-bromopropane for vapor degreasing ranged from 0.02 

to 4.42 ppm (see Appendix B, Table B-8). These measurements indicate that the highest 

concentrations are found in areas near degreasers and lower concentrations are in areas 

away from degreasers. 

1.4.6 Cleaning and painting workshops

In a study of 33 workers in a cleaning and painting workshop using 1-bromopropane 

cleaning solvents in a Japanese factory, Kawai et al. (2001) reported a geometric mean 

1-bromopropane concentration of 1.42 ppm and a maximum concentration of 27.8 ppm. 
9/25/13 RoC Monograph on 1-Bromopropane

12

1.5 Potential for environmental exposure

1.5.1 Release of 1-bromopropane to the environment

Based on the production and use of 1-bromopropane it may be released to the 

environment through various waste streams. 1-Bromopropane has also been detected in 

temperate marine macroalgae tissue and is believed to be transported from these algae to 

the marine environment. (HSDB 2006).

In a search of the National Response Center database for the time period of January 1, 

1990 to the present, “1-bromopropane” identified three chemical spill incidents and “npropyl bromide” identified one incident (NRC 2012). No Toxics Release Inventory (TRI) 

data for 1-bromopropane were identified, since 1-bromopropane is not included on the 

TRI list of toxic chemicals (EPA 2011).

1.5.2 Fate, occurrence, and exposure

No data have been identified indicating the measurement of 1-bromopropane in ambient 

air, drinking water, surface water, soil, or food. EPA has estimated 1-bromopropane 

concentrations in ambient air at a distance of 100 meters from average-adhesive use 

model facilities via air dispersion modeling to be 0.138 mg/m3[0.0274 ppm] and 1.38 

mg/m3[0.274 ppm] for high-adhesive use facilities (Wolf et al. 2003). EPA also has 

estimated daily uptake from 1-bromopropane in the environment from inhalation for a 

person living 100 meters from average-adhesive use model facilities to be 0.0537 mg/kgday and 0.537 mg/kg-day from high-adhesive use facilities.

Investigation of a wastewater tank leak at a Swiss alkyl halide factory that manufactured 

1-bromopropane at quantities reported as greater than 5 tons/year did not identify any 

1-bromopropane or its alcohol metabolite in groundwater after clean up (Schwarzenbach

et al. 1985, as cited by NTP 2003a).

1.6 Potential for exposure from other sources: consumer products

No 1-bromopropane concentration measurement data for consumer products have been 

identified. Knöppel and Schauenburg (1989) analyzed VOC emissions of household wax, 

liquid pastes, and detergents, and 1-bromopropane was included in the list of analytes; 

however, 1-bromopropane was used as an internal standard in that study and the authors 

did not report it as being present in the consumer products (HSDB 2006).

1.7 Exposure levels for people

No data for non-occupational 1-bromopropane exposure levels for people have been 

identified. 

1.8 Synthesis and summary

A significant number of people in the United States are exposed to 1-bromoproane as a 

result of widespread usage, high-production volume, and exposure to high levels of 

1-bromopropane in commercial and industrial settings. The principal uses of 

1-bromopropane are as a solvent cleaner in vapor and immersion degreasing operations to 

clean optics, electronics, and metals, as a solvent vehicle in industries that use aerosolapplied adhesives such as foam cushion manufacturing, and as a textile solvent in the 
RoC Monograph on 1-Bromopropane 9/25/13

13

dry-cleaning industry. In recent years, certain 1-bromopropane uses have increased 

because it is an alternative to ozone-depleting chemicals or suspect carcinogens; e.g., 

1-bromoprane has been used as an alternative to PERC (listed as reasonably anticipated 

to be a human carcinogen in the RoC) in the dry cleaning industry. 

Inhalation is the primary route of human exposure; dermal exposure is also possible. 

1-Bromopropane is a high-production-volume chemical with annual production ranging 

from 1 million to 10 million pounds as reported in 1998, 2002, and 2006. Based on 

occupational exposure data across several industrial sectors, 8- to 12-hour time-weighted 

average (TWA) 1-bromopropane air concentrations ranged from not detected to 380 ppm. 

1-Bromopropane air concentrations are highest for adhesives use and lowest for vapor 

degreasing. In extreme cases, vapor degreasing 1-bromopropane air concentrations may 

be as much as four orders of magnitude lower than adhesives use concentrations.

No data have been identified indicating measurable levels of 1-bromopropane in ambient 

air, drinking water, surface water, soil, or food. However, the EPA has estimated via air 

dispersion modeling that 1-bromopropane may be present in ambient air, and daily intake 

from exposure in the environment may occur, particularly for people who live near

industrial and commercial users of 1-bromopropane.
9/25/13 RoC Monograph on 1-Bromopropane

14

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RoC Monograph on 1-Bromopropane 9/25/13

15

2 Disposition and Toxicokinetics

This section describes the overall disposition of 1-bromopropane, i.e., how it can enter 

the body (absorption), what happens to it once it is in the body (distribution and 

metabolism), how it leaves the body (excretion), and the extent and/or rates of these 

processes. Section 2.1 discusses the absorption, distribution, and excretion of 

1-bromopropane for both humans and experimental animals, and metabolism is discussed 

in Section 2.2. Toxicokinetics is the mathematical description (toxicokinetic model) of 

the time course of disposition of a chemical in the body; however, no toxicokinetic 

models of 1-bromopropane were identified.

Data on disposition of 1-bromopropane are important because they can help identify the 

various factors that affect the toxicity of the chemical. These factors include routes and 

rates of absorption, tissue concentrations and their temporal changes, reactive 

metabolites, toxification and detoxification reactions, routes of elimination, and species 

differences in these factors. The mechanistic implications of these data are discussed in 

Section 5.

2.1 Absorption, distribution, and excretion

2.1.1 Absorption

Studies in humans and laboratory animals indicate that 1-bromopropane can be absorbed 

following inhalation, ingestion, or dermal contact, and both inhalation and dermal 

exposure are likely to occur in the workplace (Cheever et al. 2009, Hanley et al. 2007). 

Occupational exposure studies consistently reported a correlation between ambient air 

levels of 1-bromopropane and levels of 1-bromopropane or metabolites in urine. (See 

Section 1 for a description of these exposure studies.) An in vitro study of absorption 

characteristics of 1-bromopropane using heat-separated human epidermal membranes 

demonstrated that dermal penetration of 1-bromopropane could be substantial but the 

actual absorption depended on the type and duration of exposure (Frasch et al. 2011). 

The most relevant route of exposure for 1-bromopropane based on human exposures is 

inhalation, and metabolism studies in rats and mice show that 1-bromopropane is 

absorbed following inhalation (Garner et al. 2007, Garner et al. 2006, Ishidao et al. 2002)

or oral exposure (Jones and Walsh 1979, Lee et al. 2010a). In male Wistar rats exposed 

to 1-bromopropane vapor at either 700 or 1,500 ppm, the concentration of 

1-bromopropane in blood decreased linearly with time and was below the detection limit 

within 0.7 hours following the end of the exposure period (Ishidao et al. 2002). This 

study also reported that concentrations of bromide ion (a byproduct of 1-bromopropane 

metabolism) in rat blood decreased much more slowly, with a half-life of 4.7 to 15 days, 

depending on the exposure scenario (concentration and duration of treatment) while the 

half-life of bromide ion excreted in the urine was 5 to 7.5 days.

2.1.2 Distribution

No data on distribution of 1-bromopropane in humans was identified, and only one study 

(Garner et al. 2006) was found that reported limited data on distribution of radiolabeled 

[

14C]1-bromopropane in rats and mice after exposure by intravenous (i.v.) injection.
9/25/13 RoC Monograph on 1-Bromopropane

16

Exhaled air, urine, and feces were collected at various intervals up to 48 hours, and blood 

and tissue (reported as carcass) samples were collected 48 hours post-exposure. The total 

radioactivity recovered ranged from 83% to 103% with the largest percentages 

represented by volatile organic chemicals (VOCs) (25% to 71%), CO2 (10% to 31%) and 

urine (13% to 23%). Much smaller amounts were recovered from the total carcass (2% to 

6%) and feces (< 1% to 4%). Limited data were reported for radioactivity in liver, and no 

recovery data were reported for other individual tissues that might be potential tumor 

sites (see Section 4). The liver to blood tissue radioactivity ratios were similar (~3) 

regardless of dose, and dose-normalized 1-bromopropane ng equivalents/g of liver were 

inversely proportional to dose in both species. 

2.1.3 Excretion

Once absorbed, the majority of 1-bromopropane is rapidly cleared from the blood by 

exhalation of the unchanged compound or as either CO2 or VOCs, and by urinary 

excretion of metabolites of 1-bromopropane or the unmetabolized molecule. Only limited 

information is available for the excretion of 1-bromopropane in humans, but the presence 

of the unmetabolized molecule in urine has been described in studies of exposed workers

(Ichihara et al. 2004a, Kawai et al. 2001). Excretion of unmetabolized 1-bromopropane 

in urine in these studies of exposed workers was significantly correlated with exposure to 

1-bromopropane in air. No studies were identified that reported urinary excretion of 

unmetabolized 1-bromopropane in rodents. Bromide ion is also excreted, but the 

specificity of this ion as a biomarker for exposure to 1-bromopropane is limited because 

of a relatively high background from dietary sources, particularly seafood. As discussed 

below in the section on metabolism, several mercapturic acid derivatives of 

1-bromopropane have been identified in urine from exposed humans and experimental 

animals. Many more metabolites or potential metabolites have been identified from 

experimental animal studies using labeled 1-bromopropane and these are discussed 

below.

Other studies in experimental animals have exposed rats or mice to radiolabeled 

[

14C]1-bromopropane by intraperitoneal (i.p.) injection (Jones and Walsh 1979) or i.v. 

administration through the tail vein or jugular vein (Garner et al. 2006). Jones and Walsh 

reported that 60% of a single dose of 200 mg/kg 1-bromopropane administered to rats 

was exhaled unchanged within 4 hours with only trace amounts detected after that time. 

Only 1.4% of the total dose was exhaled as CO2 and about 45% of the metabolized dose 

was excreted in the urine after 100 hours. A much lower recovery of 3.3% of an i.p. dose 

of 200 mg/kg as urinary metabolites was reported by Walsh and Jones (1977) after 100 

hours.

2.2 Metabolism

The metabolites identified in humans are limited to those recovered in the urine of factory 

workers after exposure to 1-bromopropane. Several studies have investigated 

1-bromopropane metabolism in experimental animals, and the different metabolites 

identified in studies by different routes of exposure indicate that the metabolism is 

complex. 
RoC Monograph on 1-Bromopropane 9/25/13

17

2.2.1 Metabolites detected in humans

Several studies have monitored urine samples from humans occupationally exposed to 

1-bromopropane in order to establish biomarkers of exposure. The predominant 

metabolite detected in the urine of workers is N-acetyl-S-propylcysteine (AcPrCys), and 

levels increased with increasing 1-bromopropane ambient exposure levels (Hanley and 

Dunn 2006, Hanley et al. 2009, 2010, Valentine et al. 2007). In addition to AcPrCys, 

several other urinary mercapturic acid conjugates were identified from 1-bromopropane–

exposed workers; these included N-acetyl-S-(n-propyl)-L-cysteine-S-oxide, N-acetyl-S-(2-

carboxyethyl)-L-cysteine, and N-acetyl-S-(3-hydroxy-n-propyl)-L-cysteine (Cheever et al.

2009, Hanley et al. 2009). The oxidative metabolites that likely lead to the conjugates 

have not been reported in human studies, however no publications were identified that 

actually tested for them. Metabolism has been more extensively studied in experimental 

animals.

2.2.2 In vivo studies in experimental animals

Metabolism studies were conducted in rats and mice exposed by inhalation, oral, 

subcutaneous (s.c.), i.p., or i.v. administration and in vitro using rat liver microsomes

(Barnsley et al. 1966, Garner et al. 2007, Garner et al. 2006, Jones and Walsh 1979). The 

four urinary mercapturic acid conjugates identified in exposed workers were also 

identified in experimental animals. AcPrCys was identified in the urine of rats, mice, 

guinea pigs, and rabbits exposed to 1-bromopropane via s.c. injection. The other 

metabolites were identified in the urine of rats following oral exposure. Additional 

urinary metabolites identified from studies in experimental animals are listed in Table 

2-1, but the available studies do not agree completely with regard to metabolites detected, 

which might be due to differences in route of exposure, species tested, and detection 

methods. Overall, three major categories of metabolites have been identified: (1) 

brominated metabolites (Phase I), (2) debrominated metabolites (Phase I), and (3) 

glucuronide or glutathione conjugated metabolites (Phase II). 
9/25/13 RoC Monograph on 1-Bromopropane

18

Table 2-1. 1-Bromopropane metabolites 

Metabolite Humans

Experimental animals

Inh. Oral Inj. In vitro

N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys, 

n-propyl mercapturic acid) X

a Xb,c Xd Xe,f,g

N-Acetyl-3-(propylsulfinyl)alanine (N-acetylS-(n-propyl)-L-cysteine-S-oxide or npropylmercapturic acid)

X

a Xb Xd Xf

N-Acetyl-S-(3-hydroxypropyl)cysteine X

a Xd

N-Acetyl-S-(2-carboxyethyl)cysteine X

a Xd

1-Bromo-2-propanol X

b

Bromoacetone X

b

-Bromohydrin X

b

Glycidol X

h

N-Acetyl-S-(2-hydroxypropyl)cysteine 

(2-hydroxypropyl mercapturic acid) X

b Xd Xf,g

N-Acetyl-S-(2-oxopropyl)cysteine X

b

N-Acetyl-3-[(2-

hydroxypropyl)sulfinyl]alanine X

b

N-Acetyl-3-[(2-oxopropyl)sulfinyl]alanine X

b

N-Acetyl-3-[(2-propenol)sulfinyl]alanine X

b

2,3-Dihydroxypropylmercapturic acid X

g

1-Bromo-2-hydroxypropane-O-glucuronide X

b

3-Bromopropionic acid X

d Xg Xd

Propene X

i

n-Propanol X

j

1,2-Propanediol X

i

Propionic acid X

i

S-n-Propylglutathione X

i

S-(2-Hydroxypropyl)glutathione X

i

3-Hydroxypropionic acid X

d

S-(2-hydroxypropyl)cysteine X

d

Inh. = inhalation; Inj. = injection.

aHanley et al. 2009.

bGarner et al. 2006.

cValentine et al. 2007.

d

Jones and Walsh 1979.

eGrenby and Young 1959, 1960.

fBarnsley et al. 1966.

gWalsh and Jones 1977.

h

Ishidao et al. 2002.

iTachizawa et al. 1982.

jKaneko et al. 1997.
RoC Monograph on 1-Bromopropane 9/25/13

19

Garner et al. (2006) investigated the metabolism of 1-bromopropane in male F344 rats 

and B6C3F1 mice following inhalation or tail vein injection. These routes were selected 

because they do not involve first-pass metabolism and the inhalation route, specifically, is 

more likely to be consistent with occupational or environmental exposures compared 

with the oral and i.p. routes used by Jones and Walsh (1979). Much of the administered 

dose (40% to 70%) was exhaled unchanged. Oxidation and glutathione conjugation were 

the primary metabolic pathways (Figure 2-1). In both rats and mice, hydroxylation at the 

C2 position (forming 1-bromo-2-propanol) was the predominant pathway of oxidation. 

Although 1-bromo-2-propanol was not detected in the urine, resonances associated with 

unconjugated 1-bromo-2-propanol were detected in rat liver homogenates, and more than 

half of the urinary metabolites were derived from this metabolite. Although 

bromoacetone was not detected in the urine, its mercapturic acid conjugate, N-acetyl-S-

(2-oxopropyl)cysteine, was detected in rats at levels approaching that of N-acetyl-S-(2-

hydroxypropyl)cysteine, the mercapturic acid of 1-bromo-2-propanol. Another possible 

metabolite detected in rat liver homogenate was -bromohydrin.

Urinary metabolites in rats exposed to 1-bromopropane by i.v. injection were affected by 

dose (Garner et al. 2006). At the low dose, AcPrCys was a relatively minor component 

compared with earlier eluting peaks that included N-acetyl-S-(2-hydroxypropyl)cysteine. 

However, the relative proportion of AcPrCys increased with dose and accounted for more 

than 80% of the urinary radioactivity in the high-dose group. AcPrCys is formed by 

direct conjugation with glutathione without oxidation (Figure 2-1). In contrast, in mice 

injected i.v. with 1-bromopropane, N-acetyl-S-(2-hydroxypropyl)cysteine was the single 

predominant metabolite at all dose levels. 

A pathway overlapping in part with that described by Garner et al. (2006) was reported 

by Jones and Walsh (1979), who investigated the metabolism of 1-bromopropane in male 

Sprague-Dawley rats following five consecutive daily oral doses. Four possible metabolic 

pathways were identified (Figure 2-2). The first pathway involved direct conjugation with 

glutathione to produce the urinary metabolites AcPrCys and N-acetyl-S-propylcysteine-Soxide. The second pathway involved oxidation at C3 of 1-bromopropane to 3-bromo-1-

propanol. Pathway 3 was based on oxidation of C1 of 1-bromopropane to CO2 (hydrolysis 

to n-propanol with rapid oxidation to propionic acid and decarboxylation to CO2).

Pathway 4 is the proposed mechanism for forming N-acetyl-S-(2-hydroxypropyl)cysteine; 

however, there was no direct evidence for this pathway in vivo. Several additional 

metabolites, including 3-bromopropionic acid and n-propanol, were identified by Jones 

and Walsh that were not described by Garner et al. However, as suggested by Garner et 

al., the difference in the observed metabolites might be explained by the analytical 

methods used by Jones and Walsh, which included concentration steps that could have 

amplified several minor metabolites (see Section 2.2.5).
9/25/13 RoC Monograph on 1-Bromopropane 

20

Figure 2-1. 1-Bromopropane metabolism in male F344 rats and B6C3F1 mice 

following inhalation exposure 

Source: Garner et al. 2007, Garner et al. 2006. Structure in brackets is a proposed intermediate and was not 

isolated. FMO = flavin-containing monooxygenase, GSH = glutathione, P450 = cytochrome P450. 
RoC Monograph on 1-Bromopropane 9/25/13 

21

Figure 2-2. Metabolic pathways of 1-bromopropane in male Sprague-Dawley rats 

following oral exposure 

Source: Jones and Walsh 1979. Compounds enclosed in brackets were not isolated from the urine. 

Pathway 1: direct conjugation with glutathione; Pathway 2: oxidation at C3 to 3-bromo-1-propanol; 

Pathway 3: oxidation at C1 to n-propanol and then to CO2; Pathway 4: formation of N-acetyl-S-(2-

hydroxypropyl)cysteine. 

Possible reactive metabolites identified in these studies of 1-bromopropane metabolism 

include glycidol, -bromohydrin, and propylene oxide (1,2-epoxypropane). Glycidol was 

identified in urine samples but not quantified by Ishidao et al. (2002) as a metabolite 

resulting from exposure of rats to 1-bromopropane by inhalation. Walsh and Jones (1977) 

did not detect glycidol in rats given an i.p. injection but proposed that it was a likely 

intermediate in formation of the urinary metabolite 2,3-dihydroxypropylmercapturic acid. 

Garner et al. (2007) identified -bromohydrin as a metabolite. Propylene oxide was 

proposed as a likely metabolite by Ishidao et al. (2002) and by Jones and Walsh (1979), 

but neither group detected it in their studies. The genotoxicity and potential 

carcinogenicity of glycidol, -bromohydrin, and propylene oxide are discussed in Section 

5. 

2.2.3 In vitro studies 

Several debrominated metabolites of 1-bromopropane were identified only in studies in 

vitro using rat liver microsomes (see Table 2-1). Three metabolites of 1-bromopropane –

propene, 1,2-propanediol, and propionic acid – were identified from the in vitro P450-

catalyzed metabolism of 1-bromopropane by phenobarbital-induced rat liver microsomes; 
9/25/13 RoC Monograph on 1-Bromopropane

22

when exogenous glutathione was added to the incubation mixture, S-(1'-

propyl)glutathione and S-(2'-hydroxy-1'-propyl)glutathione were detected (Tachizawa et 

al. 1982). In another in vitro metabolism study of 1-bromopropane by rat liver 

microsomes reported by Kaneko et al. (1997) only n-propyl alcohol was reported as a 

metabolite, but the authors noted that differences between the rate of substrate 

disappearance and product formation suggested that there might be other metabolic 

pathways.

Jones and Walsh (1979) also conducted an in vitro metabolism study of 1-bromopropane. 

Oxidation of carbons 2 and 3 (C2 and C3) of 1-bromopropane was demonstrated in vitro. 

Metabolites oxidized at C3 included 3-bromopropionate and 3-hydroxypropionate. 

Evidence for C2 oxidation (i.e., formation of 1-bromo-2-propanol) was provided by the 

isolation of S-(2-hydroxypropyl)cysteine from the reaction mixture after it was reacted 

with cysteine in sodium hydroxide. 

2.2.4 Studies of metabolizing enzymes

It is clear from the available studies that most of the metabolites of 1-bromopropane are 

formed following oxidation reactions and glutathione conjugation. The proportion of 

1-bromopropane metabolized via oxidation relative to pathways dependent on direct 

glutathione conjugation was inversely proportional to dose in rats but independent of 

dose in mice (Garner et al. 2006). Garner et al. concluded that formation of AcPrCys 

results from release of a bromide ion without oxidation. Barnsley et al. (1966) also 

postulated formation of S-n-propylglutathione directly from 1-bromopropane with 

subsequent formation of S-n-propylcysteine and AcPrCys.

The importance of the cytochromes P450 (CYP) oxidative enzymes in the metabolism of 

1-bromopropane has been confirmed by the severe reduction in formation of metabolites 

when NADPH was eliminated from the incubation mixture with phenobarbital-induced 

rat liver microsomes, effectively inactivating CYP oxidation (Tachizawa et al. 1982). 

Pretreatment of rats with 1-aminobenzotriazole (ABT), a general inhibitor of CYP,

significantly reduced the number of metabolites from 10 to 1 major metabolite, AcPrCys,

which accounted for more than 90% of the total radioactivity (Garner et al. 2006). 

Results from a study on the induction of liver CYP isozymes in male and female 

Sprague-Dawley rats exposed to 1-bromopropane indicated that the expression of the 

CYP2E1 isozyme was enhanced while the signals for the other isozymes (CYP1A/2 and 

CYP2B1/2) were not, suggesting that CYP2E1 is possibly responsible for 

1-bromopropane metabolism (Kim et al. 1999b). Further evidence for the specific 

contribution of CYP2E1 to metabolism of 1-bromopropane was provided by studies with 

Cyp2e1-/-knockout and wild-type mice (Garner et al. 2007). Compared with wild-type 

mice exposed to 1-bromopropane by inhalation for 6 hours, the elimination half-life was 

more than twice as long in knockout mice (3.2 vs. 1.3 hours) exposed in the same way. In 

addition, the ratio of glutathione conjugation to 2-hydroxylation increased 5-fold, and the 

urinary concentration of N-acetyl-S-(2-hydroxypropyl)cysteine was reduced by about 

50%. These data indicate that CYP2E1 is responsible for much, but not all, of the 

oxidative metabolism of 1-bromopropane since hydroxylated metabolites were 

significantly decreased, but not completely eliminated, in knockout mice.
RoC Monograph on 1-Bromopropane 9/25/13

23

The role of glutathione conjugation was also investigated using DL-buthionine(S,R)-

sulfoximine 1-aminobenzotriazole (BSO), an inhibitor of GSH synthesis (Garner et al.

2006). Pretreatment with BSO did not significantly alter the metabolite profile for 

1-bromopropane, although there was a moderate decrease in the level of AcPrCys with a 

concomitant increase in other metabolites compared with rats that were exposed to 

1-bromopropane alone. The authors suggested that direct conjugation of 1-bromopropane 

might be a relatively minor pathway compared with oxidative metabolism in mammals.

2.2.5 Differences in metabolic pathways

Differences exist for the metabolites and metabolic pathways identified by various 

researchers. Possible explanations for these differences include the route of exposure, the 

location of the radiolabel, and other potential factors as discussed below.

The study by Jones and Walsh (1979) identified two mercapturic acid conjugates derived 

from metabolites oxidized at the C3 position (3-bromo-1-propanol and 3-bromopropionic 

acid) that were not detected in other studies. Jones and Walsh confirmed formation of 

these molecules using Udenfriend’s reagent (a mixture of iron, citric acid, EDTA, and 

oxygen) to oxidize 1-bromopropane in vitro; these conditions might have been too harsh 

and could reflect more of a chemical reaction than an in vitro metabolism study. In 

addition, Garner et al. (2006) proposed that Jones and Walsh (1979) might have 

artificially amplified these metabolites by pooling, acidifying, and concentrating a large 

volume of urine prior to analysis. Garner et al. (2006) also noted differences with the in 

vitro study of Tachizawa et al. (1982) (see Section 2.2.3). In vitro metabolism of 

1-bromopropane by hepatic microsomes from phenobarbital-induced rats produced 

propene, 1,2-propanediol, and propionic acid; S-(1'-propyl)glutathione and S-(2'-hydroxy1'-propyl)glutathione were detected when glutathione was added to the incubation 

mixture. However, none of these metabolites was detected in rat liver homogenate 

incubations or in experimental animal models. Garner et al. speculated that the use of 

phenobarbital as an inducer of CYP by Tachizawa et al. might have produced metabolites 

that are not normally generated by constitutively expressed CYPs.

The studies discussed here also reported large differences in the amounts of 

1-bromopropane exhaled as CO2. The reason for this apparent discrepancy is unclear but 

may be attributed to the particular carbon atom that was radiolabeled. Jones and Walsh 

(1979) concluded that oxidation of 1-bromopropane at the C1 position with subsequent 

oxidation to propionate and decarboxylation to CO2 was insignificant in vivo. However, 

Garner et al. (2007, 2006) concluded that a large portion of the administered dose was 

converted to CO2 regardless of the exposure route and that 1-bromo-2-propanol was the 

ultimate source of CO2 (via oxidation to bromoacetone, pyruvaldehyde, and pyruvate). 

This was supported by a significant drop in exhaled CO2 in rats pretreated with the CYP

inhibitor ABT and by a previous study (Bond et al. 1988) that reported that about 65% of 

an analogous molecule, 1-chloro-2-propanol, administered to rats was excreted as CO2. 

Bond et al. (1988) demonstrated that about 30% of the CO2 originated from C3 and about 

35% originated from C2.
9/25/13 RoC Monograph on 1-Bromopropane

24

2.3 Synthesis and summary

Studies in humans and laboratory animals indicate that 1-bromopropane can be absorbed 

following inhalation, ingestion, or dermal exposure. Occupational exposure occurs 

primarily by inhalation and dermal contact and studies of workers show a good 

correlation between urinary concentrations of 1-bromopropane, bromide ion, and 

N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys) with their 1-bromopropane breathing zone 

air concentrations. Several studies have monitored urine and blood samples in workers to 

establish biomarkers of exposure. These studies also indicate that unmetabolized 

1-bromopropane is excreted in the urine in humans but has not been reported in animal 

studies. The four urinary mercapturic conjugates identified from 1-bromopropane–

exposed workers have also been reported as urinary metabolites from studies in rodents, 

including AcPrCys, N-acetyl-S-(n-propyl)-L-cysteine-S-oxide, N-acetyl-S-(2-

carboxyethyl)-L-cysteine, and N-acetyl-S-(3-hydroxy-n-propyl)-L-cysteine. The oxidative 

metabolites that likely lead to the conjugates have not been reported in human studies; 

however, no publications were identified that actually tested for them. 

Experimental animal studies have shown that 1-bromopropane is absorbed, rapidly 

distributed, and predominantly eliminated by exhalation (approximately 40% to 70%), 

but is also excreted in the urine and feces. In rats and mice, most of the 1-bromopropane 

administered by i.v. injection was exhaled unchanged or as CO2 within 4 hours of 

exposure. Urinary metabolites accounted for 13% to 23% of the administered dose after 

48 hours. The available studies on 1-bromopropane metabolism show that CYP-catalyzed 

oxidation (primarily via CYP2E1) reactions and glutathione conjugation are the primary 

metabolic pathways. At least 16 urinary metabolites have been identified in rodent 

studies (either rats or mice), including several reactive intermediate metabolites 

(bromoacetone, glycidol, and -bromohydrin). 
RoC Monograph on 1-Bromopropane 9/25/13

25

3 Human Cancer Studies

No epidemiological studies or case reports were identified that evaluated the relationship 

between human cancer and exposure specifically to 1-bromopropane.
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RoC Monograph on 1-Bromopropane 9/25/13

27

4 Studies of Cancer in Experimental Animals

This section reviews and assesses the carcinogenicity studies in experimental animals 

exposed to 1-bromopropane. These studies were identified by searching databases, 

comprehensive reviews, and citations from studies retrieved from the literature searches 

as described in Appendix A. Identified citations were reviewed using exclusion and 

inclusion criteria that limited selection of the studies to those examining neoplastic 

lesions, non-neoplastic or preneoplastic lesions relevant to carcinogenicity, or subchronic 

studies that provide information on dose selection. Chronic (2-year) inhalation studies 

conducted by NTP and the associated subchronic (90-day) studies in mice and rats were 

the only studies identified that examined tissues for neoplastic or preneoplastic endpoints. 

The characteristics, methodology, and relevant non-neoplastic findings from the chronic 

studies by NTP and the associated subchronic studies are reported in Section 4.1. An 

assessment of the evidence for carcinogenicity is discussed in Section 4.2 and the 

recommendation for the level of evidence is provided in Section 4.3. 

4.1 Studies in experimental animals: characteristics, methodology, and relevant 

non-neoplastic findings 

Both the subchronic and chronic studies in rats and mice were conducted in the same 

facility using 1-bromopropane with purity greater than 99% and the same animal

husbandry and testing procedures as in the chronic study under FDA Good Laboratory 

Practice regulations (NTP 2011a). The subchronic studies in rats and mice were used to 

determine the exposure groups in the chronic study. B6C3F1 mice or F344/N rats were 

administered 1-bromopropane (99% pure) by whole-body exposure in inhalation 

chambers for 6 hours and 10 minutes per day, 5 days a week, for either 14 weeks 

(subchronic studies, 10 males and 10 females per exposure group) or 105 weeks (chronic 

studies, 50 males and 50 females per exposure group), with controls exposed to filtered 

air only. (Note: The additional 10 minutes of exposure were based on experimental data 

for the time required to achieve 90% of the target concentration [T90] after the beginning 

of vapor generation.) Complete necropsies and histopathology were performed on all 

animals. At necropsy, all organs and tissues were examined for grossly visible lesions, 

and all major tissues were processed and stained for histopathologic examination. 

4.1.1 Rats

Subchronic study

The subchronic study did not identify any neoplastic lesions at the exposure levels tested 

(0, 62.5, 125, 250, 500, or 1,000 ppm). Male rats exposed to 1,000 ppm had reduced body 

weight compared with controls; rats had evidence of hepatotoxicity at this dose. Sorbitol 

dehydrogenase activity was increased at 500 ppm (males only) and 1,000 ppm (males and 

females). Liver weight and cytoplasmic vacuolization were increased at 250 ppm or 

greater exposures in males. In females, liver weight increased at 125 ppm or greater, liver 

vacuolization at 500 ppm or greater, and hepatocyte degeneration was observed at 1,000 

ppm. During selection of the maximum level of exposure for the chronic study, liver

vacuolization was considered a tolerable toxicity and not life threatening, while 

hepatocyte degeneration was considered intolerable. 
9/25/13 RoC Monograph on 1-Bromopropane

28

Chronic study

Fischer 344/N rats were exposed to 0, 125, 250, and 500 ppm of 1-bromopropane based 

on decreased body weights and increased incidences of liver lesions at 1000 ppm 

reported in the subchronic study. During the chronic study, survival in males was 

significantly decreased in the group exposed to 500 ppm, and survival decreased with 

increasing level of exposure (statistically significant negative trend). Survival in females 

was not significantly decreased in a pair-wise analysis for any exposure level, but there 

was a statistically significant negative trend with the level of exposure. Body weights of 

exposed males and females were similar to those of controls.

No neoplastic lesions were found in the respiratory tract, but several non-neoplastic 

lesions, including inflammation, hyperplasia, and metaplasia were found in the upper

respiratory tract of both sexes of rats. Hyperplasia of the respiratory epithelium was 

found at significantly increased incidences in the nasal cavity of females at 125 and 500 

ppm and in the trachea of females at 500 ppm. Hyperplasia of glands in the nasal cavity, 

mostly in level II, was at a significantly increased incidence in both sexes in all exposed 

groups of rats. Significant increases in the incidences of metaplasia in females were

found in the nasal cavity as olfactory epithelium with morphology of respiratory 

epithelium at 500 ppm and in the larynx as squamous metaplasia at 500 ppm. Chronic 

suppurative inflammation of the nasal cavity had a significantly increased incidence in 

males and females at 500 ppm. Despite the high incidence of chronic active inflammation 

seen in untreated controls, the incidences of this non-neoplastic lesion were significantly

increased in the nasal cavity of females at all exposure levels, in the larynx of males at 

250 ppm and of females at 250 and 500 ppm, as well as in the trachea of females at 500 

ppm. Abscesses on the tail, Harderian gland, head, and salivary gland of five exposed rats 

were tested for bacterial growth under anaerobic and aerobic conditions. Pseudomonas 

aeruginosa was the primary isolate (4 out of 5 sites) in all aerobic cultures and 

Splendore-Hoeppli bodies were later observed microscopically in these lesions (see

discussion in Appendix E, “Immunotoxicity”). Although inflammation and infections 

were associated with immunosuppression in rats, it was not noted in the Technical Report

(NTP 2011a) whether the abscesses were directly associated with tumors. No evidence of 

suppurative inflammation was reported in the mouse study, although mice were also 

immunosuppressed after subchronic 1-bromopropane exposure.

4.1.2 Mice

Subchronic study

The NTP subchronic study did not identify any neoplastic lesions at the exposure levels

tested (0, 62.5, 125, 250, 500 ppm). Survival (number surviving/number at study start) 

was decreased in the high-dose female (5/10) and male (6/10) groups and one death at 

250 ppm in males (9/10). There was an increase in kidney, liver, and lung weights in the 

500-ppm female group, and the kidney weights of the 500-ppm male group were 

decreased.

Chronic study

Based on mortality at the highest exposure concentration, changes in organ weights, and

the incidences of various non-neoplastic lesions in the subchronic study, 1-bromopropane 
RoC Monograph on 1-Bromopropane 9/25/13

29

exposure concentrations selected for the chronic inhalation study in mice were 62.5, 125, 

and 250 ppm. During the chronic study, survival and body weights of both sexes in 

exposed groups were similar to those in control groups.

4.2 Assessment of neoplastic findings

The chronic inhalation studies in B6C3F1 mice and Fischer 344/N rats conducted by NTP 

were of sufficient duration to adequately assess the carcinogenic potential of 

1-bromopropane. Factors considered in study design were the number of animals per 

exposure group, exposure period, dose selection, monitoring of animal health, and 

complete necropsies of all animals and histopathologic examination of all major tissues. 

This study is considered a high quality study and provides strong evidence to support the 

cancer assessment. Details of study quality criteria and assessment are found in Appendix 

C. Important factors taken into account in data assessment are the significance of the 

effect as compared with the concurrent control (pairwise comparison), whether there is a 

change in the effect with dose (trend analysis), and the rarity of the event (historical 

control range). In the NTP assessments of experimental animal data in this report, a 

Poly-3 trend analysis is employed, which is similar to the Cochran-Armitage trend test 

but is survival adjusted.

In rats, there was a significantly increased incidence with a positive trend for benign 

tumors (adenoma) of the large intestine (colon or rectum) in females, but the incidence 

did not reach significance for male rats (Table 4-1). However, these are rare tumors and 

the tumor incidence exceeded the historical control range for male and female rats for 

inhalation studies and studies by all exposure routes and are considered to be of 

biological significance. (An adenomatous polyp was listed for a male rat exposed to 125-

ppm 1-bromopropane [see Appendix Table A1 of the NTP Technical Report 564, NTP 

2011a] but was not included in the data analysis conducted by the authors. Addition of 

this tumor increases the total number of benign tumors of the large intestine in all 1-

bromopropane–exposed male rats from 3 to 4 tumors, which provides additional support 

for an exposure-related effect.) The time to first incidence of tumors of the colon or 

rectum was lower with increasing dose in male rats (729 days at 250 ppm and 682 days at 

500 ppm); but no clear trend was seen with increasing dose for female rats (730 days at 

125 ppm, 607 days at 250 ppm, and 719 days at 500 ppm). Spontaneous adenoma of the 

large intestine is rare in male and female rats, occurring at a rate of less than 0.2%. 

Increased incidences of adenocarcinoma of the large intestine were observed in both male 

and female rats after oral treatment with brominated methanes (bromodichloromethane or 

tribromomethane (NTP 1987, 1989) and in male rats after treatment with glycidol (NTP 

1990), a metabolite of 1-bromopropane. Therefore, the findings of intestinal tumors after 

1-bromopropane exposure are considered to be exposure related. Although no carcinomas 

of the large intestine were observed in male or female rats in the current study, adenoma 

of the large intestine can progress to carcinoma (NTP 2011a).
9/25/13 RoC Monograph on 1-Bromopropane

30

Table 4-1. Large intestine tumors observed in Fischer 344/N rats exposed to

1-bromopropane by inhalation for 2 years 

Sex

Conc. 

(ppm)

Number of rats 

surviving to 

study 

termination

Large intestine tumor (adenoma) (% incidence)

Colon Rectum

Colon or rectum 

combined

Male 0

125

250

500

trend+

23

26

18

 13*

P = 0.009d

0/50 (0)

0/50 (0)

0/50 (0)

1/50 (2)

NR

0/50 (0)

0/50 (0)c

2/50 (4)

0/50 (0)

NR

0/50 (0.0)a,b

0/50 (0.0)

2/50 (5.3)

1/50 (2.8)

P = 0.197

Female 0

125

250

500

trend+

34

33

30

24

P = 0.028d

0/50 (0)

1/50 (2)

1/50 (2)

1/50 (2)

NR

0/50 (0)

0/50 (0)

1/50 (2)

4/50 (8)

NR

0/50 (0.0)a,b

1/50 (2.3)

2/50 (4.7)

5/50 (13.3)*

P = 0.004

Source: NTP 2011a.

NR = not reported.

*P ≤ 0.05 (compared with concurrent controls by Poly-3 test for tumor incidence or life-table pairwise 

comparisons for survival).

+Determined by Poly-3 trend test.

aNumber of animals with tumors; (Poly-3 estimated tumor incidence percent after adjustment for 

intercurrent mortality).

bHistorical control range: 0% for inhalation studies and 0%–2% for studies by all routes.

cAppendix Table A1 of the NTP Technical Report (TR 564) indicated that an adenomatous polyp was 

observed at this treatment dose, but the polyp was not included in the data analysis (see TR 569 [NTP 

2011a], Table 9).

d

Survival analysis performed by life-table trend test.

Male rats had a significant increase in the incidence of malignant or benign skin tumors 

(keratoacanthoma; keratoacanthoma or squamous-cell carcinoma combined; and 

keratoacanthoma, squamous-cell carcinoma, basal-cell adenoma, or basal-cell carcinoma 

combined) as well as significant positive trends for these three groups of skin tumors

(Table 4-2). These effects are also considered to be exposure related. Female rats had a 

significant positive trend for keratoacanthoma, squamous-cell papilloma, basal-cell 

adenoma, or basal-cell carcinoma combined, with the high-dose group (500 ppm) outside 

of the historical control range for inhalation studies and studies by all exposure routes, so 

these combined skin tumors may be exposure related. Keratoacanthomas also occurred in 

females, but the incidences were not increased compared with the concurrent or historical 

controls. Keratoacanthomas can progress to squamous-cell carcinoma, a malignant 

tumor; however, no squamous cell-carcinomas were identified in female rats.
RoC Monograph on 1-Bromopropane 9/25/13

31

Table 4-2. Skin tumors observed in Fischer 344/N rats exposed to 1-bromopropane 

by inhalation for 2 years 

Sex

Conc. 

(ppm)

Number of 

rats 

surviving to 

study 

termination

Skin tumors (% incidence )a 

KA 

KA or SCC 

combined

KA, SCC, 

BCA or BCC 

combined 

KA, SCP, 

BCA, or 

BCC 

combined

Male 0

125

250

500

trend+

23

26

18

 13*

P = 0.009d

0/50 (0.0)b

3/50 (7.4)

6/50 (15.4)*

6/50 (16.2)**

P = 0.008

1/50 (2.4)b

4/50 (9.8)

6/50 (15.4)*

8/50 (21.4)**

P =0.006

1/50 (2.4)c

7/50 (17.0)*

9/50 (22.6)**

10/50 (26.7)**

P = 0.003

NR

Female 0

125

250

500

trend+

34

33

30

24

P = 0.028d

1/50 (2)e,g

0/50 (0)

1/50 (2)

1/50 (2)

NR

1/50 (2)g

0/50 (0)

1/50 (2)

1/50 (2)

NR

1/50 (2)f,g

1/50 (2)

1/50 (2)

3/50 (6)

NR

1/50 (2.2)f

1/50 (2.3)

1/50 (2.4)

4/50 (10.6)

P = 0.05

Source: NTP 2011a.

BCA = basal-cell adenoma, BCC = basal-cell carcinoma, KA = keratoacanthoma, NR = not reported, 

NS = not significant, SCA = squamous-cell papilloma, SCC = squamous-cell carcinoma.

*P ≤ 0.05, **P ≤ 0.01 (compared with concurrent controls by Poly-3 test).

+Determined by Poly-3 trend test.

aNumber of animals with tumors (Poly-3 estimated tumor incidence percent after adjustment for 

intercurrent mortality).

bHistorical control range: 0%–8% for inhalation studies and 0%–16% for studies by all routes.

cHistorical control range: 0%–10% for inhalation studies and 0%–20% for studies by all routes.

d

Survival analysis performed by life table trend test.

eHistorical control range: 0%–2% for inhalation studies and 0%–4% for studies by all routes.

fHistorical control range: 0%–2% for inhalation studies and 0%–6% for studies by all routes.

g

Percent incidence is overall rate (non-Poly-3 adjusted).

Male rats had a significant positive trend of malignant mesothelioma (tunica vaginalis of 

the epididymis) with a significant increase in tumor incidence at the high dose that was 

slightly greater (10.8%) than the historical control range (0% to 6%) for inhalation 

studies and studies by all exposure routes (Table 4-3). Therefore, these results may be 

exposure related. A significant increase was also observed in the incidence of malignant 

or benign pancreatic islet-cell tumors (adenoma and adenoma or carcinoma combined)

for all exposure groups for adenoma and for 125 ppm and 250 ppm for adenoma and 

carcinoma combined in male rats; the incidence of adenoma and carcinoma was increased 

(but not statistically significant) at the highest exposure level (500 ppm). Although the 

tumor incidences were within the historical control range for inhalation studies and 

studies by all exposure routes, there was a significant positive trend for benign pancreatic 

islet-cell tumors (adenoma) suggesting that the tumors may have been caused by 

1-bromopropane exposure. No exposure-related response of pancreatic islet-cell tumors 

was observed in female rats. 
9/25/13 RoC Monograph on 1-Bromopropane

32

Table 4-3. Malignant mesotheliomas and pancreatic islet-cell tumors observed in 

Fischer 344/N rats exposed to 1-bromopropane by inhalation for 2 years 

Sex

Conc. 

(ppm)

Number of 

rats 

surviving to 

study 

termination

Malignant 

mesothelioma

(% incidence )a,b

Pancreatic islet cell tumor

(% incidence)b

Adenoma Carcinoma

Adenoma

or 

carcinoma 

combined

Male 0

125

250

500

trend+

23

26

18

 13*

P = 0.009g

0/50 (0.0)c

2/50 (4.9)

2/50 (5.2)

4/50 (10.8)*

P = 0.031

0/50 (0.0)d

5/50 (12.2)*

4/50 (10.4)*

5/50 (13.9)*

P = 0.043

3/50 (7.2)e

7/50 (17.0)

5/50 (13.0)

3/50 (8.3)

P = 0.0516N

3/50 (7.2)f

10/50 (24.2)*

9/50 (23.1)*

8/50 (22.2)

P = 0.093

Female 0

125

250

500

trend+

34

33

30

24

P = 0.028g

NR 0/50 (0)h,i

2/50 (4)

1/50 (2)

0/50 (0)

NR

1/50 (2)g,h

1/50 (2)

1/50 (2)

0/50 (0)

NR

1/50 (2.2)f

3/50 (6.9)

2/50 (4.7)

0/50 (0.0)

P = 0.537N

Source: NTP 2011a.

N = negative trend, NR = not reported.

*P ≤ 0.05 (compared with concurrent controls by Poly-3 test).

+Determined by Poly-3 trend test.

aEpididymis in all affected animals with other tissues variably affected.

b

Percentage reported as the adjusted rate, which takes into account the survival rate and is calculated during 

the Poly-3 test analysis.

cHistorical control ranges for inhalation studies and studies by all routes are 0%–6%.

dHistorical control range: 0%–12% for inhalation studies and 0%–14% for studies by all routes.

eHistorical control range: 2%–10% for inhalation studies and 0%–10% for studies by all routes.

fHistorical control range: 6%–18% for inhalation studies and 0%–18% for studies by all routes.

g

Survival analysis performed by life table trend test.

hHistorical control range: not reported for inhalation studies and studies by all routes.

i

Percentage reported as the overall incidence rate (non-Poly-3 adjusted). 

In female mice, there were significantly increased incidences of benign and malignant 

lung tumors (alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, and 

combined) with positive dose-response trends for benign lung tumors 

(alveolar/bronchiolar adenoma) and combined groups. Some females in the 250-ppm 

group had multiple adenomas and some females in all of the exposed groups had multiple 

carcinomas. Based on positive pairwise comparisons, positive trend data for adenoma and 

highly significant trend data for combined, and tumor incidences outside of historical 

control ranges, these results are considered to be exposure related. There was no evidence 

of neoplastic lesions in male mice (Table 4-4).
RoC Monograph on 1-Bromopropane 9/25/13

33

Table 4-4. Lung tumors observed in B6C3F1 mice exposed to 1-bromopropane by 

inhalation for 2 years 

Sex Conc. (ppm)

Number of 

mice surviving 

to study 

termination

Lung tumors (% incidence )a

Alveolar/

bronchiolar 

adenoma

Alveolar/

bronchiolar 

carcinoma

Combined

Male 0

62.5

125

250

trend+

37

33

32

36

P = 0.934d

6/50 (13.3)

c

5/50 (11.5)

4/49 (9.0)

5/49 (11.9)

b

P = 0.476N

8/50 (17.8)

c

7/50 (15.9)

b

10/49 (22.0)

b

10/49 (24.3)

b

P = 0.209

13/50 (28.3)

c

12/50 (27.3)

14/49 (30.8)

15/49 (35.7)

P = 0.225

Female 0

62.5

125

250

trend+

36

40

37

42

P = 0.363Nd

1/50 (2.2)

e

6/50 (12.8)

4/50 (8.9)

10/50 (20.8)**

P = 0.007

0/50 (0)f

7/50 (14.9)**

5/50 (11.1)*

4/50 (8.5)

P = 0.277

1/50 (2.2)

g

9/50 (19.2)**

8/50 (17.8)*

14/50 (29.2)***

P < 0.001

Source: NTP 2011a.

N = negative trend.

*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 (compared with concurrent controls by Poly-3 test).

+Trend of tumor incidence compared with the overall change in exposure levels by Poly-3 trend test.

aNumber of animals with tumors (includes multiple) (Poly-3 estimated neoplasm incidence percentage after 

adjustment for intercurrent mortality).

b

Incidence of mice with multiple lung tumors - adenoma: 0/50, 0/50, 0/50, 2/49 and carcinoma: 0/50, 2/50, 

1/50, 1/50.

cHistorical control range: not reported for inhalation studies and studies by all routes.

d

Survival analysis performed by life table trend test.

eHistorical control range: 2%–12% for inhalation studies and 0%–12% for studies by all routes.

fHistorical control range: 0%–6% for inhalation studies and 0%–12% for studies by all routes.

gHistorical control range: 2%–12% for inhalation studies and 2%–18% for studies by all routes.

As mentioned in Section 4.1.1, an inflammatory response was observed in rats, which 

could potentially be related to tumor development; however, the inflammatory response 

did not correlate with tumorigenicity. Chronic active and chronic suppurative 

inflammation were observed in the respiratory tract of both sexes of rats; however, 

incidences of lung and nasal tumors were not increased. In contrast, 1-bromopropane did 

cause lung tumors in male mice, but no chronic suppurative or chronic active 

inflammation of the respiratory tract was reported for either male or female mice. 

4.3 NTP level of evidence conclusion

These data meet the Report on Carcinogens criteria for sufficient evidence of 

carcinogenicity in experimental animals based on an increased incidence of tumors in rats 

and mice, at multiple tissue sites, and the occurrence of rare tumors. This conclusion is 

based on exposure-related neoplastic lesions in the skin of male rats, large intestines of 

male and female rats, and lung of female mice.
9/25/13 RoC Monograph on 1-Bromopropane

34

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RoC Monograph on 1-Bromopropane 9/25/13

35

5 Mechanistic Data and Other Relevant Effects

The purpose of this section is to review data that are relevant for identifying and 

evaluating the potential mechanisms of action for the carcinogenic effects discussed in 

Section 4. Data reviewed in this section include the following: (1) genetic and related 

effects (Section 5.1 with data tables in Appendix D), (2) relevant toxicological effects

(Section 5.2 and Appendix E), (3) mechanistic considerations (Section 5.3), and (4) 

carcinogenic effects of metabolites and analogues (Section 5.4). 

5.1 Genetic and related effects

1-Bromopropane has been tested in several short-term assays to evaluate potential 

induction of mutagenic or other genotoxic effects. The database of genotoxicity studies 

includes DNA and protein adducts (Section 5.1.1) in vitro studies in bacteria (Section 

5.1.2) and in mammalian cells (Section 5.1.3), and in vivo studies in rodents (Section 

5.1.4) and in 1-bromopropane–exposed workers (Section 5.1.5). Genotoxicity studies are 

also available on some metabolites of 1-bromopropane (Section 5.1.6). An overall 

assessment of the genotoxicity of 1-bromopropane is presented in the final section 

(Section 5.1.7). Data tables for genotoxicity studies discussed in Section 5.1 are provided 

in Appendix D.

5.1.1 DNA and protein adducts 

No published data were identified for 1-bromopropane DNA adducts. However, DNA 

adducts are formed by some 1-bromopropane metabolites (see Section 5.1.5), and the 

N

7

-guanine DNA adduct was formed when 2-bromopropane was incubated with 2'-

deoxyguanosine (Zhao et al. 2002) (see Section 5.4.2).

Although no in vivo studies of 1-bromopropane DNA adducts were identified,

1-bromopropane can form covalent adducts with protein in vivo (binding to sulfhydryl 

groups). One study measured S-propylcysteine (PrCys) adducts with globin and 

neurofilaments in rats after inhalation exposure (Valentine et al. 2007). Rats exposed to 

1-bromopropane for two weeks at 0 to 800 ppm had a statistically significant linear dose 

response for PrCys globin and neurofilament adducts; exposure to 50 ppm for 8 

hours/day, 5 days/week for 4 weeks produced a linear accumulation of PrCys globin 

adducts. Although there are very few data, DNA and protein adducts could be involved in 

1-bromopropane–induced toxicity and carcinogenicity (see Section 5.3).

Valentine et al. (2007) measured S-propylcysteine globin adducts in 26 female factory 

workers in China who were exposed to 1-bromopropane by inhalation and possibly by 

skin contact. Controls were age-matched workers from a Chinese beer factory. Exposure 

to 1-bromopropane was assessed via individual “passive” (diffusion) samplers, and 

exposure levels ranged from 0.34 to 49.2 ppm for the workers who gave blood samples 

and 0 to 170.54 ppm for the workers who gave urine samples. There was a significant 

increase in the S-propylcysteine adducts measured in the globin of exposed workers (1.52 

pmol/mg globin) over controls (0.11 pmol/mg globin). The level of urinary N-acetyl-S-

(n-propyl)-L-cysteine (AcPrCys) increased with increasing exposure concentrations. 
9/25/13 RoC Monograph on 1-Bromopropane

36

5.1.2 In vitro studies in bacteria

1-Bromopropane has been tested in vitro to evaluate mutagenic effects in bacterial strains

of Salmonella typhimurium and Escherichia coli. Results of the mutagenicity studies of 

1-bromopropane in bacteria are summarized in Appendix D, Table D-1.

1-Bromopropane was reported to be mutagenic in a dose-dependent manner in two tester 

strains: TA100 and TA1535, when the S. typhimurium assay was modified by using a 

closed chamber specifically designed for testing volatile substances (Barber et al. 1981). 

In this study, the authors compared the mutagenic potency of 10 volatile halogenated

alkane solvents in the standard assay versus a closed-chamber assay. They reported that 

while only 2 of the solvents were positive in the standard assay (1-bromopropane was 

negative), 7 of the 10 substances, including 1-bromopropane, were positive in the closed 

system. In the closed-system assay, results were similar both in the absence and presence 

of metabolic activation (S9), indicating that 1-bromopropane is a direct-acting mutagen. 

In standard test assays, in two independent laboratories, 1-bromopropane was reported to 

be non-mutagenic at doses tested up to 3,333 μg/plate; higher doses (to 10,000 μg/plate) 

were tested but were too toxic to evaluate (NTP 2011a). In addition, there were no 

mutagenic effects with S9 (prepared from Aroclor 1254-induced livers of rat or hamster) 

metabolic activation added to the culture at 10% or 30%. These studies were conducted 

in an open system, so the volatility of 1-bromopropane could have lowered the amount 

that the bacteria were exposed to. The observation of toxicity at high treatment doses 

indicated that exposure to 1-bromopropane did, in fact, occur, but it is unclear what the 

actual exposure levels were to the bacteria. The Barber study reported mutagenicity at 

lower doses using a modified closed system protocol; the treatment concentration was 

determined by using gas chromatography to measure 1-bromopropane in water placed in 

the chamber rather than by the amount of chemical added to the culture plate. This study 

also reported mutagenic effects for several other volatile substances that were previously 

reported as non-mutagenic when tested in the standard protocol bacterial assay.

1-Bromopropane was not mutagenic in S. typhimurium in several strains, both with and 

without S9, in two unpublished studies reviewed in NTP 2003 (Elf Atochem 1994, Kim

et al. 1998). The NTP description of the Elf Atochem study noted that the cultures were 

incubated in closed stainless steel chambers but other important details, such as protocol 

modifications for sample preparation and treatment with a volatile substance, were not 

specified. In addition, other specific details were not provided in the NTP review of these 

studies (e.g., numbers of revertant colonies in either study, as well as cytotoxicity 

observations, solvent specification, and incubation conditions in the Kim et al. study), 

which makes it difficult to evaluate the discrepancy between these and the Barber et al.

study results.

In summary, the data indicate that 1-bromopropane is a direct-acting mutagen in 

S. typhimurium, because similar findings were observed both with and without the 

addition of metabolic activation, in the only reported study that used appropriate 

methodology (treatment and incubation in a closed chamber) for testing a volatile 

substance. 
RoC Monograph on 1-Bromopropane 9/25/13

37

5.1.3 In vitro studies in mammalian cells

Available in vitro studies suggest that 1-bromopropane induces mutations and DNA 

damage in mammalian cells. Two studies were identified that utilized mammalian cells in 

vitro to assess DNA damage of 1-bromopropane in human leukocytes and mutagenicity

in mouse lymphoma cells (see Appendix D, Table D-2). The comet assay showed that in 

vitro exposure to the highest dose of 1-bromopropane in human leukocytes induced an 

increase in DNA damage as measured by comet tail moment but no increase was 

observed for lower doses (Toraason et al. 2006). In the same study, the temporal response 

to high-dose 1-bromopropane treatment was assessed using the comet assay, and DNA 

damage was significantly increased after both 4- and 8-hour exposures; DNA damage 

was higher after 8 hours compared with 4 hours. Toraason et al. also reported a dosedependent increase in the percentage of apoptotic cells in 1-bromopropane–treated human 

leukocytes. 1-Bromopropane induced mutations at the thymidine kinase locus in the 

L5178Y mouse lymphoma cell assay, both with and without the addition of S9 metabolic 

activation (Elf Atochem 1996 as cited in NTP 2003a). 

5.1.4 In vivo studies in rodents 

The micronucleus assay was used to evaluate the potential effects of a three-month 

exposure of up to 500-ppm 1-bromopropane in male and female B6C3F1 mice by 

inhalation (NTP 2011a). No increases in the frequencies of micronucleated 

normochromatic erythrocytes were reported for either sex of mice. In addition, two 

unpublished studies, reviewed by NTP (2003a), also reported that micronuclei were not 

increased in mice treated by i.p. injection or in rats exposed by inhalation to 

1-bromopropane (Kim et al. 1998 and Elf Atochem 1995, both cited in NTP 2003a). (See 

Appendix D, Table D-3 for findings from in vivo studies in rodents.)

Dominant lethal mutation assays were negative in ICR mice (Yu et al. 2008) and in 

Sprague-Dawley rats (Saito-Suzuki et al. 1982) as shown in Appendix D, Table D-3. 

Male ICR mice were administered 1-bromopropane by i.p. injection while male SpragueDawley rats were given five consecutive daily doses in olive oil by oral gavage prior to 

mating with untreated females. The dominant lethal mutation assay identifies germ-cell 

mutagens by measuring a chemical’s ability to penetrate gonadal tissue and produce 

embryonic death via chromosomal breakage in parent germ cells. Limitations for 

evaluating genotoxicity using this assay are that it does not detect somatic mutations and, 

because the spontaneous mutation frequency is high, the assay may have limited 

sensitivity for detection of small increases in induced mutation frequency (Singer et al.

2006). The study in rats also tested four other structurally related halogenated 3-carbon 

compounds that have a similar structure to a known mutagen, 1,2-dibromo-3-

chloropropane (DBCP). Only 1,2,3-tribromopropane and DBCP induced dominant lethal 

mutations; the authors suggested that in order for propanes to induce dominant lethal 

mutations, they should have bromine or chlorine on each carbon atom and 2 of the 3

halogen atoms should be bromine. 

5.1.5 Studies in exposed workers

The comet assay was used to assess DNA damage (strand breaks) in peripheral blood 

leukocytes from 64 workers (18 males and 46 females) exposed occupationally to 
9/25/13 RoC Monograph on 1-Bromopropane

38

1-bromopropane (Toraason et al. 2006) at two facilities (designated as A and B) that 

utilized spray adhesives containing 1-bromopropane. There was no unexposed population 

so the workers were divided into higher-exposure (sprayer) and lower-exposure groups 

(non-sprayers) (see Appendix D, Table D-4).

In analysis by facility (A and B) and job type (sprayer and non-sprayer), no clear 

exposure-response patterns were observed. DNA damage (as measured by tail moment) 

in leukocytes from sprayers were numerically higher for both start- and end-of-workweek 

samples than non-sprayers but none of the increases were statistically significant and 

sprayers at Facility B (lower-exposure facility) had higher measures of DNA damage 

than sprayers at Facility A (higher-exposure facility) at the start, but not at the end, of the 

work week. No exposure-response patterns were observed for DNA damage as assessed 

by tail moment dispersion coefficient.

Multivariate analyses were also performed that evaluated the association between DNA 

damage (start-of-workweek and end-of-workweek comet tail moment and dispersion 

coefficients) and three 1-bromopropane exposure indices – 1-bromopropane TWA levels, 

and serum and urinary bromide concentrations – in models that controlled for gender, 

age, smoking status, facility, and two DNA polymorphisms (GSTM1 and GSTT1). For 

each of the three exposure indices, both linear regression models using log-transformed 

exposure indices and exposure quartiles analyses were performed. Both start-ofworkweek and end-of-workweek comet tail moments in leukocytes were significantly 

associated with serum bromide quartiles; end-of-workweek values were also significantly 

associated with 1-bromopropane TWA quartiles. Although not statistically significant, all 

of the other associations between 1-bromopropane exposure indices and DNA damage

were positive, with the exception of the end-of-workweek urinary bromide. The strengths 

of this study are that the assessment of exposure to workers was at the individual level

and that these workers were exposed to a wide range of levels of 1-bromopropane, which 

allowed for the evaluation of exposure-response relationships. Multivariate analyses were

considered to be more informative than the analysis by job and facility. Limitations to 

this study include small numbers of exposed workers, no unexposed controls, and 

multiple comparisons.

These results provided limited evidence that 1-bromopropane causes DNA damage in 

vivo. 

5.1.6 Genotoxic effects of 1-bromopropane metabolites

The genotoxic effects of several known or postulated metabolites of 1-bromopropane 

have been evaluated in numerous in vitro and in vivo studies. Two reviews by the 

International Agency for Research on Cancer (IARC) provided most of the information 

for glycidol (IARC 2000) and propylene oxide (IARC 1994) and primary studies were 

used to update or supplement this information (see Appendix D, Table D-5). 

Both glycidol (known metabolite in rats) and propylene oxide (postulated metabolite) are 

mutagenic in bacteria, yeast, Drosophila, and mammalian cells; they are direct-acting 

mutagens, as the addition of metabolic activation did not change the response. Both 

metabolites have been shown to form DNA adducts, and both induce DNA damage and 
RoC Monograph on 1-Bromopropane 9/25/13

39

chromosomal damage in vitro in rodent and human cells. Available in vivo test results for 

glycidol indicate that it induces micronucleus formation but not chromosomal aberrations 

(CA) in the mouse. Studies of propylene oxide for chromosomal damage reported 

positive responses in mouse bone marrow for micronucleus induction and chromosomal 

aberration tests, as well as DNA damage in the sister chromatid exchange (SCE) assay, 

but results with monkey lymphocytes for both CA and SCE were negative. In 

occupationally exposed propylene oxide workers, DNA damage was induced in the SCE 

assay, and both DNA and hemoglobin (protein) adducts were formed. Propylene oxide 

has also been shown to bind to DNA in rodents and to hemoglobin in rodents, dogs, and 

monkeys. Other 1-bromopropane metabolites have been shown to be direct-acting 

mutagens and to induce DNA damage in bacteria. -Bromohydrin and 3-bromo-1-

propanol were mutagenic in the S. typhimurium reversion assay, and 3-bromo-1-propanol 

and 1-bromo-2-propanol induced DNA damage in E. coli.

5.1.7 Synthesis of results

Studies in vivo show that 1-bromopropane can covalently bind to protein in exposed rats 

and occupationally exposed workers. The available data provide some support that 

1-bromopropane is genotoxic as it induced mutations in bacterial and mammalian cells 

and DNA damage in human cells. There is limited evidence that DNA damage was 

induced in leukocytes from 1-bromopropane–exposed workers. 1-Bromopropane did not 

induce chromosomal damage in exposed rodents (micronucleus induction assay) or genecell mutations (dominant lethal mutation assay).

Table 5-1. Summary of 1-bromopropane genotoxicity information

Effect In vitro

In vivo

Rodents Humans

Mutation

 Bacteria

 Mammalian cells

±

a

+ NT NT

DNA damage + NT +

Micronuclei induction NT – NT

Dominant lethal mutation NT – NT

+ = positive, ± = both positive and negative, – = negative.

NT = not tested.

a

Positive in the only study whose design was appropriate for testing volatile chemicals.

Several known or postulated metabolites of 1-bromopropane have been identified as 

mutagens and two, glycidol and propylene oxide (proposed), were shown to cause 

chromosomal and DNA damage in cultured mammalian cells. Both metabolites caused 

chromosomal damage in cells from rodents exposed in vivo, and propylene oxide induced 

DNA damage in cells from exposed workers (Table 5-2). Three other 1-bromopropane 

metabolites ( -bromohydrin, 3-bromo-1-propanol, and 1-bromo-2-propanol) were 

mutagenic or caused DNA damage in bacteria (Table 5-2).
9/25/13 RoC Monograph on 1-Bromopropane

40

Table 5-2. Summary of genotoxicity data for 1-bromopropane metabolitesa

Effect 

Metabolite In vitro (cell typeb

) In vivo (mammals)

Humans

(Epidemiology studies)

DNA adducts

Glycidol

Propylene oxide 

+ (mammal)

+

 (bacteria, mammal)

NT

+ (rodents, dogs)

NT

+

Mutation

Glycidol

Propylene oxide

-Bromohydrin

3-Bromo-1-propanol

1-Bromo-2-propanol

+

c

+

c

+

 (bacteria)

+

 (bacteria)

NT

NT

–

 (germ cell)

NT

NT

NT

NT

NT

NT

NT

NT

DNA damage

Glycidol

Propylene oxide

-Bromohydrin

3-Bromo-1-propanol

1-Bromo-2-propanol

+

d

+

d

NT

+

 (bacteria)

+

 (bacteria)

NT

NT

NT

NT

NT

NT

+

NT

NT

NT

Chromosomal damage

Glycidol

Propylene oxide

+ (mammal, human)

+ (mammal, human)

± (rodents)

+ (rodents); – (monkeys)

NT

Inc

NT = not tested; Inc = inconclusive, + = positive, – = negative, ± = positive and negative results.

aDoes not include findings from insect studies or gene conversion studies in yeast. 

b

Positive in bacteria, yeast, mammalian cells, and human cells. 

c

Positive in bacteria, yeast, and mammalian cells. 

d

Positive in bacteria, mammalian cells, and human cells. 

5.2 Relevant toxicological effects

1-Bromopropane has caused neurological, developmental, reproductive, immunological, 

and hepatotoxic effects in rodents and neurological effects in humans (Lee et al. 2007a, 

Lee et al. 2010a, Lee et al. 2010b, NTP 2003a, 2011a). Studies on toxic effects were 

reviewed (see Appendix E) to determine whether they could inform potential 

mechanisms of carcinogenicity. Several studies indicate that metabolic activation and 

glutathione depletion are important factors for many of the toxic effects observed in 

rodents. Appendix E provides a brief review of the toxic effects that have been linked to 

metabolic activation and/or glutathione depletion and oxidative stress and other 

alterations, and provides background information for Section 5.3, which discusses these 

mechanisms as they relate to carcinogenicity.

5.3 Mechanistic considerations 

The biological events associated with chemically induced cancer are not completely 

understood even for chemicals that have been extensively studied and are known to cause 

cancer in humans (e.g., benzene and arsenic) (Guyton et al. 2009). It is important to 

recognize that chemicals can act through multiple toxicity pathways and mechanisms to 

induce cancer or other health effects, and the relative importance of the various pathways 

may vary with life stage, genetic background, and dose. Thus, it is unlikely that for any 
RoC Monograph on 1-Bromopropane 9/25/13

41

chemical a single mechanism or mode of action will fully explain the multiple biological 

alterations and toxicity pathways that can cause normal cells to transform and ultimately 

form a tumor.

Although no studies were identified that were specifically designed to investigate 

possible modes of action for 1-bromopropane–induced carcinogenesis, the available data 

indicate that metabolic activation, genetic damage, and oxidative stress from glutathione 

depletion are important factors. As discussed in the previous section, these factors were 

linked to several of the primary non-neoplastic toxic effects of 1-bromopropane, 

including immunosuppression, neurotoxicity, reproductive toxicity, and hepatotoxicity.

Other factors that have been associated with carcinogenesis and may be relevant for 

1-bromopropane are discussed and include immune-response modulation, altered cell 

signaling and gene expression, inflammation, and cytotoxicity and compensatory cell 

proliferation.

5.3.1 Metabolic activation and genotoxicity

As mentioned above, there is some evidence that 1-bromopropane and its metabolites are 

mutagenic and genotoxic (see Section 5.1). Metabolism of many halogenated 

hydrocarbons results in the formation of highly reactive oxidative intermediates that can 

alkylate proteins and nucleic acids (Morgan et al. 2011). Reactive metabolites of 

1-bromopropane include bromoacetone (1-bromo-2-propanone), glycidol, propylene 

oxide (proposed), and -bromohydrin (see Section 5.1.6). Bromoacetone and other 

-bromoketones have been shown to disrupt enzymatic processes by alkylating trypsin at 

histidine residues or glutathione-S-transferases at cysteine residues (Beeley and Neurath 

1968, Mitchell et al. 1998). Garner et al. (2006) reported that rats pretreated with ABT, a 

potent inhibitor of CYP, had a 10-fold reduction in hepatic radiochemical content (4.1 to 

0.46 g equivalents per gram of tissue) suggesting that oxidative metabolism leads to 

more reactive species.

5.3.2 Oxidative stress

Oxidative stress due to cellular glutathione depletion could contribute to the 

carcinogenicity of 1-bromopropane (Morgan et al. 2011). Although no studies were 

identified that directly investigated the possible role of glutathione levels and oxidative 

stress in 1-bromopropane–induced carcinogenicity, several studies have shown evidence 

that exposure to 1-bromopropane causes toxic effects in the liver and in the reproductive 

and nervous systems of mice and rats that are associated with glutathione depletion and 

oxidative stress (Huang et al. 2011, Lee et al. 2007a, Lee et al. 2005a, Lee et al. 2005b, 

Lee et al. 2010a, Lee et al. 2007b, Lee et al. 2010b, Liu et al. 2009, Liu et al. 2010, 

Subramanian et al. 2012). A dose-dependent depletion of glutathione by 1-bromopropane 

was reported in mice (Lee et al. 2007a, b), and a role for Cyp2e1 metabolism in this 

effect was indicated by a greater depletion of glutathione in wild-type mice than in 

Cyp2e1 knockout mice (Garner et al. 2007). Oxidative stress in rodents exposed to 

1-bromopropane is consistent with dose-dependent increases in oxidative stress markers 

(ROS, RNS) in rat cerebellum (Subramanian et al. 2012), increased lipid peroxidation in 

male mice (Liu et al. 2010), and altered expression of oxidative stress genes (NQO1 and 

HO-1) in mice (Liu et al. 2009, Liu et al. 2010) (for more information, see Appendix E).
9/25/13 RoC Monograph on 1-Bromopropane

42

Glutathione conjugation is generally regarded as a detoxification mechanism (Morgan et 

al. 2011). Most of the urinary metabolites of 1-bromopropane are derived from 

glutathione conjugates, thus, chronic exposure could produce levels of metabolites that 

exceed the amount of glutathione available for conjugation. Glutathione levels also may 

be depleted by oxidative metabolites that inhibit enzymes required for glutathione 

synthesis. Liu et al. (2009) also reported lower hepatocellular glutathione-S-transferase 

(GST) activity in susceptible mouse strains exposed to 1-bromopropane. Lower GST 

activity could reduce glutathione conjugation and increase toxicity. Huang et al. (2011)

reported differential expression of several proteins in the hippocampus of rats exposed to 

1-bromopropane that support the hypothesis that oxidative stress plays a role in 

1-bromopropane–induced damage. These proteins included HSP60, GRP78, DJ-1, 

GSTA3, and GSTP1. The proteins HSP60, GRP78, GSTA3, and GSTP1 were upregulated after 1-bromopropane exposure. HSP60 is a mitochondrial matrix protein 

induced by various kinds of stresses and GRP78 is an endoplasmic reticulum-resident 

molecular chaperone that suppresses oxidative stress. GSTA3 and GSTP1 belong to a 

family of detoxification enzymes that also protect against oxidative stress. DJ-1 has been 

shown to prevent oxidative stress in age-related neurodegeneration and was downregulated after 1 week of exposure. Thus down-regulation of DJ-1 could result in 

increased oxidative stress. 

5.3.3 Immunosuppression and other factors

Immune-response modulation, cell signaling, altered gene expression, inflammation, and 

cytotoxicity and compensatory cell proliferation are other key events that have been 

associated with carcinogenesis. Recent studies have shown that 1-bromopropane causes 

immunosuppression in rodents (Anderson et al. 2010, Lee et al. 2007a, Lee et al. 2007b). 

In particular, deleterious effects on T-cell numbers and subpopulations were reported. 

Since T-cells play an important role in detecting and eliminating tumor cells, a 

compromised immune system could facilitate tumor progression (Töpfer et al. 2011).

Anderson and Rice (1987) demonstrated that athymic nude mice that do not have T-cells 

were more sensitive to skin tumorigenesis that euthymic mice. In addition, data from 

genetic, disease, and drug-induced immunosuppression in humans have consistently 

shown that immunosuppression is associated with an increased risk of skin tumors and 

certain other cancers (DePry et al. 2011, Kuschal et al. 2012, Weaver 2012). However, a 

possible role of immunosuppression in 1-bromopropane–induced skin cancer in rodents 

has not been described. 

Chronic inflammation was one of the key events associated with various carcinogenic 

modes of action (Guyton et al. 2009). In a series of studies, Han et al. (2008, 2012)

investigated the effect of 1-bromopropane on nitric oxide and proinflammatory cytokine 

production and the role of NF- B in 1-bromopropane–mediated inducible nitric oxide 

synthases (iNOS) and proinflammatory cytokine expression in mouse macrophages. 

iNOS catalyzes the formation of nitric oxide and may be an important mediator of 

carcinogenesis in some circumstances. Overexpression of iNOS has been described in 

human cancer, and tumor-associated production of nitric oxide by iNOS may elevate 

tumor progression. 1-Bromopropane caused proinflammatory changes in mouse 

macrophages including upregulation of iNOS and cytokines (IL-1 , IL-6, and TNF- ),
RoC Monograph on 1-Bromopropane 9/25/13

43

enhanced the production of prostaglandin E2 (PGE2), and dose-dependently increased 

cyclooxygenase-2 (COX-2) protein and mRNA levels. Increased PGE2 production may 

contribute to the tumorigenic process through effects on cell proliferation, apoptosis, and 

vascular growth. Thus, 1-bromopropane exposure induced a variety of effects, including 

increased levels of proinflammatory cytokines, increased macrophage activation, and 

over expression of COX-2, that collectively support the assertion that 1-bromopropane 

induces inflammation.

Exposure-related increased incidences of chronic respiratory tract inflammation (nasal 

cavity, larynx, and trachea) occurred in rats, and increased incidences of cytoplasmic 

vacuolization in the nasal cavity, larynx, trachea, and bronchiolar epithelium occurred in 

mice (NTP 2011a). Bronchiole regeneration also was significantly increased in exposed 

male and female mice. These lesions are indicative of local irritant effects, but there was 

no apparent association with carcinogenic effects because lung tumors occurred only in 

female mice, and upper respiratory tract tumors were not increased in mice or rats.

There is also some evidence from neurotoxicity studies in rodents that 1-bromopropane 

causes hyperexcitability of the hippocampus due to dysfunction of -aminobutyric acid 

(GABA) feedback inhibition (Fueta et al. 2004, Fueta et al. 2002a, Mohideen et al. 2009)

(see Appendix E). Although a primary role of GABA is as an inhibitory neurotransmitter 

in the adult mammalian nervous system, there is substantial evidence that it is involved in 

the proliferation, differentiation, and migration of several cell types, including cancer 

cells (Watanabe et al. 2006). Young and Bordey (2009) reported that GABAergic 

signaling and its control over proliferation is widespread through peripheral organs 

containing adult stem cells (e.g., liver, pancreas, kidney, intestine, prostate, testis, and 

ovary). GABA is a strong inhibitor of cell proliferation; however, it is possible that 

altered GABAergic signaling in tumors cells leads to abnormal proliferation. Tatsuta et 

al. (1990) demonstrated that GABA or a GABAB receptor agonist inhibited N-methyl-N'-

nitro-N-nitrosoguanidine-induced gastric carcinogenesis in Wistar rats. Maemura et al.

(2003) examined the expression of GABA in human intramucosal colonic tumors. Tissue 

samples included 56 protruded-type colonic tumors that were classified as 

adenocarcinoma, adenoma with severe atypia, or adenoma with mild to moderate atypia. 

The level of GABA expression was proportional to the degree of atypia in colonic 

neoplasms and was proposed as a possible tumor marker. Schuller et al. (2008) reported 

that GABA may have tumor suppressor function in small airway epithelia and that 

downregulation of GABA by nicotine-derived carcinogens may contribute to lung cancer 

in smokers. 

5.3.4 Sex differences in chemical carcinogenesis

Sex differences were observed for 1-bromopropane–induced tumors in both rats and mice 

in the NTP experimental animal studies, as described in detail in Section 4. While both 

sexes of rats developed large intestinal tumors, the incidence was higher in females; skin 

tumors were induced in male rats, but the findings were only equivocal in females. In 

mice, lung tumors were observed in females but not in males. 

In a recent survey of 278 chemicals identified as carcinogenic in rats in the NTP 2-year 

bioassay, 201 exhibited statistically significant sex differences (P < 0.05) in at least one 
9/25/13 RoC Monograph on 1-Bromopropane

44

non-reproductive organ (Kadekar et al. 2012) with males showing a dominance: tumors 

were induced in non-reproductive organs in male rats for 130 chemicals and in females 

for 59. Induction of both skin tumors and tumors of the large intestine were significantly 

greater in male rats (P < 0.05), which is consistent for the skin tumors but not the large 

intestinal tumor findings for 1-bromopropane. However, this general pattern of increased 

incidence in males is based on a review of a large database of multiple chemicals, which 

may induce tumors via more than one mechanism. Greater male susceptibility to cancer 

has also been noted in surveys of human cancers (Cook et al. 2009, Edgren et al. 2012); 

however, no clear explanation for the male dominance in rats or humans was apparent.

As discussed in Section 2.2.4 and Appendix E, CYP2E1 and glutathione S-transferase

(GST) are important in 1-bromopropane metabolism and toxicity and thus probably play 

a role in carcinogenicity. There is some evidence that there are sex differences in 

enzymatic activity in 1-bromopropane–exposed rats. p-Nitrophenol hydroxylase (pNPH), 

associated with CYP2E1 expression, and NADPH b5 reductase levels increased in a dosedependent fashion and were consistently higher in male than female rats for the control 

treatment and all doses tested. GST and lipid peroxide (LPO) levels also increased with 

increasing dose; in general, GST levels were higher in males, however LPO levels were 

higher in females (Kim et al. 1999b). It is unclear how these sex differences in enzymatic 

activity translate to sex differences in tumor incidence in 1-bromopropane–exposed rats; 

some of the differences would suggest a potential increase in reactive oxygen species or 

oxidative damage (CYP2E1 in males), while others suggest a decrease (e.g., LPO*). It is 

also not known if sex differences occur similarly at other tissue sites.

In mice, an evaluation of the NTP 2-year bioassay historical control database indicates 

that there is a sex difference in the spontaneous incidence of lung tumors: 32% of males 

had tumors, compared with 8% of females (see NTP database 

http://ntp.niehs.nih.gov/go/datasearch). No studies looking at gender differences specific 

for 1-bromopropane exposure in mice were identified; however, normal CYP2E1 

expression measured in mice was found to vary by tissue type as well as by sex (Chanas 

et al. 2003). Expression was significantly greater in the kidneys of males and slightly 

higher (non-significant) in lungs of females, but no sex difference was observed in the 

liver. 

Overall, 1-bromopropane caused tumors at different sites in male and female rats and 

mice, and some data from the NTP database for chemical carcinogenesis were consistent 

with the observed pattern; however, there is limited information on sex differences in 

1-bromopropane metabolism or other mechanistic data.

5.4 Carcinogenicity of 1-bromopropane metabolites and analogues

While 1-bromopropane and other halogenated hydrocarbons are generally stable 

compounds, they can undergo metabolism or bioactivation that results in toxic effects, 

usually subsequent to dehalogenation, i.e., their toxicity is generally associated with the

reactive, electrophilic metabolites formed from the carbon skeleton rather than with the 

halide ion released from the molecule (Anders 1983). 
RoC Monograph on 1-Bromopropane 9/25/13

45

5.4.1 Metabolites

Glycidol is the only urinary metabolite of 1-bromopropane that has been tested for 

carcinogenicity; it is currently listed as reasonably anticipated to be a human carcinogen

by the NTP (2011b). Propylene oxide, a proposed intermediate metabolite of 

1-bromopropane, also is currently listed as reasonably anticipated to be a human 

carcinogen by the NTP (2011c). -Bromohydrin is another reactive metabolite of 

1-bromopropane, but it has not been tested for carcinogenicity. 

Oral administration of glycidol caused benign and malignant tumors at multiple tissue 

sites in rats and mice (NTP 1990). Organs and tissues affected in rats included the oral 

mucosa, forestomach, glandular stomach, intestines, mammary glands, skin, tunica 

vaginalis, clitoral gland, thyroid gland, brain, and Zymbal gland. Tissues affected in mice 

included the mammary glands, forestomach, Harderian gland, lung, liver, skin, uterus,

and urinary bladder. The tumor profile for glycidol was more varied than that for 

1-bromopropane but there were some similarities. In particular, glycidol and 

1-bromopropane induced mesothelioma in the tunica vaginalis covering the epididymis

and testes, benign but rare intestinal tumors, and skin tumors in rats. Glycidol also 

induced lung tumors in male mice, while 1-bromopropane induced lung tumors in female 

mice. Glycidol also has induced immunosuppressive effects in mice (Guo et al. 2000).

Propylene oxide caused benign and malignant tumors in rats and mice at several tissue 

sites when administered by inhalation, stomach tube, or s.c. injection (IARC 1994). Rats 

developed nasal cavity, adrenal gland, forestomach, abdominal cavity, and mammary 

tumors. Mice developed nasal-cavity and injection-site tumors. 

5.4.2 Analogues

1-Bromopropane is one member of the large class of halogenated alkanes, and chemical 

characteristics shared by these related molecules could be informative for the 

carcinogenicity of 1-bromopropane. In general, the presence of a halogen substituent on a 

carbon atom has an electron-withdrawing effect making the carbon atom more 

electrophilic, which increases the reactivity of the carbon atom (van Hylckama Vlieg and 

Janssen 2001). Among the halogens, bromine is recognized as a better leaving group than 

the smaller, more electronegative chlorine and fluorine atoms. Thus, halogenated, and 

particularly brominated, alkanes would be expected to more readily form activated 

intermediates that could covalently modify biological molecules. Activated intermediates 

may result from bioactivation by CYP. These bioactive (electrophilic) compounds can 

also be conjugated by the nucleophile, glutathione, a reaction catalyzed by glutathione-Stransferases (GSTs) (Anders 1982, 2001). Exposure of mice to 1-bromopropane causes 

hepatotoxicity and may be related to glutathione depletion associated with conjugate 

formation and subsequent formation of reactive oxygen species (see Section 5.2.3). Since 

glutathione is an important cellular defense mechanism against reactive oxygen species, 

reduced levels of glutathione can lead to oxidative stress, enhanced toxicity, and possibly 

carcinogenicity.

The nearest structural analogue for 1-bromopropane is 2-bromopropane, an isomer that 

has not been tested for carcinogenicity. However, 2-bromopropane has been studied in a 

number of genotoxicity assays. Similar to 1-bromopropane, 2-bromopropane caused 
9/25/13 RoC Monograph on 1-Bromopropane

46

base-pair mutations in Salmonella strains TA100 and TA1535 (NTP 2003b) and DNA 

damage in cultures of rat Leydig cells (Wu et al. 2002), but did not induce chromosomal 

aberrations in Chinese hamster lung cells. In rodents, it induced micronucleus formation 

in embryos from pregnant mice exposed to 2-bromopropane by i.p. injection but did not 

cause micronuclei in bone marrow of adult rats exposed by i.p. injection.

2-Bromopropane also formed N

7

-isopropyl guanine adducts (Zhao et al. 2002) and 

caused massive depurination (Sherchan et al. 2009a, Sherchan et al. 2009b). Unrepaired 

apurinic sites lead to lethality or base substitution errors. Although 2-bromopropane 

causes similar types of toxicities (neurological [Yu et al. 2001], hematological [Kim et al.

1999a], immunological [Anderson et al. 2010], and reproductive [NTP 2003b]), the 

primary metabolic products are different from those of 1-bromopropane.

Other analogues for 1-bromopropane are monobrominated, short-chain alkanes, such as 

bromomethane, bromoethane, 1-bromobutane, and 2-bromobutane. Bromomethane 

(methyl bromide) is classified by NIOSH as a potential occupational carcinogen (CDC 

2010) and by IARC as Group 3, not classifiable as to its carcinogenicity in humans, but 

neither it nor the bromobutane isomers have been tested in 2-year bioassays by the NTP 

or reviewed for the Report on Carcinogens. Bromoethane has been tested in a 2-year 

bioassay by the NTP, and it is listed by IARC as Group 3; it has not been reviewed by 

NTP for the Report on Carcinogens. Bromoethane is classified by the American 

Conference of Governmental Industrial Hygienists as A3, confirmed animal carcinogen 

with unknown relevance to humans.

While the examination of the potential carcinogenicity of all members of the large class 

of halogenated alkanes is beyond the scope of this document, several halogenated alkanes 

(bromodichloromethane, carbon tetrachloride, chloroform, 1,2-dibromo-3-chloropropane, 

1,2-dibromoethane (ethylene dibromide), 1,2-dichloroethane, dichloromethane, 

hexachloroethane, and 1,2,3-trichloropropane) are listed in the NTP Report on 

Carcinogens as reasonably anticipated to be a human carcinogen and classified by IARC 

as possible or probable carcinogens. In addition to the analogues described above, more 

than a dozen other halogenated alkanes have been reviewed by IARC and listed as Group 

3. No mechanistic data were identified to suggest that these molecules would act by a 

common mechanism with 1-bromopropane and they are not discussed further here.

A search of the IARC website (www.iarc.fr) identified 12 additional halogenated alkanes 

that had been reviewed by IARC and placed in Group 3, i.e., not classifiable as to their 

carcinogenicity in humans. The majority of these molecules (bromoform 

[tribromomethane], chlorodibromomethane, chloroethane, chlorofluoromethane, 

2-chloro-1,1,1,-trifluoroethane, 1,2-dichloropropane, methyl iodide, pentachloroethane, 

and 1,1,2-trichloroethane) were reported to have no epidemiological data relevant to their 

carcinogenicity and limited data in experimental animals. One other molecule 

(chlorodifluoromethane) also had limited data in experimental animals and data in 

humans were considered inadequate; the last two molecules (methyl chloride and 1,1,1-

trichloroethane) had inadequate data in both humans and experimental animals. Two 

halogenated alkanes (1,1,1,2-tetrachloroethane and 1,1,2,2-tetrachloroethane) have been 

recently listed by IARC as Group 2B, possibly carcinogenic to humans, and are pending 

publication in Volume 106.
RoC Monograph on 1-Bromopropane 9/25/13

47

6 Overall Cancer Evaluation – Synthesis of Animal, 

Human, and Mechanistic Data

This section synthesizes the information from the animal and mechanistic studies and 

applies the RoC listing criteria to that body of knowledge to reach a preliminary listing 

recommendation. No epidemiological studies were identified that evaluated the 

relationship between human cancer and exposure specifically to 1-bromopropane. As 

stated in Section 4, cancer studies in experimental animals identified 1-bromopropane–

induced tumors in the intestine, skin, and lungs that met the RoC criteria for sufficient 

evidence of carcinogenicity in experimental animals. That assessment did not consider 

data on mechanisms of carcinogenesis. This section (1) briefly summarizes the 

assessment of the cancer studies in experimental animals (as reported in Section 4) and 

(2) discusses the data on mechanisms of carcinogenesis and metabolism of 

1-bromopropane reported in Sections 2 and 5, including a synthesis of the information 

available from studies in humans. The RoC listing recommendation for 1-bromopropane 

follows the discussion.

6.1 Cancer studies in experimental animals

Inhalation exposure to 1-bromopropane increased the incidences of skin tumors 

(keratoacanthoma; keratoacanthoma and squamous-cell carcinoma combined; and 

keratoacanthoma, squamous-cell carcinoma, basal-cell adenoma, and basal-cell 

carcinoma combined) in male rats, large-intestine tumors (adenoma of the colon and 

rectum) in rats of both sexes, and lung tumors (alveolar/bronchiolar adenoma and 

carcinoma) in female mice. Increased incidences of skin tumors in male rats, intestinal 

tumors in female rats, and lung tumors in female mice were statistically significant and 

dose-related. The increased incidence of intestinal tumors in male rats, although not 

statistically significant, was considered to be of biological significance because of the

rarity of this type of tumor (incidence of less than 0.2% in historical controls). The

incidence of adenocarcinoma of the large intestine was increased in rats of both sexes 

after oral exposure to brominated methanes (bromodichloromethane or tribromomethane) 

and in male rats after exposure to glycidol, a metabolite of 1-bromopropane. Additional 

tumors that may have been related to 1-bromopropane exposure included malignant 

mesothelioma of the abdominal cavity and pancreatic islet tumors (adenoma) in male rats 

and skin tumors (keratoacanthoma, basal-cell adenoma, and basal-cell carcinoma 

combined) in female rats.

6.2 Mechanistic and other relevant data

No studies were found that evaluated mechanisms of carcinogenicity of 1-bromopropane

at the tumor sites found in experimental animals (skin, large intestine, and lung). 

However, 1-bromopropane, either directly or via reactive metabolites, causes molecular 

alterations related to carcinogenicity, including genotoxicity, oxidative stress, glutathione 

depletion, immunosuppression, and inflammation (see Section 5.3 for details). These 

alterations, observed mainly in vitro and in toxicity studies in rodents, are relevant to 

possible mechanisms of carcinogenicity in humans and support the relevance of the 

cancer studies in experimental animals to cancer in humans.
9/25/13 RoC Monograph on 1-Bromopropane

48

The available studies suggest that both direct effects and metabolic activation are 

important in 1-bromopropane–induced carcinogenesis. There is some evidence that 

1-bromopropane is directly genotoxic. It has been shown to bind to macromolecules, 

forming S-propylcysteine globin adducts in exposed animals and humans. It also caused 

mutations in bacteria (in the only reported study whose design was appropriate for testing 

a highly volatile chemical) and cultured mammalian cells with or without exogenous 

mammalian metabolic activation and DNA damage in cultured human cells without 

exogenous metabolic activation. In rodents exposed to 1-bromopropane in vivo, negative

results were reported for the only two end points measured, micronucleus formation (in 

bone marrow or peripheral blood erythrocytes) and dominant lethal mutation. However, 

the dominant lethal mutation assay detects only germ-cell mutations and is generally 

regarded as relatively insensitive for the detection of mutagenic agents. 

There is evidence suggesting that metabolic activation plays a role in the genotoxicity 

and toxicity of 1-bromopropane. Several potential reactive metabolites or proposed 

reactive intermediates have been identified in rodents, including glycidol and 

-bromohydrin, and propylene oxide has been proposed as a metabolite (see Section 2.2). 

These compounds cause genotoxic effects in vitro (including DNA adduct formation, 

mutations, and DNA or chromosome damage). Glycidol and propylene oxide cause 

chromosome damage in vivo and are carcinogenic in experimental animals. Both 

chemicals are listed in the Report on Carcinogens as reasonably anticipated to be human 

carcinogens. These reactive and genotoxic metabolites may be responsible for at least 

some of the carcinogenic effects of 1-bromopropane. As with 1-bromopropane, oral 

exposure to glycidol caused rare tumors of the large intestine in rats, as did oral exposure 

to two halogenated alkane analogues of 1-bromopropane, tribromomethane and 

bromodichloromethane.

Chronic exposure to 1-bromopropane may produce levels of oxidative metabolites that

exceed the capacity for glutathione conjugation or may inhibit enzymes required for 

glutathione synthesis. The resulting reduction in glutathione levels can lead to oxidative 

stress, increased toxicity, and carcinogenesis. Numerous studies on mechanisms of 

toxicity in rodents have shown that 1-bromopropane causes oxidative stress and 

glutathione depletion. Moreover, studies with Cyp2e1-/- knockout mice, cytochrome P450

inhibitors, or a glutathione synthesis inhibitor showed that this pathway (metabolic 

activation leading to oxidative stress from glutathione depletion) is involved in 

1-bromopropane-induced toxicity (see Appendix E for details). Although no studies have 

evaluated the role of oxidative stress in 1-bromopropane-induced carcinogenicity, 

oxidative stress is a relevant mechanism for carcinogenicity in humans.

Other effects associated with 1-bromopropane that could be relevant to carcinogenesis 

include immunosuppression and inflammation. Recent studies in rodents have shown that 

1-bromopropane causes immunosuppression, increased levels of proinflammatory 

cytokines, increased macrophage activation, and overproduction of cyclooxygenase 2. In 

addition, there is some evidence from neurotoxicity studies in rodents that 1-

bromopropane causes reduced GABAergic feedback inhibition. Although GABA’s

primary role is as an inhibitory neurotransmitter in the adult mammalian nervous system, 
RoC Monograph on 1-Bromopropane 9/25/13

49

there is substantial evidence that it is involved in the proliferation, differentiation, and 

migration of several cell types, including cancer cells.

Although the available data on 1-bromopropane metabolism, genotoxicity, and

mechanisms of action in humans are limited, they provide some support for the relevance 

of the findings in experimental animals to humans. Data on human metabolism of 

1-bromopropane suggest that metabolic pathways are similar in humans and experimental 

animals. Urinary mercapturic conjugates identified from workers exposed to 

1-bromopropane were also reported as urinary metabolites in rodents, and CYP2E1, the 

major cytochrome P450 enzyme involved in 1-bromopropane metabolism, is produced in 

human lung and other tissues. Although it is likely that humans metabolize 

1-bromopropane to reactive metabolites, no studies in humans have explored potential 

pathways leading to additional metabolites or likely intermediates identified from rodent 

or in vitro studies, such as propylene oxide, glycidol, and -bromohydrin. Studies of 

1-bromopropane-exposed workers have found S-propylcysteine adducts in globin and 

limited evidence of DNA damage in leukocytes. Case reports and epidemiological studies 

suggest that 1-bromopropane causes neurological effects, and studies in experimental 

animals have shown that glutathione depletion and oxidative stress play a role in this 

toxicity. 

6.3 NTP listing recommendation

1-Bromopropane is reasonably anticipated to be a human carcinogen based on sufficient 

evidence of carcinogenicity from studies in experimental animals. These studies found 

that exposure to 1-bromoproane caused tumors at several tissue sites in rats and mice. 

1-Bromopropane, either directly or via reactive metabolites, causes molecular alterations 

that typically are associated with carcinogenesis, including genotoxicity, oxidative stress, 

and glutathione depletion. These alterations, observed mainly in vitro and in toxicity

studies in rodents, are relevant to possible mechanisms of human carcinogenicity and 

support the relevance of the cancer studies in experimental animals to cancer in humans.
9/25/13 RoC Monograph on 1-Bromopropane

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References

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biotransformation. Trends Pharm Sci 3(C): 356-357. (Support not reported. 

Author affiliated with University of Minnesota, MN.)

2. Anders MW. 1983. Bioactivation of halogenated hydrocarbons. J Toxicol Clin 

Toxicol 19(6-7): 1982-1983. (Supported by NIEHS. Author affiliated with 

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71

Abbreviations

1-BP: 1-bromopropane

3-BPA: 3-bromopropionic acid

ABT: 1-aminobenzotriazole

ACGIH: American Conference of Governmental Industrial Hygienists 

AcPrCys: N-acetyl-S-(n-propyl)-L-cysteine

ADD: average daily dose

ALT: serum alanine aminotransferase, alanine aminotransferase

ANOVA: analysis of variance

AST: serum aspartate aminotransferase, aspartate aminotransferase

atm: atmosphere

BSO: DL-buthionine (S,R)-sulfoximine

CDC: Centers for Disease Control and Prevention

CERHR: Center for the Evaluation of Risks to Human Reproduction 

cm

2

: square centimeter

COX-2: cyclooxygenase-2

DBCP: 1,2-dibromo-3-chloropropane

DLMI: dominant lethal mutation index

DLMR: dominant lethal mutation rate

EQ: exposure quartiles model

FDA: Food and Drug Administration 

FR: Federal Register

ft: feet

GC/MS: gas chromatography/mass spectrometry 
9/25/13 RoC Monograph on 1-Bromopropane

72

GSH: glutathione

GSSH: oxidized glutathione

GST: glutathione-S-transferase

HHE: Health Hazard Evaluation

HHS: Department of Health and Human Services

HIC: highest ineffective concentration

HID: highest ineffective dose

HO-1: heme oxygenase-1

hr: hour

in: inch

i.s.: internal standard

iNOS: inducible nitric oxide synthases 

L: liter

LEC: lowest effective concentration

LED: lowest effective dose

m

3

: cubic meter

mg: milligram 

MMWR: Morbidity and Mortality Weekly Report

MN: micronuclei

mol: mole

NCE: normochromatic erythrocyte

NCTR: National Center for Toxicological Research

ND: not done

NIC: Notices of Intended Changes

NIEHS: National Institute of Environmental Health Sciences
RoC Monograph on 1-Bromopropane 9/25/13

73

NIH: National Institutes of Health

NIOSH: National Institute for Occupational Safety and Health

nPB: normal propyl bromide 

NQO1: NAD(P)H:quinone oxidoreductase

NR: not reported

NS: non-sprayer

NTP: National Toxicology Program

OHAT: Office of Health Assessment and Translation

OSHA: Occupational Safety and Health Administration

PBZ: personal breathing zone

PCE: polychromatic erythrocyte

PEL: permissible exposure limit

PERC: tetrachloroethylene (perchloroethylene)

PGE2: prostaglandin E2

ppm: parts per million

PrCys: S-propylcysteine 

r: correlation coefficient 

RoC: Report on Carcinogens

RTG: relative total growth

s.c.: subcutaneous

SD: standard deviation

SNAP: Significant New Alternatives Policy

Solv.: aerosol solvents use

SP: sprayer

TBARS: thiobarbituric acid-reactive substance
9/25/13 RoC Monograph on 1-Bromopropane

74

TLV: threshold limit value

TM: tail moment

TMD: tail moment dispersion coefficient

TWA: time weighted average

VOC: volatile organic compound

μg: microgram
RoC Monograph on 1-Bromopropane 9/25/13

75

Glossary

Aerosol solvent: A cleaning agent stored in a metal container (i.e., a hand-held can) 

under pressure and then released through a push-button valve or nozzle as a suspension of 

particles in air.

Apoptosis: Cell deletion by fragmentation into membrane-bound particles, which are 

phagocytosed by other cells.

Aroclor 1254-induced liver: Liver tissue treated with the polychlorinated biphenyl 

mixture Aroclor 1254 used as a source of S9 fraction for mutagenic and genotoxic effects 

testing.

Assembly worker: A foam seat cushion manufacturing facility employee who sprays 

adhesive on foam pieces and presses them together by hand to form the cushion. 

Assembly department workers are either sprayers or assemblers. 

Ataxia: Loss of the ability to coordinate muscular movement.

Axial exhaust fan: An air-moving device in which the air flow is parallel (or axial) to the 

shaft on which the propeller is mounted; also called a propeller fan.

Boiling point: The boiling point of the anhydrous substance at atmospheric pressure 

(101.3 kPa) unless a different pressure is stated. If the substance decomposes below or at 

the boiling point, this is noted (dec). The temperature is rounded off to the nearest °C.

Cauda epididymis: The tail of the epididymis; part of the reservoir for spermatozoa. 

CD8+ T-cell blast: An immature, undifferentiated lymphocyte that expresses the CD8 

transmembrane glycoprotein.

Chemical Data Reporting Rule: Chemical Data Reporting (CDR) is the new name for 

Inventory Update Reporting (IUR). The purpose of Chemical Data Reporting is to collect 

quality screening-level, exposure-related information on chemical substances and to 

make that information available for use by the U.S. Environmental Protection Agency 

(EPA) and, to the extent possible, to the public. The IUR/CDR data are used to support 

risk screening, assessment, priority setting and management activities and constitute the 

most comprehensive source of basic screening-level, exposure-related information on 

chemicals available to EPA. The required frequency of reporting currently is once every 

four years. 

Comet assay: A genotoxicological technique for measuring DNA damage in an 

individual cell using single-cell gel electrophoresis. Cell DNA fragments assume a 

"comet with tail" formation on electrophoresis and are detected with an image analysis 

system. Alkaline assay conditions facilitate sensitive detection of single-strand damage.

Conversion factor: A numerical factor used to multiply or divide a quantity when 

converting from one system of units to another.
9/25/13 RoC Monograph on 1-Bromopropane

76

Cooking: In dry cleaning, boiling the solvent cleaner to remove impurities. 

Cover worker: A foam seat cushion manufacturing facility employee who places covers 

around the assembled cushions and seals the cover around the cushion with adhesive. All 

workers in the Covers department are sprayers.

Dehydrodehalogenation: An elimination reaction in which a halogen is removed from 

one carbon and a hydrogen is removed from an adjacent carbon.

Disposition: The description of absorption, distribution, metabolism, and excretion of a 

chemical in the body. 

Distal latency: The interval between the stimulation of a compound muscle and the 

observed response. Normal nerve conduction velocity is above 40 m/sec in the lower 

extremities and above 50 m/sec in the upper extremities, but age, muscle disease, 

temperature, and other factors can influence the velocity.

Dominant lethal mutation assay: The dominant lethal assay identifies germ cell 

mutagens by measuring the ability of a chemical to penetrate gonadal tissue and produce 

embryonic death due to chromosomal breakage in parent germ cells.

ELISA assay: Enzyme-linked immunosorbent assay; a sensitive immunoassay that uses 

an enzyme linked to an antibody or antigen as a marker for the detection of a specific 

protein, especially an antigen or antibody. 

EPA SNAP program: The U.S. Environmental Protection Agency Significant New 

Alternatives Policy program reviews alternatives to ozone depleting substances and 

approves the use of alternatives that do not present substantially greater risk to the public 

health and environment than the substance they replace or other substitutes available. 

F0 generation: F0 generation is the initial parent generation in a multi-generation 

reproduction study. 

F1 and F2 offspring: F1 offspring is the first filial generation, which comprises offspring 

resulting from a cross between strains of distinct genotypes. The F1 generation is the 

generation resulting immediately from a cross of the first set of parents (parental 

generation, i.e., F0 generation). F2 offspring is the second filial generation, which 

comprises offspring resulting from a cross of the members of F1 generation. The F2

generation is the result of a cross between two F1 individuals (from F1 generation).

FDA Good Laboratory Practice Regulations: A quality system codified by the U.S. 

Food and Drug Administration that prescribes operating procedures for conducting 

nonclinical laboratory studies that support or are intended to support applications for 

research or marketing permits for products regulated by the Food and Drug 

Administration. 

Heat-separated human epidermal membrane: A skin sample used for dermal 

absorption testing. The method of preparation of epidermal membranes varies across 
RoC Monograph on 1-Bromopropane 9/25/13

77

species due to the inherent differences in skin morphology and follicle depth. Commonly, 

heat separation (60°C for one to two minutes) is used for human and pig skin; the 

epidermal membrane is peeled from the dermis using forceps.

Helminthes: Eukaryotic animals with worm-like appearance (i.e., small animals with 

long, slender bodies and without appendages) and mostly parasitic.

Henry’s Law constant at 25°C: The ratio of the aqueous-phase concentration of a 

chemical to its equilibrium partial pressure in the gas phase. The larger the Henry’s law 

constant the less soluble it is (greater tendency for vapor phase).

Immersion cleaning: A process in which a tank containing cleaning solvent at a 

temperature below its boiling point is used for metal parts cleaning. To use the vapor 

degreaser, the operator places the parts to be cleaned in a metal wire basket, removes the 

cover, and lowers the basket of parts by hand into the cleaning solvent. After a brief 

period of time, the operator raises the basket and allows the parts to drip-dry inside the 

degreaser. 

Karmen unit: A formerly used enzyme unit for aminotransferase activity; a change of 

0.001 in the absorbance of reduced nicotinamide adenine dinucleotide (NADH) per 

minute.

Lymphokine-activated killer cell: Killer cell lymphocytes activated in the presence of 

interleukin-2 (IL-2). Lymphokine-activated killer cells (LAKs) are cytotoxic effector 

cells with an exceptionally wide target cell spectrum including normal and malignant 

cells of different origins. LAKs exhibit a profound heterogeneity with regard to 

phenotype surface marker expression; it remains to be determined if they represent a 

unique cell lineage. 

Melting point: The melting point of the substance at atmospheric pressure (101.3 kPa). 

When there is a significant difference between the melting point and the freezing point, a 

range is given. In case of hydrated substances (i.e., those with crystal water), the apparent 

melting point is given. If the substance decomposes at or below its melting point, this is 

noted (dec). The temperature is rounded off to the nearest °C.

Molecular chaperone: Any of a diverse group of proteins that oversee the correct 

intracellular folding and assembly of polypeptides without being components of the final 

structure.

Molecular weight: The molecular weight of a substance is the weight in atomic mass 

units of all the atoms in a given formula. The value is rounded to the nearest tenth.

Natural killer cells: A type of white blood cell that contains granules with enzymes that 

can kill tumor cells or microbial cells. Also called large granular lymphocytes.

Octanol/water partition coefficient (log Kow): A measure of the equilibrium 

concentration of a compound between octanol and water. 
9/25/13 RoC Monograph on 1-Bromopropane

78

Ozone-depleting substance: A family of man-made compounds that includes, but are 

not limited to, chlorofluorocarbons (CFCs), bromofluorocarbons (halons), methyl 

chloroform, carbon tetrachloride, methyl bromide, and hydrochlorofluorocarbons 

(HCFCs). These compounds have been shown to deplete stratospheric ozone.

Personal breathing zone: A sampling area as close as practical to an employee’s nose 

and mouth, (i.e., in a hemisphere forward of the shoulders within a radius of 

approximately nine inches) so that it does not interfere with work performance or safety 

of the employee.

Phase I metabolism: metabolism of drugs or other xenobiotic molecules, usually by 

oxidation or hydrolysis and involving a cytochrome P450 monooxygenase.

Phase II metabolism: a conjugation reaction that forms a covalent linkage between a 

functional group on a xenobiotic molecule and glucuronic acid, sulfate, glutathione, 

amino acid, or acetate.

Plaque assay: An assay for antibody production by single lymphocytes using cells 

isolated from the spleen or lymph nodes of animals injected with sheep red blood cells as 

an antigen. Incubation of the antibody-forming cells together with sheep red cells in an 

agar layer with exposure to guinea pig serum as complement results in formation of 

microscopic plaques (i.e., circular areas of hemolytic clearance around a lymphoid cell) 

due to release of hemolysin.

Plate incorporation: A commonly used procedure for performing a bacterial reverse 

mutation test. Suspensions of bacterial cells are exposed to the test substance in the 

presence and in the absence of an exogenous metabolic activation system. In the plateincorporation method, these suspensions are mixed with an overlay agar and plated 

immediately onto minimal medium. After two or three days of incubation, revertant 

colonies are counted and compared with the number of spontaneous revertant colonies on 

solvent control plates.

Poly-3 test: A survival-adjusted statistical test that takes survival differences into account 

by modifying the denominator in the numerical (quantal) estimate of lesion incidence to 

reflect more closely the total number of animal years at risk.

Pyknotic shrinkage: A thickening, especially the degeneration of a cell in which the 

nucleus shrinks in size and the chromatin condenses to a solid, structureless mass or 

masses.

S9 metabolic activation: Addition of the supernatant fraction obtained from an organ 

(usually liver) homogenate by centrifuging at 9000 g-force for 20 minutes in a suitable 

medium to a biological assay (e.g., genetic toxicology) to provide metabolic enzymes.

Saw worker: A foam seat cushion manufacturing facility employee who cuts bulk foam 

with various saws.

SKF-525A: An inhibitor of drug metabolism and cytochrome P-450 activity.
RoC Monograph on 1-Bromopropane 9/25/13

79

Solubility: The ability of a substance to dissolve in another substance and form a 

solution.

Specific gravity: The ratio of the density of a material to the density of a standard 

material, such as water at a specific temperature; when two temperatures are specified, 

the first is the temperature of the material and the second is the temperature of water.

Sperm motility: Movement characteristics of spermatozoa in a fresh specimen. It is 

measured as the percentage of sperms that are moving, and as the percentage of sperms 

with productive flagellar motion such as rapid, linear, and forward progression.

Spinnerette: A small, thimble-shaped, metal nozzle having fine holes through which a 

spinning solution is forced to form a filament.

Splendore-Hoeppli reaction material: Homogeneous, eosinophilic material that coats 

the grains that are characteristic of the exudate in lesions of botryomycosis.

Sprayer: Any cushion manufacturing facility employee who works directly with 

adhesive formulations via spray application using a compressed air spray gun.

Static diffusion cell: A diffusion cell consists of a donor chamber and a receptor 

chamber between which the skin is positioned. The cell should provide a good seal 

around the skin, enable easy sampling and good mixing of the receptor solution in contact 

with the underside of the skin, and provide good temperature control of the cell and its 

contents. In a static diffusion cell, the receptor fluid is sampled at intervals and replaced 

with equal volumes of fresh receptor fluid.

Temperate marine macroalgae: Algae growing in the ocean in large seaweed form, 

generally visible to the naked eye (e.g., kelp), in regions where the climate undergoes 

seasonal change in temperature and moisture. Temperate regions of the earth lie primarily 

between 30 and 60 degrees latitude in both hemispheres. 

Time-weighted average: The average exposure concentration of a chemical measured 

over a period of time (not an instantaneous concentration).

Toxicokinetics: The mathematical description (toxicokinetic models) of the time course 

of disposition of a chemical in the body.

Vapor degreasing: A type of cleaning procedure using a refrigerated cooling coil around 

the top of the interior of a vapor chamber to condense solvent vapor into liquid droplets 

on the surface of parts to remove surface impurities. Excess solvent drips back into the 

solvent sump and is recycled as the parts ascend from the vapor to condensing zones. 

Vapor density, relative: A value that indicates how many times a gas (or vapor) is 

heavier than air at the same temperature. If the substance is a liquid or solid, the value 

applies only to the vapor formed from the boiling liquid.
9/25/13 RoC Monograph on 1-Bromopropane

80

Vapor pressure: The pressure of the vapor over a liquid (and some solids) at 

equilibrium, usually expressed as mm Hg at a specific temperature (°C).
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-1

Appendix A: Literature Search Strategy

This document identifies the data sources, search terms, and search strategies that were 

used to identify literature for the monograph on 1-bromopropane (CASRN 106-94-5). 

The literature search strategy used for 1-bromopropane involved several approaches

designed to identify potentially useful information for the broad range of topics covered

by a Report on Carcinogens (RoC) monograph, as listed below.

Properties and Human Exposure (focusing on the U.S. population)

Disposition (ADME) and Toxicokinetics

Human Cancer Studies (if available) 

Cancer Studies in Experimental Animals 

Mechanisms and Other Relevant Effects 

o Genotoxicity

o Toxicity as It Relates to Mechanisms

o Mechanisms of Carcinogenicity

The methods for identifying the relevant literature for the 1-bromopropane monograph 

including (1) the search strategy, (2) updating the literature search, and (3) review of 

citations using web-based systematic review software are illustrated in Figure A-1 and 

discussed below.

Click here to return to text citing Appendix A.
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-2 

Figure A-1. Literature search strategy and review 

 
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-3

Search strategies

Relevant literature is identified using search terms, data sources, and strategies as 

discussed below.

1. General data search: This search covers a broad range of general data sources (see 

Table A-1) for information relevant to many or all of the wide range of monograph 

topics pertaining to 1-bromopropane. 

2. Exposure-related data search: This search covers a broad range of potential sources 

(see Table A-2) for exposure-related information and physical-chemical properties. 

3. Database searches in PubMed, Scopus, and Web of Science: The majority of the 

primary literature used to draft the 1-bromopropane monograph was identified from 

searches of these three extensive databases available through the NIEHS Library. 

Synonyms, metabolites (both Phase I and Phase II), and the chemical class for 

1-bromopropane were identified from the sources listed in Table A-3 and the search 

terms are listed in Table A-4. Information on metabolites and structurally related 

chemicals may be important for evaluating potential mechanisms of carcinogenicity. 

Initial literature searches were conducted to obtain all literature (not restricted to 

topic) on 1-bromopropane, its metabolites and chemical class. The searches for the 

four debrominated Phase I metabolites of 1-bromopropane and the relevant chemical 

class brought up several thousand references and thus subsequent topic-specific 

searches were conducted to focus the search on identifying mechanistic information 

for these chemicals. See Table A-4 for details on this approach and Table A-5 for 

topic-specific search terms.

Searches for human cancer studies are somewhat unique because they involve the 

identification of search terms for exposure scenarios that might result in exposure of 

people to 1-bromopropane. The major uses of 1-bromopropane are as a 

cleaner/degreaser, as an adhesive for manufacture of foam cushions, and as a solvent 

in dry cleaning. The use of 1-bromopropane in dry cleaning is more recent, since 

2006. Because the expansion in the use of 1-bromopropane has been fairly recent, 

epidemiologic studies of workers may not be able to evaluate potential risks for

cancer, which is associated with long latency periods. Formal searches were not 

conducted for epidemiologic studies of dry cleaners because these workers would 

most likely have been exposed to other solvents such as tetrachloroethylene. 

Literature searches conducted using search terms for spray adhesive and degreaser 

industries were combined with search terms for cancer epidemiologic studies (see 

Tables A-4 and A-5). 

4. QUOSA library of occupational case-control studies: A search of the QUOSAbased library of approximately 6,000 occupational case-control studies, 

approximately 60% of which are currently available as searchable full-text PDFs, was 

conducted using the synonyms “1-bromopropane,” “propyl bromide,” and the 

CASRN number (106-94-5). 
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-4

5. Special topic-focused search: One of the key questions in the concept document on

1-bromopropane was whether the reported alterations in immune surveillance in 

rodents lead to an increased incidence of tumors. An additional literature search of the 

three databases was conducted to identify information on immunosuppression and 

chemically induced cancer using the following search terms: (cancer OR tumor OR 

neoplasm) AND (immune suppression OR immunosuppression) AND (skin OR 

dermal) AND (chemically induced). The review of these citations was limited to 

review articles. 

6. Secondary sources: Citations identified from authoritative reviews or from primary 

references located by literature search, together with publications citing key papers 

identified using the Web of Science “Cited Reference Search,” were also added.

Updating the literature search

The literature search was updated prior to submitting the draft monograph for peer review

and was updated prior to finalizing the monograph. Monthly search alerts for 

1-bromopropane synonyms, metabolites, chemical class, exposure scenarios (human 

cancer), and topic-focused searches were created in PubMed, Scopus, and Web of 

Science, and the results of these searches from the closing date of the initial search were

downloaded for review.

Review of citations using web-based systematic review software

Citations retrieved from literature searches were uploaded to web-based systematic 

review software and screened using inclusion and exclusion criteria. Multi-level reviews 

of the literature were conducted, with initial reviews (Level 1) based on titles and 

abstracts only to identify citations that could be excluded and to assign the included 

literature to one or more monograph topics; subsequent reviews (Level 2) for literature 

assigned to the various monograph topics were based on full-text (i.e., PDFs) of the 

papers and were carried out by the writer and scientific reviewer for each monograph 

section. Two reviewers, at least one of whom is a member of the ORoC at NIEHS, 

participated at each level of review.

Inclusion/exclusion questions for literature

Level 1:

1. Should we obtain a PDF of this article?

Yes

No

1. If yes, for which sections of the monograph does this article contain useful 

information? Check all that apply.

Properties and Human Exposure

Toxicokinetics (also includes ADME, i.e., absorption, distribution, metabolism, and 

excretion)

Human Cancer Studies

Studies of Cancer in Experimental Animals

Mechanisms- Genetic Toxicology
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-5

Mechanisms- Toxicity

Mechanisms of Carcinogenicity

2. If no, check the reason that applies below or enter a reason in the textbox for “Other.”

It does not contain relevant information on 1-bromopropane or any related 

substance (metabolite or structural analogues).

It is related to 1-bromopropane but does not contain information relevant to any 

topic covered by the monograph.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to primary screening can include any of 

the following:

The article specifically mentions 1-bromopropane, a metabolite, or structural 

analogue and reports information on one of the topics included in a cancer 

evaluation (see Question #1 above for a list of topics)

The article does not specifically mention 1-bromopropane, or any related 

substance, but it does one of the following:

o It reports information on one of the topics included in a cancer evaluation with 

potential for exposure to 1-bromopropane and should be included until fulltext review, which would provide more information if the study is specific for 

exposure to 1-bromopropane or a related substance.

o It reports information on an exposure scenario that could include exposure to 

the 1-bromopropane.

o It reports information on methodology that is potentially informative for 

evaluating cancer or mechanistic studies on exposure to 1-bromopropane.

o It reports information on a potential mode of action that may be informative 

for 1-bromopropane.

Level 2- Exposure:

1. Does this paper contain information that could be useful in answering the key 

questions about exposure?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding it from 

review.

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

exposure.

Other 
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-6

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to screening for the exposure section can 

include information, from either primary research papers, review articles, databases, or 

other published sources, on any of the following topics: occupational exposure, 

environmental occurrence, occurrence in consumer products, food, cigarette smoke, or 

other sources, biological indices of exposure, and Federal regulations or guidelines to 

reduce exposure.

Toxicokinetics:

1. Does this paper contain information that could be useful in answering the key 

questions about toxicokinetics?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding it from 

review.

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

toxicokinetics.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to screening for the toxicokinetics (and 

ADME) section can include (but is not limited to) information from primary research 

papers or review articles on any of the following topics: absorption, distribution, 

metabolism, excretion (ADME), toxicokinetics, and physiologically based 

pharmacokinetic models (PBPK).

Human Cancer:

1. Does this paper contain information that could be useful in answering the key 

questions about human cancer?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding it from 

review.
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-7

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

human cancer.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to screening for the human cancer 

section can include, but is not limited to, epidemiologic studies, descriptive studies, 

pooled analyses, meta-analyses, case reports, reviews, letters to editors, exposureassessment studies (for use in epidemiologic studies) and information on co-exposures 

or potential confounders and other special topics of relevance to the evaluation.

Animal Tumors:

1. Does this paper contain information that could be useful in answering the key 

questions about animal tumors?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding it from 

review.

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

animal tumors.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful information” as it applies to screening for the animal tumors section can include, 

but is not limited to, information from primary research papers or review articles on (1) 

chronic studies (ideally for lifetime of the animal) in experimental animals that are 

assessing neoplastic endpoints, non-cancer data important for cancer assessment, such as 

preneoplastic lesions that are considered part of a morphologic continuum to neoplasia, 

or (2) subchronic studies in experimental animals that provide information on 

preneoplastic lesions, neoplastic lesions, or on dose setting for chronic studies. 
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-8

Level 2- Genetic Toxicology:

1. Does this paper contain information that could be useful in answering the key 

questions about genetic toxicology?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding if from 

review.

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

genetic toxicology.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to screening for the genetic toxicology 

section can include, information from primary research papers or review articles on 

studies in experimental systems (both in vitro and in vivo) and in exposed humans 

assessing the following endpoints: both direct and indirect DNA or chromosomal 

damage, events associated with mutagenesis, cellular transformation or other related 

effects.

Level 2- Toxicity:

1. Does this paper contain information that could be useful in answering the key 

questions about toxicity?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding if from 

review.

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

toxicity.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to screening for the toxicity section can 

include any of the following: information from primary research papers or review articles 
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-9

on toxicity of 1-bromopropane to organs or tissues that were identified as tumor sites 

from studies in experimental animals.

Level 2- Mechanisms of Action:

1. Does this paper contain information that could be useful in answering the key 

questions about mechanisms of action?

Yes

No

2. If the answer to Question #1 is “No” select the reason below for excluding if from 

review.

It does not contain relevant information on the candidate substance (or one of its 

metabolites or analogues).

It is related to the candidate substance (or one of its metabolites or analogues), but 

the paper does not contain information that will help answer the key questions about 

mechanisms of action.

Other 

Note: In the context of the systematic review of literature used for 1-bromopropane, 

“useful” or “relevant” information as it applies to screening for the mechanism data 

section can include information from primary research papers or review articles on data 

related to molecular alterations associated with carcinogenicity or potential modes of 

action, such as genotoxicity, epigenetics, gene expression, immune-response modulation, 

inflammation, cytotoxicity and compensatory cell proliferation, mitogenicity, chronic 

metabolic or physiologic overload, nutrient deficiency, and interference with intercellular 

communication, for 1-bromopropane, its metabolites and analogues.
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-10

Table A-1. General sources checklist for: 1-Bromopropane

Source Name of document

A) Comprehensive sources or reviews

1) NTP technical reports NTP2011

2) NTP nomination for toxicological evaluation documents NTP1999

3) OHAT (formerly CERHR)

Public comments to CERHR- 10 listed on NTP website

NTP2003a (1BP)

NTP 2003b (2BP)

Albemarle2001a

Albemarle2001b

Atofina2001

BSC2000

BSC2001a

BSC2001b

Envirotech2001

IRTA2001

EPA2002

Envirotech2002

4) IARC monographs --

5) ATSDR Toxicological Profiles --

6) EPA IRIS --

7) NAS Reports and Publications NAS2007 (Climate 

Change)

NAS2008 (Review of 

NIOSH HHE Program)

8) WHO (IPCS) INCHEM-related documents (a-k below) --

a) CICADS --

b) EHC --

c) HSGs --

d) ICSCs IPCS2004

e) JECFA --

f) JMPR --

g) KemI-Riskline --

h) PDs --

i) PIMS --

j) SIDS --

k) UKPID --

9) California EPA Prop 65 hazard identification documents CAEP 2004

CAEPA2008

10) Health Canada HealthCanada2009a

HealthCanada, 2009b

11) New York State Department of Health- Health Topics A to Z --

B) General information sources

1) U.S. National Library of Medicine (NLM)- TOXNET --

a) HSDB HSDB2006

b) CCRIS CCRIS2008

c) GENETOX --

d) ITER --

e) LactMed --

f) CPD --

g) CTD CTD2012

2) PubChem PubChem2012

3) Kirk-Othmer Encyclopedia Wypych2006
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-11

Source Name of document

Pocius&Campbell2009

Suh2000

4) USGS (Minerals) --

C) European Union– sources to search

1) International Uniform Chemical Information Database (IUCLID) --

2) European Chemicals Agency --

3) The International Portal on Food Safety, Animal and Plant Health 

(IPFSAPH) --

4) The European Food Safety Authority --

5) European Centre for Disease Prevention and Control (ECDC) --

6) European Monitoring Centre for Drugs and Drug Addiction --

7) International Labour Organization (ILO) ILO2005

8) United Nations Environment Programme (UNEP) --
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-12

Table A-2. Exposure-related sources checklist for: 1-Bromopropane

Source Name of document

Exposure- and properties-specific sources

1) U.S. National Library of Medicine (NLM)- TOXNET --

a) ChemIDplus ChemIDplus2012

b) Haz-Map Haz-Map2012

c) HPD --

d) TOXMAP --

2) Akron database Akron2012

3) SRI Directory of Chemical Producers SRI2012

4) Chem Sources Suppliers ChemSources2012

5) National Health and Nutrition Examination Survey (NHANES) data 

studies --

6) National Occupational Exposure Survey (NOES) (1981-1983) --

7) National Institute for Occupational Safety and Health (NIOSH) -

Health Hazard Evaluations

5 HHE:

Eisenberg2010

Harney2002

Harney2003

Reh2001

Reh2002 

8) National Response Center (NRC) Database NRC2012a

NRC2012b

9) U.S. International Trade Commission (USITC)- Import/Export data USITC2012

10) EPA Toxics Release Inventory (TRI) --

11) Environmental Protection Agency (EPA) AP-42, Compilation of 

Air Pollutant Emission Factors --

12) EPA EJView Database --

13) EPA High Production Volume Chemicals (HPV Challenge Program 

Chemical List) --

14) EPA Inventory Update Rule (IUR) EPA2012

15) EPA Locating and Estimating (L&E) documents --

16) EPA/Office of Pesticide Programs (OPP) Chemical Ingredients 

Database --

17) Food and Drug Administration (FDA) Pesticide Monitoring 

Database --

18) FDA Orange Book --

19) FDA Total Diet Study --

20) Medline Plus MedlinePlus2012

21) United States Patent Office USPTO2011

USPTO2012a 

USPTO2012b 

22) Trademark Electronic Search System (TESS) --

23) Material Safety Data Sheets (MSDS) Multiple found

Sigma-Aldrich2011

24) Dow Chemical Product Safety Assessments --
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-13

Table A-3. Data sources for 1-bromopropane searches

Information type Data sources

Synonyms National Library of Medicine databases (e.g., ChemIDplus, Hazardous Substances 

Data Base)

Metabolites Cheever et al. 2009, Garner et al. 2006, Ghanayem and Hoffler 2007, Ishidao et al.

2002, Jones and Walsh 1979.

Table A-4. Literature search approach for 1-bromopropane

Substance Search terms Topics (combined with)a

1-Bromopropane 

synonyms

bromopropane, propyl bromide, and 106-94-5 None 

Chemical class 

and synonyms

bromoalkanes, alkyl bromides, haloalkanes, alkyl 

halides

Animal tumors

Genotoxicity

Toxicity 

Mechanism

1-Bromopropane 

brominated Phase 

I metabolites and 

their synonyms

3-bromopropanol, 3-bromopropionic acid, 1-bromo-2-

propanol, bromoacetone, 2-oxo-1-bromopropane, and 

alpha-bromohydrin

None 

1-Bromopropane 

debrominated 

Phase I 

metabolites and 

their synonyms

propylene oxide, n-propanol, glycidol, and 3-

hydroxypropionate

Animals tumors

Genotoxicity

Toxicity

Mechanism

1-Bromopropane 

Phase II

metabolites

1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-Spropylcysteine, N-acetyl-S-(2-hydroxypropyl)cysteine, 

N-acetyl-S-(3-hydroxypropyl)cysteine, N-acetyl-S-(2-

carboxyethyl)cysteine, N-acetyl-S-(2-

oxopropyl)cysteine, 2,3-dihydroxypropylmercapturic 

acid, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-3-

[(2-hydroxypropyl)sulfinyl]alanine, N-acetyl-3-[(2-

oxopropyl)sulfinyl]alanine, N-acetyl-3-[(2-

propenol)sulfinyl]alanine

None

Exposure 

scenario 

(Spray* AND Adhes*) or Degreas* Human cancer studies 

a

Search terms for each of these topics were developed in consultation with an informational specialist and 

are listed in Table A-5.
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-14

Table A-5. Search terms for monograph topics for 1-bromopropane

Monograph 

Topic

Search terms used in PubMed, Scopus, and 

Web of Science

MeSH terms used in 

Pubmed

Human cancer 

studies 

Cancer search terms - cancer* OR neoplas* OR 

carcinogen* OR malignan* OR oncogene* OR 

tumor* OR tumour* OR adenoma* OR carcinoma* 

OR adenocarcinoma* OR sarcoma* OR precancer* 

OR preneoplast* OR lesion* OR cyst* OR 

lymphoma* OR leukemia* OR metastas* OR cell

transform* OR cell proliferat*

Combine with AND 

Epidemiologic study search terms - person* OR 

people OR individual* OR subject* OR participant* 

OR worker* OR employee* OR staff OR human OR 

woman OR women OR man OR men OR 

epidemiolog* OR case report* OR case control OR 

cohort OR case-referent OR registry OR prevalen* 

OR inciden*

Cancer search terms -

"neoplasms"[Mesh] OR 

"carcinogens"[Mesh]

Combine with AND 

Epidemiologic study search 

terms -

"epidemiology"[Subheading] 

OR "epidemiologic 

studies"[Mesh] OR "case 

reports"[publication type] OR 

"epidemiologic factors"[mh] 

OR "epidemiologic 

methods"[mh] OR 

"persons"[mh] OR 

"occupational diseases"[mh] 

OR "occupational 

exposure"[mh] OR "vital 

statistics"[mh]

Animal 

Tumors

Cancer search terms- cancer OR neoplasm* OR 

carcinogen* OR malignan* OR oncogene* OR 

tumor* OR tumour*

Combine with AND

Animal study search terms- animal* OR mouse OR 

mice OR rat OR hamster OR "guinea pig" OR rabbit 

OR monkey OR dog

Cancer search terms-

"neoplasms"[Mesh]) OR 

"carcinogens"[Mesh]

Genotoxicity General search terms - "genetic toxicology" OR 

genotoxic*a

Endpoint-specific search terms - clastogen* OR 

"DNA strand break*" OR "unscheduled DNA 

synthesis" OR "UDS" OR aneuploid OR aneuploid* 

OR polyploid OR polyploid* OR "neoplastic cell 

transformation" OR "chromosom* aberration*" OR 

cytogenetic OR cytogenetic* OR "DNA adduct*" OR 

"DNA damage" OR "DNA repair" OR crosslink* OR 

"germ-line mutation" OR micronucle* OR mutagen 

OR mutagen* OR mutation OR mutation* OR 

oncogen* OR "sister chromatid exchange" OR "SCE" 

OR "SOS response*" OR "Ames test" OR "gene 

expression" OR "cell proliferation" OR cytotoxic OR 

cytotoxic* OR "comet assay"

"DNA Damage"[Mesh] OR 

"DNA Repair"[Mesh] OR 

"Mutagens"[Mesh] OR 

"Mutation"[Mesh] OR 

"Cytogenetic Analysis"[Mesh] 

OR "Oncogenes"[Mesh] OR 

"Mutagenicity Tests"[Mesh]a

Toxicity toxic* OR toxin*OR cytotoxic* OR (nephrotoxic* OR 

hepatotoxic* OR pneumotoxic* OR thyrotoxic*

"Toxic Actions"[Mesh]) OR 

"Toxicity Tests"[Mesh]) OR 

"adverse effects" 

[Subheading]
Appendix A RoC Monograph on 1-Bromopropane 9/25/13

A-15

Monograph 

Topic

Search terms used in PubMed, Scopus, and 

Web of Science

MeSH terms used in 

Pubmed

Mode of action (mode* AND “of action”) OR (mechanism* AND “of 

action”) OR genetic OR epigenetic OR inhibit* OR 

promot* OR interact* OR activate* OR detoxific* OR 

“oxidative damage” OR cytotoxicity

aOnly the MeSH terms (or their equivalents (i.e., “genetic toxicology” OR genotoxic* OR “DNA Damage” 

OR “DNA Repair” OR mutagens OR mutation OR “cytogenetic analysis” OR oncogenes OR 

“mutagenicity tests”) were used in the searches for debrominated metabolites.
9/25/13 RoC Monograph on 1-Bromopropane Appendix A

A-16

This Page Intentionally Left Blank
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-17

Appendix B: Human Exposure Tables and Regulations and Guidelines

Human exposure tables 

The eight tables on the following pages contain data discussed in the “Properties and Human Exposure” section (Section 1) for the 

potential for occupational exposure (Section 1.4).

Data for 1-bromopropane exposure are reported for personal (Table B-1) and area samples (Table B-2) during adhesives applications, 

personal (Table B-3) and area samples (Table B-4) during bromopropane manufacturing, personal (Table B-5) and area samples 

(Table B-6) during dry-cleaning applications, and personal (Table B-7) and area samples (Table B-8) during vapor degreasing 

applications. The symbol “–“ shown before a range of concentration values in the tables denotes “data for mean not reported.”

Click here to return to text citing Appendix B.

Table B-1. Adhesives applications – personal samples of 1-bromopropane in air, urinary biomarkers (AcPrCys and Br), and 

1-bromopropane in blood and exhaled air

Location (source) Type of job

Number 

of 

workers

1-Bromopropane in air Urinary biomarkers

1-BP in blood, 

mean conc. 

(range), mg/L

1-BP in 

exhaled 

air, mean 

conc. 

(range), 

ppm

TWA (range), 

ppm

Short-term 

conc. 

(range), 

ppm

AcPrCys, 

mean conc. 

(range), mg/(g 

– Cr)

Bromide, 

mean conc. 

(range), 

mg/(g – Cr)

Polyurethane seat 

cushion mfr. – NC 

Hanley et al. 2005, 

Hanley et al. 2006a, 

Hanley et al. 2009c

Sprayers 13a92b(45–200) – 41.1b(14.3–

127)d

195b(119–250)e– 10.4 (3.2–

20.6)f

Non-sprayers 17a11b(0.6–60) – 10.2b(0.373–

1.5)d

42.9b(5.5–149)e– 5.8 (0.13–

12.9)f

Furniture factory –

UT Majersik et al.

2007

Cushion gluer 6 108g(92–127g) – – – [– (440–1,700)]

(values reported 

in mg/dL)

–
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-18

Location (source) Type of job

Number 

of 

workers

1-Bromopropane in air Urinary biomarkers

1-BP in blood, 

mean conc. 

(range), mg/L

1-BP in 

exhaled 

air, mean 

conc. 

(range), 

ppm

TWA (range), 

ppm

Short-term 

conc. 

(range), 

ppm

AcPrCys, 

mean conc. 

(range), mg/(g 

– Cr)

Bromide, 

mean conc. 

(range), 

mg/(g – Cr)

Furniture foam 

cushion mfr. – NC 

Harney et al. 2003, 

Toraason et al.

2006h

Exposed 

workers 

(1999 HHE) 

16 81.2b(18.1–

253.9)

– – – – –

All workers 

(2001 HHE) 

40 3.7b(0.1–

280.5)

– – [465 mg/Li

(150–5,950)]

[48i(17–435)] –

Unexposed 

workers 

(2001 HHE) 

27 1.1b(0.1–4.9) – – [285 mg/Li

(150–1,510)]

[27i(17–110)] –

Exposed 

workers 

(2001 HHE) 

13i45.7b(7.2–

280.5)

– – [1,518 mg/Li

(270–5,950)]

[149i(30–435)] –

All sprayers 

(1999 HHE) 

12 107.6b(57.7–

253.9)

– – – – –

All sprayers 

(2001 HHE) 

8 101.4b(38.0–

280.5)

– – – – –

Commercial aircraft 

industry seat cushion 

mfr. – NC 

Reh et al. 2002

All workers 

(1998 HHE) 

69 168.9 (60.0–

381.2)

– – – – –

All workers 

(2000 HHE) 

30 19.0 (1.2–58.0) – – – – –

Assembly 

workersk

(1998 HHE) 

36 169.8 (60–

250.7)

– – – – –

Assembly 

workers 

(2000 HHE) 

11 18.8 (6.1–32.0) – – – – –

Sprayers 15 193 (115.3– – – – – –
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-19

Location (source) Type of job

Number 

of 

workers

1-Bromopropane in air Urinary biomarkers

1-BP in blood, 

mean conc. 

(range), mg/L

1-BP in 

exhaled 

air, mean 

conc. 

(range), 

ppm

TWA (range), 

ppm

Short-term 

conc. 

(range), 

ppm

AcPrCys, 

mean conc. 

(range), mg/(g 

– Cr)

Bromide, 

mean conc. 

(range), 

mg/(g – Cr)

(1998 HHE) 250.7)

Sprayers 

(2000 HHE) 

12 – – (12.3–

95.8)

– – – –

Assemblers 

(1998 HHE) 

20 154.7 (60.0–

234.9)

– – – – –

Cover 

workers 

(1998 HHE) 

21 197.0 (117.3–

381.2)

– – – – –

Cover 

workers 

(2000 HHE) 

12 29.2 (2.8–58.0) – – – – –

Saw workers 

(1998 HHE) 

12 117.1 (85.1–

59.2)

– – – – –

Saw workers 

(2000 HHE) 

6 1.8 (1.6–2.0) – – – – –

Sew worker 

(2000 HHE) 

1 1.2 (–) – – – – –

Furniture company 

sofa cushion mfr. –

NC 

Harney et al. 2002, 

Toraason et al.

2006m

Sprayers 

(2000 HHE)

12

(TWA), 

9 (Shortterm)

65.9 (41.3–

143.0)

– (33.7–

173.9)

– – – –

Sprayersl

(2001 HHE) 

12

(TWA), 

10 

(Shortterm)

16.6 (8.8–31.9) – (0.2–56) – – – –
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-20

Location (source) Type of job

Number 

of 

workers

1-Bromopropane in air Urinary biomarkers

1-BP in blood, 

mean conc. 

(range), mg/L

1-BP in 

exhaled 

air, mean 

conc. 

(range), 

ppm

TWA (range), 

ppm

Short-term 

conc. 

(range), 

ppm

AcPrCys, 

mean conc. 

(range), mg/(g 

– Cr)

Bromide, 

mean conc. 

(range), 

mg/(g – Cr)

Non-sprayers 

(2001 HHE) 

10 – (1.1–5.8) – – – – –

Floaters 

(2000 HHE) 

2 – (6.3–14.1) – – – – –

Exposed 

workers 

(2001 HHE) 

7 – – – 7.7n(2.5–38.0) – –

Sprayers 

(2000 HHE)

11

(TWA), 

1 (Shortterm 

ceiling)

– – (39.5–

151.9)

Sprayers 

(2001 HHE)

10 – – (< 0.14–

8)

Furniture company 

sofa cushion mfr. –

NC Ichihara et al.

2002

Sprayers 11 133 (60–261) – – – – –

Furniture foam 

cushion mfr. – NC 

Raymond and Ford 

2007

Gluers 4 – – – – [– (240–1,000)]o–

Unidentified foam 

cushion fabricators 

Raymond and Ford 

2007

Gluers 5 – (52–137) – – – – –

Adhesives mfr. – Exposed 3

a,p 3.79b

(0.264– – 0.485b(0.111– 4.51b(1.87– – 0.10q(ND–
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-21

Location (source) Type of job

Number 

of 

workers

1-Bromopropane in air Urinary biomarkers

1-BP in blood, 

mean conc. 

(range), mg/L

1-BP in 

exhaled 

air, mean 

conc. 

(range), 

ppm

TWA (range), 

ppm

Short-term 

conc. 

(range), 

ppm

AcPrCys, 

mean conc. 

(range), mg/(g 

– Cr)

Bromide, 

mean conc. 

(range), 

mg/(g – Cr)

OH Hanley et al.

2007, Hanley et al.

2010

workers 18.9) 1.22) 12.4) 0.18)

Unexposed 

workers 

8

a,p 0.325b

(0.072–

1.59)

– 0.128b(ND–

1.33)

2.01b(0.90–

3.55)

– –

aWorkers in this study were sampled on two consecutive days so the total number of samples is twice; e.g., for sprayers in Hanley et al. 2009, N = 13 x 2 = 26.

bGeometric mean.

cRaw data from Hanley et al. 2005 field study were used for analysis in Hanley et al. 2006a and Hanley et al. 2009.

dAs cited in Hanley et al. 2009. Forty-eight hour composite urinary AcPrCys concentrations, adjusted for creatinine.

eAs cited in Hanley et al. 2006a. Forty-eight hour composite urinary bromide concentrations, adjusted for creatinine.

fCombined mean, calculated from raw data reported for Day 1 post-shift sampling for 2 plants in Hanley et al. 2005 field study. Day 2 sampling data were mostly 

similar to Day 1 data. 

g

Seven hour time-weighted average and range; mean ambient air concentration = 130 ppm (range = 91 – 176 ppm).

hToraason et al. 2006 study conducted on a sub-population of 42 workers from Marx Industries NIOSH HHE who consented to participate in the study.

iEnd-of-week concentration in mg/L; geometric mean. Values reported in mg/dL.

jExposed workers included 8 sprayers and 5 other workers who were not actively spraying.

kAs noted per Reh et al. 2002, data from 1 supervisor omitted.

lDay 2 sampling results: 11 samples, mean = 16.8 ppm, range = 7.7–29 ppm. Day 3 sampling results: 11 samples, mean = 23.3 ppm, range = 14.3–34.9 ppm. Day 

1 sampling results are shown in the table. 

mToraason et al. 2006 study conducted on a sub-population of 22 workers from STN Cushion Company NIOSH HHE who consented to participate in the study.

nEnd-of-week concentration in mg/L; geometric mean.

oValues reported as 3 – 12.5 mEq/L. Conversion factor: 8 mg/dL = 1 mEq/L, Golomb 1999. 

pAs cited in Hanley et al. 2010. 

qAs cited in Hanley et al. 2007 for Day 1 post-shift sampling for 11 total workers. Day 2 sampling data were mostly similar to Day 1 data. 

Click here to return to text citing Table B-1.
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-22

Table B-2. Adhesives applications – area samples

Location (source) Type of job/area

Number of 

samples

Mean conc. (range), 

ppm

Polyurethane seat 

cushion manufacturer, 

Plant A – NC 

Hanley et al. 2005

a

Cloth cutting 2 0.9b

Sewing, south 2 14.1b

Sewing, north 2 20.4b

Spray table 1, farthest 

north

2 68b

Pillow fill 2 16.7b

Polyurethane seat 

cushion manufacturer, 

Plant B – NC 

Hanley et al. 2005a

Main glue, south of glue 

lines

1 36.9

Main glue, between glue 

lines

1 59.4

Cutting machine cage 1 1.0

Cutting table, near 

auxiliary glue line

1 10.5

Sewing table, near 

auxiliary glue line

1 2.7

Furniture foam cushion 

manufacturer – NC 

Harney et al. 2003

Focus saw area near 

springs line (1999 HHEb)

1 8.7

Cutting area adjacent to 

glue line (1999 HHE)

1 5.3

Commercial aircraft 

industry seat cushion 

manufacturer – NC 

Reh et al. 2002

Sew department, randomly 

selected stations (1998 

HHE)

11 128.1 (107.3–160.9)

Sew department, randomly 

selected stations (2000 

HHE)

5 – (1.1–1.9)

Furniture company sofa 

cushion manufacturer –

NC 

Harney et al. 2002

Middle of the saw room 

(2000 HHE)

1 7.7

Middle of the fabrication 

room (2000 HHE)

1 7.2

Middle of the poly cut 

room (2000 HHE)

1 1.7

Non-sprayers (2001 HHE) 7 – (0.01–6.1)

Furniture factory – UT 

Majersik et al. 2007

Cushion gluing 6 130 (91–176)

a

Sampling conducted on two days; data shown for Day 1 sampling. Day 2 sampling data were mostly 

similar to Day 1 data.

bTime-weighted average; two samples were collected at each location for approximately four hours each. 

For cloth cutting, the morning (AM) sample was 0.8 ppm and the afternoon (PM) sample was 1.0 ppm. 

For sewing, south, AM sample = 6.4 ppm, PM sample = 22.1 ppm; for sewing, north, AM sample = 12.3 

ppm, PM sample = 28.8 ppm; for spray table 1, farthest north, AM sample = 43.2 ppm, PM sample = 94.0 

ppm; for pillow fill, AM sample = 9.6 ppm, PM sample = 23.9 ppm.

cHHE = Health Hazard Evaluation. NIOSH conducted health hazard evaluation surveys at three facilities in 

the adhesives use sector (Reh et al. 2002, Harney et al. 2002).

Click here to return to text citing Table B-2.
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-23

Table B-3. 1-Bromopropane manufacturing – personal samples

Location 

(Source) Type of Job

Number of 

samples

Air

TWA (Range), 

ppm

Short-term Conc. 

(Range), ppm

Mfg. plant, China 

Ichihara et al.

2004a

Operators (Female 

workers)

24 – (0.9–170.5) –

Various (Male 

workers)

13 – (NDa–43.3) –

Mfg. plant, China 

Ichihara et al.

2004b

Material/Product 

handlers (Female 

workers)

23 2.92b(0.34–49.2) –

Mfg. plants, China 

Li et al. 2010b

Material/Product 

handlers (Female 

workers)

60 6.6c(0.07–106.4) –

Material/Product 

handlers (Male 

workers)

26 4.6c(0.06–114.8) –

Mfg. plant, 

unspecified 

location Ichihara

et al. 2006

Not reported 40 15.3 (0.65–73.7) –

aNot detectable; detection limit = 0.13 ppm.

bGeometric mean.

cMedian.

Click here to return to text citing Table B-3.

Table B-4. 1-Bromopropane manufacturing – area samples

Location (source) Type of job/area

Number of 

samples

Mean conc. (range), 

ppm

Mfg. plant, China 

Ichihara et al. 2004a

Various; in front of reaction pot, in 

front of stock vessel, above bottle when 

pouring solution into bottles, product 

analysis room, site outside plant for 

washing vessel

Not reported – (1.1–90.2)

Mfg. plants, China 

Li et al. 2010b

Various; reaction pot, distillation pot, 

raw product collection

30 – (2.2–22)

Various; reaction pot, distillation pot, 

recording spot

9 – (ND–16.5)

Various; reaction pot, distillation pot, 

raw product collection

64 – (ND–88)

Various; reaction pot, operation desk, 

aisle

72 – (ND–22)

ND = Not detected.

Click here to return to text citing Table B-4.
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-24

Table B-5. Dry-cleaning applications – personal samples of 1-bromopropane

Location (source) Type of job

Number of 

samples

Air

TWA (range), 

ppm

Partial shift 

conc., ppm

(minutes)

Dry-cleaning facility 1 

Eisenberg and Ramsey 

2010

Operator 2 40 (23–56) –

Cashier 2 17 (10–24) –

Dry-cleaning shops 

Blando et al. 2010a

Operator, shop A NR – (12.7–54.55) –

Operator, shop B NR 41.64 –

Operator, shop C NR – (< 0.004–0.35) –

Clerk, shop A NR – (8.31–21.85) –

Clerk, shop B NR 0.65 –

Seamstress, shop C NR < 0.004 –

Dry-cleaning facility 2 

Eisenberg and Ramsey 

2010

Operator 1 – 7.2 (209 min)

Cashier 1 – 1.5 (212 min)

Dry-cleaning facility 3 

Eisenberg and Ramsey 

2010

Operator 1 – 11 (163 min)

Dry-cleaning facility 4 

Eisenberg and Ramsey 

2010

Operator 1 – 160 (241 min)

Cashier 1 – 2.4 (246 min)

NR = Not reported.

aRanges are reported because data points were collected over a 4-day period depending on the shop owner’s 

willingness to participate in the study (i.e., Shop A has sampling data for all 4 days, Shop B for only 1 day, 

and Shop C for 3 days).

Click here to return to text citing Table B-5.

Table B-6. Dry-cleaning applications – area samples of 1-bromopropane in air

Location (source) Type of job/area Air concentration, ppma

Dry-cleaning facility 1 

Eisenberg and Ramsey 

2010

Behind dry-cleaning machine, morning 103

Behind dry-cleaning machine, afternoon 48

In front of dry-cleaning machine, morning 66

In front of dry-cleaning machine, 

afternoon

36

Dry-cleaning facility 2 

Eisenberg and Ramsey 

2010

Behind dry-cleaning machine 1.5

In front of dry-cleaning machine 6.4

Dry-cleaning facility 3 

Eisenberg and Ramsey 

2010

Front counter 8.6
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-25

Location (source) Type of job/area Air concentration, ppma

Dry-cleaning facility 4 

Eisenberg and Ramsey 

2010

Behind dry-cleaning machine 170

In front of dry-cleaning machine 33

Dry-cleaning shops 

Blando et al. 2010

Rear left of shop by machine, shop A 17.66

Front right of shop by customer counter, 

shop B

3.8

Front left of shop by customer counter, 

shop B

2.67

Rear right of shop, shop B 3.17

Rear left of shop by machine, shop B 5.4

Rear right of shop, shop C < 0.004

Rear left of shop by machine, shop C < 0.004

Rear left of shop by machine, shop D 20.47

Unidentified New Jersey 

dry-cleaning facility 

MMWR 2008

During handling of clothes 75–250 times background 

levels

aOne measurement per location was reported.

Click here to return to text citing Table B-6.
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-26

Table B-7. Vapor degreasing applications – personal samples of 1-bromopropane in air, of urinary biomarkers (AcPrCys and 

Br

-

), and of 1-bromopropane in exhaled air

Location (source) Type of job

Number 

of TWA 

samples

1-BP in air Urine

1-BP in exhaled air, 

mean conc. (range), ppm

Mean TWA 

(range), ppm

AcPrCys, 

mean conc. 

(range), 

mg/L

Bromide, mean 

conc. (range), 

mg/L

Helicopter transmission 

factory

Hanley and Dunn 2006b

Plating (Day 1) 5

a

1.55 (0.077–

3.23) 

[2.134 (0.028–

7.551)]c

8.5 (4.7–12.5) 0.17 (0.12–0.22) 

Aerospace components 

mfr., Plant A, Plant B, 

Hanley et al. 2006bb

Cell/corrosion 

treatment, nondestructive 

testing, paint 

and wire dept. 

(Plant A) (Day 

1)

7

a

0.69 (0.19–

1.1) 

[0.25 (0.0156–

0.883)]c

4.1 (1.9–8.1) 0.23 (0.12–0.38) 

Assembly prep, 

repair-overhaul, 

paint and wire 

dept. (Plant B)

(Day 1)

4

a

1.5 (0.82–2.1) [1.35 (0.607–

2.390)]c

14 (7.6–21) 0.23 (0.11–0.33) 

Hydraulic power control 

component mfr.

Hanley and Johnson 

2007bb

Assembly dept.

(Day 1)

4

a

0.85 (0.22–

1.4) 

[1.01 (0.15–

3.21)]c

3.9 (1.1–7.9) – (ND–0.20d) 

Optical prism and 

assemblies mfr.

Hanley and Dunn 2007b

Milling and 

maintenance 

workers (Day 1)

7

a

5.1 (0.52–9.8) [2.52 (0.289–

5.92)]c

13 (3.7–23) 0.90 (0.10–2.5) 

Printed electronics circuit 

assembly mfr.

Assembly dept.

(Day 1)

5

a

7.0 (1.3–14) [5.54 (0.351–

13.3)]c

34 (8.6–67) 2.9 (0.30–6.1) 
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-27

Location (source) Type of job

Number 

of TWA 

samples

1-BP in air Urine

1-BP in exhaled air, 

mean conc. (range), ppm

Mean TWA 

(range), ppm

AcPrCys, 

mean conc. 

(range), 

mg/L

Bromide, mean 

conc. (range), 

mg/L

Hanley and Johnson 

2007ab

Facilities in the five rows 

shown above, near 

degreasers and away from 

degreasers

Hanley et al. 2010b

Near degreasers

(Day 1)

22a2.63e(0.078–

21.4)

1.33f(0.0108–

24.2)

8.94f(1.69–115) –

Away from 

degreasers (Day 

1)

9

a

0.308e(0.077–

1.69)

0.115f

(0.00512–

0.726)

3.74f(1.69–15.6) –

Below-boiling vapor 

degreaser

Reh and Nemhauser 2001

Assembler 20 – (0.01–0.63) – – –

aNumber of workers is reported; note that each worker was sampled on two consecutive days so the total number of samples is x 2; e.g., for Hanley and Dunn 

2006, N = 5 x 2 = 10.

bRaw data for TWA air concentrations and urinary bromide and AcPrCys concentrations from Hanley and Dunn 2006, Hanley et al. 2006b, Hanley and Dunn 

2007, Hanley and Johnson 2007a, and 2007b field studies were used for summary analysis presented in Hanley et al. 2010. Data categorized by workers “near 

degreasers” and “away from degreasers” not presented in Hanley and Dunn 2006, Hanley et al. 2006b, Hanley and Dunn 2007, Hanley and Johnson 2007a, and 

2007b field studies.

cData reported in μg/L.

dND = not detected. 1-Bromopropane was only detected in one sample for this collection period.

eGeometric mean.

fGeometric mean. Forty-eight hour composite concentration, adjusted for creatinine; units are mg/(g-Cr).

Click here to return to text citing Table B-7.
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-28

Table B-8. Vapor degreasing applications – area samples

Location (source) Type of job/area Air concentration, ppma

Vapor degreaser

Reh and Nemhauser 

2001

On exhaust duct above degreaser 4.42

On cart, 5 feet from degreaser 1.70

Outside of cleaning room (5 samples) 0.02–0.03

On metal rack, near degreaser room door 0.02

Near degreaser room window 0.02

Five feet from degreaser room window 0.02

Office next to degreaser room 0.02

aOne measurement per location was reported.

Click here to return to text citing Table B-8.
Appendix B RoC Monograph on 1-Bromopropane 9/25/13

A-29

Regulations and guidelines

Table B-9. Existing U.S. standards and guidelines with exposure limits for 1-bromopropane (ppm)a

Type of Guideline

Duration of exposure

8 hours

Threshold Limit Value Time 

Weighted Average (ACGIH) 10

Permissible Exposure Limit (PEL) 

– Time Weighted Average 

(California OSHSB)

5

Acceptable Exposure Limit – Time 

Weighted Average 

(EPA)b

25

aAs cited in CDC 2008, FR 2003.

bThe EPA acceptable exposure limit is a non-binding, recommended, voluntary workplace exposure limit. Because there is currently no OSHA PEL for 

1-bromopropane, EPA – under the Significant New Alternatives Policy (SNAP) program – determined a safe workplace exposure to evaluate whether the use of 

1-bromopropane would pose significantly greater risk than the use of other substitutes available in the same end uses, EPA 2007. 

Note: The EPA SNAP program reviews alternatives to ozone-depleting substances and approves the use of alternatives that do not 

present substantially greater risk to the public health and environment than the substance they replace or other available substitutes. 

Table B-10 lists EPA SNAP program determinations regarding different end uses of 1-bromopropane (EPA 2007, FR 2007 -

information is current as of 1/18/13).
9/25/13 RoC Monograph on 1-Bromopropane Appendix B

A-30

Table B-10. EPA SNAP program determinations regarding different end uses of 1-bromopropane

1-bromopropane end use Substitute EPA SNAP program determination

Solvent in industrial equipment 

for metals cleaning, electronics 

cleaning, or precision cleaning

1-bromopropane as a 

substitute for CFC–113 and 

methyl chloroform

Acceptablea

Coatings 1-bromopropane as a 

substitute for CFC–113, 

HCFC–141b, and methyl 

chloroform

Acceptable subject to the use condition that use is 

limited to coatings facilities that have provided EPA 

data which demonstrates their ability to maintain 

acceptable workplace exposuresb

Aerosol solvents 1-bromopropane as a 

substitute for CFC–113, 

HCFC–141b, and methyl 

chloroform

Unacceptableb

Adhesives 1-bromopropane as a 

substitute for CFC–113, 

HCFC–141b, and methyl 

chloroform

Unacceptableb

aEPA final rule, EPA 2007.

bEPA proposed rule, FR 2007.

Note: The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) of an 8-hr timeweighted average of 10 ppm is being considered for a change to 0.1 ppm in the Notices of Intended Changes (NIC) for the 2013 TLVs 

(ESIS 2012). Exposure limits proposed by vendors of 1-bromopropane–based products range from 5 to 100 ppm (EPA 2007).

Click here to return to text citing Table B-10.
Appendix C RoC Monograph on 1-Bromopropane 9/25/13

A-31

Appendix C: Assessment of the Quality of the 

Individual Animal Cancer Studies 

Only two studies were identified that met the inclusion criteria and these studies was 

evaluated for study quality. Because similar protocols were used for the NTP 2-year 

bioassays in rats and mice and results of assessments were similar, the studies are 

considered together in the table below. Each primary study was systematically evaluated 

to determine if it is informative for a cancer assessment. Studies that were given the most 

weight in the evaluation are those that were of sufficiently long duration to identify a 

cancer endpoint (ideally an exposure approaching the lifetime of the animal), and 

provided a detailed account of the study design and data collection. Ideally, studies 

should use an exposure route comparable to human exposure and appropriate statistical 

methods in reporting of results. Comparison with historical control values is sometimes 

helpful in assessing the significance of a finding, especially in the case of rare tumors, 

lower powered studies, or assessment of background tumor incidences. The number of 

animals used in a study, the incidence of tumors in control vs. treated group, and the 

rarity of a tumor influence the statistical power of a study to detect an effect and are 

parameters that need to be taken into account in study design and results assessment. Post 

hoc power calculations can be performed. However, rare tumors will be considered in the 

assessment even if their incidence does not reach significance. Study performance 

elements for evaluating the different components of study quality are described below. 

Click here to return to text citing Appendix C in the foreward.

Click here to return to text citing Appendix C in Section 4.

NTP TR 564 Inhalation Toxicology and Carcinogenesis Studies of 

1-Bromopropane (CAS No. 106-94-5) in Rats and Mice

Substance characterization

Independent experiments were conducted in rats and mice 

at Battelle Toxicology Northwest (Richland, WA)

Is the chemistry of the substance 

well characterized?

Are the purity, solubility and 

stability adequate for attributing 

any adverse effects to the 

substance? 

Yes. Overall purity of the chemical was determined by gas 

chromatography and three impurities were identified as 1-propanol 

(0.03%), 2-bromopropane (0.02%), and di-n-propylether (0.02%); 

stability of bulk chemical, and vapor concentration throughout the 

experiment monitored against a standard by gas chromatography. 

Animal husbandry 

Are the source, species, and strain 

of the animals adequately 

described?

Yes. Rats (F344/N) and mice (B6C3F1) were from Taconic Laboratory 

Animals and Services (Germantown, NY).

Are the care, diet, housing and 

maintenance of the animals 

adequate for attributing any 

adverse effects to the substance?

Yes. The studies were conducted in and Association for Assessment 

and Accreditation of Laboratory Animal Care (AAALAC) inspected 

and approved facility; testing was also done on bedding, water and diet 

for possible chemical contamination; sentinel animals were used and 
9/25/13 RoC Monograph on 1-Bromopropane Appendix C

A-32

sera tested for subclinical disease.

Were control animals housed in 

the same room, and tested at the 

same time under the same 

conditions as the dosed groups?

Yes. Each animal was housed individually. Animal care and 

maintenance were described.

Study design

Animal model: Are the species 

and sex appropriate for 

determination of any exposurerelated effect? Were the dose 

groups randomized?

Yes. Rats and mice of both sexes were tested; there is an adequate 

historical control database on these species and strains for inhalation 

studies from this laboratory. 

Dosing and observation 

conditions: Are the study period, 

dosing period, route of exposure, 

and doses used adequate for 

determination of any adverse 

effect? 

Yes. The animals were exposed throughout most of their lifespan (2 

yr) by inhalation at a route relevant to human exposure.

Statistical Power: Does the study 

have adequate number of animals 

per group to detect an adverse 

effect, if present? 

These studies follow NCI/NTP guidelines with respect to number of 

animals (Haseman JK. 1984. Environ Health Perspect, 58: 385-392). 

Whether the adverse effect is statistically significant will depend on 1) 

what the tumor endpoint is and 2) the incidence of spontaneous tumors 

for that endpoint. Based on available historical NTP control data, skin 

tumors and intestinal adenomas in rats and the lung tumors in mice 

were were detected at approximately 70% power; mesotheliomas and 

pancreatic islet-cell tumors in rats were below 50% power.

Clinical observations, 

necropsy and pathology

Were clinical observations 

performed?

Yes. A timetable of clinical observations was reported.

Was a full necropsy done on 

these animals and was 

histopathology done on tissues 

from at least all major organs?

Yes. Complete necropsies were done on all animals. All organs and 

tissues were examined for gross lesions and complete histopathology 

was performed on all major organs.

Are pathology procedures well 

described and adequate for 

determination for any exposurerelated effect?

Yes, tissue fixation method, microscopic evaluations and quality 

assessment of the data are presented. 

Data reporting and 

statistical methods 

Is data reporting well 

characterized? 

Yes. Data are presented in a tabular format; individual animal data are 

provided in appendices.

Have tumors (benign/malignant) 

from the same organ been

appropriately combined? If so, do 

they originate from the same cell 

type? e.g., fibrosarcoma would 

not be combined with adenoma.

Yes (Rats)

Yes (Mice)

Were statistical analyses 

performed on the data and 

adequately described? 

Yes (Rats)

Yes (Mice)
Appendix C RoC Monograph on 1-Bromopropane 9/25/13

A-33

Are appropriate historical control 

data available? 

Historical control values for studies by inhalation and by all routes are 

reported.

Are these studies

informative for cancer 

assessment?

Yes (Rats)

Yes (Mice)

No major limitations on cancer study quality were found. 
9/25/13 RoC Monograph on 1-Bromopropane Appendix C

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Appendix D RoC Monograph on 1-Bromopropane 9/25/13

A-35

Appendix D: Genotoxicity Studies

The five tables on the following pages contain data discussed in the “Mechanisms and Other Relevant Effects” section (Section 5) for 

genetic and related effects (Section 5.1).

Data are reported for in vitro studies of 1-bromopropane mutagenicity in bacteria (Table D-1), in vitro genotoxicity studies of 1-

bromopropane in mammalian cells (Table D-2), in vivo studies of cytogenetic effects of 1-bromopropane in rodents (Table D-3), in 

vivo studies of cytogenetic effects of 1-bromopropane in humans (Table D-4), and a summary of in vitro and in vivo studies of 

genotoxicity of 1-bromopropane metabolites (Table D-5).

Click here to return to text citing Appendix D.

Table D-1. In vitro studies of 1-bromopropane mutagenicity in bacteria

Reference Strain Method 

LED/HID Results Cytotoxicity 

Evaluation: limitations 

and conclusionsa– S9 + S9 – S9 + S9 – S9 + S9

Barber et al.

1981

S. typhimurium 

TA98, TA100

TA1535

Plate 

incorporation; 

closed-system 

incubation 

TA98 (HID)

2,497 

μg/plateb

TA100 

(LED) 

1107 

μg/plateb

TA1535

(LED) 

603 

μg/plateb

TA98

(HID)

2,497

μg/plateb

TA100 

(LED) 

1107 

μg/plateb

TA1535

(LED)

603 

μg/plateb

–

+

+

–

+

+

NR

NR

NR

NR

NR

NR

No toxicity was observed

up to and including the 

highest dose tested (2,497 

μg/plateb) for each strain. 

For strains showing 

mutagenicity, positive 

effects were observed at 

the same doses for with or 

without S9.

Test results with other 

strains, TA1537 and 

TA1538, reported as

negative (data not 

provided by study 

authors).
9/25/13 RoC Monograph on 1-Bromopropane Appendix D

A-36

Reference Strain Method 

LED/HID Results Cytotoxicity 

Evaluation: limitations 

and conclusionsa– S9 + S9 – S9 + S9 – S9 + S9

Elf Atochem 

1994, as cited 

in NTP 2003a

S. typhimurium

TA98, TA100, 

TA1535,

TA1537,

TA1538

Protocol (plate 

incorporation

or 

preincubation) 

not specified; 

closed-system 

incubation

10,000 

μg/plate

10,000 

μg/plate

– – 10,000 

μg/plate

10,000 

μg/plate

A brief description of this 

study was presented in the 

NTP 2003 review, but 

protocol not specified, 

and number of replicate

plates and resultant data 

(i.e., numbers of 

revertants/ plate for each 

dose of the tested strains) 

were not provided. 

Insufficient information to 

evaluate because protocol 

not specified.

Kim et al.

1998, as cited 

in NTP 2003a

S. typhimurium

TA98, TA100 

TA1535,

TA1537

and

Protocol not 

specified and 

no indication if 

closed-system 

was used

5,000 

μg/plate

5,000 

μg/plate

– – NR NR A brief description of this 

study was presented in the 

NTP 2003 review, but the 

protocol was not specified 

and details on methods 

(e.g., solvent) and 

observations regarding 

cytotoxicity were not 

given. Also, the number 

of replicate plates and 

resultant data (i.e., 

numbers of revertants/

plate for each dose of the 

tested strains) were not 

provided.

Insufficient information to 

evaluate because protocol 

not specified.

E. coli

WP2uvrA

5,000 

μg/plate

5,000 

μg/plate

– – NR NR
Appendix D RoC Monograph on 1-Bromopropane 9/25/13

A-37

Reference Strain Method 

LED/HID Results Cytotoxicity 

Evaluation: limitations 

and conclusionsa– S9 + S9 – S9 + S9 – S9 + S9

NTP 2011a

(two studies, 

independent 

contract labs) 

Study 1

S. typhimurium

TA97, TA98, 

TA100, 

TA1535

Preincubation All strains: 

10,000 

μg/plate, but 

≥ 3,333 

g/plate was 

too toxic to 

evaluate

All strains: 

10,000 

μg/plate,

but ≥ 3,333 

g/plate was 

too toxic to 

evaluate

– – ≥ 3,333 

g/plate

≥ 3,333 

g/plate

All strains were tested to 

10,000 μg/plate; unable to 

adequately evaluate 

mutagenicity at doses 

≥ 3,333 μg/plate due to 

high toxicity. 

Not mutagenic at nontoxic doses. 

+S9: 10% and 30% rat or 

hamster.

Study 2 used same 

chemical lot as 2-year 

NTP bioassay.

Not mutagenic.

Study 2

S. typhimurium

TA98, TA100

Preincubation Both strains: 

5,000 

μg/plate

Both strains: 

10,000 

μg/plate

– – ≥ 3,500 

μg/plate

TA98: 

10,000 

μg/plate

+S9: 10% rat.

TA100: not toxic at 

highest dose (10,000 

μg/plate) tested. 

Not mutagenic.

E. coli

WP2uvrA/ 

pKM101

Standard 

protocol

5,000 

μg/plate

10,000 

μg/plate

– – ≥ 5,000 

μg/plate

+S9: Not toxic at highest 

dose (10,000 μg/plate) 

tested.

Not mutagenic.

LED/HID = lowest effective dose/highest ineffective dose, NR = not reported, + = positive, – = negative.

aEvaluations of some studies (as indicated) presented in this table are limited by the information provided in the cited review paper.

bReported dose levels of 1-bromopropane were determined by using gas liquid chromatography to analyze samples of distilled water that were in the test 

chambers during treatment. To facilitate comparison with other studies, data reported by these authors as μmoles per plate were converted to μg/plate. 

Click here to return to text citing Table D-1.
9/25/13 RoC Monograph on 1-Bromopropane Appendix D

A-38

Table D-2. In vitro studies of 1-bromopropane in mammalian cells 

Reference Effect Test system

Concentration

(LEC or HIC) Cytotoxicity

Results Evaluation: limitations and 

conclusionsa

-S9 +S9

Elf 

Atochem 

1994, cited 

in NTP

2003a

Mutation L5178Y mouse 

lymphoma cells

(2 experiments)

-S9: 1,000mg/L

+S9: 1,500 

mg/L

≥ 2,000 mg/L 

(10%–60% 

RTG)

+ + Adequate information provided 

in NTP review on methodology; 

reproducible two-fold increase in 

mutation frequency and evidence 

of dose response, but actual 

numbers of revertant colonies 

not available.

Evidence of mutagenicity.

Toraason et 

al. 2006

DNA 

damage 

(dose 

response)

Comet assay, 

using human 

leukocytes from 

venous blood 

from unexposed 

adult males.

LEC = 1 mM

8-hr exposure

Dose Comet tail 

(mM) momenta

0 1000

0.01 1000

0.1 1250

1.0 3500*

ND Did not perform assays in 

presence of S9, since Barber et 

al. 1981 had previously shown 

1-bromopropane to be mutagenic 

with or without added metabolic 

activation in the S. typhimurium

assay.

DNA Evidence of DNA damage.

damage 

(temporal 

response)

Comet assay, 

using human 

leukocytes from 

venous blood 

from unexposed 

adult males.

LEC = 1 mM 

4-hr exposure

Exp Comet tail

(hr) momenta

1 750

2 750

4 1250*

8 3250*

ND

Apoptosis DNA diffusion 

assay using 

human leukocytes

LEC = 0.1 mM Dose Apoptotic 

(mM) cells (%)a

0 2.75

0.01 2.50

0.1 3.25*

1.0 4.75*

ND

Exp = Exposure, LEC/HIC = lowest effective concentration/highest ineffective concentration, ND = not done, RTG = relative total growth.

*P < 0.05 (ANOVA).

aData estimated from graph.

Click here to return to text citing Table D-2.
Appendix D RoC Monograph on 1-Bromopropane 9/25/13

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Table D-3. In vivo studies of cytogenetic effects of 1-bromopropane in rodents

Reference Endpoint Species/sex/# Exposure Results Comments and evaluationa

Kim et al. 1998, 

cited in NTP 

2003a

Micronuclei Rat (SpragueDawley)

bone marrow 

males and females 

10 animals/

sex/group 

Inhalation 

0, 50, 300, 1,800 

ppm

6 hr/day for 5 

days/week for 8 

weeks 

No increases in bone 

marrow micronucleated 

polychromatic erythrocytes 

Information limited to that 

provided in summary of study in 

review; values for micronuclei 

were not provided.

NTP 2003a stated that animals 

exposed to 1,800 ppm had 

decreased bodyweight and ataxia.

Treatment doses differed by a 

factor of 6; intermediate doses 

might have been informative.

Negative.

Elf Atochem 

1994, cited in

NTP 2003a

Micronuclei Mouse (Swiss 

mice) bone 

marrow 

males and females

5 animals/

sex/group 

Intraperitoneal 

injection 

M: 0, 100, 400, 

600, 800 mg/kg

F: 0, 100, 400, 

800 mg/kg 

Two injections; 

animals sacrificed 

24 hr after last 

injection. 

Bone marrow 

micronucleated 

erythrocytes 

M: 600 mg/kg - no 

increases

F: 800 mg/kg - no 

increases 

Information limited to that 

provided in summary of study in 

review; values for micronuclei 

were not provided.

Only 800 mg/kg for females and 

600 mg/kg for males were 

evaluated for micronuclei 

because the PCE/NCE ratio in 

controls from other doses (100, 

400) were outside the historical 

control range

Negative.
9/25/13 RoC Monograph on 1-Bromopropane Appendix D

A-40

Reference Endpoint Species/sex/# Exposure Results Comments and evaluationa

NTP 2011a Micronuclei Mouse (B6C3F1) 

peripheral blood 

erythrocytes

males and females

5 animals/

sex/group

Inhalation: 3 mo

0 ppm

62.5

125

250

500

NCEb

Males Females

2.00 0.61 1.80 0.25

3.10 0.81 1.70 0.25

2.70 0.64 1.60 0.19

1.30 0.41 1.40 0.33

2.30 0.46 1.80 0.20

Percent of polychromatic 

erythrocytes (reticulocytes) was 

unaltered indicating a lack of 

bone marrow toxicity.

Negative.

Saito-Suzuki et 

al. 1982

Dominant 

lethal 

mutation 

assay

Rat (SpragueDawley) 

15 exposed males

mated with

females (1 female/ 

week/male) for 8 

weeks, examined 

vital status of 

fetuses 13-14 days 

after mating

Gavage

400 mg/kg 

5 days

Week DLMIc

1 -2.1

2 1.8

3 0.4

4 1.3

5 3.3

6 8.0

7 0.9

8 9.3

An increase in the number of 

dead implants in fetuses from rats 

mated 8 weeks after 

1-bromopropane exposure 

compared with controls was 

observed but the mutational index 

was not increased.

Negative.

Yu et al. 2008 Dominant 

lethal 

mutation 

assay

Mouse (ICR) 20 

males/exposure 

group, mated with

40 unexposed 

females (2 

females/week/

male) for 6 weeks; 

examined vital 

status of fetuses at 

15 to 17 days 

gestation

Gavage

Males exposed to 

300 or 600 

mg/kg/day 

10 days

Week DLMRd

300 600

1 0.17 -0.26

2 2.17 0.88

3 0.3 -2.71

4 3.14 -2.03

5 2.98 -4.66

6 3.68 0.27

Negative.

DLMI = Dominant Lethal Mutation Index, DLMR = Dominant Lethal Mutation Rate, NCE = normochromatic erythrocytes.

aEvaluations of some studies (as indicated) presented here are limited by the information provided in the cited review paper.

bMicronucleated NCEs/1000.

c

(1-live embryos per test female/live embryos per control female) x 100.

d

(1-[{mean of live fetuses in treated group/mean of implants in treated group} x {mean of implants in controls/mean of live fetuses in controls}]) x 100.

Click here to return to text citing Table D-3.
Appendix D RoC Monograph on 1-Bromopropane 9/25/13

A-41

Table D-4. In vivo studies of 1-bromopropane in humans

Reference Effect

Population and 

analyses Exposure Results

Evaluation: limitations and

conclusions

Toraason

et al. 2006

DNA damage 

Comet assay: 

Tail moment 

and 

dispersion 

coefficientsa; 

100 

leukocytes 

per sample

Population

64 workers (18 males 

and 46 females) at two 

spray adhesive 

facilities (A and B)

Facility A (42)

29 non-sprayers 

13 sprayers

Facility B (22)

16 non-sprayers

6 sprayers 

Analyses

Exposure to 

1-bromopropane and 

DNA damage were 

evaluated by analyses 

involving (1) facility 

and job type, and (2) 

exposure indices 

(workplace air, urine 

and serum) in 

multivariate models 

controlling for age, 

gender, facility, 

cigarette smoking and 

GSTM1 and GSTT1 

polymorphisms. 

Exposure assessed by TWA (ppm) and 

bromide serum (mg/dL) and urine levels 

(mg/dL). 

Facility/ TWA Urineb Serumb 

worker

A/NS 2 ± 2 28 ± 9 2.6 ± 0.7

A/SP 83 ± 85 238 ± 17 19.5 ± 11.4

B/NS 5 ± 1 2 ± 2 0.3 ± 0.1

B/SP 21 ± 5 10 ± 14 0.9 ± 0.3

TWA significantly correlated with both 

start-of-week and end-of-week urine and 

serum bromide concentrations

Analysis by work type and 

facility 

Facility A

NS SP

TM/Start 2517 2867

TM/End 3080* 3178

TMD/Start 562 496

TMD/End 678 752*

Facility B

NS SP

TM/Start 2856 3430

TM/End 2770 2974

TMD/Start 580 596

TMD/End 653 616

Analysis by exposure 

indices 

Tail moment - P values

Start End

TWA (log) 0.654

0.148d

Urine (log) 0.075c

0.108d

Serum (log) 0.191

0.171d

TWA (EQ) 0.567

0.016d

Urine (EQ) 0.106c0.141

Serum (EQ) 0.007c

0.049d

Dispersion coefficient – no 

statistically significant 

End-of-the-workweek DNA 

damage (TMD) was higher, 

albeit not statistically 

significant, among workers 

(sprayers and non-sprayers) at 

both facilities with GSTM1-

positive genotypes. In 

multivariate analysis, GSTM1 

had a significant effect in 

models of end-of-workweek 

DNA damage (TMD) and 

1-bromopropane TWA logtransformed levels.

The exposure quartile analyses 

might have had greater 

statistical power than the 

models using log-transformed 

values since participants with 

missing data for one exposure 

indices could be included in the 

analyses based on their ranking 

for another exposure indices.

Strengths: Wide range of 

exposures allowed for 

evaluation of exposure 

response. Assessment of

1-bromopropane exposure was 

at the individual level. 

Multivariate analyses was 

considered to be more 

informative than the analysis by 

job and facility 

Limitations: Small numbers of 
9/25/13 RoC Monograph on 1-Bromopropane Appendix D

A-42

Reference Effect

Population and 

analyses Exposure Results

Evaluation: limitations and

conclusions

associations observed 

between DNA damage and 

exposure to 

1-bromopropane in any of 

the models.

subjects, no unexposed 

controls, multiple comparisons.

Conclusion: Limited evidence 

that exposure to 

1-bromopropane causes DNA 

damage in leukocytes from 

workers. 

EQ = exposure quartiles model, ppm = parts per million, NS = non-sprayer, SP = sprayer, TWA = time weighted average, TM = tail moment, TMD = tail 

moment dispersion coefficient.

*End-of-the-workweek measures significantly higher than start-of-the-workweek measures for the same individual (paired t-test, P < 0.05).

aDispersion coefficient = variance divided by mean of tail moment from 100 leukocytes.

bEnd of week measure.

c

Significant association of facility in model.

d

Significant association of gender in model.

Click here to return to text citing Table D-4.
Appendix D RoC Monograph on 1-Bromopropane 9/25/13

A-43

Table D-5. Summary of in vitro and in vivo studies of 1-bromopropane metabolites

Test System Effect

Glycidol

Propylene 

oxide

-

Bromohydrin

3-Bromo-1-

propanol

1-Bromo-2-

propanol

-S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9

In vitro

Bacteria

Mutation#+

a

+

a

+

b

+

b

+

c, d +c, d +*, d +*, d

DNA damage +

a

+

*b

+

*, b +*, e

+

*, e

DNA adducts +

f, g

Yeast Mutation +

a

+

*, a +b

+

*, b

Gene conversion +

*, b

Insects Mutation +

*, a +b, h, i

Heritable translocation +

*, a

DNA adducts +

*, h

Mammalian cells 

(other than 

human)

Mutation +

a

+

*, a +b

Chromosomal damage +

a

+

a

+

b

+

*, b

DNA damage +

a, j

+

*, a +b

+

*, b

DNA adducts +

*, a +*, k

Human cells Chromosomal damage +

*, a +b

DNA damage +/–

a

+

*, a +b, l, m, n

In vivo

Mammals 

(rodents, dogs, 

monkeys)

Mutation (germ cell) –

b

Chromosomal damage +/–

a

+/–

b

DNA adducts +

b, k, o, p, q

Binding to protein +

b, p, r

Human: exposed 

workers

Chromosomal damage ?

b

DNA damage +

*, s

DNA adducts +

b, s

Binding to protein +

b, s

Sources: aIARC 2000, 

b

IARC 1994, 

c

Stolzenberg and Hine 1979, 

d

Stolzenberg and Hine 1980, 

eHyman et al. 1980, fMazon et al. 2009, g

Snow et al. 1994, 

hNivard et al. 2003, iVogel and Nivard 1997, jEl Ramy et al. 2007, k

Plna et al. 1999, 

lChovanec et al. 2001, mKolman et al. 1997, n

Fabiani et al. 2012,

o

Segerbäck et al. 1998, 

pRíos-Blanco et al. 2000, qRíos-Blanco et al. 2003, rCouch et al. 1996, sCzene et al. 2002.

+ = Positive in all or most of available studies; – = negative in all or most of available studies; +/– = available studies are mixed positive and negative, 

? = inconclusive (variable response in adequate study).

#Mutation test results were positive for multiple bacterial strains, except for -bromohydrin, which was positive for S. typhimurium TA100 but not TA98, and for 

3-bromo-1-propanol, which was only tested in TA100. 

*Result is based on one study.

Click here to return to text citing Table D-5.
9/25/13 RoC Monograph on 1-Bromopropane Appendix D

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Appendix E RoC Monograph on 1-Bromopropane 9/25/13 

A-45

Appendix E: Relevant Toxicological Effects 

Studies on neurological, developmental, reproductive, immunological, and hepatotoxic 

effects were identified to determine whether they could inform potential mechanisms of 

carcinogenicity. Several studies indicate that metabolic activation and glutathione 

depletion are important factors for many of the toxic effects observed in rodents. 

Appendix E provides a brief review of the toxic effects that have been linked to 

metabolic activation and/or glutathione depletion and oxidative stress and other 

alterations and provides background information for Section 5.3, which discusses these 

mechanisms as they related to carcinogenicity. 

Click here to return to text citing Appendix E in Section 4. 

Click here to return to text citing Appendix E in Section 5. 

Click here to return to text citing Appendix E in Section 6. 

Reproductive toxicity 

NTP (2003a) evaluated the reproductive toxicity of 1-bromopropane. There was 

convincing evidence that 1-bromopropane caused reproductive effects in experimental 

animals but the evidence in humans was limited to a health hazard survey conducted by 

NIOSH at a plant that used a spray adhesive that contained 1-bromopropane. Three of 42 

workers reported fertility problems (2 males and 1 female). Ichihara et al. (2002) 

presented case reports for three female workers who used a spray gun with 1-

bromopropane as a solvent. Most of the symptoms and signs were neurological in nature 

but two of the women reported irregular periods and decreased sexual desire. 

NTP (2003a) also reviewed a two-generation reproductive toxicity study that reported 

significant effects in males, females, and offspring. Reproductive capabilities were 

examined in the F0 and F1 generations, and neonatal survival, growth, and development 

were evaluated in the F1 and F2 offspring. Whole-body inhalation exposures (6 hours/day, 

7 days/week at nominal concentrations of 100, 250, 500, or 750 ppm) began at 7 weeks 

of age for the F0 parents and at weaning for the F1 generation. Exposures began at least 

70 days prior to mating. Prior to weaning on postnatal day 22, the F1 offspring were 

indirectly exposed to the test chemical in utero and through nursing. Effects in F0 parents 

included reduced sperm motility and prostate weight, abnormal sperm, increased estrous 

cycle length and ovarian follicular cysts, decreased numbers of implantation sites and 

litter size, and complete infertility in the high-dose group (750 ppm). Reproductive 

effects in F1 offspring were similar. The only significant effect reported in the F2 rats was 

reduced postnatal weight gain. Other studies reported that Wistar rats exposed to 

1-bromopropane for 12 weeks had decreased sperm count and sperm motility, irregular 

estrous cycles, and a decrease in the number of normal growing follicles (NTP 2003a, 

2011a). 

Some of the reproductive effects have been linked to metabolic activation. Garner et al.

(2007) investigated the relationship between 1-bromopropane oxidative metabolism and 
9/25/13 RoC Monograph on 1-Bromopropane Appendix E

A-46

sperm toxicity in mice. Wild-type and Cyp2e1–/–(knockout) mice (4 per group) were 

exposed to [1,2,3-

13C]-1-bromopropane at 800 ppm for 6 hours in an inhalation chamber. 

In addition, ex vivo experiments were conducted using caudal sperm (collected from the 

cauda epididymis) from unexposed wild-type and knockout mice incubated with either 

1-bromopropane or its metabolite 1-bromo-2-hydroxypropane (1-bromo-2-propanol) in a 

sealed test tube. Exposed wild-type mice had a 37% reduction in the percentage of motile 

sperm compared with unexposed controls (Table E-1a). In contrast, the percentage of 

motile sperm in exposed knockout mice was not significantly different from unexposed 

controls. In addition, liver glutathione levels were reduced by 76% in exposed wild-type 

mice compared with 47% in exposed knockout mice (Table E-1a). Epididymal sperm 

were isolated from unexposed wild-type and knockout mice and were incubated with 

0.05 mM 1-bromopropane or 1-bromo-2-hydroxypropane for 2 hours (Table E-1b). 

Sperm isolated from wild-type mice had significantly reduced motility when incubated 

with either test compound. In contrast, sperm from knockout mice did not show a 

significant change in motility when incubated with 1-bromopropane but motility was 

significantly reduced when incubated with 1-bromo-2-hydroxypropane. The authors did 

not address the apparent differences in sperm motility between wild-type and knockout 

mice in the control groups for the ex vivo experiment. Although the sample sizes used in 

these experiments were small, these data suggest that products of CYP2E1-mediated 

oxidation of 1-bromopropane (specifically 1-bromo-2-hydroxypropane) contribute to 

male reproductive toxicity.

Table E-1a. 1-Bromopropane effects on sperm motility and glutathione levels in 

wild-type or Cyp2e1–/– mice

Genotype Dose (ppm)

% Motile sperm

(N = 8)

GSH (mM ± SE)

(N = 3 to 4)

Wild-type 0

800

% change

63

40*

–37

10.6 ± 1.7 

 2.6 ± 2.5**

–76

Cyp2e1

–/–

0

800

% change

57

48

–16

13.8 ± 1.4

7.36 ± 1.0*

–47

Source: (Garner et al. 2007).

* P < 0.05 (compared with unexposed controls).

** P < 0.01 (compared with unexposed controls).

Table E-1b. Sperm motility following 2-hour incubations with 1-bromopropane 

or 1-bromo-2-hydroxypropane

Genotype

% Motile sperm (N = 3)

Control 1-Bromopropane 1-Bromo-2-hydroxypropane

Wild-type 73 39* 26*

Cyp2e1

–/–

57 43 23*

Source: (Garner et al. 2007).

* P < 0.05 (compared with unexposed controls, 3 animals/group).
Appendix E RoC Monograph on 1-Bromopropane 9/25/13 

A-47

These authors believed that reduction of sperm motility might be mediated by disruption 

of energetic pathways by metabolites (bromoacetone and -bromohydrin) derived from 

CYP-mediated oxidation of 1-bromo-2-hydroxypropane (see Figure 2-3). Studies with -

bromohydrin and its chlorinated analogue have shown that these compounds are 

converted in situ by spermatozoa into halolacetates. Halolacetates are metabolic 

inhibitors that can cause reduced sperm motility. Bromoacetone also may be further 

metabolized either to 1-hydroxy-1-bromoacetone, ultimately forming pyruvate and CO2, 

or 3-bromo-1-hydroxypropanone. 3-Bromo-1-hydroxypropanone can inhibit sperm 

motility by conversion to bromolactaldehyde and bromopyruvaldehyde, and ultimately 

yielding the metabolic poison bromopyruvate. 

Neurotoxicity 

Neurotoxic effects of 1-bromopropane were first described in rats and were later used to 

identify and analyze the initial human cases (Ichihara et al. 2011, Li et al. 2010b, MeyerBaron et al. 2012). Although the molecular mechanisms of neurotoxicity are not 

completely understood, recent studies show that the hippocampus is especially 

susceptible to 1-bromopropane–induced effects and involves oxidative stress, loss of 

ATP production, altered GABA metabolism and reduced GABAergic feedback 

inhibition, inhibition of the ubiquitination-proteosome system, changes in 

neurotransmitter receptor expression, and modifications of intracellular signaling 

cascades (Fueta et al. 2004, Fueta et al. 2002b, Huang et al. 2011, Mohideen et al. 2009). 

Other studies indicate that the neurotoxic effects of 1-bromopropane involve glutathione 

depletion, protein adducts, and degeneration of noradrenergic axons (Mohideen et al.

2011, Valentine et al. 2007, Wang et al. 2002, Wang et al. 2003). 

Studies in humans include more than a dozen case reports from the United States and an 

epidemiologic study of 1-bromopropane production factory workers in China (Ichihara et 

al. 2011, Li et al. 2010b). Signs and symptoms from the case reports were similar and 

included numbness, diminished vibration sense in the lower extremities, distal latency, 

and ataxia suggesting that sensory nerves were affected. Other effects included 

hyperreflexia, suggesting damage to the central nervous system, and neurobehavioral 

effects (memory disturbances and depressive or unstable mood). Li et al. (2010b) 

evaluated neurologic abnormalities in 60 women factory workers compared with age-, 

sex-, and region-matched controls. Significant neurological effects included dosedependent increase in the distal latency of tibial nerves, increased threshold for vibration 

sense in the toes, and decreased sensory nerve conduction velocity of the sural nerve. 

However, the exposure assessment was based on recent exposure measurement, which 

may not accurately reflect past exposure. 

Reported effects in rats include prolongation of motor distal latency, reduction of motor 

nerve conduction velocity, myelin sheath degeneration, decrease in cerebral weight, 

pyknotic shrinkage and degeneration of Purkinje cells in the cerebellum, ataxia, and 

decreased limb muscle strength (Ichihara et al. 2011). Wang et al. (2002, 2003) 

investigated the biochemical changes in the central nervous system of rats exposed to 

1-bromopropane vapors for 7 days or 12 weeks. Groups of 9 male Wistar rats were 

exposed to 0, 200, 400, or 800 ppm 8 hours/day, 7 days/week. Both studies reported a 
9/25/13 RoC Monograph on 1-Bromopropane Appendix E

A-48

dose-dependent decrease in neurospecific -enolase in the cerebrum and cerebellum 

(suggesting functional or cellular loss of neurons) with concomitant decreases in 

nonprotein sulfhydryl bases, total glutathione, and creatine kinase activity. Creatine 

kinase also has a critical active-site sulfhydryl group and may be representative of other 

proteins with a functional sulfhydryl group. Therefore, the mechanisms of 

1-bromopropane neurotoxicity may involve glutathione depletion and modification of 

functional proteins containing a sulfhydryl base. A study by Valentine et al. (2007)

demonstrated that 1-bromopropane produces S-propyl cysteine adducts on globin and 

neurofilaments in rats and globin adducts in humans and provides further support for this 

mechanism proposed by Wang et al. (2002, 2003), which is discussed below.

Valentine et al. (2007) investigated the dose responses for urinary N-acetyl-S-(n-propyl)-

L-cysteine (AcPrCys) and S-propylcysteine adducts on globin and neurofilaments as a 

function of 1-bromopropane exposure in male Wistar rats and humans. Two experiments 

were conducted in rats. In the first experiment, rats were divided into four groups (8 per 

group) and exposed to 1-bromopropane vapor at 0, 50, 200, or 800 ppm for 8 hours/day 

for 2 weeks. The second experiment included 2 groups of rats (12 per group) exposed to 

0 or 50 ppm for 8 hours/day, 5 days/week for 4 weeks. Globin adducts were measured in 

both experiments, but neurofilament adducts were measured only in the first experiment. 

In humans, urinary AcPrCys and globin S-propylcysteine adducts were determined in 

workers at a 1-bromopropane production factory. Both globin and neurofilament adducts 

showed a linear dose-dependent increase, and a significant increase in globin adducts was 

observed in exposed workers compared with control workers. The authors concluded that 

the formation of S-propylcysteine adducts on rat spinal cord protein represents a potential 

mechanism to explain the observed decrease in sulfhydryl groups reported by Wang et al.

(2002, 2003). Thus, the neurotoxic effects of 1-bromopropane may be explained in part 

by its ability to covalently bind to sulfhydryl groups in the nervous system either by 

direct addition or from reactive metabolites.

Subramanian et al. (2012) reported that several oxidative stress markers (e.g., 

thiobarbituric acid reactive substances, protein carbonyl, ROS, and reactive nitrogen 

species [RNS]) were increased in a dose-dependent manner in the rat cerebellum 

following exposure to 1-bromopropane vapor for 28 days. In addition, morphological 

changes in microglia were reported. Microglia activation in response to pathological 

stimuli in the CNS is a major source of ROS and RNS. Imbalance in the formation and 

removal of ROS and RNS results in disturbances of cellular homeostasis and 

cytotoxicity. 

Huang et al. (2011) analyzed the differential protein expression in the hippocampus of 

F344 rats exposed to 1-bromopropane at 0, 400, or 1,000 ppm, 8 hours/day, for 1 to 4 

weeks. 1-Bromopropane was shown to modify the hippocampal proteome in both a doseand time-dependent manner. Twenty-six protein spots were identified with significant 

changes (increase or decrease) in their levels of expression compared with controls. From 

these 26 protein spots, 19 proteins were successfully identified. The altered proteins were 

classified into six groups according to their functional properties and included 

nucleocytoplasmic transport, immunity and defense, energy metabolism, purine 

metabolism, neurotransmitter metabolism, and ubiquitination-proteosome pathway. 
Appendix E RoC Monograph on 1-Bromopropane 9/25/13 

A-49

These data suggest that 1-bromopropane–induced damage to the hippocampus involves 

oxidative stress, loss of ATP production, dysfunction of GABAergic feedback inhibition, 

and inhibition of ubiquitination-proteosome system. Several studies have reported an 

association between 1-bromopropane exposure and GABA inhibition (Fueta et al. 2004, 

Fueta et al. 2007, Ueno et al. 2007). Fueta et al. (2004, 2007) reported that excitability 

and convulsive behavior in rats following inhalation exposure to 700 or 1,500 ppm 

1-bromopropane was related to dysfunction of GABA-mediated feedback inhibition in 

the hippocampus. Ueno et al. (2007) also reported dysfunction of the hippocampal 

GABAergic system in male Wistar rats following subchronic inhalation exposure to 

1-bromopropane. Reduced function was related to decreased levels in the expression and 

function of GABA receptors. Although the relevance of GABA inhibition to the 

carcinogenicity of 1-bromopropane is unknown, several studies have reported that GABA 

is involved in the proliferation, differentiation, and migration of various cell types and 

that increased expression of GABA and GABA receptors have been reported in some 

tumor cells (Maemura et al. 2003, Schuller et al. 2008, Watanabe et al. 2006, Young and 

Bordey 2009). These data are briefly reviewed in Section 5.3.3. 

Hepatotoxicity 

Several studies have investigated the mechanisms underlying the hepatotoxic effects of 

1-bromopropane in mice (Lee et al. 2007a, Lee et al. 2005b, Li et al. 2010a, Liu et al.

2009, Liu et al. 2010) and rats (Ishidao et al. 2002). Lee et al. focused on the role of 

metabolism following single oral doses while Liu et al. focused on the role of oxidative 

stress and biological factors that determine susceptibility in different mouse strains 

following inhalation exposure. The findings from these studies are summarized below. 

The role of glutathione conjugation in the hepatotoxic effects of 1-bromopropane was 

investigated in male ICR mice (Lee et al. 2005a, Lee et al. 2005b) and female BALB/c 

mice (Lee et al. 2007a). These studies used similar protocols to investigate the dose 

response and the time course of effects and reported similar results. Two studies were 

conducted with male ICR mice. In the first study, male ICR mice (5 per group) received a 

single oral dose of 0, 200, 500, or 1,000 mg/kg of 1-bromopropane in corn oil and were 

sacrificed 12 or 24 hours later (Lee et al. 2005b). For the time-course study, groups of 

mice were administered a single oral dose of 1,000 mg/kg and sacrificed at 6, 12, or 24 

hours. The second study was similar to the first but also included groups pretreated with 

phenobarbital or SKF-525A, a general CYP inhibitor (Lee et al. 2010a). Female BALB/c 

mice were divided into the same treatment groups as reported above but all mice were 

sacrificed after 12 hours in the dose-response study and at 6, 12, 24, or 48 hours in the 

time-course study (Lee et al. 2007a). Hepatotoxicity parameters measured in these three 

studies included serum alanine aminotransferase (ALT), aspartate aminotransferase 

(AST), or malondialdehyde. Also liver homogenates were analyzed for glutathione 

(GSH), 1-bromopropane glutathione conjugate, or S-propyl GSH. 

Body and liver weights were not affected by 1-bromopropane exposure in male ICR 

mice; however, the activities of serum ALT and AST were significantly increased at the 

high dose 24 hours after treatment (Table E-2) (Lee et al. 2005b). Hepatic GSH levels 

decreased and S-propyl GSH levels increased with dose 12 hours after treatment but 

returned to near normal levels after 24 hours. Levels of malondialdehyde, a marker of 
9/25/13 RoC Monograph on 1-Bromopropane Appendix E

A-50

lipid peroxidation, also increased with dose and were significantly elevated in groups 

exposed to 500 or 1,000 mg/kg.

Table E-2. 1-Bromopropane effects on serum enzymes in male ICR mice

Group (N = 5)

ALT

(Karmen unit/mL ± SE)

AST

(Karmen unit/mL ± SE)

Dose-response study (mg/kg)a

0

200

500

1000

46 ± 10

33 ± 6

34 ± 2

1972 ± 1648** 

58 ± 6

70 ± 9

76 ± 7

653 ± 478**

Time-course study (hr)b

0

6

12

24

46 ± 10

38 ± 3

1031 ± 613

1972 ± 1648**

58 ± 6

106 ± 12

293 ± 120

653 ± 478**

Source: Lee et al. 2005b.

ALT = serum alanine aminotransferase, AST = serum aspartate aminotransferase.

** P < 0.01.

aMeasured at 24 hours.

b

1,000 mg/kg treatment dose.

Lee et al. (2010a) reported similar results. Serum ALT and AST were significantly 

increased by a single treatment of 1,000 mg/kg 1-bromopropane. Mice pretreated with 

phenobarbital to induce metabolic enzymes had significantly increased serum ALT and 

AST in groups treated with 750 mg/kg and above; however, groups of mice pretreated 

with the CYP inhibitor (SKF-525A) had significantly lower serum ALT and AST levels 

than mice treated with 1-bromopropane alone. In addition, thiobarbituric acid-reactive 

substance (TBARS), a byproduct of lipid peroxidation, also was significantly increased 

by 1,000 mg/kg 1-bromopropane. TBARS was not increased in animals pretreated with 

SKF-525A. Hepatotoxicity was associated with glutathione depletion by formation of 

GSH conjugates. Specifically, S-propyl and 2-hydroxypropyl GSH conjugates were 

identified in the liver, and hepatic GSH levels were significantly decreased 6 hours after 

treatment with 750 or 1,000 mg/kg. Pretreatment with phenobarbital resulted in 

significantly decreased hepatic GSH levels 6 hours after treatment with 500 or 1,000 

mg/kg compared with mice exposed to 1-bromopropane alone. Mice pretreated with 

SKF-525A showed decreased GSH only at 500 mg/kg compared with 1-bromopropane 

alone. GSH levels were restored to control levels 24 hours after 1-bromopropane 

treatment in all groups except the high-dose groups pretreated with either phenobarbital 

or SKF-525A.

Effects of 1-bromopropane exposure in female BALB/c mice were consistent with those 

reported for male ICR mice (Lee et al. 2007a). Glutathione levels in the liver and spleen 

were significantly decreased in a dose-dependent manner (Table E-3). S-Propyl 

glutathione conjugate showed dose-related increases in the liver, spleen, and serum. 

Maximum amounts were detected at 6 to 12 hours after dosing.
Appendix E RoC Monograph on 1-Bromopropane 9/25/13

A-51

Table E-3. 1-Bromopropane effects on hepatic GSH and GSH conjugate (S-propyl 

GSH) levels in female BALB/c mice

Group

(N = 5)

ALT

(Karmen 

unit/mL ± SE)

GSH 

(nmol/mg protein ± SE)

S-propyl GSH 

(nmol/mg protein ± SE)

Liver Spleen Liver Spleen Serum

Dose-response study (mg/kg)a

0

200

500

1000

28.4 ± 4.1

35.2 ± 6.4

151.2 ± 100.7

3367 ± 3111**

576.6 ± 23.8

102.6 ± 34.9**

102.2 ± 38.0**

24.2 ± 4.9**

161.5 ± 3.6

117.6 ± 8.5

126.2 ± 6.9

86.3 ± 8.7*

N.D.

3.2 ± 1.0

25.8 ± 3.2

315.6 ± 162.7

N.D.

N.D.

1.4 ± 0.5

10.3 ± 1.3

N.D.

0.04 ± 0.02

0.11 ± 0.02

5.98 ± 1.54

Time-course study (hr)b

0

6

12

24

48

28.4 ± 4.1

18.3 ± 8.9

3367 ± 3111**

10,641 ± 3592**

2209 ± 849**

576.5 ± 23.8

29.6 ± 10.8**

24.2 ± 4.9**

28.8 ± 10.2**

114.8 ± 28.0

161.5 ± 3.6

93.8 ± 10.0*

86.3 ± 8.7*

110.6 ± 10.2

135.2 ± 7.9

N.D.

409.4 ± 72.2

315.6 ± 162.7

33.1 ± 9.2

1.2 ± 0.6

N.D.

6.3 ± 2.8

10.3 ± 1.3

1.9 ± 0.7

1.3 ± 0.9

N.D.

7.20 ± 1.52

5.98 ± 1.54

0.38 ± 0.15

0.01 ± 0.01

Source: Lee et al. 2007a.

ALT = serum alanine aminotransferase, GSH = glutathione, N.D. = not detected.

* P < 0.05.

** P < 0.01.

aMeasured at 12 hr.

b

1,000 mg/kg treatment dose.

Hepatotoxic effects occurred in parallel with changes in glutathione and glutathione 

conjugate levels and were prevented by pretreatment with a general CYP inhibitor (SKF525A) (Lee et al. 2007a, Lee et al. 2005b, Lee et al. 2010a). Increases in ALT levels 

were proportional to glutathione depletion and formation of S-propyl glutathione. 

Hepatotoxic effects included centrilobular cellular swelling and vacuolization of 

hepatocytes, congestion, hemorrhage, and centrilobular necrosis. In addition, lipid 

peroxidation was significantly increased and liver catalase activity was decreased in mice 

treated with 1-bromopropane. These data suggest that the hepatotoxic effects, including 

lipid peroxidation, could be related to two different metabolic pathways. First, 

hepatotoxicity may be closely related with glutathione depletion associated with GSH 

conjugate formation and subsequent formation of reactive oxygen species. Further, 

metabolism of 1-bromopropane by CYP enzymes to toxic metabolites that are not 

associated with GSH conjugation might be an additional factor.

Liu et al. (2009) compared the susceptibility of male mice in three strains (C57BL/6J, 

DBA/2J, and BALB/cA) to 1-bromopropane–induced hepatotoxicity. Male mice (6 per 

group) were exposed to 0, 50, 110, or 250 ppm for 8 hours/day for 28 days. Hepatic 

CYP2E1 levels, glutathione-S-transferase (GST) activity, total GSH, oxidized GSH 

(GSSH), and NAD(P)H:quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1) 

mRNA levels were measured. All three strains exposed to 250 ppm developed focal 

necrosis and hepatocellular degeneration, and both parameters showed a significant 

correlation between response and dose as measured by Pearson’s coefficient (Table E-4). 

However, BALB/cA mice were the most susceptible based on liver histopathology and 
9/25/13 RoC Monograph on 1-Bromopropane Appendix E

A-52

DBA/2J mice were the most resistant strain. Baseline CYP2E1 protein levels were higher 

while total GSH content and GST activity in the liver were lower in BALB/cA than 

DBA/2J mice. NQO1 and HO-1 mRNA levels were increased at 250 ppm in BALB/cA 

but not in DBA/2J mice. NQO1 protects cells against redox cycling chemicals and HO-1 

defends against oxidant-induced injury during inflammation. Increased expression of 

NQO1 and HO-1 in the susceptible strain indicates increased oxidative stress compared 

with the resistant strain. These data indicate that CYP2E1 activity, GSH levels, and GST 

activity might explain the differences in susceptibility among the three mouse strains to 

1-bromopropane–induced hepatotoxicity.

Table E-4. Comparison of liver histopathology among three mouse strains exposed 

to 1-bromopropane

Strain N Dose (ppm)

% Necrotic area 

(mean ± SD)1

% Lobule degeneration 

(mean ± SD)a

DBA/2J 6

6

6

6

0

50

110

250

Pearson’s coefficient

0.00 ± 0.00

0.15 ± 0.02

0.23 ± 0.09

0.46 ± 0.27*

0.780*

0.00 ± 0.00

15.44 ± 9.45

14.32 ± 13.18

52.60 ± 21.88*

0.807*

C57BL/6J 6

6

6

5

0

50

110

250

Pearson’s coefficient

0.00 ± 0.00

0.28 ± 0.11*

0.49 ± 0.25*

0.88 ± 0.24*

0.879*

0.00 ± 0.00

24.27 ± 11.12*

35.78 ± 22.00*

73.03 ± 21.07*

0.819*

BALB/cA 6

6

6

4

0

50

110

250

Pearson’s coefficient

0.00 ± 0.00

0.55 ± 0.21b*

1.69 ± 0.53b*

3.80 ± 2.19b*

0.841*

0.00 ± 0.00

43.76 ± 15.16b*

62.30 ± 8.18b*

91.42 ± 9.93c*

0.920*

Source: Liu et al. 2009.

*P < 0.05 (compared with strain-matched controls).

a

Percent values were converted by arcsine transformation before statistical analysis.

b

Significantly different (P < 0.05) from either DBA/2J or C57BL/6J strain at same dose.

c

Significantly different (P < 0.05) from DBA/2J strain at same dose.

Liu et al. (2010) investigated the role of oxidative stress in 1-bromopropane–induced 

hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Nrf2 is a 

transcription factor involved in the cellular defense against oxidative stress. Male Nrf2-

null and wild-type mice (8 per group) were exposed to 0, 100, or 300 ppm 1-

bromopropane for 8 hours/day for 28 days. At the high dose, diffuse hepatocellular 

degeneration, focal and widespread necrosis, and focal inflammatory cell infiltration were 

observed in both genotypes. However, significantly larger areas of liver necrosis occurred 

in Nrf2-null mice compared with wild-type mice (Table E-5). Nrf2-null mice also had a 

higher prevalence of fatty degeneration, greater malondialdehyde levels, higher ratio of 

oxidized glutathione/reduced form of glutathione (GSSH/GSH), and lower total GSH 

content. GST activity was significantly increased in wild-type mice at 300 ppm but was 
Appendix E RoC Monograph on 1-Bromopropane 9/25/13

A-53

unchanged in Nrf2-null mice where the basal expression levels were low. Significant 

changes in the mRNA levels of several oxidative stress-related genes (including NQO1 

and HO-1) occurred in exposed wild-type mice compared with controls. Only GST Yc2 

mRNA levels were significantly increased in the high-dose Nrf2-null mice. Thus, these 

data demonstrated that Nrf2-null mice were more susceptible to 1-bromopropane–

induced liver injury and had a reduced antioxidant response compared with wild-type 

mice. The compromised antioxidant response and higher level of lipid peroxidation (as 

indicated by higher malondialdehyde levels) in Nrf2-null mice suggest that liver injury is 

related to oxidative stress. However, since liver necrosis also may contribute to lipid 

peroxidation, further studies are needed to clarify the role of oxidative stress in liver 

injury. 

Table E-5. Comparison of liver necrotic area in wild-type and Nrf2-null mice 

exposed to 1-bromopropane

Genotype

Dose (ppm)a

0 100 300

Wild-type

Nrf2-null

0.00 ± 0.00

0.00 ± 0.00

0.43 ± 0.20*

0.99 ± 0.28b,*

1.08 ± 0.36*

1.94 ± 0.60b,*

Source: Liu et al. 2010.

*P < 0.05 (compared with strain-matched controls).

a

Percent values (± SD) were converted by arcsine transformation before statistical analysis; N = 8 except 

for high-dose Nrf2-null mice where N = 6.

In contrast with the studies in mice, Ishidao et al. (2002) reported that male Wistar rats 

exposed to 1-bromopropane vapor 6 hours/day, 5 days/week for 3 and 4 weeks at 1,500 

ppm or 4 to 12 weeks at 700 ppm showed significantly decreased plasma ALT levels 

(Table E-6). Plasma AST levels were not significantly affected. Although the reason for 

the decreased ALT levels was not clear, the data indicated that plasma ALT activity was 

affected by 1-bromopropane. Another surprising finding was that the levels of P450 in 

hepatic microsomes were significantly decreased after 1-day and 1-month exposures to 

700 ppm. There is some experimental evidence that exposure to ethylene oxide may 

decrease hepatic P450 levels by attacking the heme moiety and altering heme balance in 

the liver. Propylene oxide, a structural analogue of ethylene oxide, is a possible 

intermediate metabolite of 1-bromopropane that might affect hepatic P450 levels.
9/25/13 RoC Monograph on 1-Bromopropane Appendix E

A-54

Table E-6. 1-Bromopropane effects on plasma enzymes in male Wistar rats 

Treatment 

(ppm) N

Duration 

(weeks) AST (U/L ± SD) ALT (U/L ± SD)

0

700

30

15

4

77.4 ± 16.3

80.2 ± 11.0

44.8 ± 11.5

23.6 ± 3.6**

0

700

30

10 12 110.0 ± 35.290.4 ± 21.6

60.6 ± 14.0

31.0 ± 5.3**

0

1500

10

10 3

119.7 ± 24.3

141 ± 58.5

56.8 ± 18.8

30.2 ± 9.5*

Source: Ishidao et al. 2002. 

AST = aspartate aminotransferase, ALT = alanine aminotransferase. 

*P < 0.05 (compared with group controls). 

**P < 0.01 (compared with group controls). 

Immunotoxicity 

1-Bromopropane has induced immunotoxic effects in mice (Lee et al. 2007a). Tdependent antibody response to sheep red blood cells, intracellular IL-2 production, and 

the absolute numbers of splenocyte subpopulations (total T-cells, CD4+ cells, CD8+ cells, 

macrophages, and B-cells) were all reduced in a dose-dependent manner. Thus, dose 

levels that resulted in decreased cellular glutathione and increased production of 

glutathione conjugate in spleen cells (see Table E-3) also suppressed immune function. 

These findings are consistent with studies that have shown immune function to be 

affected by intracellular glutathione (Dröge and Breitkreutz 2000). Studies in humans 

indicate that the immune system requires an optimal level of glutathione. Individuals with 

intermediate levels of glutathione generally have a higher number of CD4+ T-cells than 

individuals with lower or higher intracellular glutathione levels. Some immune functions, 

such as DNA synthesis in lymphocytes, are very sensitive to reactive oxygen 

intermediates and are favored by high levels of glutathione while certain signal pathways 

are enhanced by oxidative conditions that are favored by low intracellular glutathione 

levels. IL-2-dependent functions (including T-cell proliferation, generation of CD8+

 Tcell blasts, cytotoxic T-cell activity, lymphokine-activated killer cells, and natural killer 

cells) are particularly sensitive and are inhibited by a partial depletion of intracellular 

glutathione levels (Dröge et al. 1994). Thus, the immunotoxicity of 1-bromopropane 

could be related to glutathione depletion from formation of glutathione conjugates and 

increased oxidative stress. 

Anderson et al. (2010) also reported immunotoxic effects of inhaled 1-bromopropane in 

female B6C3F1 mice and F344/N rats. Animals (8 per group) were placed in inhalation 

chambers and exposed to 0, 125, 250, or 500 ppm (mice) or 0, 250, 500, or 1,000 ppm 

(rats) for 6 hours/day, 5 days/week, for 4 or 10 weeks. Spleen immunoglobulin (IgM) 

responses to sheep red blood cells (plaque-forming cell assay) were significantly 

decreased in mice (all exposed groups) and in rats (high-dose group only) after exposure 

for 10 weeks (see Table E-7); however, the serum IgM response (ELISA assay) was not 

affected. Although the mechanism underlying these contradictory results is unknown, it 

has been observed following exposure to other chemicals (Johnson et al. 2000, Temple et 
Appendix E RoC Monograph on 1-Bromopropane 9/25/13

A-55

al. 1993). The sensitivities of these assays can vary depending on the compound being 

tested.

Table E-7. Suppression of splenic IgM response to sheep RBC in rodents after 

inhalation exposure to 1-bromopropane for 10 weeks

Exposure

(ppm)

B6C3F1 Mouse Fisher 344 Rat

PFC/

106splenocytes

PFC/

spleen 

PFC/

106splenocytes

PFC/

spleen

0

125

250

500

1000

1752

1124*

859*

681*

ND

449

263*

181*

144*

ND

309

ND

211

209

164*

142

ND 

105

102

 79*

Source: Anderson et al. 2010 (mean values from graphs in paper; actual data provided by authors).

IgM = immunoglobulin M; RBC = red blood cells; PFC = plaque-forming cell; ND = not done.

*P < 0.05 (compared with air control).

Total spleen cells and total T-cells (CD3+) were significantly reduced in mice (all 

exposed groups) and in high-dose rats after 4-weeks exposure (Anderson et al. 2010). 

This trend was not observed after 10-weeks exposure, with the exception of a decrease in 

total T-cells in high-dose rats. The apparent recovery of splenocyte numbers by the end 

of the 10-week exposure period might be due to the ability of 1-bromopropane to induce 

its own metabolism to increase production of CO2 and other nontoxic metabolites. 

However, rats exposed to 500 or 1,000 ppm for 10 weeks also had a significant decrease 

in the CD4+/CD8–T-cell subpopulation. There were no consistent changes in natural 

killer cell activity or biological alterations in B-cell or macrophage numbers in either 

species. These data suggest that T-cells are a possible target for 1-bromopropane 

immunotoxicity, which could increase the risk of infection.

An unusual non-neoplastic finding in rats in the 2-year carcinogenicity study was the 

presence of inflammatory lesions with Splendore-Hoeppli reaction material (Morgan et 

al. 2011, NTP 2011a). These lesions were exposure related and were more common in 

males than females. Although these lesions occurred primarily in the nose and skin, other 

sites were affected. Swabs were collected from abscesses on the tail, Harderian gland, 

head, and salivary glands from five rats and cultured under aerobic and anaerobic 

conditions and Splendore-Hoeppli bodies were later observed microscopically in these 

lesions. No bacterial growth occurred under anaerobic conditions, but Pseudomonas 

aeruginosa was observed in four of five aerobic cultures. Splendore-Hoeppli bodies may 

be formed by deposition of antigen-antibody complexes and debris from host 

inflammatory cells, or from glycoproteins, lipid, and calcium derived from host 

leukocytes. Infections from fungi, helminthes, or bacteria are the typical causative agents. 

Although immunosuppression might have contributed to the development of SplendoreHoeppli bodies, it is not clear why these lesions occurred only in rats since mice were 

also immunosuppressed by exposure to 1-bromopropane in sub-chronic studies 

(Anderson et al. 2010).
9/25/13 RoC Monograph on 1-Bromopropane Appendix E

A-56

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RoC Monograph on 1-Bromopropane 9/25/13

Part 2

RoC Substance Profile
9/25/13 RoC Monograph on 1-Bromopropane

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RoC Monograph on 1-Bromopropane 9/25/13 

1

1-Bromopropane 

CAS No. 106-94-5 

Reasonably anticipated to be a human carcinogen 

First listed in the Thirteenth Report on Carcinogens (2014) 

Also known as n-propyl bromide 

Carcinogenicity 

1-Bromopropane is reasonably anticipated to be a human carcinogen based on sufficient 

evidence of carcinogenicity from studies in experimental animals. 1-Bromopropane, 

either directly or via reactive metabolites, causes molecular alterations that typically are 

associated with carcinogenesis, including genotoxicity, oxidative stress, and glutathione 

depletion. These alterations, observed mainly in vitro and in toxicity studies in rodents, 

are relevant to possible mechanisms of human carcinogenicity and support the relevance 

of the cancer studies in experimental animals to human carcinogenicity. 

Cancer Studies in Experimental Animals 

Inhalation exposure to 1-bromopropane caused tumors in two rodent species and at 

several different tissue sites, including one tissue site in rats at which tumors are rare 

(NTP 2011). 

In male rats, 1-bromopropane caused significant dose-related increases in the 

incidences of several types of benign and/or malignant skin tumors (keratoacanthoma; 

keratoacanthoma and squamous-cell carcinoma combined; and keratoacanthoma, 

squamous-cell carcinoma, basal-cell adenoma, and basal-cell carcinoma combined). Both 

female and male rats showed an increased incidence of large-intestine tumors (adenoma 

of the colon and rectum), which are rare tumors in rats. In females, the incidence was 

dose-related and statistically significantly higher than in concurrent controls, and it 

exceeded the historical control range for all routes of exposure used in studies, including 

inhalation exposure. In males, the incidence of large-intestine adenoma was not 

significantly increased, but exceeded the historical control range for inhalation-exposure 

studies, and its occurrence was considered to be biologically significant because of the 

rarity of these tumors (which occurred in less than 0.2% of the historical controls). 

Although no carcinoma of the large intestine was observed in male or female rats in this

study, adenoma of the large intestine has been shown to progress to carcinoma in other 

studies and forms a morphologic continuum with carcinoma (Deschner 1983, Chang 

1984, Nigro 1985). 

In female mice, 1-bromopropane caused significant dose-related increases in the 

incidence of benign and malignant lung tumors combined (alveolar/bronchiolar adenoma 

and carcinoma). 

These findings are supported by the observation of additional tumors in rats that 

may have been related to 1-bromopropane exposure, including malignant mesothelioma 
9/25/13 RoC Monograph on 1-Bromopropane

2

of the abdominal cavity and pancreatic islet tumors in males and skin tumors (squamouscell papilloma, keratoacanthoma, and basal-cell adenoma or carcinoma) in females.

Other Relevant Data 

1-Bromopropane is well absorbed following ingestion, inhalation, or dermal exposure. 

Occupational exposure occurs primarily by inhalation and dermal contact. Unmetabolized 

1-bromopropane has been detected in the urine of exposed workers at levels significantly 

correlated with exposure to 1-bromopropane in air (Kawai et al. 2001, Ichihara et al.

2004). 

1-Bromopropane is metabolized via several pathways; 16 urinary metabolites have 

been detected in rodents, and several other metabolites have been proposed (Jones and 

Walsh 1979, Ishidao et al. 2002, Garner et al. 2006). The primary metabolic pathways in 

rodents are oxidation reactions catalyzed by cytochrome P450 (primarily CYP2E1) and 

glutathione conjugation. The available data on human metabolism of 1-bromopropane, 

although limited, suggest that some of its metabolic pathways in humans are similar to 

those observed in rodents. Four mercapturic conjugates identified in the urine of rodents 

were also identified in the urine of workers exposed to 1-bromopropane (Hanley et al.

2009). The major metabolite, N-acetyl-S-(n-propyl)-L-cysteine, has been detected in the 

urine of exposed workers at levels that increased with increasing levels of 

1-bromopropane in ambient air (Hanley and Dunn 2006, Valentine et al. 2007, Hanley et 

al. 2009, 2010). This metabolite is produced in humans by conjugation of 

1-bromopropane with glutathione, and that reaction also releases free bromide ions, 

another useful biomarker for human exposure to 1-bromopropane (Jones and Walsh 

1979, Hanley et al. 2006). No studies were identified that tested for the occurrence in 

humans of the oxidative metabolites that are obligate intermediates to the measured 

conjugates. 

Studies on Mechanisms of Carcinogenesis 

The mechanism(s) by which 1-bromopropane causes cancer are not known. However, 

exposure to 1-bromopropane has been shown to cause molecular alterations related to 

carcinogenicity, including genotoxicity (mutations and DNA damage), oxidative stress, 

glutathione depletion, and immunomodulation. 

Studies have shown that 1-bromopropane can bind to macromolecules; it formed 

S-propylcysteine–globin adducts in exposed animals and humans (Valentine et al. 2007).

Although 1-bromopropane did not induce mutations in bacteria under standard assay 

conditions, it did induce mutations in bacteria both with and without exogenous 

mammalian metabolic activation in the only reported study whose design was appropriate 

for testing a highly volatile chemical (Barber et al. 1981). It also caused mutations in 

cultured mammalian cells with or without mammalian metabolic activation (Elf Atochem 

1996, as reviewed in NTP 2003) and DNA damage in cultured human cells without 

metabolic activation (Toraason et al. 2006). In addition, there is limited evidence of DNA 

damage in leukocytes from 1-bromopropane exposed workers (Toraason et al. 2006). In 

rodents exposed in vivo, 1-bromopropane did not increase micronucleus formation in 

bone marrow (Kim et al. 1998, as reviewed in NTP 2003) or peripheral blood 

erythrocytes (Elf Atochem 1996, cited in NTP 2003; NTP 2011) or cause dominant lethal 

mutations. However, the dominant lethal mutation assay is generally regarded as 
RoC Monograph on 1-Bromopropane 9/25/13

3

relatively insensitive for the detection of mutagenic agents (Saito-Suzuki et al. 1982, Yu 

et al. 2008).

There is evidence that metabolic activation plays a role in the genotoxicity and 

toxicity of 1-bromopropane. Several reactive metabolites (or intermediates) of 

1-bromopropane have been identified in rodents, including glycidol and -bromohydrin, 

and propylene oxide has been proposed as a metabolite (Garner et al. 2006). These 

compounds cause genotoxic effects in vitro, including DNA adduct formation, mutations, 

and DNA or chromosome damage (Stolzenberg and Hine 1979, IARC 1994, 2000). 

Glycidol and propylene oxide cause cytogenetic effects in vivo and are carcinogenic in 

experimental animals, and both substances are listed in the Report on Carcinogens as 

reasonably anticipated to be human carcinogens. These reactive and genotoxic 

metabolites may be responsible for at least some of the carcinogenic effects of 

1-bromopropane. As with 1-bromopropane, oral exposure to glycidol caused rare tumors 

of the large intestine in rats, as did oral exposure to two halogenated alkane analogues of 

1-bromopropane, tribromomethane and bromodichloromethane (NTP 1987, 1989, 1990).

Chronic exposure to 1-bromopropane may produce levels of oxidative metabolites 

that exceed the glutathione-conjugating capacity or may inhibit enzymes required for 

glutathione synthesis. Because glutathione is an important cellular defense mechanism, 

reduced levels can lead to oxidative stress, increased toxicity, and carcinogenicity. 

Numerous studies have shown that 1-bromopropane induces both oxidative stress and 

glutathione depletion (Lee et al. 2005, 2007, 2010a, Liu et al. 2009, 2010, Huang et al. 

2011). Studies with Cyp2e1-/- knockout mice, cytochrome P450 inhibitors, or a 

glutathione synthesis inhibitor showed that this metabolic activation pathway is involved 

in 1-bromopropane–induced toxicity, including neurological and reproductive effects, 

hepatotoxicity, and immunosuppression (NTP 2003, 2011, Lee et al. 2007, 2010a,b). 

Neurological effects of 1-bromopropane exposure have also been reported in humans (Li 

et al. 2010, Ichihara et al. 2012)

It is unclear whether induction of immunotoxicity by 1-bromopropane plays a role 

in tumor development. Recent studies have shown that 1-bromopropane causes 

immunosuppression in rodents (Lee et al. 2007, Anderson et al. 2010). In particular, it 

reduced the numbers of T cells and T-cell subpopulations. In addition, there is evidence 

that 1-bromopropane causes an inflammatory response. It induced dose-related increases 

in gene expression and production of proinflammatory cytokines in mouse macrophages 

(Han et al. 2008) and an inflammatory response in rats (NTP 2011). However, chronic 

respiratory inflammation and lung tumors were not associated in rodents; respiratory 

inflammation occurred in rats but not mice, whereas lung tumors occurred in mice but not 

rats.

Cancer Studies in Humans

No epidemiological studies or case reports were identified that evaluated the relationship 

between human cancer and exposure specifically to 1-bromopropane.

Properties

1-Bromopropane is a halogenated alkane that exists at room temperature as a colorless to 

pale-yellow volatile liquid with a strong, characteristic odor (NTP 2011). It is slightly 

soluble in water and in most organic solvents, including acetone, ethanol, ether, benzene, 
9/25/13 RoC Monograph on 1-Bromopropane

4

chloroform, and carbon tetrachloride. It is less flammable than many other halogenated 

alkanes at room temperature. Thermal decomposition of 1-bromopropane produces 

hydrogen bromide. 1-Bromopropane can react with oxidizing agents to form hazardous 

flammable compounds and with water to produce acids. Physical and chemical properties 

of 1-bromopropane are listed in the following table.

Property Information

Molecular weight 123.0a

Specific gravity 1.353 at 20 C/20 C

b

Melting point –110 C

a

Boiling point 64.7 C

a

Log Kow 2.10b

Water solubility 2.45 g/L at 20 C

b

Vapor pressure 110.8 mm Hg at 20°Ca

Vapor density relative to air 4.25b

Sources: aNTP 2003, 

bHSDB 2006.

Use

1-Bromopropane is used primarily as a solvent cleaner in vapor and immersion 

degreasing operations to clean optics, electronics, and metals and as a solvent vehicle in 

industries using aerosol-applied adhesives, such as foam cushion manufacturing. 

However, its use as an aerosol solvent or adhesive could be affected by the proposed U.S. 

Environmental Protection Agency (EPA) rule that finds 1-bromopropane to be 

unacceptable for these uses (see Regulations). In recent years, 1-bromopropane usage has 

increased as a result of new industrial and commercial uses as a substitute for ozonedepleting chemicals or suspected carcinogens (e.g., as an alternative to 

tetrachloroethylene in the dry-cleaning industry) (Blando et al. 2010). 1-Bromopropane 

also has potential for use as a spot remover in the textile industry; however, an evaluation 

of 1-bromopropane as a substitute for trichloroethylene concluded that chronic toxicity 

data were insufficient, and use of 1-bromopropane was not recommended until more data 

were available (Mirza et al. 2000). In the past, 1-bromopropane was used primarily as a 

solvent for fats, waxes, and resins and as an intermediate in the synthesis of 

pharmaceuticals, insecticides, quaternary ammonium compounds, flavors, and fragrances 

in generally well-controlled, closed processes (Hanley et al. 2006, NTP 2003).

Production

1-Bromopropane is a high-production-volume chemical. In 2012, 1-bromopropane was 

manufactured by at least 21 companies worldwide, including at least one company in the 

United States (SRI 2012). Reported recent and historical volumes of U.S. production, 

imports, and exports of 1-bromopropane are listed in the following table.
RoC Monograph on 1-Bromopropane 9/25/13

5

Category Year Quantity (lb)

Production + importsa2006

1998, 2002

1994

1986, 1990

> 1 million to 10 million

1 million to < 10 million

> 500K to 1 million

10K to 500K

U.S. imports:brecent 2011 10.3 million

 historical 2007 10.9 million

U.S. exports:brecent 2011 15.1 million

 historical 2007 8.8 million

Sources: aEPA 2012; EPA Chemical Data Reporting Rule, 

formerly the Inventory Update Rule.

bUSITC 2012; reported as “brominated derivatives of acyclic hydrocarbons.”

Exposure

A significant number of people in the United States are exposed to 1-bromopropane as a 

result of widespread usage, high production volume, and high levels of 1-bromopropane 

in commercial and industrial settings. 

Occupational exposure to 1-bromopropane may occur through inhalation or dermal 

contact at workplaces where 1-bromopropane is produced or used (HSDB 2006). 

Concentrations of 1-bromopropane in air (8- to 12-hour time-weighted averages [TWAs]) 

from all studies identified across several U.S. industrial sectors ranged from not detected 

to 380 ppm, with the highest concentrations being for adhesive use and the lowest for 

vapor degreasing. Sprayers in the adhesive industry had the highest exposure, which 

ranged from 18 to 380 ppm across several studies. Exposure data for 1-bromopropane 

manufacturing were not available for the United States. Manufacturing exposure reported 

from China (Ichihara et al. 2004) ranged from not detectable to 170.5 ppm for processes 

that included adding materials to large reaction pots. However, production methods 

reported in a patent application by a U.S. manufacturer included numerous control 

processes to contain 1-bromopropane, which would likely reduce potential exposure 

substantially. The graph below shows TWA 1-bromopropane exposure levels from 

representative studies of adhesive application (Hanley et al. 2006), manufacturing (in 

China; Ichihara et al. 2004), dry cleaning (Eisenberg and Ramsey 2010), aerosol solvent 

use (Graul 2012), cleaning and painting in workshops using 1-bromopropane solvents 

(Kawai et al. 2001), and vapor degreasing (Hanley et al. 2010).
9/25/13 RoC Monograph on 1-Bromopropane

6

Time-weighted-average 1-bromopropane exposure levels as geometric means (Adhesives, Other, and Vap. 

Deg.); arithmetic mean (Dry Cln.); or not reported (Manuf. and Aer. Solv.). Note: the dashed, vertical line 

represents the ACGIH threshold limit value – time-weighted average (TLV-TWA) of 10 ppm.

Among workers at polyurethane foam furniture cushion manufacturing facilities, 

geometric mean values for daily urinary bromide excretion and urinary N-acetyl-Spropylcysteine concentrations were approximately 4 times as high for adhesive sprayers 

as for non-sprayers (Hanley et al. 2006, 2009). Concentrations of 1-bromopropane in 

exhaled breath also were consistently higher among sprayers than among workers 

performing other jobs. A National Institute for Occupational Safety and Health (NIOSH) 

Health Hazard Evaluation (HHE) of a furniture foam cushion manufacturing facility

found the average difference between end-of-week and start-of-week serum bromide 

concentrations to be 23 mg/L for exposed workers, compared with 3 mg/L for unexposed 

workers (Harney et al. 2003). NIOSH HHEs and follow-ups at two facilities showed that 

1-bromopropane air concentrations (TWAs) could be reduced by 80% or more through 

implementation of NIOSH recommendations for engineering controls, such as ventilation 

improvements and enclosure of spray tables (Reh et al. 2002).

The general population may be exposed to 1-bromopropane through inhalation of 

ambient air in the vicinity of industrial facilities where 1-bromopropane is used as an 

adhesive. EPA used air dispersion modeling to estimate 1-bromopropane concentrations 

in ambient air at a distance of 100 m from model facilities. The estimated concentrations 

were 0.138 mg/m3[0.0274 ppm] for facilities with average adhesive use and 1.38 mg/m3

[0.274 ppm] for facilities with high adhesive use (Morris and Wolf 2003). EPA also 

estimated daily inhalation uptake of 1-bromopropane for a person living 100 m from a 

model facility to be 0.0537 mg/kg for average-adhesive-use facilities and 0.537 mg/kg for 

high-adhesive-use facilities. 

Based on its production levels and industrial uses, 1-bromopropane may be released 

to the environment through various waste streams. 1-Bromopropane has been detected in 

temperate marine macroalgal tissue and is believed to be transported from these algae to 

the marine environment (HSDB 2006). No data on levels of 1-bromopropane in ambient 
RoC Monograph on 1-Bromopropane 9/25/13 

7

air, drinking water, surface water, soil, food, or consumer products and no data on nonoccupational exposure to 1-bromopropane were found. 

Regulations 

California Occupational Safety and Health Standards Board (OSHSB) 

Permissible exposure limit (PEL) = 5 ppm. 

Environmental Protection Agency (EPA) 

Significant New Alternatives Policy (SNAP) Program 

The EPA SNAP program reviews alternatives to ozone-depleting substances and 

approves the use of alternatives that do not present substantially greater risk to the public 

health and environment than the substance they replace or other available substitutes. The 

EPA SNAP program has made the following determinations regarding various end uses 

of 1-bromopropane: 

Solvent in industrial equipment for metals cleaning, electronics cleaning, or precision 

cleaning as a substitute for CFC–113 and methyl chloroform: acceptable (final 

rule). 

Coatings as a substitute for CFC–113, HCFC–141b, and methyl chloroform: acceptable 

subject to the condition that use is limited to coatings facilities that have provided 

EPA data which demonstrate their ability to maintain acceptable workplace 

exposures (proposed rule). 

Aerosol solvents as a substitute for CFC–113, HCFC–141b, and methyl chloroform: 

unacceptable (proposed rule). 

Adhesives as a substitute for CFC–113, HCFC–141b, and methyl chloroform: 

unacceptable (proposed rule). 

Guidelines 

American Conference of Governmental Industrial Hygienists (ACGIH) 

Threshold limit value – time-weighted average (TLV-TWA) = 10 ppm. 

Environmental Protection Agency (EPA) 

Acceptable exposure limit (8-hour time-weighted average) = 25 ppm. 

References 

Anderson SE, Munson AE, Butterworth LF, Germolec D, Morgan DL, Roycroft JA, Dill 

J, Meade BJ. 2010. Whole-body inhalation exposure to 1-bromopropane suppresses the 

IgM response to sheep red blood cells in female B6C3F1 mice and Fisher 344/N rats. 

Inhal Toxicol 22(2): 125-132. 

Barber ED, Donish WH, Mueller KR. 1981. A procedure for the quantitative 

measurement of the mutagenicity of volatile liquids in the Ames Salmonella/microsome 

assay. Mutat Res 90(1): 31-48. 
9/25/13 RoC Monograph on 1-Bromopropane

8

Blando JD, Schill DP, de la Cruz MP, Zhang L, Zhang J. 2010. Preliminary study of 

propyl bromide exposure among New Jersey dry cleaners as a result of a pending ban on 

perchloroethylene. J Air Waste Manag Assoc 60(9): 1049-1056. 

Chang WW. 1984. Histogenesis of colon cancer in experimental animals. Scand J 

Gastroenterol Suppl 104: 27-43. 

Deschner EE. 1983. Adenomas: preneoplastic events, growth and development in man 

and experimental systems. Pathol Annu 18(Pt 1): 205-219. 

Eisenberg J, Ramsey J. 2010. Evaluation of 1-Bromopropane Use in Four New Jersey 

Commercial Dry Cleaning Facilities. Health Hazard Evaluation Report HETA 2008-

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